Tuberculosis

TUBERCULOSIS

Springer Berlin Heidelberg New York Hong Kong London Milan Paris Tokyo

M. Monir Madkour (Editor) A. Al Saif . M. Al Shahed . K. R. Al Moutaery A. Al Kudwah (Associate Editors)

Tuberculosis Foreword by

David A. Warrell

With 444 Figures in 846 Separate Illustrations, 139 in Color and 89 Tables

Springer

Editor: M. MONIR MADKOUR

Department of Medicine Armed Forces Hospital Riyadh 11159 Saudi Arabia

Associate Editors: ABDULAZIZ AL SAIF

MONA AL SHAHED

Department of Medicine Armed Forces Hospital Riyadh 11159 Saudi Arabia

Department of Radiology Armed Forces Hospital Riyadh 11159 Saudi Arabia

KALAF AL MOUTAERY

AIDA AL KUDWAH

Department of Neurosurgery Armed Forces Hospital Riyadh 11159 Saudi Arabia

Department of Dermatology Armed Forces Hospital Riyadh 11159 Saudi Arabia

ISBN 3-540-01441-1 Springer-Verlag Berlin Heidelberg Library of Congress Cataloging-in-Publication Data Tuberculosis I M. Monir Madkour, ed p.cm. Includes bibliographical references and index. ISBN 3-540-01441-1 (alk. paper) 1. Tuberculosis. 1. Madkour, M. Monir. RC311.T4172003 616.9'95--dc22

2003059067

This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitations, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer-Verlag. Violations are liable for prosecution under the German Copyright Law. Springer-Verlag is part of Springer Science+Business Media httpllwww.springeronline.com © Springer-Verlag Berlin Heidelberg 2004 Printed in Germany The use of general descriptive names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every case the user must check such information by consulting the relevant literature. Cover-Design: Erich Kirchner, Heidelberg Typesetting: Verlagsservice Teichmann, Mauer 2113150xq - 5432 1 0 - Printed on acid-free paper

Foreword

It was through his superb monograph on brucellosis, first published in 1989, that I came to know Dr. M. Monir Madkour and later to meet him in Riyadh. From this introduction, I was quick to enlist his help as an author of the Oxford Textbook ofMedicine. He has now turned his considerable talents as physician, author and editor to a disease at least as interesting but even more important, tuberculosis. Considered against the background of a large literature on this subject, Dr. Madkour's monumental monograph is distinctive in several respects. As he emphasises in his preface, his book, unlike most others published on tuberculosis in English, has not been written by western experts whose experience of the disease is based in developed countries. The Kingdom of Saudi Arabia has afforded the unusual combination of an abundance of clinical material with state-ofthe-art facilities for laboratory diagnosis, investigation, imaging and medical and surgical management. Dr. Madkour and his four associate editors, all from the prestigious Riyadh Armed Forces Hospital, have assembled a distinguished international cast of 64 authors; 29 from the Kingdom of Saudi Arabia, 16 from Europe, 12 from North America, five from Asia and two from Africa. The result is an exciting, comprehensive and original work incorporating a wide range of clinical and scientific skills and experience and carrying enormous authority. Tuberculosis is the most prevalent of all bacterial infections, existing actively or in latent form in a third of the world's population. In the developing world, almost everyone is infected and the tubercle bacillus might almost be regarded as part of the normal human condition. It is not surprising that the disease has played such an important role in the political, social, industrial, artistic and scientific history of mankind. This commanding historical perspective is clearly identified in the two opening chapters. I was fascinated by Dr. Saleh A. Bedeir's review of tuberculosis in Ancient Egypt, although the examples of Pott's disease in remains from the predynastic period may be antedated by neolithic finds near Heidelberg, Germany (5000 B.C.) and Liguria, Italy (4000 B.C.) (Formicola et al. 1987). So was it Europe that gave the world tuberculosis? In Chap. 2 ("Historical aspects of tuberculosis"), Dr. Madkour and colleagues include an important section on the achievements of Arabian medicine during the period 500-1500 A.D., usually regarded as the "Dark Ages" in Europe. The roles of the Baghdad and Cairo Schools during this era, and notably the contributions of Ibn an-Nafis, Rhazes, Avicenna and Albucasis, have certainly been neglected. Understandably, this account does not dwell on the enormous impact of tuberculosis on the arts, literature and science in Europe, especially during the nineteenth century, when this disease determined the creative life of many outstanding authors, artists and composers and supplied many fictional heroes, heroines and story lines. In Chap. 3 ("Global epidemiology of tuberculosis"), Marcos Espinal and Mario Raviglione of WHO Geneva, provide compelling evidence of the current worldwide crisis in tuberculosis control. An annual incidence of some 8 million new cases, with 2 million deaths and a case notification rate of around 50 per 100,000, shows no evidence of decline

despite the availability of effective anti-tuberculosis chemotherapy. The most chilling evidence for a failure of implementation of chemotherapy, the impact of the HIV-AIDS epidemic and emerging multi-drug resistant disease, is given in their Fig. 3.5, which predicts an increase to 10 million new cases in 2010. The epidemiological situation in the Kingdom of Saudi Arabia (Chap. 4) is complicated by the large influx of pilgrims from all over the world during the Hajj. Molecular fingerprinting of Mycobacterium tuberculosis (Chap. 5) has provided fascinating insights into the epidemiology, history and geographical origins of the pathogen, for example into the Cape coloured population of Cape Town (van HeIden 2002). Tuberculosis has become a major occupational health concern for medical personnel and others who work in high-risk communities. This important area is covered by Jaime Esteban in Chap. 7 ("Tuberculosis in Special Groups and Occupational Hazards"). There is a strong section on the microbiology, immunology, pathogenesis and pathology of tuberculosis, including a substantial review of immunology and pathogenesis by Graham Rook (Chap. 9). Pathological changes in the central nervous system are often dominated by secondary effects of obstructive or communicating hydrocephalus or the involvement of major blood vessels or cranial nerves at the base of the brain (Chap. 10). Environmental and other non-tuberculous mycobacteria, many of which have been regarded as virtually non-pathogenic in immunocompetent people, have caused lifethreatening infections in those with subtle immune deficits, for example in the IL-12dependent interferon-gamma pathway (Lammas et al. 2000; Fieschi et al. 2003) (Chap. 11). These rare deficiency syndromes provide insights into normal immune defence mechanisms, as does reactivation of latent tuberculosis by corticsteroids, anti-TNF antibodies and other agents. The section on diagnosis (Chaps. 12-15) covers conventional and newer methods, including PCR. The last decade has witnessed increasing investment in basic science research into the cell biology, genetics and immunology of tuberculosis. A landmark achievement has been the sequencing of the M. tuberculosis genome. However, these advances in the understanding of the biology of the bacillus and the host response have not yet resulted in any tangible improvements in diagnosis and management of tuberculosis patients and their contacts. One area in which recent scientific advances are beginning to make an impact on clinical practice is the diagnosis of latent tuberculosis infection. Until very recently, this relied upon the century-old tuberculin skin test, introduced by Robert Koch (Chap. 15). Blood tests measuring interferon-gamma secretion in response to purified protein derivative (PPD) may offer a more rapid and convenient approach to detecting latent infection. Cellular immune responses to PPD may, however, cross-react with BCG vaccination, just as with the delayed type hypersensitivity response to PPD detected by skin testing, resulting in poor specificity. Comparative mycobacterial genomics has identified a stretch of DNA (region of difference I, RD1) that is present in M. tuberculosis but absent from all strains of BCG vaccine. The antigens encoded by RD 1 genes thus offer the opportunity to develop more specific tests for M. tuberculosis infection. Two of these antigens, ESAT-6 and CFP10, have now been incorporated into a rapid, sensitive blood test that enumerates individual interferon-gamma-secreting T cells, the enzyme-linked immunospot (ELISPOT) assay. In active tuberculosis, EllSPOT appears to have a higher sensitivity and specificity than the tuberculin skin test (Lalvani et al. 2001). In latent infection, the absence of a gold standard reference test makes evaluation of any new test difficult, but recent studies indicate that ELISPOT successfully distinguishes latent infection from BCG vaccination and thus has a higher specificity than skin testing, while the observation that ELISPOT correlates more

closely with M. tuberculosis exposure than skin testing suggests that it may also have a higher sensitivity (Lalvani et al. 2001; Ewer et al. 2003). From the clinical point of view, tuberculosis is the most protean of all diseases, demanding inclusion in the differential diagnosis of almost every symptom, sign and abnormal result of investigation. The organ-related chapters of the book provide a thorough coverage of disease manifestations in the different age groups (Chaps. 16-18), during pregnancy (Chap. 19), in the face of immunosuppression (Chap. 29) and in the various sytems, organs and tissues (Chaps. 20-43). A great strength of the book is its inclusion of a rich variety of high-resolution pictures of clinical cases (see, for example, Chap. 36 on skin manifestations, and Chap. 40 on the eye). The clinical suspicion that allows the crucial early diagnosis of tuberculous meningitis (Chaps. 32 and 33) is particularly subtle, but the diagnosis may be difficult to confirm in the developing world. I have seen too many patients undergoing inappropriate therapeutic trials of antituberculosis chemotherapy for this condition. Tuberculous meningitis is a prevalent and commonly misdiagnosed condition that deserves a far more detailed and lengthy discussion. Compliance to the necessarily prolonged treatment regimens has been improved by the "DOTS" (directly observed treatment) strategy (Chap. 45). Once the correct treatment has been implemented, its efficacy must be monitored (Chap. 47), as the greatest threat to successful cure is drug resistance. Peter Davies provides an authoritative review of this, the most challenging obstacle to cure and control (Chap. 46). Of the many suggested ancillary treatments, corticosteroids are becoming less controversial for pericardial and pleural effusions and for tuberculous meningitis. It is to be hoped that the current large randomised controlled trial of corticosteroids in tuberculous meningitis, being conducted by The Centre for Tropical Diseases in Ho Chi Minh City, Vietnam, will finally provide decisive evidence in this long-running debate. I congratulate Dr. Madkour and his expert team of contributors for producing a timely, thorough, scholarly and truly fascinating account of one of the world's most important and complex diseases. Their book deserves to be consulted by all medical practitioners and to be read in its entirety by all infectious diseases specialists. It will surely become a classic in the literature of this disease. Oxford, UK

DAVID

A. WARRELL

References Ewer K, Deeks J, Alvarez L et al (2003) Comparison of T-cell-based assay with tuberculin skin test for diagnosis of Mycobacterium tuberculosis infection in a school tuberculosis outbreak. Lancet 361: 1168-1173 Fieschi C, Dupuis S, Catherinot E et al (2003) Low penetrance, broad resistance, and favorable outcome of interleukin-12 receptor beta-l deficiency: medical and immunological implications. J Exp Med 197:527-535 Formicola V, Milanesi Q, Scarsini C (1987) Evidence of spinal tuberculosis at the beginning of the fourth millennium B.C. from Arene Candide Cave (Liguria, Italy). American J Physical Anthropology 72:1-6 Van HeIden PD (2002) Molecular epidemiology of TB: challenging dogmas and asking new questions. IUBMB Life 53:219-223 Lalvani A, Pathan AA, McShane H et al (2001) Rapid detection of Mycobacterium tuberculosis infection by enumeration of antigen-specific T cells. Am J Respir Crit Care Medicine 163:824-828 Lammas DA, Casanova J-L, Kumararatne DS (2000) Immunodeficiency review. Clinical consequences of defects in the IL-12-dependent interferon-gamma (IFN-gamma) pathway. Clin Exp Immunol 121:417-425

Preface

In 1993, the World Health Organization declared tuberculosis a global emergency. Yet, the incidence of tuberculosis continues to rise. It is not clear, however, whether the rising incidence can be attributed to failure of control strategies, the recent impact of the HIV pandemic or the increasing problem of multidrug resistance. At present, it is estimated that one-third of the world population is infected with Mycobacterium tuberculosis, with over 8 million new cases of active disease detected every year and almost 2 million annual deaths. The impact of the present situation and the current inadequate efforts necessitates the development of a novel and alternative approach to the control and therapy measures. It is interesting to note that while the incidence of tuberculosis is generally low in developed countries, most of the authoritative textbooks on tuberculosis in the English language have been written by western experts. As an expatriate, working in Saudi Arabia, I found a rare opportunity to work in an endemic area yet enjoy the diagnostic and therapeutic facilities of developed countries. Such a combination of circumstances is rarely present in developing or developed countries. The rich clinical material is clearly reflected in this book in the form of "evidence-based" clinical practice enriched with vast numbers of images of various body organs and systems as well as by a thorough survey of all the relevant literature. The numerous figures that are present in a lot of chapters, many in colour, give a vivid picture of what is seen in clinical practice and comprise a special feature of this textbook. Separate imaging chapters were compiled whenever the inclusion with the text would have rendered the corresponding chapter unwieldy. Some of the world's most distinguished medical scientists from North America, South-East Asia, the Far East, South Africa and many European countries have contributed chapters on global epidemiology, molecular epidemiology, the molecular epidemiology of Mycobacterium bovis, polymerase chain reaction (PCR), serological methods, latent tuberculosis, prevention and control, directly observed therapy (DOT), multidrug-resistant tuberculosis, HIV and tuberculosis, thoracic surgery, new vaccines and many other clinical topics. Animal tuberculosis, which may contribute to human disease, is included in a separate chapter. The main goal of this book is to present a clear account of all aspects of tuberculosis as seen and practiced both in developing and developed countries. All authors took this into consideration while writing their chapters. Recent advances in diagnosis, prevention and control measures, and treatment are also addressed. I am humbled by the honour that was given to me by Professor David A. Warrell, Founding Director of the Centre for Tropical Medicine (Emeritus), University of Oxford and editor of the Oxford Textbook of Medicine, in agreeing to write the foreword in this book, and I am most grateful to him. Riyadh

M. MONIR MADKouR

This work is dedicated to: The renaissance of the ancient glorious Library of Alexandria, Egypt, and to those who contributed to its resurrection over the original site. Alexandria was the chief cultural and commercial center of its time, and when the Library was built in approximately 332 Be it attracted manuscripts and scholars from the entire Hellenistic world. It contained over 700,000 rolls of the work of Socrates, Plato, Aristotle, Hippocrates and all the writing of the known world, but was destroyed by a great fire. Virtual images of the ancient Library are available at UNESCO. The inauguration ceremony of the "new--ancient" Library of Alexandria in September 2002 was attended by heads of state, scientists, artists and dignitaries from all over the world. The World Health Organization, for its enormous, determined and unyielding efforts to control tuberculosis, particularly in endemic, poorly resourced, and developing countries.

Acknowledgements: I am indebted to Gen. Dr. S.M. Al Deeb and the Hospital Management Board for providing the facilities I required for this project. I am grateful to our medical library staff: R. Ahtashemuddi, S.Z. Khan, Y.S. AI-Zharani, M.A. Khushi, S.M. AI-Rakaf, S. Al-Salafi, R. AI-Sous, and A. AI-Sultan; our medical record staff: J. Al Anazi, A. Al Humaid and T. Al Shuriti; and our medical illustration staff: S. Nally, T. Michalak, D. Hargreaves, K. Jefferson, N. Morgan, R. Ponmbath, M. Horaib. Support from our colleagues from the department of microbiology, Dr. S. Bakheshwain and Dr. N. EI-Khizzi, is highly appreciated. I would like to thank Dr. M. Sofi and Dr. S.A. AI-Mohaimeed for their support. My colleagues from the department of medicine helped and supported this project, including Drs. T. AI-Tassan, B. AI-Dosary, S. AI-Faraj, A. AI-Zaid, N. AI-Qahtani and many others, and I am grateful. I would like to thank our secretaries for typing the manuscripts of my chapters and for their secretarial help: I. Andries, J. Misquith, E. Sabbagh. I would like to thank my son Amr Madkour, pre-medical student at Austin, Texas for helping me with his experience in the Internet and other computer facilities for this project during his summer vacations. My other children, Rasha, Monir and Reem, helped with typing and sending correspondence bye-mail and with MedLine searches. Without their help, my handicap in computer technology would have been insurmountable. I am most grateful to Dr. Julia Heidelmann, Dr. Ute Heilmann, Ms. Wilma McHugh and the staff at Springer-Verlag for their meticulous care and efforts in the production of this book. Despite the help I have received from others, I alone stand responsible for any shortcomings this book may contain. M. MONIR MADKouR

Contents

Historical Background

.

Tuberculosis in Ancient Egypt SALEH A. BEDEIR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Historical Aspects of Tuberculosis M. MONIR MADKOUR, KITAB E. AL-OTAIBI, R. AL SWAILEM

Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3 15

31

3 Global Epidemiology of Tuberculosis MARCOS A. ESPINAL and MARIO C. RAVIGLIONE

33

4 Epidemiology of Tuberculosis in Saudi Arabia ABDULRAHMAN A.ALRAJHI and ALI M.AL-BARRAK

45

5 The Molecular Epidemiology of Tuberculosis KATHRYN DERIEMER and CHARLES L DALEY

57

6 Molecular Epidemiology of Mycobacterium bovis ROBIN A SKUCE and SYDNEY D NEILL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

75

7 Tuberculosis in Special Groups and Occupational Hazards JAIME ESTEBAN

93

Microbiology, Immunology, Pathogenesis and Pathology

113

8 Microbiology of Tuberculosis A OLU OSOBA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 115 9 The Immunology and Pathogenesis of Tuberculosis GRAHAM A. W. ROOK

133

10 Pathology of Tuberculosis MOHAMMED AKHTAR and HADEEL AL MANA

153

11 Nontuberculous Mycobacteria JAE-JOON YIM and STEVEN M. HOLLAND

163

Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 185 12 Serologic Testing for Tuberculosis CHAKHRADHAR KOTARU and EDWARD D. CHAN. . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 187

XIV

Contents

13 PCR and Diagnosis of Tuberculosis DIANA LWILLIAMS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 199 14 Hematologic Findings in Mycobacterial Infections Among Immunosuppressed and Immunocompetent Patients GORGON AKPEK

213

15 Immunodiagnostics for Latent Tuberculosis Infection ROHIT K. KATIAL

231

Organ-related Chapters

241

General 16 Childhood Tuberculosis PETER R. DONALD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 243 17 Primary Tuberculosis in Adults M. MONIR MADKOUR

265

18 Miliary/Disseminated Tuberculosis M. MONIR MADKOUR

273

19 Tuberculosis and Pregnancy M. MONIR MADKOUR

301

Thorax 20 Post-primary Pulmonary Tuberculosis M. MONIR MADKOUR, Y. ABUSABAAH, ALI BEN MOUSA, ALI AL MASOUD . . . . . . . .. 313 21 Endobronchial Tuberculosis HEE SOON CHUNG. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 329 22 Pleural Tuberculosis M. MONIR MADKOUR, MAJDY IDREEs, M. AL SHAHED

349

23 Radiology of Pulmonary Tuberculosis MONA AL SHAHED, MOHAMMED ABD EL BAGI, M. MONIR MADKOUR . . . . . . . . . . .. 359 24 Pulmonary Function Test and Tuberculosis MAJDY M. IDREES, SIRAJ O. WALl, ABDULLA AL-AMOUDI

385

25 Thoracic Surgery for Tuberculosis YUJI SHIRAISHI

395

26 Radionuclides in Pulmonary and Extra-Pulmonary Tuberculosis DAVID HAMILTON and JAWDA AL-NABULSI

411

27 Tuberculosis of the Heart and Pericardium ERNESTO E SALCEDO and AHMAD S OMRAN

431

Contents

xv

Immune System 28 Mycobacterial Lymphadenitis

M. MONIR MADKOUR and RASHID AL KUHAYMI 29 Tuberculosis and Co-infection with the Human Immunodeficiency Virus ALIMUDDIN ZUMLA and JOHN M GRANGE

445 455

eNS

30 Spinal Tuberculosis M. MONIR MADKOUR, M. WASEF AL SEBAI, KHALAF R. AL MOUTAERY .. . . . . . . . .. 481 31 Surgical Management of Spinal Tuberculosis M. WASEF AL SEBAI, M. MONIR MADKOUR, KAHLAF R. AL MOUTAERY . . . . . . . . . .. 493 32 Tuberculosis of the Central Nervous System M. ZUHEIR AL-KAWI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 535 33 Imaging of Brain and Spinal Cord Tuberculosis FRANCIS MCGUINNESS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 547

Musculo-Skeletal and Soft Tissue 34 Extraspinal Musculoskeletal Tuberculosis M. MONIR MADKOUR, AIDA J. AL-KUDWAH, MOHAMMED ABD EL BAGI

587

35 Imaging of Musculoskeletal Tuberculosis MOHAMMED ABD EL BAGI, MONA AL SHAHED, M. MONIR MADKOUR . . . . . . . . . . .. 605 36 Tuberculosis of the Skin AIDA J. AL KUDWAH

627

Gastrointestinal 37 Abdominal Tuberculosis MOHAMMAD SULTAN KHUROO and NAIRA SULTAN KHUROO

659

38 Imaging of Gastrointestinal Tuberculosis MONA AL SHAHED and MOHAMMED ABD EL BAGI

679

Genitourinary 39 Genitourinary Tuberculosis M. MONIR MADKOUR

699

Head 40 Ocular Manifestations of Tuberculosis SHWU-JIUAN SHEU

731

41 Otorhinolaryngeal Aspects of Tuberculosis SUJATA MURANJAN

741

XVI

Contents

Endocrine 42 Endocrine and Metabolic Manifestations of Tuberculosis SOHAIL INAM and MONA AL-SHAHED

751

Vascular 43 Tuberculous Vasculitis and Mycotic Aneurysms M. MONIR MADKOUR

771

Treatment

779

44 Treatment of Tuberculosis DEAN E SCHRAUFNAGEL

781

45 Directly Observed Treatment for Tuberculosis Control ZHANG LI-XING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 801 46 Multi-Drug-Resistant Tuberculosis PETER D. O. DAVIES

809

47 Monitoring Treatment Efficiacy P. H. LAGRANGE, N. SIMONNEY, A. O. SOUSA, A. WARGNIER, J. L. HERRMANN

839

Control and Prevention. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 853 48 Tuberculosis Control in Developing and Developed Countries KEVIN SCHWARTZMAN .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 855 49 BCG and New Tuberculosis Vaccines ZHOU XING

881

50 Tuberculosis in Animals P. L. NICOLETTI

893

Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 903 About the Editor

930

List of Contributors

ABD EL BAGI MOHAMMED, MB, BCh, DMRD, FSRRCSI Department of Radiology Riyadh Armed Forces Hospital P.O. Box 7897 Riyadh 11159 Saudi Arabia

AL-KuDWAH AIDA J, MD, DD, FRCP (Ed) Consultant Dermatologist, Department of Dermatology Riyadh Armed Forces Hospital P.O. Box 7897, C-117 Riyadh 11159 Saudi Arabia

ABUSABAAH Y, ABIM Fellow, Respiratory Medicine Department of Medicine Riyadh Armed Forces Hospital P.O. Box 7897 Riyadh 11159 Saudi Arabia

AL KUHAYMI RASHID, FRCS Director of Surgery Riyadh Armed Forces Hospital P.O. Box 7897 Riyadh 11159 Saudi Arabia

AKHTAR MOHAMMED, MD, FCAP, FRCPA, FRCPath Chairman, Department of Pathology and Laboratory Medicine King Faisal Specialist Hospital and Research Centre P.O. Box 3354, MBCI0 Riyadh 11211 Saudi Arabia

AL MANA HADEEL, MD Fellow, Department of Pathology ad Laboratory Medicine King Faisal Specialist Hospital and Research Centre P.O. Box 3354 Riyadh 11211 Saudi Arabia

AKPEK GORGON, MD Assistant Professor of Medicine Greenebaum Cancer Center at University of Maryland School of Medicine 22 South Greene Street Baltimore MD 21201 USA

AL MAsouD ALI, MD Department of Medicine Riyadh Armed Forces Hospital P.O. Box 7897 Riyadh 11159 Saudi Arabia

AL-AMOUDI ABDULLA, MD, FRCP (C) Deputy Head, Department of Medicine King Faisal Specialist Hospital & Research Center Jeddah Saudi Arabia

AL MOUTAERY KHALAF R, MD, FRCS (Ed), FACS Head of Neurosurgery Riyadh Armed Forces Hospital P.O. Box 7897 Riyadh 11159 Saudi Arabia

AL-BARRAK ALI M, AmBIM, DTM & H, FRCP (C) Consultant Infectious Diseases Unit Department of Medicine Riyadh Armed Forces Hospital P.O. Box 7897 Riyadh 11159 Saudi Arabia

AL-NABULsI JAWDA, DMRD, MSc NM Nuclear Medicine Riyadh Armed Forces Hospital P.O. Box 7897 Riyadh 11159 Saudi Arabia

AL-KAwI M. ZUHEIR, MD, FACP Senior Consultant Neurologist & Deputy Chairman Department of Neurosciences King Faisal Specialist Hospital and Research Center P.O. Box 3354 Riyadh 11211 Saudi Arabia

AL-OTAIBI KITAB E, Facharzt (Urology), MD, FRCS (Edin) Director General of Medical Services Department Riyadh Armed Forces Hospital P.O. Box 7897 Riyadh 11159 Saudi Arabia

XVIII ALRAJHI ABDULRAHMAN A, MD, MPH, FIDSA Consultant and Head, Section of Infectious Diseases, Chairman, Department of Medicine (MBC #46), King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh 11211, Saudi Arabia AL SAIF A, MD, PhD, FCCP, FRCP (Lon) Consultant Respiratory Medicine Director of Medicine Riyadh Armed Forces Hospital P.O. Box 7897 Riyadh 1159 Saudi Arabia AL SEBAI M WASEF, FRCS. FFCS Consultant Spinal Surgeon Riyadh Armed Forces Hospital P.O. Box 7897 Riyadh 11159 Saudi Arabia AL SHAHED MONA, MBBS, FRCR Consultant Radiologist Department of Radiology Riyadh Armed Forces Hospital P.O. Box 7897 Riyadh 11159 Saudi Arabia AL SWAILEM R, MRCP (UK), ABIM Consultant Rheumatologist Department of Medicine Director of Postgraduate and Academic Affairs Riyadh Armed Forces Hospital P.O. Box 7897 Riyadh 11159 Saudi Arabia BEDEIR SALEH A, MD Dean, Faculty of Medicine Cairo University Kasr El-Aini Hospitals Cairo Egypt BEN MOUSA ALI, MD Department of Medicine, Riyadh Armed Forces Hospital P.O. Box 7897 Riyadh 11159 Saudi Arabia CHAN EDWARD D, MD Associate Professor of Medicine K613e Goodman Bldg. National Jewish Medical and Research Center, Denver, CO 1400 Jackson St Denver, CO 80206 USA

List of Contributors CHUNG HEE SOON, MD, FCCP Associate Professor of Medicine Seoul National University College of Medicine and Seoul Municipal Boramae Hospital affiliated to Seoul National University Hospital # 395 Shindaebang - 2 Dong Dongjak-Gu, Seoul, 156-707 Korea DALEY CHARLES L, MD Associate Professor of Medicine Division of Pulmonary and Critical Care Medicine San Francisco General Hospital Room 5K-l 1001 Potrero Ave San Francisco, CA 94110 USA DAVIES PETER D 0, DM, FRCP Director, Tuberculosis Research Unit Cardiothoracic Centre Liverpool Ll4 3PE UK DERIEMER KATHRYN, PhD Senior Research Scientist Division of Infectious Diseases and Geographic Medicine Stanford Medical Center, Stanford California, USA DONALD PETER R, MD Department of Paediatrics and Child Health Faculty of Health Sciences University of Stellenbosch P.O. Box 19063 7505, Tygerberg, South Africa ESPINAL MARCOS A, MD World Health Organization Stop TB Department Tuberculosis Strategy & Operations Ave Appia # 22 1211 Geneva Switzerland ESTEBAN JAIME, MD Department of Medical Microbiology Fundaci6n Jimenez Diaz Av. Reyes Cat6licos 2 28040 Madrid Spain GRANGE JOHN M, MSc, MD (Lon) Visiting Prof, Centre for Infectious Diseases & International Health Royal Free and University College Medical School Windeyer Institute of Medical Sciences 46 Cleveland St London WIP 6DB UK

XIX

List of Contributors HAMILTON DAVID, PhD, FIPEM Department of Nuclear Medicine Riyadh Armed Forces Hospital P.O. Box 7897 Riyadh 11159 Saudi Arabia HERRMANN J L, MD Service de Microbiologie H6pital Saint Louis Assistance Publique-H6pitaux de Paris Universite Denis Diderot 1, avenue Claude Vellefaux 75475 Paris France HOLLAND STEVEN M, MD Immunopathogenesis Unit Building 10, Room llN103 10 Center Dr. MSC 1886 Bethesda, MD 20892 1886 USA IDREES MAJDY M, MD, FRCP (C), FCCP Head, Pulmonary Function Laboratory Division of Pulmonary Medicine Department of Medicine Riyadh Armed Forces Hospital ClIO, P.O. Box 7897 Riyadh 11159 Saudi Arabia INAM SOHAIL, MBBS, FRCP (Edin), FRCP Head of Endocrinology Division Department of Medicine Riyadh Armed Forces Hospital P.O. Box 7897 Riyadh 11159 Saudi Arabia KATIAL ROHIT K, MD Associate Professor of Medicine National Jewish Medical and Research Center Denver 1400 Jackson St. Denver, CO 80206 USA KHUROO MOHAMMAD SULTAN, MD, DM, FRCP (Edin), MACP Professor, Consultant Gastroenterologist Department of Medicine - MBC 46 King Faisal Specialist Hospital and Research Centre P.O. Box 3354 Riyadh 11211 Saudi Arabia KHUROO NAIRA SULTAN, MBBS Department of Radiology King Faisal Specialist Hospital and Research Centre P.O. Box 3354 Riyadh 11211 Saudi Arabia

KOTARU CHAKRADHAR, MD Department of Medicine and Program in Cell Biology National Jewish Medical and Research Center Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, and Denver Veteran Administration Medical Center K613e, Goodman Building 1400 Jackson Street Denver, CO 80206 USA LAGRANGE P H, MD Service de Microbiologie H6pital Saint Louis Assistance Publique-H6pitaux de Paris Universite Denis Diderot 1, avenue Claude Vellefaux 75475 Paris France LI-XING ZHANG, MD Vice President & Secretary General Chinese Anti-Tuberculosis Association 5, Dong Gang Hu-Tong Beijing 100035 China MADKOUR M MONIR, MD, DM, FRCP (London) Consultant Department of Medicine Riyadh Armed Forces Hospital P.O. Box 7897, C-119 Riyadh 11159 Saudi Arabia MCGUINESS FRANCIS, MD Apt. 169, Al Haurin EI Grande 2912 Malaga Spain MURANJAN SUJATA, MS (ENT), DNB, DORL Consultant ENT Suman Apptartment, 3rd Floor 16B Naushir Bharucha Road Tardeo Mumbai 400007 India NEILL SYDNEY D., BSc, PhD Veterinary Sciences Division Department of Agriculture and Rural Development Stoney Road Stormont, Bellfast BT4 3SD UK NICOLETTI P L, DVM, MS College of Veterinary Medicine Department of Veterinary Pathology P.O. Box 110880 Gainseville Florida 32611 0880 USA

xx Ow OSOBA A, MD, FRCPath (UK), FFPath (Ireland), FWACP Consultant & Head of Microbiology

King Khalid National Guard Hospital P.O. Box 9515 Jeddah 2143 Saudi Arabia OMRAN AHMAD S, MD Consultant Cardiologist King Abdulaziz Cardiac Center, King Abdulaziz Medical City, National Guard, Riyadh, Saudi Arabia P.O. Box 22490 Riyadh 11426 Saudi Arabia RAVIGLIONE MARIO C, MD World Health Organization Stop TB Department Ave Appia # 22 1211 Geneva Switzerland ROOK GRAHAM A.W, BA, MB Bchir, MD Professor, Department Medical Microbiology Royal Free and University College Medical School Windeyer Institute of Medical Sciences 46 Cleveland Street London WIT 4JF UK SALCEDO ERNESTO E, MD Department of Cardiology King Abdulaziz Cardiac Center National Guard Hospital P.O. Box 22490 Riyadh 11426 Saudi Arabia SCHRAUFNAGEL DEAN E, MD Department of Medicine M/C 787 University of Illinois at Chicago 840 S. Wood St Chicago, IL 60612 7323 USA SCHWARTZMAN KEVIN, MD, MPH, FRCPC Assistant Professor Department of Medicine and Epidemiology And Biostatistics Respiratory & Epidemiology Unit McGill University 1110 Pine Avenue West Montreal, Quebec Canada H3A lA3 SHEU SHWU-JIUAN, MD Department of Ophthalmology Kaohsiung Veterans General Hospital 386 Ta-Chung 1st Road, Kaohsiung Taiwan 813

List of Contributors SHIRAISHI YUJI, MD Head, Section of Chest Surgery Fukujuji Hospital 3-1-24 Matsuyama Kiyose Tokyo 204 8522 Japan SIMONNEY N, MD Service de Microbiologie H6pital Saint Louis Assistance Publique-H6pitaux de Paris Universite Denis Diderot 1, avenue Claude Vellefaux, 75475 Paris France SKUCE ROBIN A, BSc, PhD Veterinary Sciences Division Stoney Road Stormont Belfast, BT4 3SD Northern Ireland

SOUSA A O,MD Service de Microbiologie H6pital Saint Louis Assistance Publique-H6pitaux de Paris Universite Denis Diderot 1, avenue Claude Vellefaux 75475 Paris France

WALl SIRAJ 0, MD, FRCP (C), FCCP Head, Division of Pulmonary Medicine Department of Medicine King Khalid Hospital National Guard Jeddah Saudi Arabia

WARGNIER A, MD Service de Microbiologie H6pital Saint Louis Assistance Publique-H6pitaux de Paris Universite Denis Diderot 1, avenue Claude Vellefaux 75475 Paris France

WILLIAMS DIANA L, PhD Molecular Biology Research Department Laboratory Research Branch National Hansen's Disease Programs At LSU-SVM, Rm 3517W Skip Bertman Dr., Baton Rouge, LA 70803 USA

List of Contributors XING ZHOU, MD Associate Prof. Pathology & Molecular Medidine Head, Division of Infectious Diseases Centre of Gene Therapeutics McMaster University Health Sciences 1200 Main Street W Hamilton, Ontario L8N 3Z5 Canada

MD Respiratory and Critical Care Medicine Seoul Natinal University College of Medicine Seoul South Korea 110744

YIM JAE-JOON,

XXI ZUMLA ALIMUDDIN, BSc, MBChB, MSc, PhD, FRCP (Lon), FRCP (Edin) Professor of Infectious Diseases and International Health Director, Centre for Infectious Diseases and International Health Royal Free & University College Medical School Windeyer Institute of Medical Sciences Room G41 46 Cleveland St London WIP 6DB UK

Historical Background

1

Tuberculosis in Ancient Egypt SALEH

A. BEDEIR

CONTENTS 1.1 1.2 1.2.1 1.2.1.1 1.2.1.2 1.2.1.3 1.2.2 1.2.3 1.2.3.1 1.3

1.4 1.5 1.6 1.7 1.8 1.8.1 1.8.1.1 1.8.1.2 1.8.1.3 1.8.1.4 1.8.1.5 1.8.1.6 1.8.1.7 1.9 1.10

Introduction 3 Predynastic Period 3 The Foundation of Egypt 4 Predynastic Period 4 Archaic Period 4 Old Kingdom 4 Development of Egyptian Language 4 A Chronology of Literature 5 From Alexander to Napoleon 5 Ancient Egyptian Art 5 Paleopathology 6 Differential Diagnosis 7 The Author's Case 7 Pulmonary and Osseous Tuberculosis in Ancient Egyptian Mummies 8 PCR and the Diagnosis of Tuberculosis in Ancient Egyptian Population 8 Environment 9 The Nile 9 Climate 9 Housing 9 Diet 9 Religion 10 Sports and Recreation 10 Physique 10 The Medical Papyri 10 Sanatorial Treatment 11 References 12

1.1 Introduction In all probability, tuberculosis is older than the human race, and different species in the genus Mycobacterium may have caused the disease in mammals, birds, reptiles and fish (Breed et al. 1957). Tuberculosis in man and other animals, both warm-blooded and cold-blooded, may have arisen from a common Mycobacterium ancestor many millions of years ago (Cockburn and Cockburn 1980). Other authors believe that tuberculosis in man may be of much more recent origin. The earliest report on presumptive tuberculosis in ancient Old World human remains is an article by Bartels (1907) on a Neolithic skeleton found near Heidelberg, Germany. The fourth and fifth thoracic vertebrae have collapsed and fused with the sixth vertebra, creating an angulation often seen in spinal tuberculosis (Ortner and Putschar 1981).

1.2 Predynastic Period Tuberculosis has existed for thousands of years in Egypt and Nubia, as shown by art forms and skeletal material. The ancient Egyptian obtained his first tuberculosis bacillus from the close contact with livestock that occurred after the Neolithic revolution, as early as 3300 B.C., during the initial herding period of Fayoum (Filer 1995). One of the earliest examples of spinal tuberculosis has been found at excavations at the predynastic site of Adaima, 8 km south of Esna. The chronological order of Ancient Egyptian Dynasties are given here according to:

S. A. BEDEIR, MD Dean, Faculty of Medicine, Cairo University, Kasr El-Aini Hospital, Cairo, Egypt

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

a. b. c. d.

Foundation of Egypt Development of Egyptian Language A Chronology of Literature From Alexander to Napoleon

S.A. Bedeir

4

1.2.1 The Foundation of Egypt 1.2.1.1

Predynastic Period Badarian Period

Naqada I Period

Naqada II Period

Naqada III Period

5000-4000 B.C. First evidence for

4000-3500 B.C. Development of pottery in Egypt

3500-3150 B.C. First major towns culture

3150-3000 B.C. First hieroglyphs

1.2.1.2

Archaic Period Dynasty I

Dynasty II

3050-2815 B.C. Unification of Egypt; royal tombs at Abydos

2815-2600 B.C. Royal tombs at Saqqara

1.2.1.3 Old Kingdom Dynasty III

Dynasty IV

2660-2600 B.C. First pyramids

2600-2470 B.C. Great pyramids at Giza

1.2.2 Development of Egyptian Language Archaic Period

Old Kingdom

First Intermediate Period

Dynasties I-II 3050-2660 B.C. Earliest script

Dynasties III-IV 2660-2200 B.C. Old Egyptian

Dynasties VII-XIa 2200-2070 B.C. Transition to Middle Egyptian, which lasts through the Middle Kingdom, dynasties Xlb-XIII

Second Intermediate Period

New Kingdom

Third Intermediate Period

Dynasties XIV-XVII 1650-1550 B.C. Middle Egyptian

Dynasties XVIII-XX 1550-1070 B.C. Middle Egyptian transition to Late Egyptian

Dynasties XXI-XXV 1070-664 B.C. Late Egyptian Demotic

Late Period

Graeco-Roman Period

Coptic Period

Dynasties XXVII-XXXI 664-332 B.C. Late Egyptian

Dynasties XVIII-XX Ptolemies 332-30 B.C. Demotic

Romans Byzantines 30 B.C.-A.D. 395 A.D. 395-640 Demotic Coptic Demotic

5

Tuberculosis in Ancient Egypt

1.2.3 A Chronology of Literature Archaic Period

Old Kingdom

First Intermediate Period

Middle Kingdom

Dynasties I-II 3050-2660 B.C. Labels; short inscriptions only

Dynasties III-IV 2660-2200 B.C. Pyramid texts, first biographies

Dynasties VII-XIa 2200-2070 B.C. Decrees, biographies

Dynasties XIb-XIII 2070-1650 B.C. Coffin texts, stories, wisdom texts

New Kingdom

Third Intermediate Period

Graeco-Roman Period

Dynasties XVIII-XX 1550-1070 B.C. Book of the Dead; "Historical" texts

Dynasties XXI-XXV 1070-664 B.C. Major mythological texts: continue through Later Period, Dynasties XXVI-XXXI

Ptolemies Romans 332-30 B.C. 30 B.C.-A.D. 395 Increasing Greek influence

1.2.3.1 From Alexander to Napoleon Coptic Period

Ptolemaic Period

Roman Period

332-30 B.C. Egypt ruled by heirs of Alexander the Great

30 B.C.-A.D. 395 A.D. 395-640 Egypt made a Egypt part of Roman province the Eastern Empite, based on Constantinople

Arab Period

Ottoman Period

A.D. 640-1517 GeneralAmr conquers Egypt for the Caliphs

A.D. 1517-1805 The Turkish Sultan Selim I invades and incorporates the country into his empire

Spinal tuberculosis, or Pott's disease, is more likely to be found in an archaeological context. Evidence for pulmonary tuberculosis is less tenable, as the bacilli disappear soon after the death of the victim. The discovery of lung collapse or pleuritic adhesions in some mummies has been mentioned as evidence of its existence, but other conditions may cause these complications.

1.3

Ancient Egyptian Art Pott's disease is well presented in both ancient Egyptian art and human remains. Several clay statuettes of men, dating to the Predynastic period, have been considered to be cases of Pott's disease. The men are depicted with humped spines and an emaciated look that suggests tuberculosis. Yet some of the figures are in large clay bowls, which may reflect a style of burial (Filer 1995). A wooden figurine in the Brussels Museum, probably Predynastic period, shows an angular deformity of the spine and chest, strongly suggesting Pott's disease. A gardening scene from the tomb of Ipwy of the 19th dynasty shows a

gardener with a humped back denoting Pott's disease (Fig. 1.1). In the Cairo Museum, there is an Old Kingdom statue with a humped spine and a concomitant deformity of the chest (Fig. 1.2). A false door from a mastaba tomb of Ankh-my-was of the Old Kingdom (4th to 5th dynasty), now preserved in Glyptotek Ny Carlsberg, Copenhagen, represents the deceased with a deformed upper part of the torso, indicating Pott's disease (Cave 1939). The tomb of Seshen Nufer I from the 4th dynasty near the Giza pyramids compromises the scene of a humped-back serving maid clearly suffering from Pott's disease (Mahmoud 1998). Ruffer (1921) described two drawings denoting tuberculosis of the spine. The first, in Beny Hassan, shows affection of the lower cervical and upper dorsal spine. The other, in Tel EI-Amarna, dates back to the 18th dynasty and shows the kyphosis is in the lower dorsal and upper lumbar region. There are many representations of humped-back servants in the tomb chapels, but it is difficult to distinguish between Pott's disease, Porter's hump, ankylosing spondylitis and simply poor posture. In Pott's disease, the deformity is localized and the angulation is usually in the form of a gibbus. The chest wall may show a corresponding deformity.

6

S.A. Bedeir

Fig. 1.1. A scene from the tomb of Ipwy, 19th dynasty, Deir el-Medinah. A gardener irrigating a garden with a "shadouf". His spine appears to have Pott's disease

Fig. 1.2. An Old Kingdom statue with a humped back and chest deformity denoting Pott's disease

1.4

A 4- to 6-year-old girl from the Ptolemaic period, whose mummy is in the Bolton Museum, appears to have Pott's disease. Lines of growth arrest (Harris line) are shown at the ends of the long bones due to the long period of disease and stress (Filer 1995). When the tomb of Iurudef at Saqqara was excavated in 1991, an intrusive burial of a non-royal female was found to have

Paleopathology There are several reports of lesions attributed to tuberculosis in Egyptian skeletal materials and mummies. The classic, and perhaps the most convincing case of skeletal tuberculosis, comes from the 21st dynasty, or about 1000 B.C. It is the mummy of Nespaheran, a 25 to 30-year-old Egyptian priest of Amun, near Thebes. It was found among a cache of 44 priests of Amun. The spine is acutely angulated due to destruction of the lower thoracic and upper lumbar vertebrae. A huge abscess cavity is present in the sheath of the right psoas muscle (Ruffer 1910, 1921; Cave 1939; Reyad 1960; Kamal 1964; Filer 1995; Nunn 1997). The drawing, by Mrs. Cecil M. Firth, was first introduced by Ruffer in 1910 and is now a classic (Fig. 1.3). Most of the known possible cases from the Predynastic to the 21st dynasty were reviewed by Morse et al. (1964). Buikstra et al. (1993) added new cases. Flinders Petrie and Quibell collected 13 specimens with tuberculosis affection from 2000 graves in Naqada (Nunn 1997). Derry (1938) reported nine cases. The Nubian collection of the Royal College of Surgeons of England contained many cases of skeletal tuberculosis, but many were lost together with their records during an air raid in 1941. Morse et al. (1964) described a single case of a mummy with a collapsed lung and pleural adhesions, which are common complications of tuberculosis.

Fig. 1.3. Nespaheran, a priest of Amun from the 21st dynasty. The side view shows marked kyphosis of the spine and, in the front view, a large cold abscess cavity is seen in the right psoas major muscle. The anterior abdominal wall is removed

Tuberculosis in Ancient Egypt

7

severe degeneration of the spine with marked angulation and a possible paravertebral abscess. Iurudef was a high Memphite official in the household of Princess Tia, sister of Rameses II of the 19th dynasty. It is believed that the woman, who died at approximately the age of 20 years, had lived her life as an invalid and only survived through family care (Walker 1991). It is interesting to note that one of the possible causes of the early death of Tutankhamen is tuberculosis (Reyad 1960).

1.5 Differential Diagnosis Although there is very little doubt that tuberculosis was the cause of the pathological findings in most of the reported cases, it is sometimes difficult to exclude compression fractures of the spine, osteomyelitis, spinal metastasis degenerative spondylosis, fungal infection and bone cysts.

Fig. 1.4. Tuberculosis of the right iliac bone and right sacroiliac joint, of a male aged 35-39 years old at time of death. Giza necropolis. There is ankylosis of the sacroiliac joint, erosion of the iliac bone and the sacrum and a round defect in the iliac bone

1.6 The Author's Case I was privileged to have the opportunity to examine the Giza collection of disarticulated skeletons, which should be considered one of the most important materials in the history of archaeology and archaeopathology. The material belongs to a very important period, the Old Kingdom, which was when the great pyramids were built. The United Nations Educational, Scientific and Cultural Organization (UNESCO) had added the entire archaeological area of Giza to its list of world heritage, as it is the oldest and most famous necropolis in the world. The material includes the skeletal remains of two different classes that lived in the same country during the same period of the third millennium B.C. The high officials and the dignitaries were buried in the western cemetery and the workmen and artisans were buried in the southeast cemetery. The excavations were headed by Reisner in 1942 and Hawass in 1994. Skeleton number 1932 (male) is one of the high officials buried in the western cemetery. His age at the time of death was between 35 years and 39 years. The right iliac bone and the adjoining right side of the sacrum are markedly affected by a chronic infective condition (Fig. 1.4). There is complete bony ankylosis of the right sacroiliac bone (Fig. 1.5). The outer part

Fig. 1.5. Radiograph of the specimen in Fig. 1.4

of the bone is markedly eroded, with bone buildup at the iliac crest and parts of the iliac bone and sacrum. The greater trochanter of right femur shows exuberant bone formation (Fig. 1.6). It seems that the tuberculous cold abscess trickled down along the gluteal muscle to involve the trochanter in the tuberculous process. The sacroiliac joint is the most common site of the pelvis that is affected by tuberculosis (Ortner and Putschar 1981) and chronic tuberculous affection of the greater trochanter is a characteristic lesion that affects young adults more than children. The spine and the hip joints do not show obvious pathological or radiological changes. The differential diagnosis of this case is pyogenic osteomyelitis, which is very rare in ancient Egyptian

8

S.A. Bedeir

1.7 Pulmonary and Osseous Tuberculosis in Ancient Egyptian Mummies

Fig. 1.6. Chronic tuberculosis of the greater trochanter of the right femur. Same case as in Fig. 1.4. There is erosion of the bone and exuberant bone buildup denoting a good healing reaction. There is no involvement of the femoral head

skeletal remains (Wood-Jones 1910). Patients with hematogenous osteomyelitis were expected to die from toxemia and pyemia before the inflammation produced manifested bone changes. The skeletal response to the tubercle bacilli is dependent on the virulence of the organism and the host response. If the host had little ability to defend himself, then tuberculosis could cause a progressive type of acute disease and early death. If the host's resistance was considerable, it is presumed that the disease then would be chronic, with the possibility of extensive healing and exuberant bone reaction. In our case, we believe that the patient's resistance was good, as manifested by the complete bony fusion of the right sacroiliac joint, the marked bone healing reaction of the iliac bone and the excessive bony build-up of the greater trochanter. The patient was one of the high dignitaries of the king. He most likely enjoyed eating a good, nutritive diet and lived in an appropriate house. It is interesting to comment on the presence of three healed fractures of both ulnae and left fibula. Fracture of the ulna is usually considered a "parry" injury, in which the patient tried to fend off a blow using the forearm. These injuries, which were in different stages of healing, indicate that our patient was active and aggressive during his life.

Pulmonary tuberculosis has been suspected by many authors to have occurred in ancient Egyptian populations (Cockburn et al.1975). The first to prove its occurrence, with microscopic confirmation of the presence of Mycobacterium tuberculosis bacilli, was Zimmerman (1979) from Michigan, USA. This author reported his anatomical and microscopic finding on the mummy of an ancient Egyptian child of five years of age belonging to Dra-Abu-el-Naga, found on the road to the Valley of the Kings, the tombs of the officials of 19th and 20th dynasties (1314-1085 B.C.). The author described the anatomical features that suggested pulmonary and osseous tuberculosis with recurrent and finally fatal pulmonary hemorrhage. Ziehl-Neelsen stain of a bone specimen showed scattered acid-fast bacilli. In a more recent report, pulmonary tuberculosis in an ancient Egyptian mummy was diagnosed and confirmed by polymerase chain reaction (PCR) (Nerlich et al. 1997). These German authors described their excavation findings at the tombs of the Nobles at Thebes-West in Upper Egypt. They reported a mummy of 35-year-old male dated from the New Kingdom (1550-1080 B.C.). These authors noted residue of the affected right lung with extensive pleural adhesions while the pleura of the left lung were normal. They also found two lumbar vertebral bodies severely affected anteriorly with lytic lesions and new bone formation. Specimens from both lungs were examined using PCR-amplification ofmycobacterial DNA. A specific positive band was identified from right lung specimens but not from the left unaffected lung. This was probably the first confirmed case of pulmonary tuberculosis using PCR in an ancient Egyptian mummy (Nerlich et al. 1997).

1.8 peR and the Diagnosis of Tuberculosis in Ancient Egyptian Population Many authors have tried to use the relatively recently acquired knowledge and development of DNA molecular technology for various purposes (Leek 1979; Harrison and Connolly 1969, David 1997). Svante Piiiibo (1985) used this technology, aiming at studying the descent and relationship of the ancient pharaonic families, individual relationships between members of these families and population in the Nile Valley. The author sampled 23 mummies from various

Tuberculosis in Ancient Egypt

dynasties between the 6th dynasty (2370-2160 B.C.) up to the Roman times. The ages ofthese mummies ranged between one-year-old boys to older ages, as estimated by the radiocarbon age technique of accelerator mass spectroscopy. Blunt-ended extract material was mixed with E. coli DNA polymerase with labeled radioactive nucleotides. The author concluded that recombinant DNA techniques could allow the study of the descent of the ancient Egyptian pharaonic families and their individual relationships. However, this author failed to recognize what would become the much wider use of this technique-detecting diseases in ancient Egyptian pharaonic population and families. The molecular approaches to DNA probe analysis using a nucleic acid-base methodology was originally described in early 1980s. It has been used extensively and has begun to have a major influence on current clinical management of various diseases. Several methods of PCR assays have been developed and IS6110 PCR can be done with a turnaround time of 24-36 h. It is a rapid and reliable molecular approach that can detect Mycobacterium tuberculosis DNA directly from clinical specimens. Such advances in investigative techniques have been exploited by many scientists and researchers who aim to trace diseases to an ancient time. In a large series of ancient Egyptian cadavers, Zink and colleagues (2001) from Munich, Germany, collected 41 skeletal specimens. Four were from Abydos (3000 B.C.) and thirty-seven were from Thebes-West, Upper Egypt (2120-500 B.C.). Three had typical macromorphological evidence of skeletal tuberculosis, 17 showed probable disease and 21 were without morphological skeletal changes. DNA was extracted from bone specimens and amplified by PCR with a primer pair that recognized the Mycobacterium tuberculosis complex insertion sequence IS611O. Nine of these cases were positive for Mycobacterium tuberculosis DNA. Two of the three cadavers with typical macromorphology of osseous tuberculosis had positive results for Mycobacterium tuberculosis DNA. Five of those with probable and two of those without morphological changes had positive results for Mycobacterium tuberculosis DNA. The authors concluded that their findings confirmed the relatively frequent occurrence of tuberculosis in ancient Egypt, dating back to 3000 B.C.

1.8.1 Environment

The lives of ancient Egyptians were shaped by their environment. The geography of Egypt was, and is still, like that of no other country. The Nile valley

9

was enclosed by deserts that protected Egypt against invasion, which resulted in long periods of stability. 1.8.1.1 The Nile

The Nile played a central role in daily life. Between July and October of each year, the Nile flooded its banks, depositing a rich and fertile layer of alluvial slit on the land. Inundation saved an enormous labor in the transportation of water and renewed the fertility of the land. 1.8.1.2

Climate Herodotus stated that the good health of the ancient Egyptians was due to the lack of variability in the weather. The Egyptian sky was blue almost all year round. The sun's rays nourished the Egyptians'bodies with vitamin D, and decreased the incidence of rickets. The dry, hot climate of Egypt is better suited to the preservation of human remains than that of any other country in the world. However, heat encourages flies, which were responsible for the spread of infections, especially eye infections and diarrhea. The Sahara (Khamasin) winds blew up dust storms and sand particles, resulting in chest infection, pneumoconiosis, laryngitis and sinusitis. 1.8.1.3 Housing The hot and dry climate influenced the design of ancient Egyptian housing. Houses varied from the large, villa-like houses of the top members of society to the small, crowded houses, with limited amount of light and space, of the poor people. In Amarna, smoke-blackened roof timbers indicated a heavy passage of soot. Tuberculosis thrived in such conditions of ill-housing and bad ventilation. 1.8.1.4

Diet Egyptians were already enjoying reasonably healthy and varied diets. Food production was not a major problem in Egypt, provided that the inundation of the Nile occurred every year. The main cereal crops were barley and emmer, with wheat being introduced only in the late period. Barley was used to make loaves and beer. Vegetables and fruits were grown on a large scale. Many of the familiar varieties were known: grapes, figs,

S.A. Bedeir

10

dates,pomegranates, melons, onions, leeks, cucumbers, lettuce, garlic, lentils and chickpeas. These provided many of the vitamins essential for good health. The ancient Egyptians consumed a wide variety of animal products, including cattle, sheep, goats and pigs. They kept sheep for producing wool, milk, cheese and meat. They ate ducks, geese, pigeons and quails. Hens were known only during the Ptolemaic period. The ancient Egyptians consumed fish that was fresh or dried and salted. Pure salt has been found from the sixth dynasty, but the method of preparation is unknown. Dates or honey was used for sweetening. Bee keeping was actively practiced, and honey was used to prepare medicines. The funerary offerings for King Unas of the fifth dynasty included: • Milk, three kinds of beer, five kinds of wine, ten loaves, four of bread, ten cakes, fruit cakes, four meats, different cuts, joints, roast, spleen, limb, breast, tail, goose, pigeon, figs, ten other fruits, three kinds of corn, barley, spelt, five kinds of oil and fresh plants (Nunn 1997). 1.8.1.5 Religion

Religion had a beneficial effect on the general health of the ancient Egyptians. Sacred holidays allowed them to rest and go to the temples to see the King. The poor people took their shares from the offerings. Vacations and ceremonial activities had the effect of raising the morale of the people. They had to take baths using running water and natron to clean their bodies. Men would shave their hair and women removed their unwanted hair. The ancient Egyptians believed that diseases were caused by excessive food, thus they used drugs and suppositories to evacuate their stomachs and bowels three times every month. 1.8.1.6 Sports and Recreation

Athletic sports were an ancient Egyptian invention. The ancient Egyptians were skilled in wrestling, stick combat, gymnastics, ball games, hunting, fishing and bull fighting. Families played cup games and board games (senet). They also enjoyed music, singing, and dancing. 1.8.1.7 Physique

The ancient Egyptians were small; the mean height of the males was 1.67 cm and the females 1.53 cm.

The arithmetic mean age at death was 36 years in the dynastic period. There are very few burials of people over the age of 60 years (Sarry EI-Din 1995). Pepi II and Rameses II survived to well in their eighties.

1.9 The Medical Papyri Although there can be no doubt of the existence of tuberculosis in ancient Egypt, many authors believe that nothing in the medical papyri can be directly related to the disease. The medical papyri do not contain any clear descriptions of tuberculosis (Ortner and Putschar 1981; Steinbock 1976). However, Ebbell (1937) and Kamal (1964) believe that the Ebers Papyrus (Ebers 1875) contains the description of two cases with tuberculosis of the cervical lymph nodes. The first case is described in section 860, column 195; Ebbell entitled the section "Soft Tuberculosis Gland". The section is translated as follows: \'Jl "Information about enlarged cystic node in his neck" - Examination: if you examine a man having an enlarged cystic node in his neck, and you find it like the thymus(?) gland because of its softness at palpation and its white discharge ... (empty space). - Diagnosis: you shall then say concerning him he has enlargement of the cystic node in his neck. An ailment I will treat by surgery to protect the vessels. - Treatment: you shall prepare medicines to treat him by a bandage that makes the cyst open through the skin: acacia seyal, pea, fruit, animal blood, insect's blood, honey, common salt (and other things). Grind. Mix together and bandage. «I The second case, section 861, reads as follows: - Title: information about enlarged infected node in the neck of a man. - Examination: if you examine an enlarged infected node in the neck of a man. After it is enlarged and removed the skin that covered it, and caused suppurating granulation for many years and months. It discharges a secretion like the seminal fluid of synodontis (a type of fish). - Diagnosis: you shall then say concerning him he has an enlarged infected node. An ailment I will treat. - Treatment: you shall prepare the medicines for him: wax or fat, As(?), ink, salt, goose fat, fruit(?) Galena. Heat and bandage the neck (Fig. 1.8),

Tuberculosis in Ancient Egypt

11

Fig.I.7. Healed fractures of the right ulna and left fibula of the same case as in Fig. 1.4

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Fig.1.8. Ebers papyrus, part of paragraph 861, describing a chronic tuberculous node in the neck. Arabic translation by Kamal (1964)

The Ebers Papyrus was purchased in Luxor by Edwin Smith in 1862. George Ebers referred to the Papyrus in 1873, and it is now in the University Library of Leipzig. It was translated into English by Dr. Ebbell in 1836. It comprises 110 pages and is by far the longest of the medical papyri. It is in very good condition and the handwriting is clear. It was written in 1534 B.C. It is claimed that the Ebers' Papyrus (or at least parts of it) date back to an ancient origin.

1.10 Sanatorial Treatment In 1938, Derry excavated four possible cases of spinal tuberculosis from two neighboring graves. In one grave, Derry found the remains of a man and a

woman and, in the other grave, he found the skeletons of two adult males and a nine-year-old boy. This cluster of cases was regarded as evidence of a cemetery for a tuberculosis sanatorium. The other possibility is that the individuals were related and acquired the disease from a common source of infection within the family. The ancient Egyptians knew sanatorial treatment. The sanatorium was a building in which patients could be totally or partially immersed in healing holy water. In certain temples, incubation or "temple sleep" was practiced; the patients were allowed to dream in the hope of receiving a cure from a deity (Quirke 1992). Sanatorial treatment was practiced in the great temples of Hathor and Dendera. Certain basins were supplied with water from the sacred lake, which could be made more curative by allowing it to ft.ow over healing statues and certain texts. The effect of the sacred water was obtained by drinking it (Dunn 1997).

S.A. Bedeir

12

Parts of Deir el-Bahri temple (Fig. 1.9) are considered by certain authorities to be the first sanatorium in history. The temple was established by Queen Hatshepsut in the 18th dynasty, 1500 B.C. Patients and invalids from different countries visited the sanatorium and stayed beside its columns, hoping for recovery. During the Ptolemaic period, Imhotep (Fig.UO) and Amenhotep, the son of Hapu, were worshipped on the upper terrace of the temple at Deir el-Bahri, where the faithful and sick gathered to request grace from the two gods of medicine. In 1923, Sir William Osler said that Imhotep was "the first figure of a physician to stand out clearly

from the mists of antiquity" (Nunn 1997). Milne and Joseph (1914) concluded that the temple was used as a sanatorium, and currently visitors can see the writings of patients who wrote while sitting; the levels of these writings corresponded with the heights of the patients. Frequently, the writings include the name and occupation of the patient as well as the times of his arrival and departure. One of those paragraphs reads as follows: I am Andropachus from Macedonia. I came to visit Amenotis. I was very ill, but now I am cured thanks to the mighty God. I ask you merciful God to give us all good health. Goodbye (Reyad 1960).

References

Fig. 1.9. Deir el-Bahri. Is it the first sanatorium in the world?

Fig.1.10. Statue of Imhotep. He was the patron of science, medicine and writing-one of the "wise men" of the past. Graeco-Roman period, Cairo Museum

Bartels P (1907) Tuberkulose in der Jiingeren Steinzeit. Arch AnthropoI6:243-250 Breed RS, Murray EGD, Smith NB (eds) (1957) Bergey's manual of determinative bacteriology. Williams and Wilkins, Baltimore Buikstra AE, Baker BJ, Cook DC (1993) What diseases plagued the ancient Egyptians? A century of controversy considered. In: Davies WV, Walker R (eds) Biological anthropology and the study of Ancient Egypt. British Museum Press, London, pp 231-250 Cave AJE (1939) The evidence forthe incidence of tuberculosis in ancient Egypt. Br J TubercoI33:142-152 Cockburn A, Cockburn E (eds) (1980) Mummies, diseases and Ancient cultures. Cambridge University Press, Cambridge Cockburn A, Barraco RA et al (1975) Autopsy of an Egyptian mummy. Science 187:1155-1160 David AR (1997) Disease in Egyptian mummies: the contribution of new technologies. Lancet 349:1760-1763 Derry DE (1938) Pott's disease in ancient Egypt. Med Press Circ 197:196-199 Ebbell B (1973) The Papyrus Ebers. Oxford University Press, London Ebers GM (1875) Papyros Ebers (two vols). Englemann, Leipzig Filer J (1995) Disease. British Museum Press, London Harrison RG, Connolly RC (1969) Microdetermination of blood group substances in ancient human tissue. Nature 224:326 Hawass Z (1996) The workmen's community at Giza plateau. Sonderdruck aus Haus und Palast in alien Agypten. Internationales Symposium, 8 bis 11 April 1992 in Kairo. Kamal H (1964) Ancient Egyptian medicine (two vols). Egyptian Organization for editing, translation and distribution (in Arabic) Leek FF (1979) Teeth and bread in ancient Egypt. J Egyptian ArchaeoI58:126-132 Mahmood MMR (1998) Occupational rehabilitation of the disabled in Ancient Egypt. Thesis, Master's degree, Helwan University Milne M, Joseph R (1914) The sanatorium of Der el-Bahri. J Egypt Archaei 1:96-99 Morse D, Brothwell DR, Ucho PJ (1964) Tuberculosis in Ancient Egypt. Am Rev Respir Dis 90:524-541 Nerlich AG, Haas CJ et al (1997) Molecular evidence for tuberculosis in an ancient Egyptian mummy. Lancet 350:1404

Tuberculosis in Ancient Egypt Nunn JF (1977) Ancient Egyptian medicine. British Museum Press, London Ortner DJ, Putschar WGJ (1981) Identification of pathological conditions in human skeletal remains. Smithsonian Institution Press, Washington DC Quirke SGT (1992) Ancient Egyptian religion. British Museum Press, London Reisner GA (1942) History of Giza necropolis, vol I. Cambridge Harvard University Press, London Reyad N (1960) Ancient Egyptian Medicine. Karnak Press, Cairo (in Arabic) Ruffer MA (1910) Pott'sche Krankheit an einer agyptischer Mumie aus der zeit der 21 Dynastie. Zur historischen Biologie der Krankheitserreger, 3. Heft, Giessen Ruffer MA (1921) Studies in palaeopathology of Egypt. University of Chicago Press, Chicago Sarry El-Din AM (1995) Comparative study of skeletal material from Giza old Kingdom with Sudanese Nubia. Thesis, PhD degree, Cairo University

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Steinbock RT (1976) Paleopathological diagnosis and interpretation. Bone diseases in ancient human populations. Thomas, Springfield, Illinois Svante Piiiibo (1985) Molecular cloning of ancient Egyptian mummy DNA. Nature 314:644-645 Walker R (1991) Skeletal remains. In: Raven MJ (ed) The tomb of Iurudef, a Memphite official of Rameses II. Egyptiam Exploration Society, London, pp 55-76 Wood-Jones F (1910) General pathology (including diseases of the teeth). In: Elliot-Smith G, Wood-Jones F (eds) The Archaeological Survey of Nubia Report for 1907-1908, vol II. Report on human remains. National Printing Department, Cairo, pp 263-292 Zimmerman MR (1979) Pulmonary and osseous tuberculosis in an Egyptian mummy. Bull NY Acad Med 55: 604-608 Zink A et al (2001) Molecular analysis of skeletal tuberculosis in an ancient Egyptian population. J Med Microbiol 50: 355-366

2

Historical Aspects of Tuberculosis M. MONIR MADKouR, KITAB

E. AL-OTAIBI, R. AL SWAILEM

2.1 2.2 2.3

2.25 2.26 2.27 2.28 2.29

M. M. MADKouR, MD, DM, FRCP Consultant, Department of Medicine, Riyadh Armed Forces Hospital, P.O. Box 7897, C-119, Riyadh 11159, Saudi Arabia K. E. AL-OTAlBI, MD, FRCS Director General of Medical Services Department, Riyadh Armed Forces Hospital, P.O. Box 7897, Riyadh 11159, Saudi Arabia R. AL SWAILEM, MRCP (UK) Consultant Rheumatologist, Department of Medicine, Riyadh Armed Forces Hospital, P.O. Box 7897, Riyadh 11159, Saudi Arabia

Tuberculosis was first described by ancient Egyptian doctors who described clearly the clinical features and medical and surgical treatment of scrofula (Fig.8, Chap. 1). The Ancient Egyptian artists contributed to the description through their exquisite paintings, which showed spinal tuberculosis and its gibbous deformity (Fig. 1, Chap. 1). The first known sanatorium in the history of mankind was established by the Ancient Egyptians and is now open to visitors (Fig. 9, Chap. 1). Archaeological and anthropological studies indicated that tuberculosis infected the Chinese, Indo-European and pre-Columbian American tribes (Buikstra 1983; Powell 1992; Verano and Ubelaker 1992; Paulsen 1987). Hippocrates (460-361 B.C.) described tuberculosis as "phthisis" and considered it to be an inherited and non-contagious disease (Chadwick and Mann 1978). Galen of Pergamon (130-200 A.D.) believed that tuberculosis was contagious. From Galen's time until the 8th century, nothing of significant importance in the history of tuberculosis occurred. The Middle Ages in European history, also known as the "Dark Ages" (approximately 500-1500 A.D.) roughly corresponded to the "Golden Age of Islam." Scholars in Islamic medicine, such as Rhazes, Avicenna and Albucasis, described symptomatology, pathology and predisposing factors for the development of tuberculosis. Avicenna, suggested the communicable nature of tuberculosis. Avicenna's "Canon of Medicine" was translated to Latin and served as foundation for university courses in medicine between 1250 and 1600 in Europe (Cruse 1999). Bimaristan (house of the sick) was first established in Baghdad by the famous Harun AI-Rashid in 803. Ibn an-Nafis (AI-Quraishi, d. 1288) discovered pulmonary circulation (Magner 1992).

CONTENTS Islamic Medicine During Europe's Dark Ages 16 The Pulmonary Circulation and Ibn an-Nafis 16 Islamic Medicine and Its Scientific Contribution to Tuberculosis 17 2.4 The Germ Theory 18 2.4.1 Miasma or Contagion 18 2.5 Percussion by an Amateur Musician 19 2.6 Laennec 19 2.6.1 Laennec's Work on Tuberculosis 19 2.6.2 Laennec's Invention of the Stethoscope 19 2.6.3 Laennec's Tubercles 19 2.7 Gaspard Laurent Bayle (1774-1816) 20 2.8 "Tubercle" and "Tuberculosis" 20 2.9 The White Plague 20 2.10 Robert Koch (December 11, 1843-May 27,1910) 21 2.10.1 The Discovery of the Tubercle Bacillus 21 2.10.2 Koch's Secret Cure (Tuberculin) and the Storm That Followed 22 2.10.3 The Ziehl-Neelsen Stain, or Koch-EhrlichRindfleisch-Ziehl-Neelsen Method? 23 2.11 Franz Ziehl (1857-1926) 23 2.12 Friedrich Karl Adolph Neelsen (1854-1894) 24 2.13 Paul Ehrlich 24 2.14 The Evolution of Tuberculosis Treatment 25 2.15 Climatological and Sanatorium Therapy 25 2.16 Sanatorium-Bimaristan or Deir el-Bahri 26 2.17 Artificial Lung Collapse Therapy 26 2.18 Thoracoplasty 26 2.19 Plombage 27 2.20 Pulmonary Resection 27 2.21 The History of BCG 27 2.22 The History of Chemotherapy for Tuberculosis 27 2.23 Streptomycin and Modern Antituberculosis Therapy 27 2.24 Animal and Human Trials on the Efficacy of Streptomycin 28

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

Para Aminosalicyclic Acid (PAS) Isoniazid 28 Rifampicin (Rifampin) 28 Drug Therapy for Cure 28 Conclusion 29 References 29

28

M. M. Madkour et aI.

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During the early development of the industrial revolution in Europe (approximately 1780), the incidence of tuberculosis increased and reached epidemic proportions. It was the most common cause of death in the 18th century. In Europe, from the later part of the 18th century throughout the 19th century, progress and advances have been achieved in the diagnosis of tuberculosis. France was the champion, with many French scholars such as Corvisart, Bayle, Laennec and Villemin, greatly advancing our understanding of tuberculosis. The breakthrough in the field of the diagnosis of tuberculosis was made by the Germans. Robert Koch discovered the causative bacillus in 1882 and Ziehl-Neelsen reported the staining method to identify the bacillus in 1882-1888. In 1895, Roentgen discovered Roentgen's X-ray, an advanced investigative method. Despite the identification of the bacillus, the discovery of antibiotics and their use for tuberculosis treatment lagged behind for over 60 years. However, surgical interventions for the treatment of tuberculosis started much earlier than chemotherapy. The human immunodeficiency virus (HIV) epidemic started in 1981 and its association with the resurgence of tuberculosis in areas where the disease had been controlled is a major setback in the fight against tuberculosis. As there is no cure for HIV at present, its management is reminiscent of tuberculosis prior to the antibiotics era.

2.1 Islamic Medicine During Europe's Dark Ages The Middle Ages of European history, from approximately 500 to 1500 A.D., an era also popularly known as the Dark Ages, roughly corresponds to the Golden Age of Islam. The great sages of Islamic medicine were established and studied in their own right and not just in terms of their role in preserving classical Greek medicine. Latin translation of the works of many brilliant Islamic scholars, including Rhazes, Avicenna and Albucasis, were most influential in Europe. Other Arabic scholars held prominent status in medical knowledge and practice in the Muslim world that had no parallel in the west (Magner 1992). During the European Dark Ages, western scholars were merely interested in recovering Greek medical knowledge and had less interest in the practical aspects of Islamic medicine, such as the development of hospitals and clinical training. In 750, Baghdad was

established as the capital of the Islamic Empire and by the end of the 10th century, Baghdad and Cairo had developed into independent centers of scholarship (Magner 1992). The library in Cairo had over 100,000 volumes of manuscripts. Baghdad had 36 public libraries by 1258, the year when the Moguls conquered the city and its great libraries were destroyed.

2.2 The Pulmonary Circulation and Ibn an-Nafis Western scholars long maintained that Arabic medical manuscripts were a Greek translation and lacked originality. However, the strange story of Ibn an-Nafis (AI-Qurashi, d. 1288) and his discovery of the pulmonary circulation demonstrates that such previous assumptions were unsound. The discovery and the writings of Ibn an-Nafis on pulmonary circulation were essentially ignored until 1924, when an Egyptian physician (Dr Muhyi ad-Din at-Tatawi) presented his doctoral thesis to the Medical Faculty of Freiburg, Germany and brought it to the attention of Prof. Max Meyerhof (Magner 1992). Dr. Lois N. Magner (1992), from the Department of History, Indiana, USA, in his book, A History of Medicine; wrote: "In the midst of a fairly conventional discussion of the structure and function of the heart, Ibn an-Nafis departed from the accepted explanation of the movement of the blood. His description of the two ventricles of the heart accepts the Galenic doctrine that the right ventricle is filled with blood and the left ventricle with vital spirit. His next statement, however, boldly contradicted Galen's teachings on the pores in the septum. An-Nafis insisted that there were no visible or invisible passages between the two ventricles and argued that the septum between the ventricles was thicker than other parts of the heart in order to prevent the harmful and inappropriate passage of blood or spirit between them. Thus, to explain the path taken by the blood, he reasoned that after the blood had been refined in the right ventricle, it was transmitted to the lung where it was rarefied and mixed with air. The finest part of this blood was then clarified and transmitted from the lung to left ventricle. That is, the blood can only get into the left ventricle by way of the lungs. Perhaps some still obscure Arabic, Persian, or Hebrew manuscript contains a commentary on the curious doctrines of Ibn an-Nafis, but there is as yet no evidence that later Arab authors or European anatomists were interested

Historical Aspects of Tuberculosis

in these anti-Galenic speculations. Thus, although Ibn an-Nafis did not influence later writers, the fact that his concept was so boldly stated in the thirteenth century should lead us to question our assumptions about progress and originality in the history of science. Since only a small percentage of the pertinent manuscripts have been studied, edited, translated, and printed, the question may go unanswered for quite some time:'

2.3 Islamic Medicine and Its Scientific Contribution to Tuberculosis Nothing of significant importance in the history of tuberculosis occurred until the 9th and 10th centuries, when the Islamic physicians Rhazes, Avicenna and Albucasis wrote excellent descriptions of the symptomatology, pathology and predisposing factors for the development of the disease. The communicable nature of tuberculosis was also suggested by Avicenna, who believed in the curability of the disease (Lyons and Petrucelli 1978). Rhazes (Abu Bakr Muhammad Ibn Zakariya alRazi) (850-925) was a brilliant physician who practiced medicine in Baghdad and at various locations in Iran. He has been known as the greatest physician of the Islamic world. He is considered one of the most scientifically minded physicians of the Middle Ages and one of the greatest physicians of all time (Magner 1992). He was the author of over 200 medical and philosophical treatises, including his massive masterpiece the Continens, or Comprehensive Book of Medicine, which was translated into Latin by the Jewish physician Faraj Ibn Salim (known in Latin as Farragut) for King Charles of Anjou (Magner 1992). Rhazes' manual of the healing arts Kitab al-Mansori (Almansour) was very influential in the West into the 16th century. He was chosen as director of one of the first great hospitals in Baghdad and selected the most healthful location for it. Rhazes provided clear insight into the relationship between patients and physicians, the signs and symptoms that the physician thought significant, the type of treatment given, the family background and occupation of the patient. Rhazes' book on smallpox and measles highlighted an extraordinary ability of his clinical acuteness, diagnosis, therapy and concepts of diseases. Mesue (Yuhanna Ibn-Masawayh) was the court's physician to four Abbasid Caliphs during the late 8th and first half of the 9th centuries. He was a brilliant

17

physician and renowned clinician and teacher. He wrote influential texts on nosology and therapeutics. One of the 9th century physicians was Joannitius (Hunay Ibn-Ishaq AI-Ibadi), who was proficient in Greek, Syriac and Arabic and translated many Greek medical texts. He wrote about many diseases, including a monograph on ophthalmology. Haly Abbas (Ali Ibn AI-Abbas AI-Majusi), who died in 994 and who wrote the famous Kitab AI-Malaki (also known as Kamil AI-Sinaa Filtib), one of the most concise and well-recognized expositions of GrecoIslamic medicine, was a physician at the Buwayhid court (Johnston 1993; Gallagher 1993; Risse 1993, quoted by Bishop and Neuma 1970). Avicenna (Abu-Ali AI-Husayn Ibn-Sina) (9801037) was also known as a "Prince of Physicians" (Cruse 1999). He was the first scholar to create a complete philosophical system in the Arabic language and his influence in medicine cannot be underestimated. Some critics indicated that his influence could not be challenged by other physicians, which therefore inhibited further development in medicine. At the age of ten, Avicenna memorized the Qur'an and turned to the natural sciences and to learning medicine. He soon realized that some things could only be learned by experience rather than solely from books. Early in the 11 th century, he wrote his leading medical encyclopedia, Canon of Medicine, a five-volume study dealing with physiology, nosology, etiology, symptomatology and therapy, pathology and the preparation of compound remedies. His enormous knowledge influenced the Islamic world and was translated into Latin. The Latin translation served as foundation for university courses in medicine between 1250 and 1600 in Europe (Cruse 1999). Significant advances made by Arab physicians served to teach European physicians during the 8th through the 11 th centuries. A well-known, brilliant Jewish physician in Arabic medicine was Maimonides (l135-1204), who translated "Canon of Medicine" into Hebrew and served as a liaison for medical knowledge between East and West (Cruse 1999). Rhazes, Avicenna and Albucasis wrote about the virtues of dry air and consuming fresh milk as climatological therapy. They linked the ulcers of the lungs to those of the extremities. They advised on the values of using camphor in sugar roses and believed in the curability of the disease. Avicenna suggested the communicable nature of tuberculosis. Avicenna gave an excellent description of the clinical features and pathology of tuberculosis in Arabic script. Avicenna, Rhazes and Haly Abbas described the people who were at great risk of developing tuberculosis as

18

having narrow chests, thin bodies and ages between 18 years and 30 years. They described the symptoms of tuberculosis (known in Arabic as; As'sul or Ad'daran) as fever (more so at night), sweating, malaise, anorexia, weight loss, cough, expectoration of sputum, hemoptysis and swelling of the legs. Al Majousi also described clubbing of the fingers in patients with tuberculosis (Al-Amoud 1993).

M. M. Madkour et al.

2.4 The Germ Theory 2.4.1 Miasma or Contagion

The idea that tuberculosis can be transmitted by contact is an ancient folk belief, but it was generally ignored in Hippocratic doctrine (Magner 1992). PhysiAlbucasis or Abu'l-Qasim (936-1013): Abu'l-Qasim cians and scientists have argued since antiquity about KalafIbn-'Abbas al-Zahrawi (Albucasis), an extremely the terms contagion theory and miasma theory as the ascetic man who devoted much of his time to work- cause of diseases. The miasma theory of disease was ing among the poor, wrote a more specialized guide known as disease-inducing noxious and contaminated to Arab Surgery. His book on Surgery and Instruments air and the theory was applied until the 19th century. is one of the first comprehensive illustrated treatises The contagion theory of disease was suspected by on this subject. He practiced in Cordoba, Spain and Fracastoro who published On Contagion in 1546. wrote an encyclopedic study that contained an influ- Girolamo Fracastoro (1478-1553) was an Italian phyential section on surgery based on Greek sources and sician, scientist, mathematician, astronomer, geologist his own findings (Magner 1992). and poet. He created the story of the shepherd named Pharmacology, alchemy and optics were other Syphilis, who brought about the first outbreak of areas of great interest to Arab scientists. Arabic trea- syphilis because he cursed the sun and became the first tises on medical pharmacology, including drug prod- victim of the new pestilence. Fracastoro's contagion ucts and their nomenclature and aromatic medicinal theory of disease interested and inspired the microbiplants, were written in the 8th to the 11th centuries. ologists of the 19th century, and he was regarded as the first to give an exposition of germ theory. Although the AI-Kindi (800-870): Yaaqub Ibn-Ishaq-Al-Kindi wrote microscope was invented at the end of the 16th century, a medical formulary and served as a model for Arabic its use to establish the existence of tiny "animalcules" treatises on pharmacology, botany, zoology and min- was not applied until the 17th century by Antoni Van eralogy. Persian and Indian drugs that were unknown Leeuwenhoek (1632-1723) who described "little anito Hippocrates and Galen appeared in such formular- mals" (Magner 1992). Professor Jacob Henle of Zurich (1809-1895) ies, as did new kinds of drug preparations. The eleventh century chemist and author Abu AI- wrote, "physicians blamed disease on miasma, which Biruni composed a treaties on pharmacy in which they defined as something that mixed with and poihe listed 720 drugs, including metallic compounds, soned the air, but no one had ever demonstrated the for the treatment of diseases. Such expansions led to existence of miasma with scientific instruments". the establishment of a medical pharmacy (Johnston Henle's hypothesis was that "Contagia Animata" 1993; Gallagher 1993; Risse 1993). (living organisms) caused contagious diseases Islam devoted secular institutions to care for (Magner 1992). the sick, named bimaristan, a Persian term meanGiovanni Cosimo Bonomo (d.1697) was the first to ing "house for the sick." The first bimaristan was provide convincing evidence that scabies was caused established by Ibn Barmak in Baghdad before the by a tortoise-like mite. He also provided the contiguyear 803, during the rule of the famous "Harun ous nature of scabies, "the itch", from one person to AI-Rashid". Inmates came from all sectors of the another by means of bedding or clothing. Yet, the population, including psychiatric patients (Galla- itch mite observation was not used as an example gher 1993). Bimaristans were operated by a direc- of other infectious diseases (Magner 1992). Agostino tor, medical staff, pharmacist, servants (as nurses) Bassi (1773-1857) also showed that silkworm disease and had their own libraries, which contained many could be transmitted to healthy silkworms and sugmedical texts. They also offered educational experi- gested its contiguous nature. In 1839, Lucas Schonences for medical students serving apprenticeships. lein (1793-1864) a German professor of medicine Lectures and discussions by famous physicians were reported his finding of the fungus that caused ringoffered for students who were issued licenses for worm. In the second half of the 19th century, Louis practicing medicine if they had successfully com- Pasteur and Robert Koch developed medical microbiology as a new science in the late 19th century. pleted theoretical and clinical courses.

Historical Aspects of Tuberculosis

2.5 Percussion by an Amateur Musician Leopold Joseph Avenbrugger (1722-1809) was an Austrian physician who worked in Vienna, he was also a gifted amateur musician and composer. Using his sensitive ear and musical talent, he invented chest percussion as a diagnostic procedure. His published work, entitled Invention Novum, became a landmark in the history of medicine. He gave an account of a new diagnostic method called "chest percussion", also known as "chest thumping", which could give the physician insight into the internal status of the chest cavity by carefully evaluating the sounds produced by chest percussion (Magner 1992). Only few physicians paid attention to Avenbrugger's invention until Jean Nicolas Covisart (1755-1821) published a translation and commentary in 1808.

2.6 Laennec Rene Theophile Hyacinthe Laennec (1781-1826) was a leading French physician, known for his work on tuberculosis, a disease that he certainly died from at the early age of 45. He postulated that all tubercular phenomena (phthisis, scrofula and miliary) constituted a single disease, which therefore raised the theories of etiology. His invention of the initial primitive stethoscope in 1816 made some of his critics scoff at the perceived value of his instrument. However, in 1825 his instrument was referred to as "Laennec's immortal work". Laennec was born in 1781 at Quimper in Brittany, northwest France. At the age of 14 1/2 years, he studied medicine at Nantes under his uncle, Guillaume Francois Laennec, rector of Nantes University. He later went on to study in Paris in 1801 and qualified in 1804. He was awarded many prizes and was asked to withdraw from some competitive examinations so as not to discourage his fellow-pupils.

2.6.1 Laennec's Work on Tuberculosis The extensive pathological anatomy made by Laennec was recorded in his 800-page manuscript, still in existence in Nantes and Paris, but was never published. He identified the various stages of pulmonary consumption and defined the tubercle that was

19

found in many other body organs. During his work, Laennec was subjected to many cuts to his fingers while cutting through the cadavers, which possibly contributed to his contracting and dying from the disease (Keers 1981; Sakula 1981).

2.6.2 Laennec's Invention of the Stethoscope While examining a stout female patient in 1816 at Necker hospital, he used tightly rolled sheets of paper attached to a wooden model in order to better hear her heart sounds. This primitive stethoscope of his went through many variations of form and material throughout the 19th century. He published his first book on auscultation in 1819, titled Del' Auscultation Mediate etc. This book introduced a diagnostic tool into medicine for the first time. He also wrote the most clear, accurate and almost complete account of chest diseases. While working in Cornwall, UK in 1821, Dr. John Forbes (later Sir John), translated Laennec's book into English, abridged and condensed. The first edition of Forbes' translation seriously underestimated the role and influence of Laennec's stethoscope, but in the second edition he admitted that he had been wrong in this estimation.

2.6.3 Laennec's Tubercles Laennec wrote on "phthisis Pulmonalis" and "of the essential, or anatomical character of tubercles in the lung" and stated: "The existence, in the lungs, of those peculiar productions to which the name of Tubercles has been restricted by modern anatomists, is the cause, and constitutes the true anatomical character, of Consumption". Laennec then went on to describe the appearances of tubercles, tracing them from their first, observable state, in which he wrote that they vary from the size of a millet seed to that of a hemp seed (and may be called miliary tubercles), to the ultimate fibro-cavernous destruction of lung substance (Bishop 1981). Later, he wrote: "There is perhaps no organ free from the attack of tubercles, and wherein we do not, occasionally discover them in our examination of phthisical subjects. The following are the parts in which I have met with these degenerations, and I enumerate them in the order of their frequency: the bronchial, mediastinal, the cervical,

M. M. Madkour et al.

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and the mesenteric glands; the other glands throughout the body; the liver - in which they attain large size, but come rarely to maturation; the prostate - in which they are often found completely softened, and leave, after their evacuation by the urethra, cavities of different sizes; the surface of the peritoneum and pleura, in which situations they are found small and very numerous,... the epididymis, the vasa deferentia, the testicle, spleen, heart, uterus, the brain and cerebellum, the bodies of the cranial bones, the substance of the vertebra or the point of union between these and the ligaments, the ribs, and lastly, tumours of the kind usually denominated scirrus or cancer, in which the tuberculous matter is either intimately combined with, or separated in distinct patches from, the other kinds of morbid degeneration existing in them." (p. 11; quoted from Bishop 1981). Laennec restored the hope and confidence for a cure or suspension of symptoms for patients suffering from tuberculosis. He discussed remedies that has been used since antiquity, such as blood-letting, mercurial salivation, emetics, charcoal, mushrooms, red cabbage, the conserve of roses, crabs, oysters, frogs, chocolate, alcohol, opium, cinchona, preparation of lead, hydrocyanic acid and the use of a swing for the cure of phthisis (Bishop 1981). Laennec never embraced these remedies, and it was said that his approach to medicine was Hippocratic.

2.7 Gaspard Laurent Bayle (1774-1816) A French physician, Laennec's friend and one-time co-worker, published the result of his research on tuberculosis. He carried out extensive pathological studies of 900 post-mortem specimens. He recognized and reported six types of pulmonary consumption including: tubercular phthisis, glandular phthisis, phthisis with melanosis, ulcerous phthisis, calculous phthisis and cancerous phthisis. He noted "Four of his ex-named varieties of phthisis represented one disease, tuberculosis in varying phases of developmene' He contributed ideas to the knowledge of the pathology and the unity of tuberculosis although he failed to grasp the etiological identity of one phase with another (Bishop 1981). Thomas Young (1773-1829), a well-known London physician who initially studied medicine at St. Bartholomew's Hospital in London (Bishop 1973) wrote A Practical and Historical Treatise on Consumptive Diseases published in London in 1815. He devoted nearly 12 pages to Bayle and wrote:

"Mr. Bayle's elaborate work has very lately been introduced to the English public, with no small parade, by his translator Dr. Barrow; and it must not be denied that it contains much valuable matter, although the practical importance of anatomical observations in general may have been somewhat overrated by the author. The translator talks of the propriety of some legislative measures for enforcing the keeping of registers of cases in all public hospitals, observing that, if such a regulation were adopted, France would not 'long exult as at present in her claim to preeminence, either in pathological or practical knowledge'" (p. 447; quoted by Bishop 1973).

2.8 "Tubercle" and "Tuberculosis" The term "tubercle" was first used by Franciscus (Francois) de la Boe, also known as Sylvius of Leyden (1416-1672), an outstanding Dutch anatomist and iatrochemist. He attempted to classify catarrhal diseases into groups distinguished by the chemical qualities of the humor produced-either alkaline or acidic in nature. He established the first university chemical laboratory at Leyden. He was the first to use the term "tubercle" and stated that tubercles were often seen in the lungs of consumptives (Johnston 1993). The term "tuberculosis" was first used by Laennec and his friend and colleague, Bayle. Laennec postulated that all tubercular phenomena (phthisis, scrofula and miliary) constitute a single disease and raised the theory of etiology.

2.9

The White Plague "I decided to entitle this presentation ...by avoiding the unfashionable word 'tuberculosis' and substituting a more romantic appellation:' noted Professor John F. Murray, University of California, San Francisco, when he gave "The 1989 J. Burns Amberson Lecture", entitled: "The White Plague". He hoped to stimulate an interest in and recruit an audience for his lecture, and certainly he did. Prof. Murray went on to say, "I borrowed my title from that of a book by Rene and Jean Dubos, who borrowed it, in turn, from Oliver Wendell Holmes, Sr., who first used 'the white plague' in 1861 to describe the enormity of the problems caused by tuberculosis at the time:' The phrase

21

Historical Aspects of Tuberculosis

"the white plague" has intrigued many historians, such as Dr. Allen B. Weisse (1995) from the University of New Jersey Medical School who wrote: "I wondered if the 'white' in 'white plague' related to race, pathology, the appearance of the patient or perhaps some other aspect of the disease". Although the population of Western Europe and the USA is predominantly white, non-whites are more susceptible to the disease than whites. Pathological appearance of the lesion in early post-mortem descriptions included terms such as "tumor albus, or white swelling" as in Richard M. Burke's book, An Historical Chronology of Tuberculosis (Myers 1977). Others described hepatic lesions as "the white tubercle of the liver", while Matthew Baillie (in 1703) described pulmonary tubercle as gray, or, as noted by the great Laennec, grayish or, following caseation, yellowish (quoted by Weisse 1995). If "white" reflected the patients' appearance, Dr. Weisse explained, clinicians have often commented on flushed skin rather than pallor reflecting the febrile state. The term "plague", from the Latin "to blow or strike", is an epidemic disease causing a high rate of mortality: pestilence. Early prehistoric ancient Greeks knew tuberculosis when over 130,000 persons died over a 5-year period (430-426 B.C.). Hippocrates (460-370 B.C.) was alive in Greece during that plague but he used the term "phthisis" to describe the rapidly progressive pulmonary form of the disease, which later became known as "galloping consumption". In the USA and Western Europe during the 18th and 19th centuries, tuberculosis was one of the most common causes of death (the other was cholera, the black death), and the usual chronic course of the illness was well recognized. Therefore the term "plague" was obviously a misnomer when referring to tuberculosis (Weisse 1995).

2.10 Robert Koch (December 11, 1843-May 27,1910) While working on anthrax in 1877, Robert Koch, a great German physician and bacteriologist, was the first to demonstrate that a specific pathogen caused a specific disease. He discovered tubercle bacillus on 24 March 1882 as the cause of tuberculosis. On 17 September 1883, while working in Alexandria, Egypt, he discovered Vibrio cholerae, but was unsuccessful in transmitting the infection to an experimental animal. This made his critics doubt his "postulates", which were not fulfilled; a criterion that he determined in

order to relate an organism as a causative agent to a disease. He also discovered the method of transmission of bubonic plague and sleeping sickness as well as other tropical diseases. One day after his birthday, on 12 December 1905, Koch received the Nobel Prize. Heinrich Herrmann Robert Koch was born on 11 December 1843 in Clausthal, a small mining city located between Hannover and Gottingen. He was the 3rd in a family with 11 (surviving) children (9 boys and 2 girls) and was closely attached to his mother. He was interested in photography, mathematics and natural sciences as a child. He studied English and French and was fluent. He joined Gottingen University at age 19 years to become a teacher but decided to change to studying medicine. He graduated at the age of 23 years and wanted to become a ship's doctor but gave up his idea in favor of becoming engaged to his sweetheart, Emmy Fraatz. He worked as medical assistant in Hamburg General Hospital as a source of income, but the income was not enough to provide for a family. He married Emmy on 16 July 1867. However, he had financial difficulties as he moved to other jobs. He volunteered in the Franco-German war in 1870 after having been rejected for army service because he was nearsighted. In 1872, he took an exam for District Medical Officer. His work on anthrax began in 1875. At the end of that year, he discovered the causative organism after inoculating a rabbit through the ear and showing the bacteria on microscopic examination (Brock 1999). The discovery of the etiology of anthrax made Koch famous among the intellectuals.

2.10.1 The Discovery of the Tubercle Bacillus Tuberculosis was strongly suspected to be a contagious disease before the discovery of the bacillus. In 1865, it was shown by a French physician, Jean Antoine Villemin (1827-1892), that tuberculosis was transmissible to experimental animals; however, the suspected causal organism had never been seen (Brock 1999). In August, 1881, Koch started his experimental studies, aiming at identifying the causative organism. On 24 March 1882, Koch gave his historic lecture in Berlin on the discovery of the bacillus. He was aware that the presence of the organism did not indicate that it was the cause of the disease. He proposed a criteria in order to make such an association, which became known as "Koch's Postulates". The postulates are a series of steps that should be followed to prove that a specific organism is the cause of a specific disease. The organism

22

must be isolated and grown in a pure culture and the pure culture must induce the disease when injected in experimental animal. Koch himself failed to fulfill his postulate when he discovered Vibrio cholerae as the cause of cholera while working in Alexandria, Egypt on 17 September 1883. He was not successful in establishing an animal model at that time and his postulates were thrown back at him by his critics in a proceeding of the first cholera conference. An editorial that appeared in the «British Medical Journal" in 1884 (quoted by Brock 1999) noted, «Of course, the whole point turns on whether Dr. Koch has made out that the comma-bacillus is really the cause of the disease. In order to demonstrate that a given bacterium is the cause of a disease, it must be proved: 1) that a special bacterium with definite characteristics marking it out from other forms of bacteria, is constantly present in the parts affected 2) that his bacterium is present in sufficient numbers to account for the disease 3) that it is not similarly associated with other diseases 4) that this bacterium can be cultivated apart from the body, and that its introduction into lower animals is followed by the same effects as the introduction of the infective material itself" In response to his critics, Koch wrote,«The comma bacillus is a specific bacterium, found exclusively in association with Asiatic Cholera. As long as this statement is not contradicted, all of my conclusions regarding the diagnostic utility of this bacterium and its relation to the pathology of cholera remain valid. However, my opponents state that a causal relationship between the comma bacillus and cholera has not been established because it has not been possible to induce cholera artificially in experimental animals. This objection is not valid because Professors Rietsch and Nicati succeeded, during the last cholera epidemic in Marseille, to bring about cholera-like symptoms in dogs and guinea pigs, provided the bile duct had been tied off and a pure culture of the comma bacillus injected directly into the duodenum... These studies have been recently repeated here in my laboratory, using a pure culture diluted so much that less than one-hundredth of a drop was injected... With few exceptions, the treated animals died in 1.5-3 days... These animal studies have been extended in other directions and have shown without a doubt that the comma bacillus is pathogenic. Under these circumstances, it would be very advisable to avoid completely any inoculation studies in humans (as has been recently discussed), and restrict all inoc-

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ulation studies to guinea pigs and other experimental animals" (quoted by Brock 1999).

2.10.2 Koch's Secret Cure (Tuberculin) and the Storm That Followed In August, 1890, Koch dramatically reported secret research in a speech given at the 10th International Congress of Medicine in Berlin. He implied that he found a cure for tuberculosis and said: «[after long study of many chemicals 1I have at last found substances which both in the test-tube and in the living body prevent the growth of the tubercle bacilli. All such investigations... are very exhausting and slow; and my experiments with these substances, though lasting more than a year, are not yet concluded, so that all I can say at present is that if guinea pigs are treated they cannot be inoculated with tuberculosis, and guinea pigs which already are in the late stages of the disease are completely cured, although the body suffers no ill effects from the treatment. From these experiments I will draw no other conclusion at present than that it is possible to render pathogenic bacteria within the body harmless without ill effect on the body itself" (quoted from Brock 1999). News spread rapidly and thousands of patients traveled from all over Europe to Berlin, seeking the injections of «Koch's lymph" hoping to get cured. His new «remedy" was tried on a human at the Charite Hospital, but the validity of the cure were doubted. Tuberculous patients commonly showed a strong reaction to injection with tuberculin as a hypersensitivity reaction and became known as «Koch Phenomenon;' Later «tuberculin" was used as an important diagnostic test. Koch injected himself with the tuberculin and reported fever, rigor, joint pains, nausea and vomiting which improved after 12 h to few days. He refused to describe the method of tuberculin preparation and was severely criticized for not revealing the nature of his remedy. In 189011891, it became clear that Koch's tuberculin had no therapeutic value but was of great diagnostic use. The compound was known as «remedy" or «Koch's lymph:'but in 1891 Koch and Libbertz labeled it «tuberculin". The stress of the tuberculin storm created by his cynical critics was intense and Koch arranged for a long vacation to Egypt in 1891, leaving his son-in-law in charge of tuberculin and the Institute for Infectious Diseases (Magner 1992). The «tuberculin" crisis had severely affected Koch's scientific life. He became acquainted with Hedwig Frieberg, a pretty, 17-year-old art student.

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His relationship with his wife Emmy had been deteriorating and they eventually divorced in 1891. He married Hedwig on 13 September 1893, when he was 50 years and she was 20 years of age. They lived together until he died in 1910. Hedwig Koch died on 16 June 1945. "In his lifetime, Robert Koch did more to single handedly advance the world's understanding of microbes as causes of disease than any other man, with the exception only of his great French rival Louis Pasteur" (James Strick, who wrote the foreword to Thomas D. Brock's book, Robert Koch: A Life in

appear brown, while the tubercle bacilli on the other hand, stain a beautiful blue. Moreover, all other bacteria which I have investigated to date, with the exception of the lepra bacilli, take on a brown colour with this staining method. The color contrast between the brown stained tissue and the blue tubercle bacilli is so striking that the latter, which are present often only in very small number, nevertheless, are to be found and identified with the greatest certainty" (pp. 227-228 in the original: Koch 1882; the translation is that of William de Rouville, 1938, pp. 854-55).

Medicine and Bacteriology, 1999). 2.10.3 The Ziehl-Neelsen Stain, or Koch-EhrlichRindfleisch-Ziehl-Neelsen Method? The history of staining the tubercle bacilli started when Koch's made his discovery of the tubercle bacillus on 24 March 1882. The translation of Koch's first publication on the subject on 10 April 1882 Die Aetiologie der Tuberculose was translated by William de Rouville in 1938 and quoted in the Bishop and Neumann (1970) paper on the history of the Ziehl-Neelsen Stain. Koch's method of staining the tubercle bacillus included the three most important factors: the use of a chemical substance that made staining possible (mordant), heat, and decolorizing. He wrote: "The material to be examined is prepared in the usual manner for examining for pathogenic bacteria, and either spread on the cover slip, dried and heated or cut into sections after fixation in alcohol. The cover slips or sections are placed in a staining solution of the following constitution: 200 cc of distilled water are mixed with 1 cc of a concentrated alcoholic solution of methylene blue, shaken up, and then 0.2 cc of a 10% solution of potassium hydroxide is added with repeated shaking. This mixture must show no precipitate after standing for several days. The materials to be stained remain in this solution for 20 to 24 hours. By heating the solution to 400C in a water bath this time can be shortened to a half to one hour. Following this the cover slips are covered with a concentrated aqueous solution of vesuvin (Bismarck brown) which is filtered each time before using, and one to two minutes rinsed with distilled water. When the cover slips come from the methylene blue, the attached layer appears dark blue and markedly (p. 222) overstained. During the treatment with vesuvin this blue colour is lost and it appears stained a faint brown. Under the microscope all the constituents of animal tissue, that is, the cell nuclei and their products of disintegration

2.11

Franz Ziehl (1857-1926)

A neurologist at Lubeck, Franz Ziehl was born in Germany at Wismar in Mecklenburg-Schwerin. He qualified and worked in Heidelberg as assistant in a medical clinic from 1881 until 1886. He moved to Lubeck in 1887 to work as neurologist until his death on 7 April 1926. Ziehl published his first paper on staining the tubercle bacillus on 12 August 1882 and described how he had modified Ehrlich's method by changing the mordant from aniline to carbolic acid. He wrote: "Up to the present we have not been able to obtain the pure constituents of aniline oil. As it was necessary to use a substance belonging to the aromatic series we tested such a one, the reaction of which was known to us from that second aniline oil, namely carbolic acid" (Ziehl 1882 p. 451, quoted by Bishop and Neuman 1970). Description of the acid-fastness of the bacilli by Ziehl was published in another paper on 25 April 1883, entitled "On the staining of tubercle bacilli" (Ziehl 1883b, quoted by Bishop and Neumann 1970). "The importance of finding tubercle bacilli especially with regard to diagnosis and prognosis" was the title of another paper made by Ziehl that appeared on 31 January 1883 and reported the finding of the bacilli in 73 cases of pulmonary tuberculosis and concluded: "1.In most cases of pulmonary tuberculosis tubercle bacilli may be found; exceptions do occur. 2. The finding of tubercle bacilli may confirm the diagnosis of tuberculosis. In some cases the differential diagnosis is possible by this finding. 3. If tubercle bacilli cannot be found, it is not always possible to exclude tuberculosis. 4. The number and kind of tubercle bacilli do not allow any prognostic conclusions." (Ziehl 1883a, quoted by Bishop and Neuman 1970).

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2.12 Friedrich Karl Adolph Neelsen (1854-1894) A German pathologist born at Utersen, Holstein, Neelsen studied, qualified and worked as assistant at the Pathology Institute at Leipzig in 1876 until 1878. Between 1878 and 1885 he had a similar position at Rostock and became a professor in 1884. He moved to Dresden in 1885 and worked as Prosector at the Staedtisches Krankenhaus. He died at the age of 40 years on 11 April 1894. His death was almost certainly due to tuberculosis, as he suffered from emaciation, cough, progressive hoarseness and general deterioration. These symptoms started in the autumn of 1893. In 1883, Neelsen combined ZieW's mordant with Ehrlich's red stain fuchsin in staining the tubercle bacillus. Neelsen published the first article on the subject on 14 July 1883 in a German journal "Centralblattfur die medicinischen Wissenschaften". The title of the article was "A casuistic note on the theory of tuberculosis" and noted: "In this case I used first as a staining fluid a threequarter per cent solution of fuchsin in 5% carbolic acid with admixture of some alcohol and decolorized with 25% sulphuric acid. This method, which I have used almost exclusively for a long time, gives in my hands better results than the other methods (perhaps only because I am most accustomed to it)" (Neelsen 1883 p. 500, quoted by Bishop and Neuman 1970).

2.13

Paul Ehrlich

A German bacteriologist and pathologist born in 1863, Ehrlich made an improvement of Koch's method of staining the tubercle bacillus. His first communication on the subject was made to the Berlin Society ofInternal Medicine on 1 May 1882. He used decolorization with a mineral acid, used a red stain, fuchsin, and changed the mordant to aniline oil instead of alkaline methylene blue. He wrote: "After these remarks I wish to briefly report the method. I have worked almost exclusively with dry preparations, Le. of sputa, but I have done controlled trials which have proved that the method is also applicable to section preparations. I proceed by taking out a small particle with a dissecting needle from the sputum and squeezing it flat between two cover glasses, and I have found that those 0.10 to 0.12 mm are best. Under these conditions it is easy to obtain uniformly thin layers from the small plug of sputum. Then both glasses are torn from each other and one then gets two

M. M. Madkour et aI.

thin layers, which can easily be air-dried. These preparations are not yet suitable. Usually I have done this by keeping the preparations for one hour at 100 to 110oe; however there exists a more convenient method which I have seen used in the Kaiserliches Gesundheitsamt and which consists in passing the air-dried preparations three times through the flame of a Bunsen burner. For staining I use water, saturated by aniline oil, which may be prepared in a few minutes by shaking water with surplus aniline oil and filtering it through a moistened filter. To the water-clear fluid obtained in this way one adds drop by drop a saturated alcoholic solution of fuchsin or methylene violet until a distinct opalescence indicates saturation with the dyestuff. Upon this fluid the preparations are made to float and staining is adequate within a quarter to half and hour. The colour of the tubercle bacilli does not disappear under the influence of vesuvin (Bismarck brown) or only very slowly. It is necessary to use an acid and I soon turned to the use of strong, I may even say heroic ones. A mixture consisting of 1volume of official nitric acid and 2 volumes ofwater can be recommended. Under its influence one sees the preparation grow pale within a few seconds, yellow clouds rise and the preparation becomes white:' "If one examines the preparation at this stage, it is seen to be decolorized and only the bacillus has maintained its intensive staining. It might be possible to examine such a preparation, but the technical difficulties of focusing the bacillus are extremely great. It is recommended to stain the background yellow if the bacilli are violet, and blue if they are red." "I have succeeded in staining the bacillus with all basic aniline dyes, even with Bismarck brown, and hence it follows that the substance of the bacillus itself does not differ from that of other bacilli in its staining properties. But the discrimination of the tubercle bacillus by staining depends on the presence of a surface layer with characteristic and specific properties. The first of these to which Koch's technique is pointing is that the covering layer is permeable only to dyes under the influence of alkalis'." (Ehrlich 1882 pp. 269-270) In 1882, Edvard Georg Rindfleisch, a Wiirzburg pathologist, made an improvement on Koch's method of staining tubercle bacillus by heating the slide instead of putting it in hot water. Historians of tuberculosis made good accounts in the literature of the history of the staining methods of the tubercle bacillus since its first discovery by Robert Koch in 1882. The time between 1882 and 1888 was noted by Predohl, where all the methods of staining Koch's bacillus have been described. He was the first to mention the words, the Ziehl-Neelsen

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method, and noted,"I must describe the modification of Ziehl's method given by Neelsen". The phrase Ziehl-Neelsen method of staining tubercle bacilli was not mentioned in the first edition of Edgar March Crookshank's book of bacteriology in 1886. Although his list included both Ziehl's and Neelsen's methods, the phrase"Ziehl-Neelsen method" was not used. In the fourth edition in 1896, Crookshank noted: "The Ziehl-Neelsen method is preferred by the author for sections and cover-glass preparations;' The phrase and label of the Ziehl-Neelsen method may have become known sometime between 1890 and 1893 (Bishop and Neumann 1970). These two German doctors, Ziehl and Neelsen, described their methods nearly 100 years ago. These methods remain in use at present and will always be in the literature of tuberculosis.

2.14 The Evolution of Tuberculosis Treatment From the time of the Ancient Egyptians, Hippocrates, Galen, and the Middle Ages, up until the early 19th century, little has been added to the therapy of tuberculosis. The ancient Egyptians treated scrofula with surgery and dressings (see Chap. 1). Hippocrates' treatment was simple and related to confinement into the temples of health, resting, praying, drinking milk, dieting, exercising and avoidance of extreme weather. Drug treatment was not emphasized. Five centuries later, Galen added little to the classic Hippocratic treatment for pulmonary tuberculosis. Galen recommended bed rest, gargles, application of plasters to the chest and head and the diet and dry air ofhealth resorts. Such concepts of treatment for tuberculosis remained for more than 1000 years. In medieval Europe, scrofula was more common than the pulmonary form of the disease. It was customary to believe in the "King's touch", in which the kings of France and England were believed to have the power to cure scrofula simply by touching its victims. This custom originated in the 12th century and persisted until the 18th century (Risse 1993; Gallagher 1993; Johnston 1993). The Oxfordshire village of Stanton St. John was burdened with scrofula, "The King's Evil". Its residents desired the cure by the touch. The touching was performed by English sovereigns from Edward the Confessor to Queen Anne. Those who did not respond chose a range of equally efficacious modes of therapy accompanied by prayer. Records at Stanton St. John indicated that certificates attested to the eligibility of parishioners to practice "The King's Touch" (Crawfurd 1911).

In North America, early in the 17th century, the Reverend Cotton Mather, famous for his persecution of witchcraft in Salem, wrote a medical work entitled The Angel of Bethesda, which quoted Galen on therapy and directed the patient to repent his sins. He recommended a concoction obtained by strangling two roosters, beating them to a pulp, boiling them in a mixture of wine and water, straining the mixture through a cloth and adding raisins, hartshorn, maidenhair and saffron (Rosenblatt 1973).

2.15 Climatological and Sanatorium Therapy During the early industrial revolution, around 1780, the recorded mortality rate due to tuberculosis in England was 1,120 per 100,000 population (Rogers 1969). Early in the 19th century the mortality rate started to decline and the 19th century was called the century of tuberculosis. Treatment of tuberculosis at the beginning of the 19th century was summarized in a thesis of Edward Delafield published in 1816 (quoted by Rogers 1969). Delafield recommended blood letting, emetics, mercury, opiates, digitalis and Peruvian bark. He recommended sea voyages and mild climate, particularly in the south of France. He speculated that the nausea of seasickness was the principle that explained the benefits of sailing. In 1834, Samuel Morton, who studied in Paris and was lectured by Laennec, Bayle and Louis, published the first American textbook on tuberculosis (Rogers 1969). Morton deplored blood letting for the treatment of tuberculosis and was in favor of the effect of climate, particularly cold, dry atmosphere. Many other authors in the 19th century were interested in climatotherapy and recommended other areas, such as the Rocky Mountains and Pike's Peak. Rogers (1969) quoted from Disturnell (1867) who quoted reports of surgeon G.K. Wood, of the US Army, stationed at Fort Laramie, Wyoming: "The climate of these broad and elevated table-lands which skirt the base of the Rocky Mountains on the east, is especially beneficial to persons suffering from pulmonary diseases, or with a scrofulous diathesis... It is of great importance that the climate of this region should be generally known..." Daniel Dark (1850), quoted by Rogers (1969), described the Missouri river and its environs around Fort Leavenworth in a work entitled, "Journeys of health on the great plains;' He wrote: 1. The patient escapes from malaria, or that condition of the atmo-

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sphere, which, in the larger portions of the Great Valley, gives origin to intermittent and remittent fevers, too often followed by infirmities for which a change of locality is the only effectual remedy. 2. He is constantly immersed in a dryer air.... 4. He lives on a reduced, solid, and simple diet. ..6. He takes regular saddle exercise...8. He is divested of his old cares..... 9. He is redeemed from the dominion of empiricism and polypharmacy." In the second half of the 19th century, climatography was well established. The American Climatological Association was formed in 1884 and held the first meeting in Washington, D.C. in 1908. The Sixth International Congress on Tuberculosis was held, and W. Jarvis Barlow of Los Angeles said, "The high altitude treatment received great impetus from this congress:' The transactions of the congress of 1908 showed something quite different: "The apogee of high altitude therapy have been reached and its advocacy would slowly subside thereafter" (Rogers 1969). The name of the "American Climatological Association" was changed in 1914 and again in 1933 as the problem of the efficacy of altitude therapy was a classic case of the problem of multiple variables. In 1960, Spriggs (quoted by Rogers 1969) published an article and said, "What statistical evidence there was for the value of rest treatment does not nowadays convince.....". By the time of World War II, climatotherapy in the United States was a dead issue (Rogers 1969; Wilson 1979).

2.16 Sanatorium-Bimaristan or Deir el-Bahri "I am Andropachus from Macedonia. I came to visit Amenotis. I was very ill, but now I am cured thanks to the mighty God. I ask you merciful God to give us all good health. Goodbye:' These were the writings in hieroglyphic by an ancient sick Greek patient on the wall of Deir el-Bahri temple, which was believed by Milne and Joseph (1914) to be the first Sanatorium in history (see Chap. I). Nowadays visitors can see the writing of patients who sought cure in this sanatorium "Temple:' Bimaristan (houses of the sick in Persian) were first established in 803 by the famous "Harun AIRashid" in Baghdad. Sanatorium, is a word that comes from the Latin Sanatorius meaning "an establishment providing therapy" (Wright 1988). In 1836, George Bodington, a practitioner in Birmingham, UK, was the first to propose housing tuberculosis patients in one build-

ing (Rosenblatt 1973). His aim was to provide these patients with diet, physical activities and fresh air, but the proposal failed for lack of support. The first sanatorium for the treatment of patients with pulmonary tuberculosis was opened in 1859 in Gorbersdorf, Germany by Dr. Hermann Breemer (Rosenblatt 1973). He believed that mountain air and exercise were beneficial. Many other sanatoria were opened, and perhaps one of the most famous was Trudeau Sanatorium in Saranac Lake, N.Y. It was established by Edward L. Trudeau in 1885, a young New Yorker who decided on a sudden impulse to become a doctor as he passed by the College of Physicians and Surgeons while walking along Fourth Avenue in 1868. Shortly after graduation, he was struck by tuberculosis. Fifty years later, the number of sanatoria in the USA had increased to 600 with a total bed capacity of 95,000.

2.17 Artificial Lung Collapse Therapy Bourru (1774) in Paris was the first to think of inducing artificial lung collapse,aiming at the arrest ofthe disease, but the concept was not given a clinical trial (Rosenblatt 1973). An attempted trial to induce pneumothorax in two tuberculous patients by Carson had failed, but despite these failures its concept was intriguing. In 1835, McRuer from the USA and Houghton and Strokes from the UK were successful and their patients improved. Others had similar encouraging experiences, including Cayley (1885) who used the therapy in a patient who had had a pulmonary hemorrhage (Rosenblatt 1973). The most significant work on artificial pneumothorax therapy was reported by Carlo Forlanini (b. 1847) in 1882. He used an apparatus to force nitrogen gas through a tube and a needle inserted into the patient's pleural cavity and was successful (Rosenblatt 1973). Pneumothorax remained popular despite its therapeutic limitations and complications, such as development ofpleural effusion, emphysema and increased mortality, and remained in use until the 1940s.

2.18 Thoracoplasty Rib resection to collapse and close tuberculosis cavities (thoracoplasty) was a popular operation in the late 19th and early 20th centuries. The first tho-

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racoplasty was performed by de Cerenville in 1885, and in 1909, Braver introduced a two-stage technique to reduce the surgical shock that was noted in the one-stage thoracoplasty (Rosenblatt 1973). Phrenic nerve crush was used to paralyze the diaphragm and compress the affected lung. Pneumoperitoneum with phrenectomy were popular in the 1930s and early 1940s (Godfrey and Norman 1969).

2.19 Plombage Plombe is a word introduced by Professor Custodis of Dusseldorf, Germany to describe the implants he used to produce infolding of the sclera in cases of retinal detachment. Plombage (a French word meaning stopping) is the procedure of packing the pleural cavity with inert material. Extrapleural pneumothorax by instillation of oil to maintain lung collapse was first suggested by Mayer 1913 (quoted in Magner 1992), but was not used until two decades later. Insertion of plombe from fatty tissue, paraffin or Lucite balls into the extrapleural space was called plombage. The procedure was used to provide permanent compression of the underlying diseased lung, particularly with large peripheral cavities.

2.20 Pulmonary Resection In 1883, Block (quoted in Magner 1992) was the first to perform pulmonary resection for tuberculosis in man. The patient died and at autopsy there was no evidence of tuberculosis. Block shot himself. In 1884 Kronlein (quoted in Magner 1992) resected apical tuberculosis in two patients and both died. Later, despite advances in surgery in the pre-antibiotics era, postoperative mortality was high.

2.21 The History of BCG Leon Charles Albert Calmette (b.l863) and Camille Guerin (b.l872) were French bacteriologists working in the Pasteur Institute in Lille. Their work on the vaccine began in 1908 on a strain of Mycobacterium tuberculosis isolated by Nocard from a cow that had tuberculous

mastitis. An attenuated bovine bacillus was first isolated in 1921 by Calmette and Guerin after years of laboratory cultivations. The attenuated strain of tubercle bacillus was incapable of producing tuberculosis in any laboratory animals (Calmette 1923). In 1930, a tragic incident occurred whereby administration of a virulent tubercle bacilli stored in the same refrigerator as the BCG led to the death of 67 German babies in Lubeck. BCG was initially given to many infants in France as an oral vaccine but the Scandinavians pioneered its administration intradermally in 1950.

2.22 The History of Chemotherapy for Tuberculosis The antibiotics era began in 1928 when Alexander Fleming (1881-1955), a Scottish bacteriologist and immunologist in London, discovered the effect of the mold Penicillium notatum on bacteria. His discovery remained a laboratory curiosity until World War II. "Fleming, recalled that neither bacteriologists nor physicians paid any attention to penicillin until the introduction of sulphonamide" (Quoted from Magner 1992 p. 353). A sulfur containing red dye called Prontosil, which protected mice from staphylococcal and streptococcal infections was discovered by Domagk in 1932. Gerhard Domagk (1895-1964) was a German chemist and pathologist. In 1935, Domagk reported "A contribution to the chemotherapy of bacterial infections;' and with that report he initiated the age of chemotherapy. Prontosil and other sulfonamides, including promizole and diasone, were hailed as "miracle drugs" in the 1930s. In 1939 Domagk was awarded the Nobel Prize for Physiology and Medicine "For the discovery of the antimicrobial effect of Prontosil;' but Nazi officials would not allow him to accept it. He finally received the Nobel Medal in 1947. Sulfonamides were tried on patients with tuberculosis but were found to be of little value (Hinshaw et al. 1944,1946; Hinshaw 1969).

2.23 Streptomycin and Modern Antituberculosis Therapy In 1943, Selman A. Waksman (1888-1973) and coworkers isolated streptomycin from two strains of

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an actinomycete species. Much of the initial work was done by his graduate student, Albert Schatz. Waksman was a Russian immigrant to the USA who, in 1915, graduated from the Agricultural College of Rutgers University in New Jersey (Ryan 1992). He published a book titled, Principles of Soil Microbiol-

ogy.

2.24 Animal and Human Trials on the Efficacy of Streptomycin Experimental trials of streptomycin on animals infected with tuberculosis and on tuberculous patients demonstrated its efficacy (Feldman et al. 1947; Hinshaw et al. 1946; Pfuetze et al. 1955) and by the late 1940s streptomycin's effectiveness was clearly established. Schatz shared royalties with Waksman but did not share the Nobel Prize, which was awarded to Waksman alone. The use of streptomycin as a single agent for the treatment of tuberculosis was difficult (Cooke et al. 1946).

2.25 Para-Aminosalicyclic Acid (PAS) Dr. Jorgen Lehmann was born in Denmark and graduated from a Swedish medical school. He went to New York as a research fellow then returned back to work as Chief of Chemical Pathology in Goteborg, Sweden. He developed PAS in 1943, after synthesizing analogues and various derivatives of salicylic acid in Swedish laboratories. PAS was first used as a topical agent for the treatment of tuberculous fistulous tract caused by cervical scrofula or by intrapleural installation in patients with tuberculous empyema. The first oral tablets of PAS were used in October 1944 and in 1946, Lehmann reported a preliminary laboratory and clinical report on the drug (Lehmann 1946, 1964). Feldman and colleagues (1947) from Mayo clinic tried PAS on animals infected with tuberculosis and found it to be effective (Feldman et al. 1947). The British Medical Research Council (MRC) study on using PAS alone, streptomycin (SM) alone or PAS plus SM found SM alone was superior to PAS alone and that their combination showed clinical and radiological improvement with reduced emergence of resistant organisms (British Medical Research Council 1950).

2.26 Isoniazid Isoniazid (isonicotinic acid hydrazide, INH) was first synthesized by Meyer and Malley in Prague (Meyer and Malley 1912). However, it was not until 1942 that its antituberculous effect was noted by Chorine (1942). In 1951-1952, Hoffman-La Roche, Squibb in the USA, and Bayer in Germany independently and simultaneously developed INH. The first clinical trial of INH alone for the treatment of tuberculous patients was in Seaview Sanatorium, New York in 1951 by Robitzek and Selikoff (Robitzek and Selikoff 1952; McDermott 1969).

2.27 Rifampicin (Rifampin) The initial microbiologically active components of the rifamycin group were obtained from organisms of the species Amycolatopsis mediterranei found in the soil of a French pine forest in 1957 by Lepetit Research Laboratory in Milan. The microbiologically active components were nicknamed "Rififi" after a popular French movie. Rifamycin B had no intrinsic microbiological activity, but the spontaneous breakdown product, rifamycin SV, was active but was not absorbed by the gastrointestinal tract. Collaboration between Lepetit (Milan) and Ciba-Geigy (Basel), laboratories synthesized a product that was better absorbed orally, and more active for a prolonged period (Maggi et al. 1965; Hobby and Lenert 1968; Sensi 1983).

2.28 Drug Therapy for Cure The principle of multi-drug therapy of tuberculosis was found in the 1960s to be the cornerstone of any effective treatment regimen, as it also prevented the development of drug resistance (Canetti 1962; Mitchison 1965). Canetti (1962) proposed the principle of twophase chemotherapy: in the first phase, with a high cavitary load of bacilli, intensive combined chemotherapy is required, and in the second phase, with a small load of bacilli, continued and prolonged therapy with isoniazid alone is sufficient. Mitchison (1965) recommended initial therapy with a threedrug combination.

Historical Aspects of Tuberculosis

The British Medical Research Council trial recommended three drugs for the first 6 weeks and two drugs for a total of 1 year (British Medical Research Council 1962). Long-term therapy, though effective, was expensive and compliance of patients was difficult. Short-course therapy on large-scale trials, first introduced in East Africa by the British Medical Research Council using several 6-month regimens (East African/British Research Council 1973, 1974), clearly established their effectiveness.

2.29 Conclusion Tuberculosis has been known and recorded since antiquity by the Ancient Egyptians and by Greek, Arab, European and other scholars. Despite the development of knowledge on the pathology and clinical features, the cause remained unknown till the discovery of the bacillus late in the 19th century. The discovery of antibiotics lagged behind the identification of the causative organisms. In the 1930s and 1940s, the use of antibiotics in the treatment oftuberculosis marked a new and distinct era in the history of tuberculosis. Despite the application of antibiotics and subsequent developments of other new anti-tuberculous drugs over the following years, tuberculosis remained a common disease in developing countries. The discovery of HIV in 1981 and its effect on the resurgence of tuberculosis both in developing and developed countries together with the development of drug resistance, remains a challenge.

References Al-Amoud M (1993) The history of tuberculosis. Saudi Med J 14:515-520 Bishop PJ (1973) Thomas Young and his 'A practical and historical treatise on consumptive diseases', 1815. Tubercle 54:159-164 Bishop PJ (1981) Laennec: a great student of tuberculosis. Tubercle 62: 129-134, 147-148 Bishop PJ, Neumann G (1970) The history of the Ziehl-Neelsen stain. Tubercle 51:196-206 British Medical Research Council (1950) Treatment of pulmonary tuberculosis with streptomycin and para-aminosalicyclic acid: a Medical Research Council investigation. BMJ 2:1073-1085 British Medical Research Council (1962) Long-term chemotherapy in the treatment of chronic pulmonary tuberculosis with cavitation: a report to the Medical Research Council by their Tuberculosis Chemotherapy Trials Committee. Tubercle 43:201-219

29 Brock TD (1999) Robert Koch - a life in medicine and bacteriology. ASM Press, Washington DC Buikstra JE (1983) Prehistoric tuberculosis in the Americas (Evanston, Ill.: Northwestern University Archeological Program, 1981) (reviewed by William D Sharpe). Trans Stud Coll Phys Phil 5(5):278-281 Calmette A (1923) Tubercle Bacillus Infection and tuberculosis in Man and Animals (trans WB Soper and GH Smith). Williams and Wilkins, Baltimore MD (quoted by Evans CC, 1998, Clinical tuberculosis, 2nd edn. Davies, Chapman and Hall Medical) Canetti G (1962) The eradication of tuberculosis: theoretical problems and practical solutions. Tubercle 43:301-321 Chadwick J, Mann WN (1978) Hippocratic writings. Penguin, NewYork,pp 117-118 Chorine V (1942) Action de l'amide nicotinique sur les bacilles du genre Mycobacterium. CR Acad Sci (Paris) 220: 150-151 Cooke RE, Dunphy DL, Blake FG (1946) Streptomycin in tuberculous meningitis. Yale J Bio Med 18:221-226 Crawfurd R (1911) The king's evil. Oxford Cruse JM (1999) History of medicine: the metamorphosis of scientific medicine in the ever-present past. Am J Med Sci 318:171-180 East African/British Medical Research Council (1973) Controlled clinical trial of four short-course (6-month) regimens of chemotherapy for treatment of pulmonary tuberculosis. Second report. Lancet 1:1331-1338 East-African/British Medical Research Council (1974) Controlled clinical trial of four short-course (6-month) regimens of chemotherapy for treatment of pulmonary tuberculosis. Third report. Lancet 2:237-240 Feldman WH, Karlson AG, Hinshaw HC (1947) Para-aminosalicyclic acid in experimental tuberculosis in guinea pigs. Proc Sraff Meet Mayo Clin 22:473-479 Gallagher NE (1993) Islamic and Indian Medicine. In: Kiple KF (ed) The Cambridge world history of human disease. Cambridge University Press, Cambridge, pp 27-34 Godfrey LG, Norman CD (1969) Surgical history of pulmonary tuberculosis: the rise and fall of various technical procedures. Can J Surg 12:381-388 Hinshaw HC (1969) Tuberculosis chemotherapy: reminiscences of early clinical trials. Scand J Respir Dis so: 197- 203 Hinshaw HC, Pfuetzek and Feldman WH (1944) Chemotherapy of clinical tuberculosis with promin (Promizole). Am Rev Tuber 50:52-57 Hinshaw HC, Feldman WH, Pfuetze KH (1946) Treatment of tuberculosis with streptomycin. A summary of observations on one hundred cases. JAMA 132:778-782 Hobby GL, Lenert TF (1968) The antimycobacterial activity of Rifampin. Am Rev Respir Dis 97:713 Johnston WD (1993) Tuberculosis. In: Kiple KF (ed) The Cambridge world history of human disease. Cambridge University Press, Cambridge, pp 1059-1068 Keers RY (1981) Laennec: his medical history. Thorax 36:91-94 Lehmann J (1946) Para-aminosalicyclic acid in the treatment of tuberculosis. Lancet 1: 15-16 Lehmann J (1964) Twenty years afterward: historical notes on the discovery of the antituberculous effect of para-aminosalicyclic acid (PAS) and the first clinical trials. Am Rev Respir Dis 90:953-956 Lyons A, Petrucelli R (1978) Medicine, an illustrated history. Abrams, New York

30 Maggi N, Pallanza R, Sensi P (1965) New derivatived of Rifamycin Sv. Antimic. Agents Chemother 5:765 Magner LN (ed) (1992) A history of medicine. Dekker, New York Magner LN (1992a) Islamic medicine. In: Magner LN (ed) A history of medicine. Dekker, New York, pp 133-152 Magner LN (1992b) The scientific revolution and the circulation of the blood. In: Magner LN (ed) A history of medicine. Dekker, New York, pp 189-216 McDermott W (1969) The story of INH. J Infect Dis 119: 678-683 Meyer H, Malley J (1912) Hydrazine derivatives of pyridinecarboxyclic acids. Monatsh 33:393-414 Mitchison DA (1965) Chemotherapy of tuberculosis: a bacteriologist's viewpoint. BMJ 1:1333-1340 Murray JF (1989) The white plague: down and out, or up and coming? Am Rev Respir Dis 140:1788-1795 Myers JA (1977) Captain of all these men of death. Tuberculosis historical highlights. Green, St Louis Paulsen HJ (1987) Tuberculosis in the native American: indigenous or introduced? Rev Infect Dis 9:1180-1186 Pfuetze KH, Pyle MM, Hinshaw HC et al (1955) The first clinical trial of streptomycin in human tuberculosis. Am Rev TubercoI71:752-754 Powell ML (1992) Health and disease in the late prehistoric southeast. In: Verano JW, Ubelaker DH (eds) Disease and demography in the Americas. Smithsonian Institution Press, Washington DC, pp 41-53

M. M. Madkour et al. Risse GB (1993) History of western medicine from Hippocrates to Germ theory. In: Kiple KF (ed) The Cambridge world history of human disease. Cambridge University Press, Cambridge, pp 11-27 Robitzek EH, Selikoff IJ (1952) Hydrazine derivatives of isonicotinic acid (Rimifon, Marsilid) in the treatment of active progressive caseous-penumonic tuberculosis. A preliminary report. Am Rev Tubercol 65:402-428 Rogers FB (1969) The rise and decline of the altitude therapy of tuberculosis. Bull Hist Med 43:1-16 Rosenblatt MB (1973) Pulmonary tuberculosis: evolution of modern therapy. Bull NY Acad Med 49: 163-196 Ryan F (1992) The Forgotten Plague: how the battle against tuberculosis was won and lost. Little Brown, Boston Sakula A (1981) RTH Laennec 1781-1826 his life and work: a bicentenary appreciation. Thorax 36:81-90 Sensi PG, Greco AM, Ballotta R (1959/1960) Rifomycin I. isolation and properties of Rifomycin Band Rifomycin complex. Antibiot Annu 262 Verano JW, Ubelaker DH (eds) (1992) Disease and demography in the Americas. Smithsonian Institution Press, Washington DC Weisse AB (1995) Tuberculosis: why "The white plague"? Perspect Bioi Med 39:132-138 Wilson JL (1979) History of the American Thoracic Society. Am Rev Respir Dis 119:177-184 Wright KW (1988) A history of the Onondaga Sanatorium for the treatment of tuberculosis. NY State J Med 137-145

Epidemiology

3

Global Epidemiology of Tuberculosis MARCOS

A.

ESPINAL

and

MARIO

C. RAVIGLIONE

CONTENTS 3.1 3.2 3.2.1 3.2.2 3.2.3 3.3 3.3.1 3.3.2 3.3.3 3.4 3.5 3.6 3.7

Introduction 33 Exposure and Infection with M. tuberculosis 33 Exposure 33 From Exposure to Infection 34 Magnitude of Infection Worldwide 34 Active Tuberculosis 34 Risk of Disease 34 Morbidity 35 Mortality 36 The Impact of HIV/AIDS on the Epidemiology of Tuberculosis 37 The Impact of Multidrug-Resistant Tuberculosis 38 Future Trends of Tuberculosis 38 Concluding Remarks 40 References 41

3.1 Introduction Tuberculosis has been present in the lives of human beings for many centuries. Evidence of bone lesions suggestive of tuberculosis in mummies of North America, Peru, and Egypt confirms the ancient impact of this disease on early civilizations (Rothschild et al. 2001; Nerlich et al. 2000; Salo et al. 1994). More than 50 years after the introduction of anti-tuberculosis chemotherapy, one-third of the world population is estimated to be infected with Mycobacterium tuberculosis and active disease remains a worldwide pandemic, with more than eight million new cases

M. A. ESPINAL

World Health Organization, Stop TB Department, Tuberculosis Strategy & Operations, Ave Appia 22, 1211 Geneva, Switzerland M. C. RAVIGLIONE World Health Organization, Stop TB Department, Ave Appia 22, 1211 Geneva, Switzerland

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

every year and almost two million deaths annually (Corbett et al. 2003). Despite the existence of a proven comprehensive cost-effective strategy-DOTS-aimed to reduce mortality, morbidity, and transmission of the disease, only 32% of the estimated new smearpositive tuberculosis cases worldwide were managed under this strategy in 2001. The emergence of the human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) and of multidrug-resistant tuberculosis (MDR-TB-resistance to at least isoniazid and rifampicin) have posed additional challenges to tuberculosis control. In order to accelerate control efforts and overcome these threats, partnership efforts by the international community and a revised framework for tuberculosis control have been launched at the beginning of this new century. This chapter will review the epidemiology of infection and disease with M. tuberculosis globally, present morbidity and mortality data, discuss the impact of HIV and MDR-TB, and examine future trends.

3.2 Exposure and Infection with M. tuberculosis 3.2.1 Exposure

Tuberculosis is caused by bacilli belonging to the M. tuberculosis complex, especially the human variety. Tuberculosis caused by milk contamination with M. bovis is not an issue any longer. Likewise, tuberculosis caused by M. africanum is rarely reported. The natural history of tuberculosis can be described in four different stages: exposure, infection, disease, and death. Exposure to M. tuberculosis is influenced by the number of infectious cases and the duration of their infectiousness. The intensity of exposure will depend on various factors, including population density, family size, climatic changes, and age of sources of infection (Rieder 1999).

34

3.2.2 From Exposure to Infection M. tuberculosis infection is usually airborne. The probability of infection depends on the number of infectious droplet nuclei that remain suspended in the air and the duration of exposure of a susceptible individual. Droplets ofless than 5 f.lIll diameter transmit M. tuberculosis (Sonkin 1951). Coughing is the main source of air droplets, but they can also be generated by sneezing and talking (Wells 1955; Riley and O'Grady 1961). The number of bacilli present in the source case is estimated to be between 102 and 104 in nodular lesions and between 8 107 and 10 in cavitary lesions (Canetti 1965). Smearpositive tuberculosis cases constitute by far the most important source of infection (Styblo 1991). The presence of infection is usually measured with the tuberculin intradermal skin test through the assessment of the size of induration generated by the test. Incidence of infection is usually estimated through the risk of infection (also called annual risk of tuberculosis infection; or ART!) from tuberculin prevalence surveys. The risk of infection also suggests the extent of transmission of M. tuberculosis in the past. The ART! has been defined as the probability that any individual will be infected with M. tuberculosis in 1 year. It has been the basis of several exercises to estimate the global magnitude of tuberculosis (Sudre et al. 1992; Dolin et al. 1994; Murray and Lopez 1997). Styblo estimated that in the absence of tuberculosis control, an annual risk of infection of 1% corresponded roughly to an incidence of new smear-positive tuberculosis cases of 50 per 100,000 population (Styblo 1985). The disadvantages of tuberculin prevalence surveys include high costs and technical problems inherent to the application and reading of the tuberculin test. Furthermore, HIV infection has made the interpretation of tuberculin prevalence surveys very difficult and the previously established fixed relationship between ART! and incidence of smear-positive cases is no longer valid. Thus, in many settings it is not possible to obtain accurate and reliable data of the levels of infection and estimates need to be constructed.

3.2.3 Magnitude of Infection Worldwide

M. A. Espinal and M. C. Raviglione

models suggest various prevalence patterns in different regions of the world. In high-income countries the population most infected is that above 65 years of age. In Europe with the decline of the risk of infection by an estimated 10-12% annually, the young generations are basically free of tuberculosis infection (Styblo et al. 1969; Sutherland et al. 1971; Styblo 1991). In the Netherlands, data from military recruits suggest that between 1910 and 1939, the annual risk of infection was already declining by 5.4% annually, largely due to isolation of cases and better socio-economic conditions. Such a declining trend increased further up to 12.9% annually between 1940 and 1969, concomitant to the introduction of milk pasteurization and antituberculosis drugs (Styblo et al. 1969). Likewise, in the United States the risk of infection has been declining for several decades. Data from Navy recruits show that the proportion of positive reactions to the tuberculin test fell from 6.6% in 1949-1951 to 3.1% in 1967-1968 and to 1.5% in 1980-1986 (Comstock 2000). The scenario is completely different in resourcelimited countries, where young generations and economically productive populations are still currently subject to a high risk of infection with M. tuberculosis. This is due to a slower decline of the annual risk of infection that was estimated at 1-6% per year in the 1980s (Cauthen et aI.1988). Estimates released by the World Health Organization (WHO) in 1991 suggested that one-third of the world population, or 1.7 billion people, were infected with M. tuberculosis (Kochi 1991). Revised estimates suggested that in 19971.86 billion people [32% of the world population] were infected with the tuberculous bacillus (Dye et al.1999). These numbers are not much different from newly revised estimates, which suggest that in 2000 1.8 billion people were infected with M. tuberculosis, again one third of the world population (Corbett et al. 2003). South-East Asia and Africa, with an estimated 46% and 31% of their populations infected with M. tuberculosis, were the most affected regions of the world.

3.3 Active Tuberculosis 3.3.1 Risk of Disease

Prevalence of infection with M. tuberculosis varies according to demographic (age, sex, place) and socioeconomic (crowding, poverty, confinement) determinants and the degree of contact and intensity of exposure. Empirical data available and mathematical

Tuberculosis develops as a result of progression of primary infection, exogenous reinfection, or endogenous reactivation. The highest risk of disease is posed immediately (first 24 months) after infection is acquired. With

35

Global Epidemiology of Tuberculosis

time, the risk declines. In the United States, 82,269 children between 1to 18 years of age who reacted positively to the tuberculin skin test were followed for 20 years (Comstock et al. 1974). Two incidence peaks of active disease where identified: at ages 1-4 years, and during late adolescence and early adulthood. Another cohort of children followed for 20 years in Great Britain showed that almost half of the tuberculosis cases developed in the first 2 years of age and 68% in the first 5 years after infection (D'Arcy Hart and Sutherland 1977). The accepted principle is that the risk of disease is greatest within the first 2 years following infection and after about 7 years starts to level off, remaining low and unchanged over the following decade and, usually, during lifetime. The lifetime risk of progression from infection to disease is estimated to be about 10% if the infection has been acquired during childhood (Comstock et al. 1974). Half of the risk is during the 12-24 months post-infection. Several factors have been identified that are responsible for progression to active disease. These include HIV infection, spontaneously healed fibrotic lesions, malnutrition, age, sex, use of immunosuppression agents, medical conditions including silicosis, a variety of neoplastic disorders, and diabetes. The contribution of many of these factors to the pandemic of tuberculosis is probably not very extensive, because their prevalence is low or they are weakly associated with an increase risk of disease. HIV infection is the most potent risk factor for tuberculosis yet identified. The risk of tuberculosis in people co-infected with M. tuberculosis and HIV has been shown in several studies to range from 5% to 15% per year (Hopewell and Chaisson 2000). Differences in the quantification of the risk of tuberculosis among HIV-infected individuals are especially related to the degree of immunosuppression as measured by the CD4+ lymphocyte counts. Studies conducted in the last 10 years using DNA fingerprinting techniques have suggested that half of tuberculosis cases are attributable to recent or ongoing transmission in some settings (Wilkinson et al. 1997; Godfrey-Faussett et al. 2000). Even in low-prevalence settings, where previously most disease was though to be due to reactivation, one third of cases have been attributed to ongoing transmission (Small et al.1994; Alland et al. 1994; Borgdorff et al. 1997).

3.3.2 Morbidity

Tuberculosis started to decline in Europe by the 19th century, a trend that mirrored the increase in

industrialization, better sanitation, and improvement of living conditions (Evans 1998). This trend was accelerated after the introduction of chemotherapy by mid 20th century. As of today, tuberculosis in Western Europe, Australia, Canada, Japan, and the United States is only a problem of selected groups as the general population of these countries is minimally affected. Only 5% of the world burden of tuberculosis is estimated to be in the industrialized world (Corbett et al. 2003). The highest toll of tuberculosis in industrialized countries is predominantly among immigrants from high-prevalence settings, the homeless, intravenous drug addicts, and HIVinfected people. Since 1980 yearly case notifications to WHO have allowed monitoring and modeling of the future impact of the tuberculosis pandemic (Raviglione et al. 1997a; World Health Organization 2003). Overall, tuberculosis notifications to WHO have remained at around 60 per 100000 people since 1980, with little fluctuations (Fig. 3.1). In industrialized countries data show that tuberculosis continues its declining trend, after a few years of stagnation in the late 1980s and early 1990s. Tuberculosis notifications in Asia and Latin America have remained fairly stable throughout the years, without significant changes. On the other hand, tuberculosis notifications in Africa and Eastern Europe have shown very different epidemiological trends. In sub-Saharan Africa, notifications have been increasing on average 10% per year since 1980, largely due to the HIV/AIDS epidemic. In the former Union of Socialists Soviet Republics (USSR) tuberculosis was declining at 5% per year up to 1990; thereafter, it started to increase at 8% per year due to deteriorating socioeconomic conditions leading to poverty, congestion, malnutrition, and to the collapse of the public health system and of Case notiticafion rate (pe, 100,000)

80

60

40

20

o 1980

1985

1990

1995

2000

Years

Fig. 3.1. Global trend in the tuberculosis case notification rate. Source: Global Tuberculosis Control. World Health Organization Report 2003. WHO/CDS/TB2003316

M. A. Espinal and M. C. Raviglione

36

tuberculosis control efforts. In the recent years rates of increase have started to slow down. The most recent data show that, in the year 2001, 3,813,109 (62 per 100,000 people) cases were notified worldwide, of which 59% were notified in Asia and 21 % in Africa (Fig. 3.2). Of the two million cases notified in Asia, India, China, Bangladesh, the Philippines, and Indonesia accounted for 87%. In Africa, of the 811,172 cases notified, Nigeria, Ethiopia, South Africa, the Democratic Republic of Congo, and Kenya accounted for 53%. Of the 22 high-burden countries of the world responsible for 80% of the global caseload, 18 are located in Asia and Africa. The global notification of smear-positive cases in 2001 was 1,602,153 (26 per 100,000 people), of which 59% were notified in Asia and 23% in Africa. Notification data have been pivotal to track the tuberculosis pandemic; however, they do not reflect the true picture of the global situation. Lack of access to health services, poor capacity to suspect and diagnose cases, and under-reporting are some of the issues that limit the significance of notification data. Therefore, estimates are needed in order to have a clearer picture of the burden of disease. Several figures have been published in the past 25 years, ranging from 4 million new tuberculosis cases in 1977 to 8.3 million cases in 2000 (Bulla 1977; Sudre et al.1992; Murray et al. 1993; Dolin et al. 1994; Raviglione et al. 1995; Murray and Lopez 1997; Dye et al. 1999; Corbett et al. 2003). These estimates have been useful in portraying the global situation of tuberculosis; however, the earlier studies only provided data for regions of the world and not for individual countries. Using several sources of data, expert

opinion and mathematical methods, WHO estimated the burden of disease for 212 countries individually for 1997 (Dye et al.1999). There were 16 million prevalent tuberculosis cases worldwide and 8 million (range: 6.311.1 million) new cases for a case rate of 136 per 100,000 people. Of these, 3.5 million were smear-positive for a case rate of 60 per 100,000 people. Eighty percent of all new cases were in 22 countries. Newly revised estimates for 2000 report 8.3 million (range: 7.3-9.2 million) new tuberculosis cases (Fig. 3.2) for a case rate of 137 per 100,000 people, of which 3.7 million were smear-positive for a case rate of 61 per 100,000 people (Corbett et al. 2003). Incidence in adults 15-49 years was estimated to be 5.4 million for a case rate of 172 per 100,000 people. The greatest incidence rate was in sub-Saharan Africa (290 per 100,000 people). However, the greatest number of cases (more than five million) is estimated to be in Asia including 3.2 million cases in India and China. Between 1997 and 2000, the increase of new tuberculosis cases and incidence rates were at 1.8% and 0.4% per year respectively. The greatest rise was observed in Eastern Europe and sub-Saharan Africa due to reasons explained earlier.

3.3.3 Mortality Today, HIV/AIDS is the most important condition influencing tuberculosis mortality. Other factors include lack of access to chemotherapy, missed diagnosis, late diagnosis, treatment default, and multidrug-resistant tuberculosis.

Cc:nual and Eastc:tn Europe

410000 c.... cslimalCd (87 per 100 000 pop)

326 739 cases notified (70 per 100 000 pop)

'

.....

LatIn America

360 000 ...... CIIiD*Od (70 per 100000 pop) 215842 _ _lIIed (42 per 100 000 pop)

I 900 000 cues Cllilllllled (290 per 100000 pop)

811 In caseSDOlified (115 per 100 000 pop)

Fig. 3.2. Estimated and notified tuberculosis cases in the world,

2000

Global Epidemiology of Tuberculosis

Tuberculosis mortality has decreased to a minimum in the industrialized world. Mortality in European countries was highest between the late 18th century and early 19th century, reaching 50-60% of all tuberculosis cases, after 5 years of diagnosis (Drolet 1938; Thompson 1943). Thereafter, mortality declined with the introduction of chemotherapy and currently is not a major issue. A different pattern, however, is observed in resource-limited countries, regardless of the availability of effective chemotherapy for more than 50 years. In the 1980s and 1990s, various studies estimated that almost three million deaths were due to tuberculosis globally (Styblo 1983; Dolin et al. 1994). The general impression today was that these numbers were overestimating the magnitude of mortality from tuberculosis because of the very high case-fatality ratio, which in the past was at around 30% (Enarson and Rouillon 1998). In the absence of treatment the case-fatality ratio is estimated to be around 50%. However, such a high estimate may not be completely accurate, as already many countries were providing chemotherapy. In 1997 Murray & Lopez new estimates reported two million deaths from tuberculosis worldwide (Murray and Lopez 1997). However, these numbers excluded deaths due to HIV. Recent estimates suggest that mortality from tuberculosis may be lower than previously estimated (Corbett et al. 2003) and that 1.82 million tuberculosis deaths (30 per 100,000 people) occurred in 2000. Ninetyeight percent of such deaths were in resource-limited countries and 226,000 were attributable to HIV.

3.4 The Impact of HIV/AIDS on the Epidemiology of Tuberculosis In a very short period of time, spanning over 20 years, the HIV/AIDS pandemic has rampaged all regions of the world and today more than 60 million people may have been infected with HIY. The impact of HIV/AIDS on the tuberculosis pandemic has been devastating. The Joint United Nations Program on HIV/AIDS (UNAIDS) estimates that 42 million individuals are currently living infected with HIV (UNAIDS 2002). An estimated five million became infected in 2002 and 800,000 of them were children. Three-quarters of the world population infected with HIV live in sub-Saharan Africa and a further 17% in Asia. HIV/AIDS has claimed more than 22 million deaths in the past two decades.

37

Worldwide tuberculosis is the most common HIV-associated disease of public health importance occurring in AIDS patients. As mentioned already, HIV is the strongest risk factor for reactivation of tuberculosis infection. However, the impact of HIV infection on the tuberculosis pandemic is not only limited to reactivation of tuberculosis infection. Consistent evidence shows that people infected with HIY, who later become infected or reinfected with M. tuberculosis, progress faster to full-blown tuberculosis than people who are infected with M. tuberculosis but not with HIV (Di Perri et al. 1989; Daley et al. 1992; Girardi et al. 2000a; Sonnenberg et al. 2001). Fortunately, HIV-infected tuberculosis patients do not appear to be potent transmitters of M. tuberculosis. In fact, household contact studies have consistently shown that HIV-infected people with tuberculosis are less likely to transmit the tubercle bacilli to their close counterparts than HIV-uninfected people with tuberculosis (Klausner et al.1993; Elliot et al.1993; Cauthen et al. 1996; Espinal et al. 2000a). Therefore, the ART! may not be affected in spite of the increasing tuberculosis incidence in high HIV-prevalence settings. Eleven million adults aged 15-49 years (0.36% prevalence) were estimated to be co-infected with HIV and M. tuberculosis in 2000 (Fig. 3.3), of which 9.5 million were in sub-Saharan Africa and 2.3 million in South-East Asia. The overall global prevalence of HIV among new adult tuberculosis cases has been estimated to be 11% (Corbett et al. 2003). However, in sub-Saharan Africa, this figure is 38%, the highest worldwide, compared with only 5.9% in the Americas and 3.2% in South-East Asia. Furthermore, in some African countries such as Cote d'Ivoire, Malawi, South Africa, Uganda, and Zambia prevalence in new tuberculosis cases can be as high as 40-78% (Raviglione et al. 1997b). Also, several sub-Saharan African countries have reported continued increases in tuberculosis notifications (Fig. 3.4), regardless of

Fig. 3.3. Estimated distribution of adults infected with HIV and tuberculosis, 2000. Source: World Health Organization

38

M. A. Espinal and M. C. Raviglione

No~flca~on Rates

(xl00.000)

500

450

ZImbabwe

400 350 300 250

••

•• •,

200 150

! /

Kenye Melewl UR T nzanle

0-------1980

1985

1990

1995

2000

Years

Fig. 3.4. Tuberculosis trends in selected African countries 1980-2001. Source: World Health Organization

the existence of successful national tuberculosis control programs (Narain et al. 1992). The proportion of new tuberculosis cases attributable to HIV/AIDS in sub-Saharan Africa in 2000 was 31 % or 421,000 cases. This proportion is very well above the global estimate of 9% (511,000 cases). This clearly shows the negative impact that HIV/AIDS is posing over tuberculosis in this region of the world.

3.5 The Impact of Multidrug-Resistant Tuberculosis Drug resistance to at least isoniazid and rifampicin, a combination known as MDR-TB, is, after HIV/AIDS, the most important threat to tuberculosis control. Surveillance efforts launched in the 1990s by WHO and the International Union Against Tuberculosis and Lung Disease (IUATLD) have shown that the magnitude of the tuberculosis problem is grossly of drug-susceptible cases (World Health Organization 1997,2000; PablosMendez et al. 1998; Espinal et al. 2001). Data from 67 countries/sites show a global prevalence of MDR-TB of 1% in new cases of tuberculosis and 9.1% in previously treated cases. However, the same data also show that MDR-TB is a severe problem in several countries of Eastern Europe including Estonia, Latvia, and Russia. Areas of India and China also show concerning MDRTB prevalence. The problem appears to be less severe in Africa and Latin America. Several of these countries did not follow internationally recommended guidelines for tuberculosis control-DOTS-until just recently. For instance, in several former Soviet Union countries, interventions that are customarily used for tuberculo-

sis control include long hospitalization of tuberculosis cases, individualized treatment regimen, and unsupervised administration of therapy (Perelman 2000). Hospitalization of tuberculosis cases in the absence of infection control measures can be a major vehicle for the rapid dissemination of MDR-TB. Lack of standardization of treatment and use of inadequate regimens without proper supervision are clearly conducive to creation and spread of drug-resistant bacilli (World Health Organization 1997) On the other hand, countries implementing sound tuberculosis control measures for many years such as Benin, Botswana, Chile, Cuba, Kenya, and Uruguay have reported a very low prevalence of MDR-TB (World Health Organization 2000). Since the available data are limited and more than half of the world countries have not yet been surveyed, a mathematical model has estimated the magnitude of MDR-TB globally (Dye et al. 2001). This model suggests that in 2000 3% (273,000, 95% confidence intervals: 185,000 and 414,000) of all new estimated tuberculosis cases were MDR-TB. Eight of the twenty-two high-burden countries of the world, from which data are not available yet, were estimated to have more than 4000 cases of MDR-TB each. These countries need to be surveyed urgently in order to have a clear picture of the magnitude of the problem. If current estimates prove accurate, the impact of MDR-TB on tuberculosis control in these countries may be overwhelming, as the management of MDRTB is more costly, complex, and lengthy than that of drug-susceptible tuberculosis. MDR-TB is a man-made problem and most countries with a high prevalence have a history of poor tuberculosis control. The spread and evolution of MDR-TB will depend on the efforts these countries are willing to undertake to accelerate tuberculosis control according to recognized and tested international guidelines. The only effective way of preventing MDR-TB from becoming a problem of the magnitude of drug-susceptible tuberculosis is by ensuring the cure of all tuberculosis cases susceptible to first-line drugs under proper management conditions (Dye et al. 2002a). In addition, careful management of MDRTB with second-line drugs will be also needed in settings where the problem is at epidemic levels.

3.6

Future Trends of Tuberculosis Tuberculosis is expected to continue increasing in the first decade of the XXI century. About ten million

Global Epidemiology of Tuberculosis

39

new tuberculosis cases are expected in 2010, if current tional130,OOO extra new smear-positive tuberculosis trends continue and control efforts are not accelerated cases on average every year have been recruited (Fig.3.5) (Dye 2000). Several factors are expected to under DOTS since 1996. In order to achieve the influence such trends. These include lack of political global targets by 2005, an annual average of 360,000 will to effectively expand tuberculosis control, the extra new smear-positive tuberculosis cases needs to HIV/AIDS pandemic, drug resistance, lack of involve- be detected and treated under DOTS. Detection and ment of the private sector in tuberculosis control, provision of short-course chemotherapy to these increasing poverty, demographic changes, the current cases may halve tuberculosis incidence in low HIVburden of M. tuberculosis infection worldwide, and prevalence areas in about 10 years at a rate of decline lack of better tools to speed-up prevention, diagnosis, of 5-10% annually (Dye et al.1998).At the moment, this is not happening; thus, tuberculosis will continue and cure of tuberculosis cases. Strong focus on the expansion of effective tuber- to spread uncontrolled in many settings. culosis control is the key to reverse the current trends HIV/AIDS is another factor that will continue of tuberculosis worldwide. In 1991 WHO adopted impacting the tuberculosis pandemic for several the DOTS strategy for tuberculosis control (World years to come, unless effective measures beyond Health Organization 1991), which was later labeled DOTS and specific to HIV-associated tuberculoas one of the most cost-effective health interventions sis are implemented to reverse the current trends. available (World Bank 1993). The effectiveness of WHO has estimated that there will be 3.5 million DOTS has been successfully tested in the field with new tuberculosis cases in sub-Saharan Africa in impressive results (Suarez et al. 2001; Dye et al. 2000). 2005 (World Health Organization 2001). It is now As of 2001, 155 countries have implemented DOTS widely accepted that in spite of the existence of good , which is increased from only 10 countries in 1991 tuberculosis control programs in this continent, (World Health Organization 2003). However, in many DOTS alone cannot reverse the increasing toll of of these countries population coverage by DOTS is HIV-associated tuberculosis (de Cock and Chaisson low. Today, only half of the world's population lives 1999; Elzinga and Nunn 2002). Therefore, intensive in countries implementing DOTS. Furthermore, only collaboration between tuberculosis and AIDS con32% of the estimated new smear-positive tuberculo- trol programs, exploring novel options designed to sis cases in the world were detected and managed enhance control of the two diseases should be impleunder DOTS conditions in 2001, which means that mented. Useful strategies to test in field conditions 68% of the world infectious cases were managed with include active tuberculosis case-finding and making unclear or inappropriate strategies. voluntary counseling and HIV testing widely availMathematical modeling suggests that if tubercu- able not only to tuberculosis patients but also to the losis control is not expanded effectively and quickly, general population in order to facilitate entry into the global targets of 70% case-detection and 85% preventive and treatment strategies. In particular, cure rate among new tuberculosis cases will not be administration of preventive therapy with isoniazid achieved until 2013 (Dye et al. 2002b). Only an addi- and highly active antiretroviral therapy (HAART) to people with HIV/AIDS needs strong and urgent consideration. The current evidence shows that therapy New TB cases ('OOOs)lyear with isoniazid prevents reactivation of tuberculosis among HIV-infected people who are tuberculin skin 12000 test positive (WHO/UNAIDS 1999). There is also 10000 increasing evidence that HAART can reduce the 8000 _ _ risk of tuberculosis by more than 80% by restoring immunocompetence (Girardi et al. 2000b; Jones et al. 6000 2000; Badri et al. 2002; Santoro-Lopes et al. 2002). The threat of MDR-TB on tuberculosis control 4000 efforts cannot be undermined. Current estimates suggest that at least 80% cure rate will be needed to prevent or control an epidemic of MDR-TB, assum70% of new MDR-TB cases are detected annually ing 1995 2000 2005 2010 Years and that the reproductive fitness of MDR strains Fig. 3.5. Global tuberculosis pandemic. New cases annually to is similar to that of drug-susceptible strains (Dye 2010. Source: World Health Organization and Williams 2000). Such a cure rate may be only

r

2~L

--

40

M. A. Espinal and M. C. Raviglione

achieved by the careful introduction of second-line to control tuberculosis worldwide suggest that US drugs, as short-course chemotherapy cannot achieve $1 billion per year is needed to achieve the global an 80% cure rate among MDR-TB cases (Espinal et targets in the 22 high-burden countries (Floyd et al. al. 2000b). However, most resource-limited countries 2002). A further US $200 million per year are needed lack experience in dealing with longer, more expen- for low- and middle-income countries outside the 22 sive and more toxic treatment regimens employing high-burden countries. Of the estimated total costs second-line drugs (Gupta et al. 200l). Thus, feasible needed for the 22 high-burden countries, 69% is and cost-effective strategies are needed to address currently contributed by the government of these MDR-TB in countries with high MDR-TB prevalence countries and only a minor 4% is contributed by within the current framework of tuberculosis control the international community. The remaining 27% or (Espinal et al.1999). Operational research in this field US $300 million per year is the financial gap that the is ongoing and preliminary evidence suggests that 22 high-burden countries will need to fill to control management of MDR-TB with second-line drugs in tuberculosis. However, new financial resources will resource-limited settings is feasible and cost-effec- not be all that is needed. Innovative approaches to tive when a strong tuberculosis control program is in increase case finding and cure rates are necessary, as place (Suarez et al. 2002). Fortunately, it appears that is a sound strategy to human resource development, MDR-TB is more of a focal problem, limited to some if new funds are to be spent effectively. settings or countries, rather than a global problem of Demographic changes will also play their role in the magnitude of drug-susceptible tuberculosis (Dye keeping tuberculosis incidence at high rates in the current decade. Changes in the age structure of the and Espina1200l). Involving the private sector in tuberculosis control population of the developing world will certainly needs to be strongly pursued. A large proportion of contribute to increasing rates of tuberculosis. Most tuberculosis patients in high prevalence countries of the population of resource-limited countries is including India, Pakistan, Philippines, Vietnam, and young, contrary to the industrialized world where Uganda first approach a private practitioner (Uplekar the population is increasingly aging. Children of et al. 200l). A study in India suggested that 88% of poor countries infected with M. tuberculosis that are rural and 85% of urban patients with tuberculosis entering the economically productive age will defifirst went to a private practitioner (Uplekar et al. nitely be at risk of developing active disease. Since 1998). Strategies to involve the private sector are one third of the world population is infected with currently under testing. The challenge will be their M. tuberculosis infection, the vast majority of which implementation on a wider scale. Nevertheless, with- are in resource-limited countries, the joint effects of out involving private practitioners the international demographic changes and the high burden of M. community will not achieve tuberculosis control in tuberculosis infection will impact negatively on the morbidity and mortality of tuberculosis. many countries. Finally, the lack of new tools to speed-up control Growing poverty is another factor that will prevent tuberculosis incidence from declining in the and elimination of tuberculosis is another major next several years. Poverty has been always associ- obstacle to overcome. New vaccines, drugs and diagated with tuberculosis (Moore-Gillon 1998). The nostics are not expected to be available for at least the decreasing incidence of tuberculosis in Europe in next 10 years (Freire and Roscigno 2002; Perkins and the 19th century was parallel to the reduction of Kritski 2002). For instance, the neglect in the field poverty. Recently, the most clear impact of poverty of new drugs has been so immense that, in the last on the incidence of tuberculosis has been observed in 25 years, only 16 new chemical entities out of 1393 Russia. The economic downfall in Russia, due to the were marketed for tropical diseases, including tubertransition from the socialist economy model to the culosis (Trouiller et al. 2002). market economy one, has been linked to the growing incidence of tuberculosis observed in the last decade (Dye 2000). Tuberculosis is one of the three major diseases of 3.7 poverty along with HIV/AIDS and Malaria. The 22 Concluding Remarks tuberculosis high-burden countries, where increasing poverty is making control of infectious diseases The tuberculosis pandemic will be affecting human an enormous task, are all very limited in resources. lives for many more decades. While much progress Recent estimates regarding the resources needed has been made in the last few years, control of tuber-

Global Epidemiology of Tuberculosis

culosis is only slowly becoming a priority in many countries. Clearly strong financial, political and managerial actions are needed in order to accelerate DOTS coverage, reach the WHO global targets, and incorporate new tools in disease control. To move forward, a Stop TB partnership was created in 1998 to ensure that endemic countries are adequately supported technically and financially to control tuberculosis (Raviglione and Pio 2002). The original framework for tuberculosis control (World Health Organization 1994) has been also recently revised to widen the scope of DOTS, and make it more comprehensive and more patient-centered in order to address some of the current threats to tuberculosis control (WHO 2002). Nevertheless, current efforts are not sufficient. To make tuberculosis control more efficient and efficacious, novel interventions need to be added urgently in high HIV/AIDS and MDR prevalence settings or where private practitioners are not involved in national tuberculosis control efforts, or where health system changes are not addressing tuberculosis control as a top priority. The recent creation of the Global Fund to Fight AIDS, Tuberculosis, and Malaria offers a tremendous opportunity to change the future of the tuberculosis pandemic if resources are properly used. The world should not miss it; otherwise, tuberculosis will continue to be a major scourge to individuals and communities.

Acknowledgements. Thanks to C. Dye and C. Watt for providing some of the maps and figures.

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41 Comstock GW, Livesay VT, Woolpert SF (1974) The prognosis of a positive tuberculin reaction in childhood and adolescence. Am J Epidemiol 99: 131-138 Comstock GW (2000) Epidemiology of tuberculosis. In: Reichman LB, Hershfield ES (eds) Tuberculosis: a comprehensive international approach. Dekker, New York, pp 129-156 Corbett et al (2003) The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med 163:1009-1021 Daley C et al (1992) An outbreak of tuberculosis with accelerated progression among persons with the human immunodeficiency virus. An analysis using restriction-fragmentlength polymorphism. N Engl J Med 326:231-235 D'Arcy Hart P, Sutherland I (1977) BCG and vole bacillus vaccines in the prevention of tuberculosis in adolescence and early adult life. Final report to the Medical Research Council. Br Med J 2:293-295 De Cock KM, Chaisson RE (1999) Will DOTS do it? A reappraisal of tuberculosis control in countries with high rates of HIV infection. Int J Tuberculosis Lung Dis 3:457-465 Di Perri et al (1989) Nosocomial epidemic of active tuberculosis among HIV-infected patients. Lancet 21:502-504 Dolin PJ, Raviglione MC, Kochi A (1994) Tuberculosis: a global overview of the situation today. Bull WHO 72:213-220 Drolet GJ (1938) Present trend in case fatality rates in tuberculosis. Am Rev Tuberculosis 37:125-151 Dye C (2000) Tuberculosis 2000-2010: control, but not elimination. Int J Tuberculosis Lung Dis 4:S146-S152 Dye C, Espinal M (2001) Will tuberculosis become resistant to all antibiotics? Proc R Soc Lond Bioi Sci 268:45-52 Dye C, Williams BG (2000) Criteria for the control of drug-resistant tuberculosis. Proc Nat! Acad Sci USA 97: 8180-8185 Dye C et al (1998) Prospects for worldwide tuberculosis control under the WHO DOTS strategy. Lancet 352:1886-1891 Dye C et al (1999) Global burden of tuberculosis: estimated incidence, prevalence, and mortality by country. J Am Med Assoc 282:677-686 Dye C et al (2000) Evaluating the impact of tuberculosis control: number of deaths prevented by short-course chemotherapy in China. Int J Epidemiol 29:558-564 Dye C et al (2001) Worldwide incidence of multidrug-resistant tuberculosis. J Infect Dis 185:1197-1202 Dye C et al (2002a) Erasing the world's slow stain: strategies to beat multidrug-resistant tuberculosis. Science 295: 2042-2046 Dye C et al (2002b) Low access to a highly effective therapy: a challenge for international tuberculosis control. Bull WHO 80:437-444 Elliot A et al (1993) The impact of HIV-l on infectiousness of pulmonary tuberculosis: a community study in Zambia. AIDS 7:981-987 Elzinga G, Nunn P (2002) TB and HIV: joint problems, joint solutions? Bull WHO 80:469-470 Enarson DA, Rouillon A (1998) The epidemiological basis of tuberculosis control. In: Davies PDO (ed) Clinical tuberculosis, 2nd edn. Cambridge University Press, Cambridge, pp 35-52 Espinal MA et al (1999) Rational DOTS-Plus for the control of MDR-TB. Int J Tuberculosis Lung Dis 3:561-563 Espinal MA et al (2000a) Infectiousness of Mycobacterium tuberculosis in HIV-1 infected patients with tuberculosis: a prospective study. Lancet 355:275-280

42 Espinal MA et al (2000b) Standard short-course chemotherapy for drug-resistant tuberculosis: treatment outcome in 6 countries. J Am Med Assoc 283:2537-2545 Espinal MA et al (2001) Global trends in resistance to antituberculosis drugs. N Engl J Med 344:1294-1303 Evans CC (1998) Historical background. In: Davies PDO (ed) Clinical tuberculosis, 2nd edn. University Press, Cambridge, pp 1-33 Floyd K et al (2002) Resources required for global tuberculosis control. Science 295:2040-2041 Freire M, Roscigno G (2002) Joining forces to develop new weapons against TB: together we must. Bull WHO 80:429 Girardi E et al (2000a) Impact of the HIV epidemic on the spread of other diseases: the case of tuberculosis. AIDS 14:S47-S56 Girardi E et al (2000b) Impact of combination antiretroviral therapy on the risk of tuberculosis among persons with HIV infection. AIDS 14:1985-1991 Godfrey-Faussett P et al (2000) Tuberculosis control and molecular epidemiology in a South African gold-mining community. Lancet 356:1066-1071 Gupta R et al (2001) Responding to market failures in tuberculosis control. Science 293:1049-1051 Hopewell PC, Chaisson RE (2000) Tuberculosis and human immunodeficieny virus infection. In: Reichman LB, Hershfield ES (eds) Tuberculosis: a comprehensive international approach, 2nd edn. Dekker, New York, pp 525-527 Jones JL, Hanson MS, de Cock KM (2000) HIV-associated tuberculosis in the era of highly active antiretroviral therapy. Int J Tuberculosis Lung Dis 4:1026-1031 Klausner JD et al (1993) Mycobacterium tuberculosis in household contacts of human immunodeficiency virus type-lseropositive patients with active pulmonary tuberculosis in Kinshasa, Zaire. J Infect Dis 168: 106-111 Kochi A (1991) The global tuberculosis situation and the new control strategy of the World Health Organization. Tubercle 72:1-6 Moore-Gillon JC (1998) Tuberculosis and poverty in the developed world. In: Davies PDO (ed) Clinical tuberculosis, 2nd edn. Cambridge University Press, Cambridge, pp 383-393 Murray CJ, Lopez AD (1997) Mortality by cause of eight regions of the world: global burden of disease study. Lancet 349:1269-1276 Murray q, Styblo K, Rouillon A (1993) Tuberculosis. In: Jamison JT, Mosley WH, Measham AR, Bobadilla JL (eds) Disease control priorities in developing countries. Oxford University Press, New York, pp 233-259 Narain JP, Raviglione MC, Kochi A (1992) HIV-associated tuberculosis in developing countries: epidemiology and strategies for prevention. Tubercle Lung Dis 73:311-321 Nerlich AG et al (2000) Ancient Egyptian prosthesis of the big toe. Lancet 356:2176-2179 Pablos-Mendez A et al (1998) Global surveillance for antituberculosis-drug resistance, 1994-1997. N Engl J Med 338: 1641-1649 Perelman MI (2000) Tuberculosis in Russia. Int J Tuberculosis Lung Dis 4:1097-1103 Perkins M, Kritski AL(2002) Diagnostic testing in the control of tuberculosis. Bull WHO 80:512-513 Raviglione MC et al (1995) Global epidemiology of tuberculosis: morbidity and mortality of a worldwide epidemic. J Am Med Assoc 273:220-226 Raviglione MC et al (1997a) Assessment of worldwide tuberculosis control. Lancet 350:624-629

M. A. Espinal and M. C. Raviglione Raviglione MC et al (1997b) Tuberculosis and HIV: current status in Africa. AIDS II:SI15-S123 Raviglione MC, Pio A (2002) Evolution of WHO policies for tuberculosis control, 1948-2001. Lancet 359:775-780 Rieder HL (1999) Epidemiologic basis of tuberculosis control, 1st edn. International Union Against Tuberculosis and Lung Disease, Paris Riley RL, O'Grady F (1961) Airborne infection: transmission and control. Macmillan, New York Rothschild BM et al (2001) Mycobacterium tuberculosis complex DNA from an extinct bison dated 17,000 years before the present. Clin Infect Dis 33:305-311 Salo WL et al (1994) Identification of Mycobacterium tuberculosis DNA in a pre-Columbian Peruvian mummy. Proc Nat! Acad Sci USA 91:2091-2094 Santoro-Lopes G et al (2002) Reduced risk of tuberculosis among Brazilian patients with advanced human immunodeficiency virus infection treated with highly active antiretroviral therapy. Clin Infect Dis 34:543-546 Small PM et al (1994) The epidemiology of tuberculosis in San Francisco. A population-based study using conventional and molecular methods. N Engl J Med 330: 1703-1709 Sonkin LS (1951) The role of particle size in experimental airborne infection. Am J Hyg 70:185-196 Sonnenberg P et al (2001) HIV-l and recurrence, relapse, and reinfection of tuberculosis after cure: a cohort study in South African mineworkers. Lancet 358:1687-1693 Styblo K (1983) The epidemiological situation of tuberculosis and the impact of control measures. Bull Int Union Against Tuberculosis 58: 179-186 Styblo K (1985)The relationship between the risk of tuberculous infection and the risk of developing tuberculosis. Bull Int Union Against Tuberculosis 60:117-119 Styblo K (1991) Epidemiology of tuberculosis, 2nd edn. Royal Netherlands Tuberculosis Association, The Hague Styblo K, Meijer J, Sutherland I (1969) The transmission of tubercle bacilli - its trend in a human population. Tuberculosis Surveillance Research Unit report no 1. Bull Int Union Against Tuberculosis 42:1-104 Suarez PG et al (2001) Epidemiological impact of tuberculosis control in Peru. J Infect Dis 184:473-478 Suarez PG et al (2002) Feasibility and cost-effectiveness of standardised second-line drug treatment for chronic tuberculosis patients: a national cohort study in Peru. Lancet 359: 1980-1989 Sudre P, ten Dam G, Kochi A (1992) Tuberculosis: a global overview of the situation today. Bull WHO 70:149-159 Sutherland I et al (1971) Annual risks of tuberculous infection in 14 countries, derived from the results of tuberculin surveys in 1948-1952. Bull Int Union Against Tuberculosis Lung Dis 45:75-114 Thompson BC (1943) Survival rates in pulmonary tuberculosis. Br Med J 2:721 Trouiller P et al (2002) Drug development for neglected diseases: a deficient market and a public-health policy failure. Lancet 359:2188-2194 UNAIDS (2002) Joint United Nations Program on HIV/AIDS I World Health Organization. AIDS epidemic update. 02.46E. UNAIDS, Geneva Uplekar M et al (1998) Tuberculosis patients and practitioners in private clinics in India. Int J Tuberculosis Lung Dis 2: 324-329

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World Health Organization (1994) Global tuberculosis programme. Framework for effective tuberculosis control. WHO/TB/94.179. WHO, Geneva World Health Organization (1997) Anti-tuberculosis drug resistance in the world. WHO/TB/97.229. WHO, Geneva World Health Organization (2000) Anti-tuberculosis drug resistance in the world. Report no 2: prevalence and trends. WHO/CDS/TB/2000.278. WHO, Geneva World Health Organization (2001) Global tuberculosis control. WHO Report 2001. WHO/CDS/TBI2001.287. WHO, Geneva World Health Organization (2002) An expanded DOTS framework for effective tuberculosis control. Int J Tuberculosis Lung Dis 6:378-388 World Health Organization (2003) Global tuberculosis control: surveillance, planning, financing. WHO report 2002. WHOI CDS/TBI2003.316. WHO, Geneva

4

Epidemiology of Tuberculosis in Saudi Arabia ABDULRAHMAN A. ALRAJHI and ALI M. AL-BARRAK

CONTENTS 4.1 4.1.1 4.1.2 4.1.3

4.2 4.3 4.3.1 4.3.2 4.3.3 4.3.4 4.3.5 4.3.6 4.4 4.5

General Epidemiology 45 Incidence of Pulmonary Tuberculosis 46 Incidence of Extrapulmonary Tuberculosis 48 Prevalence of Infection 49 Epidemiology of Drug-Resistant M. tuberculosis 51 Tuberculosis in Certain Populations 51 The Elderly 52 Diabetics 52 Persons Infected with Human Immunodeficiency Virus 52 Hemodialysis Patients 53 Cancer and Bone Marrow Transplant Patients 54 Solid Organ Transplant Recipients 54 Mycobacterial Other than M. tuberculosis 54 Conclusion 55 References 55

tion of transmission, number of infected persons without active disease, distribution of drug-resistant tuberculosis, and tuberculosis in certain populations. There are no data on the impact of tuberculosis on community, economy or development. Mortality data are not available either.

4.1 General Epidemiology

Measuring the size of tuberculosis in a community is not as easy as it may appear initially. The disease course and the community it afflicts are constantly changing. Definitions used for various tuberculosis cases are not standardized and surveillance appliTuberculosis is older than recorded history. Typical cation in the field has enormous variations. The lesions of spinal tuberculosis were noted in Neolithic community is also changing its composition, living human remains and paintings. Pre-Islam Arab poetry standards, and exposure between members. There are several measures to indicate the size of had described the disease and its association with a non-cure. The writings of Moslem physicians indi- tuberculosis as a community problem. Before the cate that the disease was well known along with its era of tuberculosis chemotherapy discovery and its risk factors, symptoms and complications. Some of use in treatment, an indirect measure, which could the factors in this part of the world were encourag- also assess the impact of the disease, was mortality. ing the introduction of the organism on a continu- Tuberculosis chemotherapy and control measures ous basis through commerce; as the peninsula was make mortality an imprecise measure of disease involved in commerce roads, and pilgrims were extent in the community. Another measure identified early in the 20th century is tuberculin skin test. It is coming from all corners. The purpose of this chapter is to present the a useful measure to identify the prevalence of infecavailable epidemiology about tuberculosis in Saudi tion in a community at a certain point of time and to Arabia. It includes data on numbers of new cases follow trends. Unfortunately, the value of tuberculin annually, type of tuberculosis involvement, demo- testing is affected by BeG vaccination, exposure to graphics of affected patients, geographic distribu- nontuberculous mycobacteria, and waning immunity (Thompson et al. 1979). A third measure was used in some areas, which is field surveillance by chest X-ray A. A. ALRA1HI, MD, MPH, FIDSA and sputum cultures from community samples. This Consultant and Head, Section of Infectious Diseases, Chairman, Department of Medicine (MBC #46), King Faisal Specialist Hos- method has to be repeated so incidence rates can be pital and Research Centre, P.O. Box 3354, Riyadh 11211, Saudi measured. Indirectly, incidence can be estimated to Arabia be half of the prevalence, considering the disease A. M. AL-BARRAK, AmBIM, DTM & H, FRCP (C) Consultant Infectious Diseases Unit, Department of Medicine, lasts for 2 years without treatment. Another epidemiRiyadh Armed Forces Hospital, P.O. Box 7897, Riyadh 11159, ologic concept was developed; annual risk of tuberculosis infection reflects the probability of a person Saudi Arabia M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

A. A. Alrajhi and A. M. AI-Barrak

46

becoming infected within a given year. This measure requires a prevalence assay on multiple occasions in order to be precise. BCG vaccination will influence prevalence rates that are measured using Mantoux tuberculin test. Lastly, the World Bank has attempted to estimate the economic impact of tuberculosis in its 1993 World Development Report though disability-adjusted life years (DALYs), the years that are consumed by various diseases, including tuberculosis (World Bank 1993). This chapter will attempt to present available data on these various measures pertaining to Saudi Arabia. Tuberculosis is a reportable disease in Saudi Arabia. The Ministry of Health (MOH), represented by Preventive Medicine has been collecting data on newly diagnosed cases of tuberculosis annually. These incidence rates are published every year. Some of the information included was gender, age, nationality, and type of tuberculosis involvement. These rates are the only available data at population level. Although they may not include all cases because of reporting deficiency from care providers, they provide valuable means to monitor trends. These data have been considered along with the social, developmental, and economic changes in the country.

Case identification and treatment is considered one of the most important components of tuberculosis control and prevention. The annual incidence rates of pulmonary tuberculosis were higher for foreigners compared with Saudis. In 1996, the rate was 23.9 cases per 100,000 population for non-Saudis compared with 7.4 cases per 100,000 population for Saudis (Ministry of Health 1996). The female and male rates for Saudis were almost similar,6.5 and 8.3 cases per 100,000 population, respectively. For non-Saudis, these rates were 22.7 for males and 26.9 cases per 100,000 population for non-Saudi females. Certain regions of the country consistently scored higher rates. Aseer, ]azan, and Holy Makkah have higher rates than Hail and Gaseem. Table 4.1 summarizes incidence rates for pulmonary tuberculosis in various groups and regions over the period of 1996-1997. Apart from reported pulmonary tuberculosis, investigators have attempted to estimate incidence

Cases per 100.000 population 1600 1400 1200 1000 800

-

I---

-

400

I---

-

200

-

I---

-

600

4.1.1 Incidence of Pulmonary Tuberculosis The first available incidence rate of pulmonary tuberculosis was in 1970. During that year, there were 76,748 new cases of pulmonary tuberculosis, making a rate of 1298.5 cases per 100,000 population per year (Ministry of Health 1979). Over the subsequent years, incidence rate of pulmonary tuberculosis has decreased steadily to 166.1 cases per 100,000 population in 1979. Figure 4.1 depicts the trend of incidence rates over the 10 years of the 1970s. Incidence of reported pulmonary tuberculosis continued to decrease steadily during the 1980s and the 1990s. For the year 1980, the incidence rate was 135 cases per 100,000 population. In 1997, the rate has dropped to 12 cases per 100,000 population (Ministry of Health 1997). When considering other changes in the health care system availability, advances in diagnosis capabilities, improved reporting associated with communications improvement, this steady reduction becomes more impressive, Fig. 4.2. This reduction was attributed to BCG vaccination program that have been started many years ago, and more importantly, the active screening program for foreign workers coming to the country (Ministry of Health 1996).

o

70

71

72

73

74

-

75 Year

.• • •

76

77

78

79

Fig. 4.1. Annual incidence rates of pulmonary tuberculosis in Saudi Arabia, 1970-1979 (Ministery of Health: Annual Health Report)

Reported cases per 100,000 population 140 120 100 80 60 40 20

o

••

III1IIIIII

80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 Year

Fig. 4.2. Annual incidence rates of pulmonary tuberculosis in Saudi Arabia, 1980-1997 (Ministery of Health: Annual Health Report)

Epidemiology of Tuberculosis in Saudi Arabia Table 4.1. Annual incidence rates of pulmonary tuberculosis in various groups and regions during 1996-1997 (Ministry of Health 1997,1996) Group

Rates per 100,000 population

12.0 Overall Nationality Saudis 7.4 Non-Saudis 23.9 Gender 8.3 Saudi, male Saudi, female 6.5 Non-Saudi, male 22.7 Non-Saudi, female 26.9 Regions 20.5 Jazan Makkah 17.0 Riyadh 13.9 Eastern 10.9 Hail 2.6

rates at community level (Zaman 1991a; Milaat et al. 1994; el-Kassimi 1994). However, these efforts have not provided more reliable data than Ministry of Health annual reports. Milaat et al reviewed all tuberculosis cases in a regional chest hospital in Jeddah for 1 year, 1989-1990. Population data were obtained from MOH records to calculate incidence rates. The overall incidence rate was estimated at 63.4 cases per 100,000 populations. Extrapulmonary tuberculosis was found in 7.6% of all cases. There were 2.6 cases of tuberculosis in non-Saudis for each one case of tuberculosis in Saudis from the same population number (99.6 non-Saudis and 38.8 Saudi tuberculosis cases per 100,000 population). Reporting tuberculosis cases from the private health care facilities has been grossly deficient. This is noted in Jeddah, where private medicine provides care for a large proportion of population in that region. Milaat and colleagues think that the higher estimated rate noted in Jeddah relative to the country in general is related to the crowding and high immigrant population in Jeddah. In addition, Jeddah serves as the major port of entry for visitors to the two holy cities. This is suggested by peaking of cases during the 11th and 12th Hijra months. In a nationwide survey, positive Mantoux reaction was noted to be three times higher in the Western region than the nation as a whole (AI-Kassimi et al. 1993). AI-Kassimi has calculated incidence rates from the annual risk of infection (AI-Kassimi 1994). The result was double the rates from reported cases to MOH. He correctly points to the problem of under-notification by health care providers to MOH. The high rates of tuberculosis as infection and incidence of active disease are reflected in the pro-

47

portion of patients admitted with pneumonia that end up diagnosed as having pulmonary tuberculosis. In a review of 112 patients admitted with pneumonia over the year 1983 at Riyadh Military hospital, tuberculosis was confirmed in 7.1% of them. In fact, it was only second to Streptococcus pneumoniae (Mohamed and Evans 1987). Some of the radiological changes noted in tuberculosis patients could also be seen in patients with community acquired bacterial pneumonia (AI-Dabbagh et aI.1991)."Unusual" chest radiography findings were noted in 13% of 714 patients with pulmonary tuberculosis in two hospitals in Jeddah. Cavities were seen in 78% of all patients, suggesting a prolonged and unrecognized disease. The most common radiological finding, however, was upper or multilobar lesions, seen in 86% of patients. However, more severe pneumonia requiring intensive care had a slightly different etiology (Dahmash et al. 1994; Dahmash and Chowdhury 1994). In a university hospital in Riyadh, 113 patients were admitted to the intensive care unit with pneumonia between 1991 and 1992. Patients were followed prospectively, 50 patients (44%) had hospital-acquired pneumonia. Out of the community acquired pneumonias, 9 (14.3%) were due to M. tuberculosis, which was second only to S. pneumoniae, isolated from 10 patients but far more fatal than S. pneumoniae-5 of 9 (55.6%) compared with 2 of 10 (20%) (Dahmash and Chowdhury 1994). The population at risk for pulmonary tuberculosis remains large in Saudi Arabia. Cases of pulmonary tuberculosis most frequently involve young adults between 15 years and 35 years of age (AI-Dabbagh et al. 1991; AI-Hajjaj et al. 1991). This seems to be the case for last thousand years (AI-Amoud 1993). Some argue that this is related to the number at risk being higher in the age group because of the immigrant work force. However, this is not the reason, as the calculated rates are still highest for the young age group (Ministry of Health 1996). In the large review of 1566 cases of pulmonary tuberculosis at Riyadh Chest Hospital between 1983 and 1987, 41 % of patients were aged 21-30 years (AI-Hajjaj et al. 1991). These patients were admitted for therapy initiation at a rate of 32.6 cases monthly. Around 52% of patients were non-Saudis, mostly from Yemen, 20% of all patients. A concerning phenomenon in this cohort is the high rate of "old" cases, which represent 29% of the cases with most of the patients being Saudis. They had more hemoptysis and were more difficult to cure. Sputum smear positivity was relatively high at 75%. The conversion rate was low at two months (80%). These patients from Riyadh had larger proportion of lower

48

lung field tuberculosis compared with Jeddah-lO.3% compared with 5.3% (AI-Dabbagh et al.199l; Pandya et al. 1990). These percentages represent the post primary infection. The patients from Riyadh had higher rates of sputum positive smears-84% compared with 75% for all pulmonary tuberculosis cases. Pulmonary tuberculosis from the South Region of Saudi Arabia has been characterized in a prospective study managed at the Chest Hospital in Abha between 1989 and 1991 (al-Wabel et al. 1995) One hundred ninety patients were admitted; 69.5% of them had no previous diagnosis of tuberculosis. As in other areas of the country, the group aged 20-40 years constituted more than 34% of all cases. In this region, patients older than 60 years were 25% of all patients with pulmonary tuberculosis. Unlike in the central or western regions, less than 25% of patients were nonSaudis. Another peculiar finding in these patients was the high proportion of diabetics (21 %), reflecting the higher rates of diabetes in elderly nationals. Sputum smears were positive in 42% of patients, posing a considerable risk for disease transmission from these cases. Radiologically, cavitary lung lesions were noted in 38% of patients, lower lung field in 3.2%, and miliary pattern in 1.3%. Saudi Arabia hosts millions of foreigners as part of the workforce, visitors for business, or Hajj and Omrah. Many of the workers come from countries where tuberculosis is highly endemic. Screening for these workers is performed before they obtain their visas and after they arrive. In spite of this, they represent more than 50% of tuberculosis cases in a large city like Riyadh (AI-Hajjaj et al. 1991). The impact of these cases is not limited to economy, but to the extent of increasing the hazard of tuberculosis infection. Drug-resistant M. tuberculosis is also of major concern as these patients come from areas where drug-resistant rates are very high. Screening for tuberculosis is not applied to visitors, including pilgrims for Hajj and Omrah. Alzeer et al. (l998) reviewed the microbiology of pneumonia in patients admitted during Hajj of 1994 (l414 H). Out of 64 admitted patients, M. tuberculosis was the causative agent in 13 (20%) patients. It was the most common agent for pneumonia identified, followed by S. pneumoniae and coliforms in 9% and 11%, respectively. Radiographic features of tuberculous and non-tuberculous pneumonias were the same. This high rate of tuberculosis among pilgrims was thought to be the reason for the above national annual risk of infection noted in pilgrim-receiving cities (AI-Kassimi et al. 1993). An earlier report of the 1991-1992 Hajj season did not attempt to obtain respiratory speci-

A. A. Alrajhi and A. M. AI-Barrak

mens other than expectorated sputum (EI-Sheikh et al.1998). The focus was mainly on bacterial and viral pathogens. Nevertheless, two patients of eighty-six (2.3%) with lower respiratory tract infection had positive smears for acid-fast bacilli.

4.1.2 Incidence of Extrapulmonary Tuberculosis Extrapulmonary tuberculosis requires tissue sampling to confirm diagnosis. This may not be available to many health care facilities. Subsequently, diagnosis is delayed if attempted. The number of reported extrapulmonary tuberculosis cases are even smaller than the number of actual cases. The annual Health Reports of the MOH started presenting data on extrapulmonary tuberculosis in 1989. The annual incidence rate of reported extrapulmonary tuberculosis was 3.7 cases per 100,000 population nation-wide in 1989 (Ministry of Health 1989). This figure decreases to 1.7 per 100,000 population in 1993 (Ministry of Health 1993). This rate has been steadily increasing to 4.7 cases per 100,000 population in 1997, Fig. 4.3 (Ministry of Health 1997). During the same time frame, reported pulmonary tuberculosis rates were decreasing (Ministry of Health 1997). The increasing rates of reported extrapulmonary tuberculosis may have resulted from better diagnostic facilities, which identified more cases, and better reporting by health providers. Earlier reports describe their series in their local hospitals. In 1982, Froude and Kingston reviewed 162 cases diagnosed with extrapulmonary tuberculosis between 1979 and 1981 from King Faisal Specialist Hospital and Research Centre (Froude and Kingston 1982). Although this finding may be due to referral pattern, CNS disease (including spine involvement) was the

New cases per 100 population

5 4.5 4 3.5 3 -

I-I--

f---

2.5 2

f---

1.5

I---

1 0.5

o

I---

-

I---

I---

I---

-

-

I---

I---

I---

-

-

I---

f---

'--r-

~

1989

1991

1992

1993

1994

Year

f---

I--

-

I---

I--

-

f---

I--

I---

I--

I---

I--

I---

I--

f---

I--

-

1995

1996

'-

1997

Fig. 4.3. Annual incidence rates for extrapulmonary tuberculosis in Saudi Arabia, 1989-1997 (Ministery of Health: Annual Health Report)

49

Epidemiology of Tuberculosis in Saudi Arabia

most common, comprising 36% of cases, followed by lymphadenopathy 22%, gastrointestinal disease 16%, and surprisingly, disseminated disease was diagnosed in 14% of the extrapulmonary tuberculosis cases. The morbidity associated with extrapulmonary tuberculosis can be very high. Seventeen patients (11 %) had spinal cord damage related to vertebral involvement. During the same study period of 27 months, six new pulmonary tuberculosis cases were diagnosed every month. Around the same time, a similar report was published about patients from Jeddah. Mokhtar and Salman published details of 125 patients with extrapulmonary tuberculosis in 1983 (Mokhtar and Salman 1983). Lymph node involvement was identified in 54% of the patients, followed by abdominal disease and urogenital disease in 16% each, and bone and joints in 10%. Surprisingly, only one CNS disease was diagnosed as meningitis. During the same period, 20 new cases of pulmonary tuberculosis were diagnosed every month. In their Hospital, Mokhtar and Salman found extrapulmonary tuberculosis in 15% of all tuberculosis cases identified. In 1980, incidence of tuberculosis was 120 cases per 100,000 population in Jeddah (Mokhtar and Salman 1983).

Fig. 4.4. Distribution of involvement in extrapulmonary tuberculosis (Froude and Kingston 1982)

10 CNS 0 Lymph node 0 Urogenital • Abdominal 0 Bone & Joint • Othenl

Fig. 4.5. Distribution of involvement in extrapulmonary tuberculosis (Mokhtar and Salman 1983)

4.1.3 Prevalence of Infection Human exposure to M. tuberculosis will result in infection. No disease may be apparent initially. After a variable period of time and factors related to host immunity, M. tuberculosis will be reactivated, resulting in disease. The prevalence of infection can be measured by the tuberculin test. In 1908, Mantoux described his intradermal test, which was developed to a purified protein derivative (PPD) in 1934 by Seibert (Schein and Huebner 1995). When this test was applied to a large population, it was realized that most people get infected without having active disease. This test, known as Mantoux, tuberculin, and PPD served as good tools to measure the proportion of the population that had been exposed to M. tuberculosis. In a rural area in the western region of Saudi Arabia in 1979, prevalence of pulmonary tuberculosis was as high as 1% of the population (Hammam et al.1979). In Saudi Arabia, the first reference of testing of asymptomatic population for tuberculosis exposure was in 1979. Out of81,006 subjects tested, 48,483 (59.9%) subjects had a positive test. During the same year, 66% of tested males were positive, compared with 40% of tested females. These percentages were higher with the increasing age of the subjects (Ministry of Health 1979). Although no details are available on these subjects as to whether or not they are patient contacts, these percentages give an indication of how common tuberculosis infection is in the area. Problems of the test, its administration, or interpretation may influence the prevalence estimation towards the underestimation side. Subsequent to 1980, many field studies published in peer-reviewed journals have reported the tuberculin skin testing results. Saudi Arabia has been among the middle prevalence countries (2-14%) according to the classification proposed by the International Union Against Tuberculosis (AI-Kassimi et al. 1993). The World Health Organization (WHO) expert committee on tuberculosis recommends continuing early life vaccination until the percentage of tuberculin reactor entering school drops to 2%, which is a low prevalence level (WHO 1964). The protective effect of BCG vaccination does not last beyond 10 years. Saudi Arabia has adopted a BCG vaccine given at birth. In a national immunization coverage survey in 1991, BCG immunization coverage was high (99%) both in urban and rural area settings, but the western and southern area had slightly lower coverage (Farag et al.1995). In early 1990s, community based studies for the prevalence of Mantoux reaction were done at

A. A, Alrajhi and A, M. AI-Barra!<

50

different regions of Saudi Arabia. In a nationwide community survey, about 24% of the children aged 5-14 years were not vaccinated (AI-Kassimi et al. 1993). The prevalence of positive Mantoux reaction (10 mm induration) in children not vaccinated aged 5-14 years was 6%, and was 4% in Saudi nationality. In this age group, there was marked difference in prevalence between urban and rural dwellers (10% and 2%, respectively). This difference was more in western (20% and 1%) and southern (12% and 1.5%) provinces. The authors have attributed this to the presence of settlers after pilgrimage in the western province and Yemeni laborers' exemption from medical screening in the south, adjacent to their country. The prevalence of positive Mantoux reaction increased with age steadily to peak at age 45-64 years at 56% for non-vaccinated and 70% for BCG vaccinated subjects, Fig. 4.6.

a

100%

101W. North Region

Central Region

80%

/

60%

.. ,

......

40%

?'

.•...

....

-

"'~'-"

~

20%

\

'5-14

80%

+------------f-----l

60";'

+-------------.I--.....--l

40";' + - - - - - - - - - : ;......'--------,_-----l

\

20";'

'

0%

Bener and Abdullah confirmed the above finding in another Saudi Arabia population sample (Bener and Abdullah 1993). Positive Mantoux reaction was significantly higher among BCG recipient subjects in all age groups, male gender, nationalities, and occupations. Studies from different regions of Saudi Arabia confirmed the finding of this prevalence (elKassimi et al. 1991; Bener 1990; Abdullah et al. 1991; AI-Kassimi et al. 1991). In the central region, 7% of unvaccinated children aged 4 to 14 years had positive Mantoux reaction, while 15% of those vaccinated were positive. There was increased prevalence of Mantoux positivity with age, more in the BCG-vaccinated population. There was a steep upward increase in prevalence of positivity between age 5 years and 14 years and 25 years and 34 years, probably due to an increased number of a previously infected expatriate population who are workers in the age group

+-----::.-=---:+---'--'-----------1

.......

0% +-~...,....-"""T""-__r-__.--..__----l 15-24

35-44

25·34

45-64

65+

5-14

15-24

100% 80%

.

40% 20%

0";'

•

'

60";'

+-------+----\;--'---1

40"/. t - - - - - : : f - -.....-'---+----I

25-34

35-44

45-64

+------.f---:.-'------4----I +-:....,r--__r-"""T""-...,....-T""'i~

65+

'5·14

100% 80%

35-44

45-64

65+

I··... No-BeG - - - BCG·Recipients 1

Nation-wide

60%

+-----/---.....=-----=----.-=-.•-..-..-..-...

40%

+----/---:;,L,,-..-,..-•-..

20%

+--.,,4---::.,....:....-----------1 ~

0%

15·24 25-34 Age groups

Age groups

b

65+

+ - - - - - - - - -...----1

0% 15-24

45-64

80%

20%

'5-14

35-44

100"1. South Region

Eastern Region

60%

25-34

Age groups

Age groups

•....

'

....

.'

- -1

--:..:----------1

7" ••

+------.--..__--.-----.--...,....---1 5-14

15-24

25-34

35-44

Age groups

45-64

65+

1.. ···No-BCG

--BCG-Recipients

I

Fig.4.6. a: Rates of positive Mantoux test in various regions in BCG-recipient and non-recipient population (el-Kassimi et al. 1991; Bener 1990; Abdullah et aI. 1991; AI-Kassimi et aI. 1991) b: Rates of positive Mantoux tests nationwide in BCG-recipient and non-recipient population (Al-Kassimi et aI. 1993)

Epidemiology of Tuberculosis in Saudi Arabia

51

25-44 years, and an increased opportunity to acquire infection by adolescents as they leave the sheltered life of young age. Saudi nationality again had lower prevalence, but higher prevalence in male gender than in female. Urban dwellers had, in general, higher prevalence. In the northern area, only 4% of unvaccinated children aged 5-14 years had a positive Mantoux reaction. A positive Mantoux reaction was seen in significantly more BCG-vaccinated subjects (manifested only in adults) and in older age groups. The overall prevalence of positive Mantoux reaction in the unvaccinated group was 19% and reached its peak (58%) in the 65+ age group, while in those vaccinated was 15%. The overall rate of positivity in males was 37% which is significantly higher than in women (12%). There was no difference in subjects living status, nationality, level of education, and history tuberculosis in the family or chest symptoms. In the Eastern area, 5% of unvaccinated children aged 5-14 years had a positive Mantoux reaction. Again, a positive Mantoux reaction was seen in significantly more BCG-vaccinated subjects (manifested only in adults) and in older age groups. In the Southern area, 4% of unvaccinated children aged 5-14 years had a positive Mantoux reaction. Again, a positive Mantoux reaction was seen in significantly more BCG-vaccinated subjects and in older age groups. The overall prevalence of a positive Mantoux reaction in the unvaccinated group was 26% and reached its peak (67%) in the 65+ age group, while in those vaccinated was 17%. The overall rate of positivity in male was 35% as opposed to 42% in female with difference between the sexes is more marked in the 25-64 year age group. There was significant difference between urban and rural residents, and in nationality status. In 1992, MOH has established the National Tuberculosis Control Committee. The field application of the National Tuberculosis Control Program was implemented in Riyadh in 1996 according to WHO guidelines (AI-Hajjaj 2000).

pulmonary tuberculosis. Certain "Chest Hospitals" had the facilities to isolate and test susceptibility of M. tuberculosis. Testing in these facilities was not done for all isolates. Health reports did not include the limited data on drug susceptibility. Thus, patterns and distribution of drug-resistance are not known at the community level. Other health care facilities were performing susceptibility on their isolates. Many reports of sensitivity patterns were published (Schiott et al. 1985; AIOrainey 1986; AI-Orainey et al. 1989; Zaman 1991b; Jarallah et al.I992; Ellis et al.1996; AI-Jama et al.1999; Khan et al. 2001; Alrajhi et al. 2002). These reports used different methodologies, definitions, and various ways of presenting the data. So any epidemiological analysis of these reports lacks the necessary details to identify patterns, geographic and population distribution. Rates varied as high as 43.7% resistant to at least one of the first-line agents and as low as 8.7% of isolates being resistant. Table 4.2 summarizes the published data on drug resistance. Two reports on drug resistance rates appeared from the same institutions over two periods of time. Khan et al have shown clearly that resistance rates were increasing between the period of 1993-1995 and the period of 1996-1998 This increase was statistically significant for one or more antituberculous agents and for all first-line agents singularly except for ethambutol and pyrazinamide (Khan et al. 2001). On the other hand, from King Faisal Specialist Hospital and Research Centre, where most of tuberculosis cases are Saudis, the resistance rates were not statistically significant between the period 1989-1994 and the period 1995-1999 (Alrajhi et al. 2002). As most of the reported resistance rates came from referral centers, they may not represent the actual rates in the community as a whole. In a recent report by the WHO, no data from the Eastern Mediterranean Region, where the Kingdom of Saudi Arabia is grouped, were included (WHO 1997).

4.2 Epidemiology of Drug-Resistant M. tuberculosis

4.3 Tuberculosis in Certain Populations

The reporting procedures of all tuberculosis cases in Saudi Arabia did not include the susceptibility results of isolated organisms. Microbiological diagnosis at point of care areas did not attempt to grow the organisms. Diagnosis was limited to smears of respiratory specimens and histopathological findings for extra-

As M. tuberculosis activity is closely related to host immunity, rates of reactivation of a latent infection will depend mostly on host-related factors. Thus reactivation rates will vary widely among various patient and non-patient populations. Over the next few sections, available data of disease prevalence in various populations will be reviewed.

52

A. A. Alrajhi and A. M. AI-Barrak

Table 4.2. Drug-resistance rates against isoniazid and rifampin from various reports Author (Reference year) Year

Region

Total

Schiott et aI. (1985) AI-Orainey (1986) AI-Oraineyet aI. (1989) Zaman (1991b) Jarallah et aI. (1992) Chowdhury and Kambal (1992) Ellis et aI. (1996) AI-Jama et aI. (1999)* Khan et aI. (2001) AIrajhi et aI. (2002) Total**

Not indicated 1979-1982 1986-1988 Not indicated 1986-1988 1987-1991

Jazan Riyadh Riyadh Jeddah Taif Riyadh

103 1968 432 483 678 214

42 82 84 86 44 20

(40.8%) (4.2%) (19.4%) (17.8%) (6.5%) (9.3%)

42 113 104 8

(9.7%) (23.4%) (15.3%) (3.7%)

1989-1994 1989-1998 1996-1998 1995-2000

Mixed Eastern Western Mixed

289 1239 101 320 5827

22 211 29 29 649

(7.6%) (17%) (28.7%) (9.1%) (11.1 %)

9 (3.1 %) 78 (6.3%) 21 (20.7%) 9 (2.8%) 405 (10.5%)

Isoniazid number (%)

Rifampin number (%)

Isoniazid and rifampin, no (%)

21 (20.4%)

20 (19.4%)

**

**

At least resistant to one agent

38 (8.8%) 70 (14.5%) 26 (3.8%) 7 (3.3%)

45 259 92 145 153 24

(43.7%) (13.2%) (21.3%) (30%) (22.6%) (11.2%)

8 (2.8%) 34 (2.7%) 21 (20.7%) 9 (2.8%) 233 (6.0%)

25 302 30 36 1111

(8.7%) (24.4%) (29.7%) (11.3%) (19.1%)

* Report included mycobacteria other than tuberculosis ** Rifampin and MDR rates are calculated without Ref. no. (AI-Orainey 1986)

4.3.1 The Elderly The high prevalence of tuberculosis in Saudi Arabia increases with age. As health care improves and life expectancy is prolonged, more population is at risk of tuberculosis reactivation with advanced age. A report from a teaching hospital in Riyadh has outlined the diagnostic challenges of tuberculosis in the elderly (Dahmash et al. 1995). Dahmash et al. reported on 80 patients older than 60 years admitted with tuberculosis between 1988-1993. Pulmonary tuberculosis accounted for 80% and miliary tuberculosis in 20% of these patients. Diagnosis was delayed in 23% of patients, and 21 % died during the same admission. Of the cohort that had follow-up in the same hospital, 21 % died (9 of 43), seven had miliary tuberculosis and two had pulmonary tuberculosis. Fatality occurred within the first two months of therapy. Another problem in elderly patients with tuberculosis is intolerance to antituberculous chemotherapy. In their series, Dahmash et al. reported adverse effects in 18% of the patients.

4.3.2 Diabetics

Diabetes mellitus is higWy prevalent in Saudi Arabia. Prevalence in the general population ranges between 7% in males of rural areas to 15% in females from urban areas. It increases with age, and one of every two females above 50 years had diabetes (Al-Nuaim 1997). The association of tuberculosis and diabetes mellitus is well documented and is directly proportional to

insulin requirements (Boucot et al. 1952). Pandya et al. (1991) noted that out of 1566 patients with pulmonary tuberculosis at Riyadh Chest Hospital between 1983 and 1987,136 (8.7%) had diabetes mellitus. The proportion was higher for Saudi patients (13%) compared with non-Saudi patients (5%) with tuberculosis. However, prevalence of diabetes mellitus in patients with pulmonary tuberculosis does not seem to be higher than in the general population (AI-Nuaim 1997). Over a 4-year period starting in 1995, diabetes mellitus was found in 6.2-15.5% of active tuberculosis seen in Riyadh Chest Hospital (AI-Hajjaj 2000).

4.3.3 Persons Infected with Human Immunodeficiency Virus

The Human Immunodeficiency Virus (HIV) and its Acquired Immunodeficiency Syndrome (AIDS) global epidemic have had a profound impact on global tuberculosis (Narain et al. 1992). Saudi Arabia is no exception when it comes to interaction between HIV and M. tuberculosis. In fact, the high prevalence of tuberculosis infection at an early age makes the impact of HIV/AIDS on tuberculosis reactivation more pronounced. Among the HIV/AIDS patients at King Faisal Specialist Hospital and Research Centre, 11 out of 233 patients had culture-proven tuberculosis, giving a rate of 4.7% for reactivation. Some patients presented with tuberculosis before they were known to have HIV infection. As of 1999,7 of 171 HIV positive patients (4.1%) had tuberculosis (Aljurf et al. 1999). Screening of all tuberculosis patients for HIV infection has been recommended.

53

Epidemiology of Tuberculosis in Saudi Arabia

4.3.4 Hemodialysis Patients

a center in Abha, southwest of the country, tuberculosis was diagnosed in 13 patients (4.8%) out of 270 dialysis patients after a mean of 19 months on dialysis. Pulmonary tuberculosis was found in 8 patients (62%) in contrast to other reports finding higher percentages of extrapulmonary tuberculosis (al-Homrany 1997). From Jeddah, two dialysis centers reported 17 tuberculosis cases among 210 dialysis patients with a prevalence rate of 8.1% (Shohaib et al. 1999). Again, as in Abha, ten patients had pulmonary involvement and nine had lymph node involvement. Table 4.3 summarizes the numbers of patients on dialysis and tuberculosis in various published reports. Hemodialysis patients who developed tuberculosis and completed therapy did not relapse after kidney transplantation (Hussein et al. 1996). Reactivation oflatent infection seems to be the role rather than a primary infection. However, this depends on the prevalence of disease in the community. The other co-morbid illnesses in hemodialysis patients, such as viral hepatitis, diabetes, and hypertension make chemotherapy in this population complex and in need of close monitoring. PPD test in patients on hemodialysis with tuberculosis is unreliable. Reports of positive test rates ranged from zero to 62% of patients. High level of clinical suspicion for tuberculosis is essential for prompt diagnosis and therapy institution. A unique report has prospectively evaluated the risk of tuberculosis in patients with renal impairment not requiring dialysis (AI Shohaib 2000). Al Shohaib has prospectively followed 80 patients with a creatinine clearance of 40 ml/min or less for 3 years in Jeddah. At enrollment, all patients had a normal chest X-ray examination and 50% of patients had a positive PPD test of more than 10 mm induration. During follow-up, eight patients (10%) developed tuberculosis, four pulmonary, two renal, one meningitis, and one adenitis. Four of them had a positive PPD test at enrollment. AIl had an excellent response to a nine-month course except the meningitis case, who was treated for one year. This study has provided valuable data on patients with renal

As of 1999, there were 5706 patients receiving hemodialysis in Saudi Arabia; 2084 patients started hemodialysis in 1999 (Jondeby et al. 2001). These patients started recently on hemodialysis are older on average, and 16% of them have diabetes mellitus. In fact, in 1999-initiated patients alone, 40% of them have diabetes mellitus. Uremia associated impaired cell mediated immunity is well documented (Wilson et al. 1965). In 1974, the first report of tuberculosis in dialysis patients was published (Pradhan et al. 1974). This increased incidence continues until the late 1990s (Cengiz 1996; Murthy and Pereira 1997). In 1990, the first report from Saudi Arabia on tuberculosis in hemodialysis patients was published by AI-Khader et al. (1990) Forty-two out of fifty dialysis centers in the Kingdom responded to a questionnaire. Tuberculosis was diagnosed in 4.4% of 1450 patients on chronic hemodialysis. Around fifty percent had lymphadenitis and less than one third had pulmonary involvement. On average, tuberculosis patients were older, mean age 42 years compared with general dialysis patients, mean age of 33 years. The report did not indicate the period on hemodialysis that preceded tuberculosis diagnosis. In 1991, Mitwalli reported on tuberculosis in dialysis patients at one hospital in Riyadh (Mitwalli 1991). Patients were diagnosed with tuberculosis after either one or two months on dialysis. Of 26 dialysis patients, 7 (27%) were diagnosed with tuberculosis, predominantly, lymphadenitis (57%), and only one with pulmonary tuberculosis as pleurisy. From another dialysis center in Tau, western province that provides hemodialysis to 325 patients, 30 patients (9.2%) had tuberculosis. Again extrapulmonary tuberculosis was predominant (70%) mostly lymphadenopathy (57%). Pulmonary tuberculosis accounted for 30% of tuberculosis cases (Hussein et al.1990, 1994) Frequently, pulmonary tuberculosis in hemodialysis patients is associated with pleurisy. From

Table 4.3. Number and percentage of dialysis patients with tuberculosis in Saudi Arabia Author, Reference year Al-Khader*, (Al-Khader et aI. 1990) Mitwalli (1991) Hussein et al. (1994) Al-Homrany (1997) Shohaib et al. (1999) Total

Years covered

Region

Total on dialysis

Mixed

1450

64

4.41

26 325 270 210 2281

7 30 13 17 131

26.92 9.23 4.81 8.1 5.74

1989-1990 Riyadh 1980-1993 Al-Hada 1986-1993 Abha 1992-1997 Jeddah

Patients with Percent tuberculosis

* From a survey of 42 dialysis centers, some cases may be reported in other reports

54

impairment without dialysis and risk for tuberculosis. However, time of tuberculosis reactivation in relation to renal impairment course was not indicated, and no attempt was made to identify risk factors for reactivation. An indirect estimate for the tuberculosis reactivation rate in this population can be made at one case for every 30 persons per year. This is equal to 3300 cases annually per 100,000 population, a rate more than 51 times the general population in Jeddah (Milaat et al. 1994). This study also provides evidence that PPD test is unreliable in this population to identify patients at risk for tuberculosis-reactivation.

4.3.5 Cancer and Bone Marrow Transplant Patients

Neoplasia constitute a major immune compromise with and without cytotoxic therapy. In hematologic malignancies, tuberculosis reactivation has been reported from developed countries. However, data from developing countries are limited. The King Faisal Specialist Hospital and Research Centre in Riyadh has been performing bone marrow transplantation and tuberculosis was diagnosed in 4 (0.6%) of 641 adult recipients of bone marrow transplantation between 1986 and 1997 (Aljurf et al. 1999). Diagnosis in these severely immunocompromised hosts was delayed. Two patients died before tuberculosis was diagnosed. Rates of tuberculosis in bone marrow transplantation patients in developed countries ranged between 0.1% and 2.0%. For some reason, tuberculosis reactivation rates in bone marrow transplantation patients in Saudi Arabia are lower than expected given the prevalence rate in the country and degree of immune suppression in these patients. Another group of cancer patients in which tuberculosis rates have been poorly evaluated is lymphoma patients. They have a considerable degree of immunosuppression, even prior to chemotherapy. Lymphoma is one of the most common cancers in Saudi Arabia (Cancer registry report: KFSH-RC). There are no reports on lymphoma cohorts who developed tuberculosis to assess the reactivation risk. Among a group of 3921 lymphoma patients at King Faisal Specialist Hospital and Research Centre, culture-proven tuberculosis was documented in 26 patients (0.7%). Rates were similar between Hodgkin's and non-Hodgkin's disease. Pulmonary tuberculosis was noted in ten patients, extrapulmonary in thirteen patients and three had disseminated disease. Diagnosis was delayed and mortality was high at 46%. Three of the twelve mortalities

A. A. Alrajhi and A. M. AI-Barral<

were diagnosed to have tuberculosis post-mortem (Neamatallah et al. 2000).

4.3.6 Solid Organ Transplant Recipients

The immunosuppressive therapy used in solid organ transplant patients enhances the chances for reactivation of tuberculosis (Barber and Sugar 1994). This has been documented from a kidney transplant series at King Faisal Specialist Hospital and Research Centre in Riyadh. Qunibi et al. (1990) reviewed 403 kidney-transplanted patients over 9 years. Tuberculosis was documented in 14 cases, a rate of 3.5%. This rate was thought to be 50 times higher than the annual incidence rate. Pulmonary tuberculosis was diagnosed in 29% of the cases, disseminated in 64%. One case acquired infection from the transplanted kidney. At the same institution, King Faisal Specialist Hospital and Research Centre, two liver transplant patients developed tuberculosis out of a cohort of 72 patients. The rate is 2.7%, close to the rate in kidney transplant recipients (A. Alrajhi, unpublished data).

4.4

Mycobacteria Other than M. tuberculosis

Mycobacterial species other than M. tuberculosis (MOTT) has not been studied well in Saudi Arabia. This could be due to non-culture methods of identifying tuberculosis in some centers, difficulty in identifying non-tuberculosis mycobacterium, or considered as contamination. Zaman found 9% (47 isolates) of mycobacterium isolates are nontuberculosis at National Guard Hospital in Jeddah over 2 years (Zaman 1991a). M. fortuitum and M. chelonei were the most prevalent. Respiratory and urogenital tracts were most frequently affected. At King Faisal Specialist Hospital and Research Centre in Riyadh, MOTT was found in 396 (64%) of the 620 mycobacteria isolates over a 3-year period between 1987 and 1989 (Brodie and Qadri 1990). M. aviumintracellulare complex was cultured most frequently. Respiratory specimens were the most frequent source of positive source. This high incidence is probably due to bias in patient population selection in this tertiary care center, which treats transplanted and malignancy patients. There is a need for reliable data collection to be able to establish the true incidence and prevalence of

Epidemiology of Tuberculosis in Saudi Arabia

MOTT in Saudi Arabia. Progress in health care has led to an increase of numbers in immunocompromised patients who are predisposed to these organisms. Specimens processed for mycobacteria need to be cultured and processed even if they are MOTT.

4.5 Conclusion Saudi Arabia has been in the middle percentage countries affected by tuberculosis. The incidence of reported pulmonary tuberculosis continued to decrease steadily during the 1980s and the 1990s. However, extra-pulmonary tuberculosis has resurged late in the 1990s. The incidences around the Kingdom differ according to area of high traffic of a population during a short time, e.g., Jeddah area and Hajj or a concentration of a certain population. There is alarming data of increasing multi-drug resistance tuberculosis. There is an increasing demand for nationwide studies on incidence and prevalence of tuberculosis in different populations in the new centuries in order to asses the effect of the national tuberculosis program that was established last decade.

References Abdullah A et al (1991) Tuberculosis epidemiology survey: Mantoux test results from Central region of Saudi Arabia. Saudi Med J 12:107-110 Al-Amoud M (1993) The history of tuberculosis. Saudi Med J 14:515-520 AI-Dabbagh A, El-Deeb H, AI-Baghdadi T (1991) The radiographic features of pulmonary tuberculosis observed for the Western region of Saudi Arabia. Ann Saudi Med 11: 194-200 Al-Hajjaj M (2000) The outcome of tuberculosis treatment after implementation of the national tuberculosis control program in Saudi Arabia. Ann Saudi Med 20:125-128 AI-Hajjaj M et al (1991) Pulmonary tuberculosis in Saudi Arabia: a retrospective study of 1566 patients. Ann Saudi Med 11: 443-447 Al-Homrany M (1997) Successful therapy of tuberculosis in hemodialysis patients. Am J NephroI17:32-35 Al-Jama A, Borgio F, Al-Qatari K (1999) Patterns of resistance to antituberculous drugs in Eastern Province, Saudi Arabia. Saudi Med J 20:927-930 Aljurf M et al (1999) Mycobacterium tuberculosis infection in allogeneic bone marrow transplantation patients. Bone Marrow Transplant 24:551-554 Al-Kassimi F (1994) Review of tuberculosis in Saudi Arabia. Saudi Med J 15:192-195 Al-Kassimi F et al (1991) Mantoux Reaction Survey conducted

55 in the Northern region of Saudi Arabia. Ann Saudi Med 11:315-321 Al-Kassimi F et al (1993) Nationwide community survey of tuberculosis epidemiology in Saudi Arabia. Tubercle Lung Dis 74:254-260 AI-Khader A et al (1990) Prevalence of tuberculosis in the dialysis population in Saudi Arabia. Saudi Kidney Dis Transplant Bull 1:155-157 Al-Orainey I (1986) Resistance to standard antituberculous drugs in Saudi Arabia. Saudi Med J 7:363-368 Al-Orainey let al (1989) Resistance to antituberculosis drugs in Riyadh, Saudi Arabia. Tubercle 70:207-210 Alrajhi AA, et al (2002) Risk factors for drug-resistant Mycobacterium tuberculosis in Saudi Arabia. Saudi Med J 2002; 23:305-310 Al Shohaib S (2000) Tuberculosis in chronic renal failure in Jeddah. J Infect 40:150-153 AI-Wabel A et al (1995) Spectrum of pulmonary tuberculosis in the Asir Region of Saudi Arabia. Saudi Med J 16:105-107 Al-Wabel A et al (1997) Symptomatology and chest roentgenographic changes of pulmonary tuberculosis among diabetics. East Afr Med J 74:62-64 Alzeer A et al (1998) Tuberculosis is the commonest cause of pneumonia requiring hospitalization during Hajj (pilgrimage to Makkah). J Infect 36:303-306 Barber T, Sugar MA (1994) Mycobacteriossis and nocardiosis in the immunocompromised host. In: Robin RH, Young LS (eds) Clinical approach to infection in the compromised host. Plenum, New York, pp 251-253 Bener A (1990) Prevalence of tuberculosis infection in ABHA and BAHA. Eur J EpidemioI6:376-381 Bener A, Abdullah A (1993) Reaction to tuberculin testing in Saudi Arabia. Indian J Publ Health 37:105-110 Boucot K, Cooper D, Dillon E et al (1952) Tuberculosis among diabetics: the Philadelphia survey. Rev Tuberculosis 65:127 Braun M et al (1991) A retrospective cohort study of the risk of tuberculosis among women of childbearing age with HIV infection in Zaire. Am Rev Respir Dis 143:501-504 Brodie L, Qadri SM (1990) Isolation of mycobacteria other than that of tuberculosis at a major tertiary care hospital in Saudi Arabia. Med Sci Res 18:257-258 Cengiz K (1996) Increased incidence of tuberculosis in patients undergoing hemodialysis. Nephron 73:421-424 Chowdhury M, Kambal A (1992) Mycobacterial resistance in a general hospital in Riyadh Saudi Arabia. Med Sci Res 20: 21-22 Dahmash N, Chowdhury M (1994) Re-evaluation of pneumonia requiring admission to an intensive care unit: a prospective study. Thorax 49:71-76 Dahmash N et al (1994) Infections in critically ill patients: experience in MICU at a major teaching hospital. Infection 22:264-270 Dahmash N et al (1995) Diagnostic challenge of tuberculosis of the elderly in hospital: experience at a university hospital in Saudi Arabia. J Infect 31:93-97 El-Kassimi F (1994) The annual risk of tuberculosis infection used as predictor of the future incidence of smear-positive cases. Respir Med 88:589-592 El-Kassimi F et al (1991) Tuberculin survey in the Eastern Province of Saudi Arabia. Respir Med 85:111-116 Ellis M et al (1996) High proportion of multi-drug resistant Mycobacterium tuberculosis in Saudi Arabia. Scand J Infect Dis 28:591-595

56 EI-Sheikh S et al (1998) Bacteria and viruses that cause respiratory tract infections during the pilgrimage Haj season in Makkah, Saudi Arabia. Trop Med Int Health 3:205-209 Farag M et al (1995) National immunization coverage survey Saudi Arabia, 1991. J Trop Pediatr 41:S59-S67 Froude J, Kingston M (1982) Extrapulmonary tuberculosis in Saudi Arabia, a review of 162 cases. King Faisal Special Hosp Med J 2:85-95 Hammam H, Kamel L, Hidayat N (1979) Third Saudi Medical Conference, Dammam Hussein M, Bakir N, Roujouleh H (1990) Tuberculosis in patients undergoing maintainence dialysis. Nephrol Dial Transplant 5:584-587 Hussein M et al (1994) Observations in a Saudi-Arabian dialysis population over a 13-year period. Nephrol Dial Transplant 9: 1072-1076 Hussein M, Mooij J, Roujouleh H (1996) Tuberculosis in hemodialysis patients. Saudi J Kidney Dis Transplant 7:6-9 Jarallah J et al (1992) High rate of rifampicin resistance of Mycobacterium tuberculosis in the Taif region of Saudi Arabia. Tubercle Lung Dis 73:113-115 Jondeby M et al (2001) Caring for hemodialysis patients in Saudi Arabia. Saudi Med J 22:199-204 Khan M et al (2001) Increasing resistance of M. tuberculosis to anti-TB drugs in Saudi Arabia. Int J Antimicrob Agents 17:415-418 Mackay A, Cole R (1984) The problem of tuberculosis in the elderly. Quart J Med 212:497-510 Milaat W et al (1994) Epidemiology of tuberculosis in Jeddah region, Saudi Arabia. Saudi Med J 15:133-137 Ministry of Health (1979) Tuberculosis. First Annual Health Report, 1979. Ministry of Health, Riyadh, pp 199-208 Ministry of Health (1991) Tuberculosis. Annual Health Report, 1991. Ministry of Health, Riyadh, pp 252-258 Ministry of Health (1996) Tuberculosis. Annual Health Report, 1996. Ministry of Health, Riyadh, pp 35-37 Ministry of Health (1997) Tuberculosis. Annual Health Report, 1997. Ministry of Health, Riyadh, pp 46-49 Mitwalli A (1991) Tuberculosis in patients on maintenance dialysis. Am J Kidney Dis 18:579-582 Mohamed A, Evans D (1987) The spectrum of pneumonia in 1983 at the Riyadh Armed Forces Hospital. J Infect 14:31-37 Mokhtar A, Salman K (1983) Extrapulmonary tuberculosis. Saudi Med J 4:317-322 Murthy B, Pereira B (1997) A 1990 s perspective of hepatitis C, human immunodeficiency virus, and tuberculosis infections in dialysis patients. Semin NephroI17:346-363 Narain 1, Raviglione M, Kochi A (1992) HIV-associated tuber-

A. A. Alrajhi and A. M. AI-Barrak culosis in developing countries: epidemiology and startegies for prevention. Tubercle Lung Dis 73:311-321 Neamatallah A, Alrajhi N, Alrajhi A (2000) Mycobacterium tuberculosis infection during lymphoma chemotherapy. 10th European congress of clinical microbiology and infectious diseases, Stockholm, Sweden Pandya L et al (1990) Lower-lung-field tuberculosis in Saudi Arabia. Ann Saudi Med 10:374-377 Pandya L et al (1991) Pulmonary tuberculosis in diabetic patients. Ann Saudi Med 11:293-296 Pradhan R et al (1974) Tuberculosis in dialyzed patients. JAMA 229:798-800 Qunibi W et al (1990) Mycobacterial infection after renal transplantation - report of 14 cases and review of the literature. Quart J Med 77:1039-1060 Schein M, Huebner R (1995) Tuberculin skin testing. McGrrawHill, New York, pp 73-75 Schiott C et al (1985) Incidence of drug resistance amongst isolates of Mycobacterium tuberculosis recovered in the Gizan area, Saudi Arabia. Saudi Med J 6:375-378 Selwyn P et al (1989) A prospective study of the risk of tuberculosis among intravenous drug users with human immunodeficiency virus infection. N Engl J Med 320:545-550 Shanks N, Khalifa I, Al Kalai D (1983) Tuberculosis in Saudi Arabia. Saudi Med J 4:151-156 Shohaib S, Scrimgeour E, Shaerya F (1999) Tuberculosis in active dialysis patients in Jeddah. Am J NephroI19:34-37 Styblo K (1980) Recent advances in epidemiological research in tuberculosis. Adv Tuberculosis Res 20:1-63 Thompson N et al (1979) The booster phenomenon in serial tuberculin testing. Am Rev Respir Dis 119:587-597 WHO (1964) WHO technical report series no 290. World Health Organization, Geneva WHO (1997) Anti-tuberculosis drug resistance in the world. The WHO/IUATLD global project on anti-tuberculosis drug resistance surveillance 1994-1997. World Health Organization, Geneva Wilson W, Kirkpatrick C, Talmage D (1965) Suppression of immunologic responsiveness in uremia. Ann Intern Med 62:1-8 World Bank W (1993) World development report 1993: investing in health. Oxford University Press, Oxford Zaman R (199Ia) Tuberculosis in Saudi Arabia: epidemiology and incidence of Mycobacterium tuberculosis and other mycobacterial species. Tubercle 72:43-49 Zaman R (1991b) Tuberculosis in Saudi Arabia: initial and secondary drug resistance among indigenous and nonindigenous populations. Tubercle 72:51-55

5

The Molecular Epidemiology of Tuberculosis KATHRYN DERIEMER and CHARLES 1. DALEY

CONTENTS 5.1 5.2 5.3 5.3.1 5.3.2 5.3.3 5.3.4 5.3.5 5.3.6 5.4 5.4.1 5.4.2 5.4.3 5.4.4 5.4.5 5.5

Introduction 57 Genotyping Methods 57 Commonly Used Secondary Typing Methods 59 PGRS Typing 59 Spoligotyping 59 Other PCR-Based Methods 59 Comparisons of Different Typing Methods 60 Methodological Issues in Interpreting IS6110 RFLP Typing 60 Whole Genome and Microarray Technologies 62 Lessons Learned Using Molecular Epidemiology 62 Contact and Outbreak Investigations 62 Community Epidemiology and Tuberculosis Control 65 Exogenous Reinfection with M. tuberculosis 66 Geographical Distribution and Dissemination of M. tuberculosis 67 Evaluation of Laboratory Cross-contamination 68 The Future of Molecular Epidemiology 69 References 70

5.1 Introduction The ability to track specific strains of Mycobacterium tuberculosis as they spread through a population is critical for our understanding of the transmission and pathogenesis of tuberculosis. However, until recently, the only phenotypic markers that distinguished different strains of M. tuberculosis were drug resistance patterns and mycobacterial phage typing (Gruft et al. 1984). Molecular genotyping techniques that allow us to differentiate isolates of K. DERIEMER, PhD Senior Research Scientist, Division of Infectious Diseases and Geographic Medicine, Stanford Medical Center, Stanford, California, USA C. 1. DALEY, MD Associate Professor of Medicine, Division of Pulmonary and Critical Care Medicine, San Francisco General Hospital, Room 5K-1, 1001 Potrero Ave, San Francisco, CA 94110, USA

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

M. tuberculosis for the purpose of tracking strains in the community and designing prevention and control strategies to block further transmission of M. tuberculosis are now available. Molecular epidemiology combines the straintyping capabilities of genotyping with conventional epidemiologic approaches in order to study the distribution and determinants of disease occurrence. Molecular techniques can help address epidemiological problems that cannot be approached or would be more difficult to address by conventional methods. Epidemiologic investigations that incorporate genotyping of M. tuberculosis have been used to provide novel information about the spread of tubercle bacilli in mini-epidemics and outbreaks, to determine the risk factors for transmission in a community, to distinguish exogenous re-infection from relapses, to track the geographic distribution and spread of strains ofM. tuberculosis of public health importance, and to identify instances of laboratory contamination (Foxman and Riley 2001). This chapter updates current knowledge about the accomplishments and future directions of this relatively new field.

5.2

Genotyping Methods Until recently, drug susceptibility testing and phage typing were the only bio-markers available for epidemiological studies of M. tuberculosis, both of which have serious limitations. Drug susceptibility test results can change in a strain as the strain acquires resistance to one or more antimicrobials during treatment. Bacteriophage typing of M. tuberculosis is oflimited value for epidemiologic studies as only a few phage types can be recognized and thus, it cannot adequately distinguish between different strains (Rado et al. 1915; Grange et al. 1978; Engel 1978; Crawford and Bates 1984). During the past decade, several nucleic acid-based genotyping methods based on the variations in the

58

K. DeRiemer and C. L. Daley

sequence in bacterial genomes were developed. These new methods allow us to accurately distinguish between different strains of M. tuberculosis. The most widely used method is referred to as restriction fragment length polymorphisms (RFLP) analysis (Fig. 5.1). Specific restriction endonucleases cleave the mycobacterial DNA at the sites of specific repetitive sequences, producing DNA restriction fragments of different lengths. The restriction fragments can be separated by size using conventional agarose gel electrophoresis and the banding patterns of these restriction fragments can be detected by staining the gel with ethidium bromide (Collins and de Lisle 1985, 1987; Swaminathan and Matar 1993). However, the resulting genotype pattern contains thousands of fragments and is very difficult to read and interpret. In order to decrease the number of fragments to be compared, the chromosomal DNA restriction fragments are probed with specific, repetitive, labeled DNA fragments (Eisenach et al. 1988; Reddi et al. 1988). Only the genomic DNA restriction fragments that are complementary to and hybridize with the probe are visible, resulting in fewer bands and a more readable band pattern. An internationally accepted, standardized protocol for RFLP typing of the M. tuberculosis complex Chromosomal DNA

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was published in 1993 and is still used today (van Embden et al. 1993). This method takes advantage of a specific, well-characterized, repetitive element insertion sequence 6110 OS611O) (Thierry et al. 1990). It was originally thought that IS6110 insertions occur randomly (Zhang et al.1992) but this was disproved when the H37Rv strain of M. tuberculosis was sequenced (Philipp et al. 1996; Cole et al. 1998). Between 0 and 25 copies of IS611 0 are found in almost all strains of the M. tuberculosis complex (van Soolingen et al.1993; Agasino et al.1998). The position and number of copies of the IS6110 elements varies from strain to strain; this variability in the chromosome of M. tuberculosis is exploited to distinguish between different strains (Cave et al.1991; van Soolingen et al. 1991). The RFLP band patterns of strains may be compared visually or scanned optically by a computerized reading system and matched to a reference library of strain profiles (Woelffer et al.1996; Heersma et al.1998). When used in conjunction with standardized international databases and computer-assisted analysis, this approach allows comparisons of strains between different laboratories in widely separated geographical regions. However, the standardized method of IS6110 RFLP typing has several disadvantages. It is slow, labor intenDigested DNA

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Fig. 5.1. Method ofI56110-based restriction fragment length polymorphisms (RFLP) analysis. Depicted are two strains of Mycobacterium tuberculosis, labeled 1 and 2. The location and number of the insertion sequence, 156110, is noted by the small black rectangles. A. The first step in the process is the extraction of the chromosomal DNA. B. The extracted DNA is then cleaved with a restriction endonuclease (PvuII). Note that in reality, thousands of fragments are created. C. After digestion, the DNA fragments are separated according to size by gel electrophoresis. In reality, this process results in thousands of bands that are nearly confluent on the gel. D. Hybridization with probe for 156110 results in a gel with bands only containing the 156110 element. Thus, there are fewer bands and the pattern is easier to read. The two strains can be seen to differ in the number of bands (i.e., the number of 156110 copies in the genome) and the location of the bands (i.e., the size of the restriction fragments)

59

The Molecular Epidemiology of Tuberculosis

sive, and technically demanding. It requires a relatively large amount (e.g. 2 j.1g) of high-quality DNA from each strain of M. tuberculosis, an amount that can only be extracted from a large number of bacteria grown from clinical material. For isolates with less than six copies of IS6110 (less than six bands in the RFLP pattern), it has relatively poor discriminatory power and should be supplemented by analyses with other probes. Finally, sophisticated computer software and technical support are required to compare, analyze, and interpret large numbers of IS6110 RFLP band patterns. Despite these limitations, IS6110 RFLP typing remains the most commonly used method in molecular epidemiologic studies of M. tuberculosis and is considered the gold standard technique.

S.3 Commonly Used Secondary Typing Methods Several basic assumptions underlie our interpretation of genotyping results. For example, we assume that two strains with an identical IS6110 RFLP pattern have a common origin, albeit, perhaps, remote. In addition, we assume that strains with identical IS6110 RFLP band patterns with multiple bands are more likely to have a common origin and be clonal than are strains with relatively few bands. Strains with few bands or low copy numbers in the RFLP pattern could appear identical by chance alone. A secondary probe, such as the polymorphic guanine/cytosinerich repetitive sequences (PGRS) or spoligotyping can be used to further differentiate between strains with low copy numbers (Burman et al. 1997b). Early comparative studies showed that using multiple molecular techniques in a single study provided better discrimination between strains and insight for phylogenetic groupings (Bifani et al. 1999). Today, most molecular epidemiologic studies rely on IS611 0 RFLP typing and a secondary typing method, such as PGRS or spoligotyping, for those isolates with less than six bands in the IS6110 RFLP band pattern.

system uses the polymorphic GC-rich repeat sequence contained in the recombinant plasmid pTBN12 as a probe (Cousins et al. 1992; Ross et al. 1992). The main disadvantage of the PGRS typing system is that some of the PGRS regions include many non-perfect repeats and the patterns that PGRS typing generates are complex and difficult to interpret. In addition, PGRS typing is less discriminatory than IS6110-based RFLP genotyping. Despite these limitations, PGRS genotyping is a commonly used secondary typing method.

5.3.2 Spoligotyping Spoligotyping is a polymerase-chain-reaction (PCR)based method that interrogates a small direct repeat (DR) sequence with 36-base pair (bp) repeats interspersed with short, unique, non-repetitive sequences (Hermans et al. 1991; Groenen et al. 1993; Kamerbeek et al. 1997). All of the unique, non-repetitive sequences, or "spacers:' between the direct repeats can be amplified simultaneously using one set of primers. Strains are differentiated by the number and position of the spacers that are missing from the complete spacer set. The complete spacer set is defined by sequencing this region from a large number of isolates of M. tuberculosis. This spacer oligotyping or "spoligotyping" is more rapid and easier to perform than IS6110 RFLP typing, making it an excellent tool in resource-poor settings. However, it has a lower level of discrimination than IS6110 RFLP typing (Diaz et al.1998; Goyal et al.1999). Nevertheless, it can be used to validate the IS6110 RFLP typing results, to further differentiate strains with low IS6110 copy numbers (less than six bands in the RFLP pattern) (Wilson et al.1998; Bauer et al.1999; Goyal et al. 1999; Yang et al. 2000; Soini et al. 2001), and to show more distant phylogenetic relationships among isolates. As recommended in several studies (van Soolingen et al. 1995; Stauffer et al. 2000), spoligotyping could be used as a preliminary screening step, to be followed by another typing method with greater discriminatory power.

5.3.1 PGRSTyping

5.3.3 Other peR-Based Methods

The most common repetitive DNA sequences in the genome of M. tuberculosis are the PGRS, a triplet repeat of GTG, and the major polymorphic tandem repeat (Hermans et al. 1992; Ross et al. 1992; Poulet and Cole 1995; Chaves et al. 1996). The PGRS typing

Relative to IS6110 RFLP genotyping, PCR-based methods are easier to perform, require small amounts of genomic DNA, and can even be performed on nonviable organisms or directly from clinical specimens,

60

K. DeRiemer and C. L. Daley

thereby eliminating the lengthy time required to culture M. tuberculosis (Driscoll et al. 1999; Qian et al. 1999; Taylor et al. 1999). Several other PCR-based typing assays have been developed using IS6110 as the target. Mixer-linked PCR (Haas et al. 1993) ligationmediated PCR (Bonora et al.1999), heminested inverse PCR, IS6110 inverse PCR, IS6110 ampliprinting, and double-repetitive (DR) element PCR (Friedman et al. 1995a) are among the techniques developed to date. None of these techniques have been studied or applied as extensively as IS611O-based RFLP genotyping. Analysis by variable number tandem repeat (VNTR) is a PCR-based method that differentiates between strains by identifying the number and length of exact tandem repeats present in an isolate, independently of the IS6110 polymorphisms (Skuce et al. 2002). A high-resolution typing method based on the VNTRs of mycobacterial interspersed repetitive units (MIRUs) based on 12 specific intergenic regions of the M. tuberculosis genome has been proposed (Mazars et al. 2001; Supply et al. 2002). In a study of 72 clinical isolates, the correlation between genetic relationships inferred from MIRU-VNTR and IS6110-RFLP typing was highly significant. Relative to IS611 0 RFLP typing, MIRU-VNTR profiling is fast, appropriate for strains regardless of their IS611 0 RFLP copy number, and permits rapid comparison of results from independent laboratories using a binary data classification system.

5.3.4 Comparisons of Different Typing Methods Despite the development of these different methods, IS6110 RFLP remains the most widely used genotyping method for the molecular epidemiology of

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5.3.5 Methodological Issues in Interpreting 156110 RFLPTyping While the methods for generating IS6110 RFLP patterns are well-standardized, the interpretation of these patterns depends on the epidemiological question being asked and the stability of the IS6110 element in the mycobacterial genome. Genetic markers that change rapidly obscure epidemiological links, whereas those that are too stable suggest direct links and relatedness where true links do not exist. In well-defined outbreak settings, some tuberculosis patients may have isolates whose RFLP band patterns differ by one or two insertion elements (Fig. 5.3) (Daleyet al. 1992). This latter observation suggests that as a strain spreads through the community, the strain is evolving and produces progeny with subtle variations in their RFLP patterns and the rate at which these changes occur is

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tuberculosis and is the gold standard to which other methods are compared. In an inter-laboratory study, Kremer and colleagues compared most of the currently available molecular typing methods for M. tuberculosis (Fig. 5.2) (Kremer et al. 1999). Five RFLP typing methods including IS611O, IS1081, PGRS, the DR and the (GTGh repeat as probes were highly reproducible. Of the PCR-based methods that were compared, VNTR typing, mixed-linker PCR, and spoligotyping were highly reproducible between different laboratories. However, the double repetitive element PCR, IS611 0 inverse PCR, IS611 0 ampliprinting and arbitrarily primed PCR were not very reproducible. The most discriminatory methods were IS6110 RFLP typing and the mixed-linker PCR.

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Fig. 5.2. Comparison of different genotyping methods. Depicted above are patterns of ten Mycobacterium tuberculosis complex duplicate samples obtained by various typing methods. The methods are ordered from most to least reproducible (left to right). The 156110 RFLP patterns are shown as representatives of the Pvull-based RFLP method. Numbers in vertical direction indicate duplicate samples. (Adapted from Kremer et al. 1999)

61

The Molecular Epidemiology of Tuberculosis

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-0" Fig. 5.3. Restriction fragment length polymorphisms (RFLP) patterns of M. tuberculosis isolates obtained from an outbreak of tuberculosis in an HIV congregate living site (A) and controls living in San Francisco at the same time (B). The first two lanes are the RFLP patterns of M. bovis, BCG, and M. intracellulare. Cases 1 and 2 (A) were receiving antituberculosis therapy when they entered the facility. Tuberculosis developed in the remaining patients while they lived in the facility. Note the shift of the band in the upper part of lane 11. (Adapted from Daley et al. 1992)

important (Bifani et al. 1996). At least two studies have shown that the 156110 RFLP band patterns of different strains of M. tuberculosis are relatively stable, with a half-life of approximately 3-4 years (Yeh et al. 1998; de Boer et al.1999). Therefore, the 156110 element should be useful for studying transmission of M. tuberculosis over relatively short periods of time. To interpret the results of 15611 0 RFLP strain typing and other typing methods, we assume that epidemiologically related strains will have the same genotype pattern and epidemiologically unrelated strains will have different patterns. Ideally, strain typing will provide a clear, objective basis for identifying an outbreak strain and distinguishing it from epidemiologically unrelated isolates. Many studies of tuberculosis have extended these assumptions to define clusters of patients in the community whose isolates had identical or nearly identical genotype patterns. Clustering has often been equated with recent or ongoing transmission, and the factors associated with clustering have been sought as a means to identify and target subpopulations with substantial ongoing transmission

(Glynn et al.1999a). Since the first large-scale molecular epidemiologic studies of tuberculosis transmission using 156110 RFLP typing, it has generally been accepted that tuberculosis cases with identical 156110 RFLP band patterns that are isolated from two or more persons in the same community represent recent or ongoing exogenous infection and rapid progression to disease. By contrast, patients whose isolates of M. tuberculosis have genotype patterns that do not match any other isolates in the community are considered to be unique. Unique isolates likely represent disease caused by reactivation of latent tuberculosis infection (LTBI) (Alland et al. 1994). Molecular techniques enable us to distinguish tuberculosis due to recent or ongoing infection versus reactivation of LTBI and to estimate the fraction of active tuberculosis transmission in a community. However, some strains may be identical for reasons other than recent transmission and there is not always an epidemiological link between patients whose isolates have identical genotype patterns. For example, a large proportion of the isolates from newly diagnosed tuberculosis cases in a relatively stable, rural population in the United States showed high degrees of clustering based on 156110 RFLP typing, but most of the patients had no discernible contact or other epidemiological links among themselves (Braden et al. 1997). Similar findings were reported from Malawi and Kenya; some strains from a large rural area had identical genotype patterns, but there were no discernible epidemiological links between the patients (Godfrey-Faussett and Stoker 1992). Combined, such studies suggest that the epidemiological interpretation of molecular epidemiologic studies may be confusing in areas where it likely that ancestral, endemic, well-conserved strains with stable genotype patterns occur. The amount of transmission represented by clustering using molecular typing techniques will depend on the sampling strategy and duration of the study (Murray 2002; Murray and Narde1l2002b). Undersampling can bias the estimates of the proportion of tuberculosis cases that were likely caused by recent tuberculosis transmission and it can bias the estimates of the risk factors associated with clustering. When an early hospital-based study of tuberculosis transmission in New York City, USA, was re-examined and adjusted for potential sampling bias, the revised estimate of the odds ratio of the association of human immunodeficiency virus (HIV) and clustering increased from 2.7 to 23.6 (Murray and Alland 2002a). No study has 100% case ascertainment, and incomplete sampling will underestimate the proportion of tuberculosis cases that are clustered, even if the number of tuber-

K. DeRiemer and C. 1. Daley

62

culosis cases included in the study is large (Glynn et al.1999a,b). Biases may also be introduced if a molecular epidemiologic study does not cover an adequate time period. 1\vo population-based studies that have been ongoing for more than 10 years (San Francisco [Small et al. 1994; Jasmer et al. 1999] and the Netherlands [van Soolingen et al. 1999]), showed that the percentage of clustered strains was high during the first 2 years and declined thereafter. Clustering based on less than 2 years of sampling is unlikely to identify the source and secondary cases in a chain of transmission, and will likely underestimate the amount of recent transmission.

genomic deletions can be detected relative to the reference strain, depending on the array. Because deletions in the M. tuberculosis genome rarely occur independently at exactly the same chromosomal locus, they can be considered unique and irreversible genetic events. The number and distribution of deletions provide a genomic pattern that can be used to construct phylogenetic relationships and to determine whether the loss of specific genes is related to the phenotype of a strain, such as its transmissibility or antigenicity (Salamon et al. 2000; Kato-Maeda et al. 2001).

5.3.6 Whole Genome and Microarray Technologies

Lessons Learned Using Molecular Epidemiology

Until recently, the main purpose of developing typing techniques using molecular markers was to differentiate between strains of M. tuberculosis and to identify chains of transmission. There is rising interest in identifying the genotype of specific strains and their correlations with specific clinical manifestations and other phenotypes, such as increased infectivity, virulence, or hyper-mutability. DNA sequencing is still too expensive and too complex to be applied to make direct comparisons of genomic sequences of multiple strains of M. tuberculosis, and it is likely that all strains vary to some degree at the nucleic-acid base level. However, it is now possible to analyze short segments of DNA for sequence similarities and differences. For example, genomic fragments can be amplified using PCR, and an automated DNA-sequencing procedure can be used to directly sequence the PCR-amplified DNA fragment. This approach allows a DNA fragment of 300- to 500-bp to be sequenced in 24 h (Tracy and Mulcahy 1991). In the future, improved automation of target amplification and direct sequence analysis may make this a practical approach for laboratories. Strains of M. tuberculosis can also be compared based on the whole genome sequence using DNA microarrays and DNA chip technology. These techniques allow simultaneous detection of the variation at many different genomic sites by analysis of the amount and specific location of mycobacterial DNA (Gingeras et al. 1998). Briefly, the genome of a strain of M. tuberculosis is compared with that of a known, sequenced reference strain by hybridization on an array containing thousands of oligonucleotides on a limited surface. Differences in gene expression and

Molecular genotyping has revolutionized our ability to track strains of M. tuberculosis as they spread through a community. Studies of the molecular epidemiology of tuberculosis have elucidated both suspected and unsuspected transmission, identified weaknesses in conventional contact investigations, identified risk factors for recent infection with rapid progression to disease, demonstrated exogenous reinfection with different strains, and documented the existence of laboratory cross-contamination as a cause for false-positive cultures.

5.4

5.4.1 Contact and Outbreak Investigations Conventional tuberculosis contact investigations use the"stone-in-the-pond" or concentric circle approach to collect information and to screen household contacts, coworkers, and increasingly distant contacts for tuberculosis infection and disease (Veen 1992). However, the concentric circle method may not be adequate in many out-of-household settings and there are considerable limitations with this approach. Molecular epidemiology has helped to identify some of these limitations. In low-incidence areas such as San Francisco (Small et al. 1994), Zurich (Pyffer et al. 1998), and Amsterdam (van Deutekom et al. 1997), a relatively small proportion (5-10%) of the cases that had identical IS6110-based genotyping patterns were actually identified as a contact by the source case. This suggests that unsuspected transmission of tuberculosis occurs and is not easily traced by con-

The Molecular Epidemiology of Tuberculosis

ventional contact tracing investigations. In a 5-year, population-based study in the Netherlands, contact investigations of persons in five of the largest clusters identified epidemiological links between them based on time, place, and risk factors. However, tuberculosis transmission also occurred through only short-term, casual contact that was not easily detected in routine contact investigations (van Soolingen et al. 1999). In a high-incidence area in Barcelona, Spain (163 tuberculosis cases/lOO,OOO population), there was 61.5% concordance between the genotype pattern and conventional contact tracing (Solsona et al. 2001). In that study, the authors concluded that conventional contact tracing was useful for identifying new tuberculosis cases, but it did not provide much information about the chains of transmission and how to block or prevent them. In a population-based molecular epidemiological study in an urban community in the San Francisco Bay area, 75 (33%) of 221 cases had the same strain of M. tuberculosis. Thirty-nine (53%) of the seventythree patients developed tuberculosis because they were not identified as contacts ofsource case-patients; twenty case-patients (27%) developed tuberculosis because of delayed diagnosis of their sources; and thirteen case-patients (18%) developed tuberculosis because of problems associated with the evaluation or treatment of contacts; and one case-patient (1 %) developed tuberculosis because of delay in being elicited as a contact. This study suggested that even in a community that has implemented the essential elements of tuberculosis control, ongoing transmission of M. tuberculosis will continue to produce cases unless patients are diagnosed earlier and contacts are more completely identified (Chin et al. 2000). Some populations, such as the urban homeless, present unique challenges for those conducting conventional contact investigations. However, studies that incorporate genotyping are able to provide information about the chains of transmission in these groups (Barnes et al. 1996; Gutierrez et al. 1998; Kimerling et al. 1998; Lemaitre et al. 1998; Dobbs et al. 2001). A prospective study of tuberculosis transmission in Los Angeles, California, USA identified 162 patients who had culture-positive tuberculosis, and interviewed the patients to identify their contacts and whereabouts (Barnes et al. 1997). Genotyping using 156110 RFLP typing and PGRS analysis were performed on all isolates of M. tuberculosis from these patients. Patients whose isolates had identical or closely related genotyping patterns were considered clustered, and the degree of homelessness and the instance of a patient using daytime services at

63

three shelters were independently associated with clustering. Ninety-six (59%) of one hundred and sixty-two patients were in eight clusters, but only two of the ninety-six clustered persons named others in the cluster as contacts. Thus, traditional contact investigations did not reliably identify patients infected with the same strain of M. tuberculosis. This study demonstrated that locations at which the homeless congregate are important sites of tuberculosis transmission for both homeless persons, who sleep at the shelters, and non-homeless persons, who use the facilities during the day. The authors recommended that strategies to reduce tuberculosis transmission should be based on locations rather than on personal contacts. Additional studies support the idea that specific locations can be associated with recent or ongoing tuberculosis transmission. A study among predominantly HIV-seropositive gay men in Houston, Texas, found that barhopping, or visiting many bars in the same neighborhood each night, was associated with being in an IS6110 RFLP cluster, representing ongoing tuberculosis transmission (Yaganehdoost et al.1999).A population-based molecular epidemiologic study of tuberculosis transmission in Orizaba, southeastern Mexico, identified clandestine bars as the main site of ongoing tuberculosis transmission and bar patrons as the main sources of tuberculosis transmission in the community (Garda-Garda et al. 2000). In a case-control study of tuberculosis among non-institutionalized HIV-infected patients in King County, Washington, USA, six HIV-infected persons with the same strain of M. tuberculosis had contact at one or more of three bars and this was the only identifiable epidemiologic link among them (Tabet et al. 1994). Additional tools, such as geographic information systems (GIS) data, can add to molecular epidemiologic studies. In a 30-month prospective, city-wide study of all tuberculosis cases in Baltimore, Maryland, USA, using traditional contact investigations and IS6110-based genotyping, 46% (84/182) of isolates were clustered and 32% (58/182) were defined as being recently transmitted. Only 24% (20/84) of clustered cases had an identifiable epidemiologic link of recent contact. Using GIS data, there was significant spatial aggregation of the 20 clustered cases with epidemiologic links in geographic areas of the city with low socioeconomic status and high drug use (Bishai et al.1998). These findings and those described previously suggest that location-based control efforts may be more effective than contact tracing for early identification of cases, at least in some populations.

64

When a second case of tuberculosis is recognized as part of a contact investigation, it is generally assumed that the two cases harbor the same strain of M. tuberculosis, with one as the source-case and the other as the secondary case. Several studies have used genotyping to determine whether the contacts that had tuberculosis were, in fact, secondary cases or whether they were unrelated to the source case. Of 11,211 contacts evaluated in San Francisco, USA, there were 66 pairs of culture-positive index and contact cases (Behr et al. 1998). In the 54 pairs for whom genotyping was available, the index and contact cases were infected with a different strain of M. tuberculosis 30% of the time. Unrelated infections were more common among foreign-born, particularly Asian, contacts. The drug susceptibility pattern was more likely to be discordant in those pairs who harbored different strains. Similar findings have been reported from Denmark and the Netherlands (Sebek 2000). These studies highlight the fact that secondary cases are not always related to the presumed index case and that in areas with high rates of drug resistance, providers should be careful when assuming that the drug susceptibility patterns between the pairs are the same. Genotyping has been particularly useful in defining the presence and scope of tuberculosis outbreaks by identifying otherwise unsuspected and undetected transmission in the community. Traditionally, outbreak investigations depended on contact tracing in the field. This strategy can be ineffective in tuberculosis outbreaks if patients do not live in stable settings and either do not know or are unwilling to reveal the names of contacts. By identifying tuberculosis patients whose isolates have identical strains of M. tuberculosis, genotyping can infer epidemiologic links or connections between individuals and can highlight locations or settings where tuberculosis transmission is occurring. An outbreak of tuberculosis among the residents of a housing facility for HIV-positive persons in San Francisco, California, USA, was one of the first molecular epidemiologic studies that demonstrated the usefulness of genotyping techniques and helped to validate the IS611 a-based typing method (Fig. 5.3) (Daley et al. 1992). The isolates from persons who were part of the institutional outbreak had identical IS611 a RFLP banding patterns, but tuberculosis patients who were unrelated to the outbreak had different strain typing patterns. This study was timportant because it validated the IS6110 RFLP strain typing method in a well-characterized outbreak setting prior to its application in other epidemiologic studies and public health settings. The study also demonstrated the speed

K. DeRiemer and C. L. Daley

with which tuberculosis can spread through an HIVinfected population and the importance of specific locations as sites of transmission. Molecular epidemiology studies have demonstrated the impact that a single patient can have on the epidemiology of a community. A single patient was directly or indirectly responsible for 6% of the tuberculosis cases in San Francisco, including those in the HIV residential care facility noted above (Daley et al. 1992). In another report, IS6110 RFLP analysis showed that a single homeless tuberculosis patient with highly infectious pulmonary tuberculosis likely infected 42% (41197) of contacts who were regular customers and employees of a neighborhood bar that he patronized and caused disease in 14 (34%) of these contacts. Isolates of M. tuberculosis were available for 12/14 of the tuberculosis cases; all had identical IS611 aRFLP band patterns (Kline et al. 1995). In many instances, outbreak investigations are able to detect and document unsuspected transmission. For example, an early study using genotyping ofM. tuberculosis documented the spread of infection and the development of disease to specific individuals who mixed with marginalized drug users, mainly restaurant workers (Genewein et al. 1993). Transmission links between individuals with only casual contact were detected. The study elucidated the details and dynamics of a community sub-epidemic of tuberculosis in a way that went beyond traditional contact tracing and routine surveillance, and facilitated public health interventions designed to limit the tuberculosis transmission. Molecular epidemiologic techniques have confirmed suspected and unsuspected tuberculosis transmission in places such as crack houses (Leonhardt et al. 1994), sites of illegal floating card games (Bock et al. 1998), schools (Kim et al. 2001; Bauer et al. 2000), hospitals (Edlin et al. 1992; Haas et al. 1998), and clinics. Genotyping has been used in several tuberculosis outbreaks in prisons to identify the magnitude of transmission among jail inmates and prisoners, among inmates and guards, and from persons in the jail or prison to members of the community (Ferreira et al. 1996; Chaves et al. 1997; March et al. 2000; Hanau-Bercot et al. 2000; Mohle-Boetani et al. 2002). Tuberculosis transmission has also been demonstrated among groups such as church choirs (Mangura et al. 1998), interstate transgender social networks (Anonymous 2000b), and renal transplant patients (Jereb et al. 1993), as well as from patient to health care provider (Wilkinson et al. 1997) and from health care providers to patients (Frieden et al. 1996a,b; Ikeda et al.1995). Some quite unusual sources of tuberculosis transmission have been confirmed with molecular epidemiologic methods. For example,

The Molecular Epidemiology of Tuberculosis

65

processing contaminated medical waste resulted in transmission of M. tuberculosis to at least one medical waste treatment facility worker (Johnson et al. 2000). Genotyping was also used to document unsuspected bronchoscopy-related transmission and the cross-contamination ofpatients (Agerton et al.1997; Michele et al. 1997; Ramsey et al. 2002). In some instances, molecular typing may reveal outbreaks caused by more than one strain of M. tuberculosis and therefore, more than one likely source of infection. In other situations, molecular typing can effectively rule out an outbreak and thus avoid an expensive epidemiologic investigation and inappropriate interventions. Because of its usefulness, genotyping of M. tuberculosis has become a routine tool for outbreak investigations in many hospitals and health departments.

5.4.2 Community Epidemiology and Tuberculosis Control Tuberculosis results from rapid progression from a recently acquired infection, reactivation of LIBI, or

occasionally from exogenous reinfection (Small and Fujiwara 2001). Most molecular epidemiology studies have assumed that the proportion of clustered isolates in a population reflects the amount of recent or ongoing transmission of M. tuberculosis. Some studies established epidemiological links between clustered tuberculosis cases, inferring that the tuberculosis cases are part of a chain of transmission from a single common source or from several common sources (Genewein et al. 1993; Small et al. 1994). The number and proportion of tuberculosis cases that are in clusters, representing recent or ongoing tuberculosis transmission, have varied from study to study (Table 5.1). The frequency of clustering has varied from 17-18% in low incidence areas such as Vancouver, Canada and Norway to 30-40% in urban areas in the United States. Among gold miners in South Africa, 50% of tuberculosis patients were found to be in clusters. However, it is difficult to make meaningful cross-study comparisons because the studies differ in a number of important ways, including the population studied, the proportion of all tuberculosis cases studied, the duration of the study, the definition of clustering, and the method of secondary typing used.

Table 5.1. Frequency of clustering and risk factors for clustering in selected studies Study (period)

Location

Study population

N

Ever Risk factors for clustering clustered

Small et al. 1994 (1991-1992) Alland et al. 1994 (1989-1992)

San Francisco, USA

Community-based

473

40%

New York City, USA Hospital-based

104

38%

Bishai et al. 1998 (1994-1996) Bauer 1998 (1992-1996) van Soolingen et al. 1999 (1993-1997)

Baltimore, USA

182

46%

Acquired immune deficiency syndrome US-born HIV-seropositive Hispanic ethnicity Younger age Drug-resistant tuberculosis Low income Intravenous drug use

Community-based

Denmark, including Country-based Greenland Netherlands Country-based

1549

49%

Analysis not performed

4266

46%

Godfrey-Faussett et al. 2000 (1995) Dahle et al. 2001 (1994-1998) Hernandez-Garduno et al. 2002 (1995-1999)

South Africa

Gold miners

419

50%

Norway

Country-based

698

18%

Male gender Urban residence Dutch and Surinamese nationality Long term residence in Netherlands Treatment failure Time spent working in mines Analysis not performed

Vancouver, Canada

Community-based

793

17%

Diel et al. 2002 (1997-1999)

Hamburg, Germany Community-based

423

34%

Lockman et al. 2001 (1997-1998)

Botswana

301

42%

Community-based

Canadian-born aboriginals Canadian-born non-aboriginals Injection drug users Alcohol abuse History of contact tracing Unemployment Imprisonment

66

K. DeRiemer and C. L. Daley

The proportion and rate of clustering has been interaction between years of residence in the United used as an indicator to assess the performance of States and HIV infection; tuberculosis among foreigntuberculosis control programs. In an evaluation of born persons was more likely to result from recent tuberculosis transmission over a seven-year period in transmission among those who were HIV-infected San Francisco, the number and proportion of clustered and more likely to result from the reactivation of tuberculosis cases declined, particularly among the LTBI among those who were not infected with HIV US-born population. This was attributed to the imple- (Geng et al. 2002). The investigators recommended mentation of targeted tuberculosis prevention and that tuberculosis prevention and control strategies control programs such as screening high-risk popu- need to be targeted to the large number of foreignlations and the implementation of directly observed born persons in New York City who have LTB!. therapy to ensure high cure rates (Jasmer et al. 1999). The factors associated with clustering may be A recent study in New York City showed that as tuber- complex. For example, in a study of South Africa gold culosis case rates fell from recent high levels, the pro- miners, tuberculosis patients who had failed treatportion of cases caused by clustered isolates (i.e., cases ment at entry to the study were more likely to be in of tuberculosis due to recent transmission) decreased. clusters (adjusted OR = 3.41,95% confidence interval The proportion of tuberculosis cases caused by recent CI 1.25-9.27), and patients with multidrug-resistant transmission dropped from 63.2% in 1993 to 31.4% in tuberculosis were more likely to have failed tuberculo1999 (Geng et al. 2002). They also reported that tuber- sis treatment but less likely to be clustered than those culosis was unlikely to result from recent transmission with a drug-susceptible strain (OR = 0.27, 95% CI in persons born outside the United States. By contrast, 0.09-0.83). HIV seropositivity was common (53.6%) an 8-year study in Greenland showed that the annual but was not associated with clustering. Apparently, incidence of tuberculosis increased from 85/100,000 persistently infectious individuals who had previously in 1990 to 172/100,000 in 1997 and the percentage of failed treatment were responsible for one third of the culture positive tuberculosis cases in RFLP clusters tuberculosis cases in this population. In addition, the increased to 85%, reflecting micro-epidemics among World Health Organization's targets of70% case detecadults and young children in small, isolated settle- tion and 85% cure (World Health Organization 2002) ments (Soborg et al. 2001). were not sufficient to interrupt tuberculosis transmisConventional epidemiological methods can be used sion; indicators that are more closely linked to the in combination with molecular typing techniques to rate of ongoing tuberculosis transmission, are needed identify the risk factors associated with recent infec- (Godfrey-Faussett et al. 2000). tion and rapid progression to disease (Table 5.1). Some of the risk factors that are associated with recent infection are specific to a particular community, 5.4.3 whereas others are common to tuberculosis patients Exogenous Reinfection with M. tuberculosis in different geographical areas. For example, young age, being in an ethnic minority group, homelessness, Molecular typing can determine whether a patient and substance use have been identified in more than with a recurrent episode of tuberculosis has a relapse one study as being associated with recent infection with the previous strain of M. tuberculosis or exog(Small et al. 1994; Alland et al. 1994; Friedman et al. enous reinfection with a new strain (Table 5.2). In one 1995b; Barnes et al.1997; van Deutekom et al.1997). In of the earliest studies using genotyping to examine San Francisco, for example, among persons less than reinfection, Godfrey-Faussett and colleagues reported 60 years of age, Hispanic ethnicity (odds ratio OR = that the IS6110 RFLP band patterns from patients in 3.3, P = 0.02), black race (OR = 2.3, P = 0.02), birth in Malawi were different in pairs of isolates from four the United States (OR=5.8, P <0.001) and a diagnosis patients. The isolates were from different body sites of acquired immune deficiency syndrome (OR = 1.8,P in two patients, and from different episodes in the = 0.04) were independently associated with being in a other patients (Godfrey-Fausset and Stoker 1992). Since then, several groups have shown that exogcluster (Small et al.1994). In a recent study in New York City (Geng et al. enous reinfection can occur in both immunocom2002), birth outside the United States, age of 60 years promised and immunocompetent persons. More or older, and diagnosis after 1993 were factors inde- recently, researchers have tried to quantify the rate pendently associated with having a unique strain, at which exogenous reinfection occurs and assess while homelessness was associated with clustering its potential impact on tuberculosis transmission or recent transmission. There was also a significant dynamics. In Cape Town, South Africa, where there

67

The Molecular Epidemiology of Tuberculosis

Table 5.2. The frequency of exogenous reinfection in selected studies. NA not available, HIV+ Seropositive for the human immunodeficiency virus (HIV), HIV- Seronegative for HIV, AIDS Acquired immune deficiency syndrome, TB Tuberculosis Study (period)

Study site

Study population

Small et aI. 1993a (1987-1991)

Kings County Hospital, New York City

6

0

Godfrey-Faussett et aI. 1994 (1989-1991) Das et aI. 1995

Nairobi, Kenya

AIDS patients with positive culture 17 for> 1 year or Increasing drug resistance 31 TB recurrences NA

11 5

4 (36%) 1 (20%)

Gilks et aI. 1997 (1989-1992) Sudre et aI. 1999 (1988-1996) Van Rie et aI. 1999 (1992-1998) Chaves et aI. 1999 (1993-1994)

Nairobi, Kenya

Recurrence or isolated positive culture HIV + and HIV- women

30 32 4

30 32 4

11 (37%) 29 (91%) 2 (50%)

Switzerland

HIV cohort with two isolates

20

20

2 (10%)

Cape Town, South Africa Madrid, Spain

Recurrent TB

48

16

12 (75%)

11

9

2 (22%)

Sonnenberg et aI. 2000 (1995) Lourenc;o et aI. 2000 (1990-1994) Caminero et aI. 2001 (1991-1996) Fitzpatrick et aI. 2002 Bandera et aI. 2001 (1995-1999)

Gauteng Province, South Africa Rio de Janeiro, Brazil

HIV infected Spanish inmates who remained culture positive for >4 months HIV + and HIV- gold miners

57

48

2 (4%)

12

12

3 (25%)

23

18

8 (44)

de Viedma et aI. 2002 (1988-1999) Kriiiiner et aI. 2002 (1994-1999)

Madras, India

Patients with two episodes of tuberculosis or two isolates

Patients Patients with with reinfection genotyping

Gran Canaria Island, Spain Kampala, Uganda;

HIV + patients with multiple isolates Two positive cultures> 12 months apart HIV + and HIV - TB recurrences

NA

40

9 (23)

Lombardy, Italy

Recurrent TB separated >6 months NA

32

5 (16)

Madrid, Spain

HIV + and HIV - cases with two isolates> 100 days apart Treatment failures

172

43

14 (33)

35

11

11 (100)

Tartu, Estonia

is a high incidence of tuberculosis and ongoing transmission, 16 of 698 patients had more than one episode of tuberculosis of whom 75% (12/16) had pairs of isolates of M. tuberculosis with different IS6110 -based genotyping patterns (van Rie et al. 1999). Episodes of tuberculosis reinfection in areas with a low incidence of tuberculosis, such as the Netherlands (de Boer and van Soolingen 2000), the Canary Islands (Caminero et al. 2001), and Northern Italy (Bandera et al. 2001), are uncommon compared with those in high-incidence regions. In the study in Northern Italy, a four-fold increased risk for reinfection was observed among immigrant patients compared with Italian subjects. In contrast, a higher risk of relapse rather than reinfection was evidenced in HIY-positive subjects and in patients infected with multidrug-resistant tuberculosis. A person can be simultaneously infected with more than one strain of M. tuberculosis. Multiple infections were demonstrated in a patient in San Francisco, California (Yeh et al. 1999), in two patients who worked in

a medical-waste processing plant in Washington State (Braden et al. 2001) and among prisoners in Spain (Chaves et al. 1999). These observations indicate that simultaneous infections with multiple strains of M. tuberculosis occur in immunocompetent hosts and may be responsible for conflicting drug-susceptibility results. Knowing whether mixed infection is occurring is important because the susceptibility patterns of the two strains may be different and different treatment regimens may be needed (Niemann et al. 2000). In addition, some cases of suspected exogenous reinfection may be due to initial infections that include more than one strain.

5.4.4 Geographical Distribution and Dissemination

of M. tuberculosis

Surveillance networks incorporating conventional and molecular epidemiologic techniques were estab-

68

lished during the 1990s by the Centers for Disease Control and Prevention (CDC) and the European community to track long-distance dissemination of tuberculosis and to help suggest rational tuberculosis prevention and control strategies to interrupt such transmission (Glynn et al. 1999a; Castro and Jaffe 2002; Crawford et al. 2002). Several of the strains identified in outbreaks have been associated with large clusters that are widely dispersed both geographically and temporally, possibly because they are either more transmissible or they are more likely to cause disease once transmitted than are other strains (Murray and Nardell 2002b). In an early comparison of the strains present in New York City and San Francisco, California, USA, the most widely prevalent strain of M. tuberculosis from New York City was isolated from only one of 755 patients in San Francisco-a traveling salesman (Casper et al. 1996). A comparison of the strains of M. tuberculosis from San Francisco and the East Bay, two distinct regions separated by the San Francisco Bay, only 53 of 724 (7.3%) had genotype patterns that matched at least one isolate from the other region. Of 375 isolates from San Francisco with unique band patterns, only nine (2.4%) matched patterns of East Bay isolates. These population-based data suggest that in the San Francisco Bay Area, M. tuberculosis does not rapidly spread across geographic boundaries and tuberculosis control should focus on transmission within defined areas (Bradford et al. 1998). The most widely reported example of the geographical dissemination of a particular strain of M. tuberculosis is that of the "Beijing" and "W strains" (Bifani et al. 2002; Glynn et al. 2002) A multidrugresistant strain of M. tuberculosis called the "Wstrain" caused many cases of tuberculosis and deaths attributable to tuberculosis among patients and healthcare workers in nosocomial outbreaks and in other institutional settings in New York City during the 1990s (Anonymous 1993; Bifani et at. 1996). This same strain was later found in other parts of the United States (Agerton et al. 1999). By the late1990s, the "w strain" was recognized as a member of the "Beijing family" of strains. A study performed in Beijing, China in 1995 reported that 85% of the isolates were strains with greater than 66% similarity among their IS6110 RFLP patterns (van Soolingen et al. 1995). This "Beijing family" of strains was also detected in high proportions among strains in other parts of Asia (Anh et al. 2000), the former Russian Federation (Kurepina et al. 2000), Estonia (Kriiiiner et al. 2001), Latin America (Diaz et al. 1998), and Europe (Niemann et al. 2000).

K. DeRiemer and C. 1. Daley

Beijing strains, including the "w strain" and its variants, have an insertion of IS611 0 in the genomic dnaA-dnaN locus (Kurepina et al. 1998). Based on several early technical studies and a review of 16 studies of the Beijing or W strains that gave results on their spoligotyping, the W family and Beijing family strains have an identical, characteristic spoligotype based on DNA polymorphism in the direct repeat region that only contain spacers 35-43 (van Soolingen et al. 1995; Bifani et al. 1999; Sola et al. 1999; Soini et al. 2000; van Crevel et al. 2001; Glynn et al. 2002). Because this family of strains is so widespread and is often drug-resistant, there is concern that these strains are biologically hyper-mutable, hyper-virulent, and have a predilection for acquiring drug resistance. But as of this writing, comparable data are not available for other, Widespread strains. There may be a link between geographic location and the number of IS6110 copies. In low incidence areas with a high proportion of tuberculosis cases attributable to reactivation of LTBI and immigration (e.g. the Netherlands, San Francisco, Switzerland, and Norway), the IS6110 RFLP patterns are highly polymorphic. But in some areas of Asia, a high proportion of the isolates of M. tuberculosis contain no copies or very few copies ofIS611O. Specific clones or families of clones may be predominant in a specific geographical area. For example, two distinct populations of isolates were detected in Guinea-Bissau, a former Portuguese colony, one West African and the other European (Kallenius et al.1999). In the western Pacific region, the isolates from eight countries could be divided into three groups based on the mode of the copy number (Park et al. 2000). In Tunisia, 62% of the isolates belong to three genotype families that share greater or equal to 65% similarity in the IS611 0 RFLP patterns and in Ethiopia, 52% of the isolates belong to four genotype families (Hermans et al. 1995). As noted in the studies described above, there can be significant geographic variation in IS611 O-based genotype patterns. Therefore, it will be important to evaluate the geographic variation in new typing systems to determine their utility in different regions and populations.

5.4.5 Evaluation of Laboratory Cross-contamination Although laboratory cross-contamination of M. tuberculosis isolates was demonstrated during the 1980s using bacteriophage typing (Jones 1988), genotyping has become the most widely used tool for determin-

The Molecular Epidemiology of Tuberculosis

69

ing whether or not laboratory cross-contamination sary, and potentially toxic treatment for the patient, and has occurred. Careless specimen processing, contami- increased costs and burdens for both patients and local nated reagents (de C Ramos et al.1999), and contami- health care providers (Burman et al.1997a; Burman and nation with H37Ra, an avirulent reference strain of M. Reeves 2000; Northrup et al. 2002). tuberculosis that is used for standardization of laboratory procedures, can cause laboratory cross-contamination. A small but important proportion of cases with laboratory cross-contamination were detected 5.5 in every institution that looked for it (Anonymous The Future of Molecular Epidemiology 2000a; Perfecto et al. 2000; Breese et al. 2001; Chang et al. 2001; Jasmer et al. 2002). As a result, some settings Molecular genotyping, in combination with convenroutinely use genotyping to evaluate specimens for tional epidemiologic investigations, will continue to be possible laboratory cross-contamination. used to detect laboratory contamination, to describe Early investigations focused on the isolates of disease outbreaks, and to identify previously unsusM. tuberculosis that were processed together in the pected chains and locations of tuberculosis transmislaboratory and had identical IS6110 RFLP patterns, sion in the community. In addition, molecular epidebut were from at least one otherwise asymptomatic miologic methods will continue to play an important patient (Small et al. 1993b; Dunlap et al. 1995). In role identifying appropriate public health intervenNew York City, an isolate was collected from every tions and measuring their impact. The development of patient with a positive culture for M. tuberculosis real-time amplification based genotyping techniques during a I-month period, including both incident will likely improve our ability to do effective, timely and prevalent cases, and IS61 10 RFLP analyses were contact and outbreak investigations. performed. Of the 441 patients, 3% had clinical, laboRecent sequencing of the genome of M. tuberratory, and RFLP evidence of falsely positive cultures culosis has demonstrated that the IS6110 element for M. tuberculosis (Frieden et al. 1996b). The geno- is not distributed at random in the genome of the typing of all M. tuberculosis isolates from a I-year tubercle bacillus (McHugh and Gillespie 1998). The period in a 700-bed urban hospital in Chicago, USA, insertion sequence, and thus the number of RFLP revealed only one possible instance of nosocomial bands, is significantly more likely to be present at transmission and five (2.7%) false-positive M. tuber- some positions than would be expected by chance culosis cultures from 183 patients (French et al.1998). alone. This may interfere with the epidemiological Among isolates collected prospectively over 5 years interpretation of relatedness of strains. Improved, from a municipal health department laboratory, four more precise molecular typing techniques based on percent (8/199) of the culture-positive patients were specific genomic phenomenon such as point mutations, polymorphisms, and deletions will likely to be identified as probable or definite false-positives. Laboratory cross-contamination should be sus- developed in the near future. pected when there is a single positive culture in a cliniCurrent molecular epidemiologic approaches will cally well patient with negative acid fast bacillus (AFB) soon intersect with developments in mycobactesmears and no other evidence of tuberculosis. If the iso- rial genomics and other disciplines in many excitlate was cultured within one week of another specimen ing ways. The availability of the complete genome and has an identical genotype pattern, then laboratory sequence of M. tuberculosis now makes it possible cross contamination is likely. Laboratory cross-contam- to use a variety of typing techniques that can help ination should also be suspected when there is a sudden distinguish between different species and clonal increase in culture positive isolates without an epidemi- groupings of strains with specific phenotypic charological or clinical explanation. Published studies have acteristics such as transmissibility, pathogenicity, used IS6110 RFLP typing, VNTR typing (Gascoyne- or resistance to antimicrobial agents. Genome-wide Binzi et al. 2001), or spoligotyping (Nivin et al. 2000) analyses using techniques such as microarrays for to detect and evaluate laboratory cross-contamination. gene expression profiling or the detection of genomic Regardless of the typing method used, investigations deletions can be used to evaluate specific strains and of possible cross-contamination are based on good to determine the genetic basis of important phenocommunication between the laboratory and clinicians. typic traits. As molecular typing techniques improve, When laboratory or inter-patient cross-contamination molecular epidemiology will become an increasing occurs, it can result in an incorrect diagnosis, unneces- important tool in the prevention and control of sary clinic visits and consultations, lengthy, unneces- tuberculosis, globally.

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6

Molecular Epidemiology of Mycobacterium bovis ROBIN A. SKUCE and SYDNEY D. NEILL

CONTENTS 6.1 6.2 6.3 6.4 6.5 6.6 6.7 6.8 6.9 6.10 6.11

Introduction 75 Bovine Tuberculosis 75 Epidemiology in Developed Countries 76 Epidemiology in Developing Countries 77 Epidemiological Typing 78 The Genetics of the M. tuberculosis Complex Bacteria 78 Strain Typing Methodology 79 Standardisation and Method Performance Evaluation 84 M. tuberculosis Molecular Epidemiology: Lessons Learned 85 M. bovis Molecular Epidemiology: Studies and Trends to Date 85 Conclusions 88 References 89

that includes farmed and feral animals, wildlife and also humans (O'Reilly and Daborn 1995). Its epidemiological pattern in developing and developed countries can be very complex. It is classified as a List B disease by the Office International des Epizootiques (OlE) and considered of socio-economic importance as well as public health significance, as it impacts significantly on the international trade of animals and animal products and hence locallivelihoods (Cousins 2001; Cousins and Roberts 2001).

6.2 Bovine Tuberculosis

Bovine tuberculosis is a chronic infection of animals, particularly cattle, and is caused by the tubercle bacillus Mycobacterium bovis. It is usually characterised by formation of nodular granulomas or tubercles, 6.1 particularly in the lungs and in the lymph nodes of Introduction the respiratory tract but lesions also may occur in In 1998 the World Health Organisation (Cosivi et al. the mesenteric lymph nodes, liver, spleen and other 1998) estimated that the incidence of human tuber- organs. Presentation of the disease is variable with culosis would be 88 million, resulting in 30 million an absence of clinical signs in less advanced infecdeaths for the period 1990-1999 and the majority tion, often the case in the majority of infected cattle of cases would be in developing countries. In these in developed countries with regular testing strategies countries, tuberculosis, caused by Mycobacterium (Neill 1994). It may also present non-specifically, with bovis, is present in animals. However, surveillance clinical signs such as weakness, anorexia, emaciation and control programmes for animal tuberculosis in and coughing in advanced cases. In most countries these countries are often inadequate or non-existent. diagnosis of tuberculosis in cattle is usually by tuberConsequently, the epidemiology of M. bovis in public culin skin testing, measuring delayed-type hypersensihealth issues remains largely unknown (Cosivi et al. tivity. However, in countries where prevalence of infec1998). M. bovis has an exceptionally broad host range tion is extremely low or freedom from infection has been declared, meat inspection alone is employed for diagnosis and surveillance. More recently, application of assays for bovine interferon-y has been employed R.A.SKUCE,BSc,PhD to indicate infection (Neill et al. 1994). Supporting Veterinary Sciences Division, Stoney Road, Stormont, Belfast, laboratory confirmation using bacteriological culture BT4 3SD, Northern Ireland techniques is also often employed. S. D. NEILL, BSc, PhD Bovine tuberculosis still can have serious, adverse, Veterinary Sciences Division, Department of Agriculture and financial consequences in agricultural regions of the Rural Development, Stoney Road, Stormont, Bellfast BT4 3SD, UK world (Bennett et al.1999; Cousins 2001; Cousins and M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

76

Roberts 2001; Goodchild and Clifton-Hadley 2001) and is considered a potential human health risk in some countries (Cosivi et al. 1998). Farmers incur financial losses from decreases in meat and milk production, carcass condemnations and restrictions on animal movement. Bovine tuberculosis presents a serious barrier to cattle trade within and between countries and there is considerable expenditure, usually by governments, on testing and compensation. Most European countries, through the introduction of voluntary and subsequently compulsory eradication programmes, experienced dramatic success in reducing the incidence of bovine tuberculosis. However, despite initial progress, eradication has not yet been achieved in all countries (European Commission Report 1998). Some European countries, e.g., the United Kingdom, have considerable regional variability with sporadic outbreaks, particularly in South-West England and Northern Ireland. Mycobacterium bovis infection in humans may result from ingestion of contaminated milk, inhalation via aerosols or through contact with infected clinical material. Pulmonary disease in humans, due to M. bovis is clinically, radiologically and pathologically indistinguishable from pulmonary tuberculosis caused by M. tuberculosis (O'Reilly and Daborn 1995). However, transmission of M. bovis from human to human is considered much less efficient than such transmission of M. tuberculosis (van Soolingen 2001). Evidence for transmission of M. bovis between humans is considered rare and largely anecdotal and equally rare are reports of humans infecting cattle (O'Reilly and Daborn 1995). Mycobacterium bovis tuberculosis was once common in children, affecting the cervical lymph nodes, the intestinal tract or the meninges, as a result of feeding infected cows milk. By 1937 up to 25% of tuberculosis cases in the USA and UK were due to M. bovis infections (Cousins 2001). The introduction of pasteurisation for milk and milk products, together with abattoir meat inspections significantly reduced this incidence and bovine tuberculosis in children is currently negligible. It was the recognition of the public health risk that prompted the introduction of control and eradication programmes for bovine tuberculosis in many countries in the early part of the last century (Cousins 2001). The success of such schemes has resulted in a low prevalence, or absence, of M. bovis infection in most national cattle herds, particularly in countries with advanced agriculture practices. This was reflected in a dramatic drop in the incidence of human tuberculosis due to M. bovis. However, the zoonotic nature of M. bovis still places

R. A. Skuce and S. D. Neill

farmers, abattoir workers and veterinarians at risk (Grange 2001).

6.3

Epidemiology in Developed Countries

In developed regions of the world, several countries have been unable to eradicate this disease, despite rigorously implementing comprehensive and costly strategies. The primary route of infection for cattle is respiratory but alimentary infection, cutaneous, congenital and genital routes have been recorded (Neill 1994). Social behaviour of cattle in an environment of intensive farming and a high degree of live cattle trade, together with the potential of M. bovis survival on pasture and inanimate objects contribute to exposure and facilitate subsequent spread of infection (Morris et al. 1994). Many countries, previously endemic for bovine tuberculosis, have now been declared tuberculosis-free, following intensive test and slaughter policies (Cousins and Roberts 2001). However, where there is interplay between infected wildlife and domestic animals, control has proven problematic. It is now evident that better understanding of this disease and its epidemiology is essential to overcome the impeded progress in some countries. Postulations on the residue of infection have included deficiencies in skin test specificity and sensitivity, poor cattle testing and the presence of reservoirs of M. bovis in cattle and wildlife. Traditional farming practices with significant cattle movement, intensive farming with high stocking densities and poor boundary fencing between farms allowing cattle 'nosing' between neighbouring farm herds have also been cited (Neill 1994; O'Reilly and Daborn 1995). In Ireland, inter-bovine spread of tuberculosis was identified as the single most important source of infection (Neill 1994).However,wildlife reservoirs are increasingly being considered a significant risk and responsible for protracted eradication programmes (Cheeseman et al. 1989; Livingstone 1992; Gallagher and Clifton-Hadley 2001). In the United Kingdom and Ireland, badgers (Meles meles) and feral deer (Cervus elaphus) are recognised wildlife reservoirs of M. bovis (Cheeseman et al. 1989; Hughes and Rogers 1994; Gallagher and Clifton-Hadley 2001). Badgers are indigenous and a protected species in the United Kingdom and Ireland with estimates in Great Britain of approximately 250,000 badgers, in Northern Ireland 30,000 (Hughes and Rogers 1994)

Molecular Epidemiology of Mycobacterium bovis

and 250,000 in the Republic of Ireland. The contribution of wildlife to tuberculosis in cattle in the United Kingdom and Ireland is not known precisely and this can be controversial with regard to the badger. One epidemiological study of risk factors for tuberculosis in dairy herds in Northern Ireland suggests that, although infected cattle may playa significant role in the transmission of tuberculosis, the importance of badgers may have been underestimated (Denny and Wilesmith 1999). In New Zealand, in marked contrast to Australia, tuberculosis in cattle is also exacerbated by a wildlife reservoir and maintenance host, the possum (Trichosurus vulpecula). Endemic infection in possums constitutes a major obstacle to disease control and eradication in some areas (Morris et al. 1994; de Lisle et al. 2001). Globally,M. bovis has been estimated to contribute 3.1 % of all human tuberculosis cases (2.1 % of pulmonary tuberculosis and 9.4% of extra-pulmonary tuberculosis) (Cosivi et al. 1998). In developed countries, such cases are now relatively rare and estimated at less than 1% of all tuberculosis cases, and are probably due to reactivation of dormant lesions amongst the elderly (Grange 2001). M. bovis has been isolated from HIV-infected individuals in some developed countries, with an additional serious complication of high primary resistance to isoniazid, streptomycin and pyrazinamide (Guerrero et al. 1997). Although M. bovis is thought to be less virulent and also less transmissible in humans than animals, human-to-human transmission of multi-drug resistant (MDR) M. bovis strains, over a relatively short interval, was demonstrated in Paris. HIV-induced immunosuppression may lower host immune responses and lead to overt disease more rapidly than under normal conditions. The true incidence of M. bovis infection in humans appears to be underreported, probably owing to the similar clinical presentation to M. tuberculosis infection but also to the fact that many diagnostic laboratories often would not have differentiated M. tuberculosis and M. bovis isolates.

6.4 Epidemiology in Developing Countries On the whole, there is very limited epidemiological information on bovine tuberculosis in cattle in the developing world (Cosivi et al.1998). Most cattle are in regions where no formal control measures are applied and implementation of a recognisable testand-slaughter policy would be considered excep-

77

tional. Information on M. bovis prevalence in other species is also very limited. In a study of 56 African countries, 33 provided information about M. bovis infection in animals. However, few reported M. bovis infection in humans (Kazwala et al. 2001a,b). The M. bovis cases reported in some developing countries may just be the tip of the iceberg, as, for example in Tanzania, medical authorities do not recognise M. bovis as a risk to human health. There has also been a lack of interest amongst medical practitioners and microbiologists in requesting speciation after primary isolation of mycobacteria from patients. In many developing countries there is little or no pasteurisation of milk or milk products and many people live a pastoral lifestyle, in close contact with their cattle, with resultant exposure to tuberculosis where present. Milk-borne infection is the main cause of non-pulmonary tuberculosis in areas where bovine tuberculosis is common and uncontrolled (Daborn et al. 1996). In Africa, approximately 85% of cattle and 82% of humans live in areas where bovine tuberculosis is only partially controlled (Cosivi et al. 1998). Approximately 90% of the total milk produced in Africa is consumed fresh or soured. Therefore, the consumption of unpasteurised milk, contaminated by M. bovis, is a likely route of zoonotic tuberculosis transmission to humans. In the remaining regions of these countries, control programmes operate only partially. It is evident that in Africa, Asia and Latin America/ Caribbean, significant human populations work in close physical contact with animals, and therefore zoonotic tuberculosis represents a significant, but in reality, unquantified risk. The global HIV epidemic adds a further complication. Tuberculosis is a major opportunistic infection, if not the most common infection, for HIV-infected individuals, the majority of whom live in developing countries. In those countries in which M. bovis infection is present in animals and where favourable conditions exist for zoonotic transmission, zoonotic tuberculosis is a serious public health threat. Zoonotic tuberculosis in HIV-positive individuals also resembles M. tuberculosis infection. WHO estimate that 70% of people (6.6 million) co-infected with tuberculosis and HIV live in sub-Saharan Africa (Cosivi et al.1998). In African countries, M. bovis infects a higher proportion of exotic dairy breeds (Bos taurus) than crossbred beef cattle and indigenous zebu cattle (Bos indicus) (Cosivi et al. 1998). In intensive conditions, a death rate from tuberculosis of up to 60% in zebu cattle has been recorded, with animal crowding con-

78

tributing to disease transmission. Tuberculosis control and eradication strategies, although understood, are inconsistently applied and usually not sustained in developing countries, largely due to lack of finance and trained professionals. Therefore there is obviously an increased likelihood of underestimation of zoonotic tuberculosis, the full economic implications of which is often overlooked.

R. A. Skuce and S. D. Neill

6.6 The Genetics of the Mycobacterium tuberculosis Complex Bacteria

The M. tuberculosis complex (Rastogi et al. 2001) comprises M. tuberculosis, M. africanum, M. bovis, M. microti and M. bovis BCG (Behr 2001), as well as newly characterised bacteria M. canetti (van Soolingen et al. 1997b) and M. caprae (Aranaz et al. 1999). Isolates with characteristics intermediate between M. tuberculosis and M. bovis have also been reported (Kallenius et al. 1999). The bacteria in the 6.5 Epidemiological Typing complex are usually regarded as subspecies and are characteristically 99.9% similar at the nucleotide Advances in molecular technologies have enabled level, with identical16S rRNA sequences (Brosch et specific identification and subsequent recognition al. 2002). However, there are distinct phenotypic difof strains of many pathogens involved in animal and ferences between the 'subspecies', not least their host human infections (van Belkum et al. 2001; van Belkum range and pathogenicity. M. bovis has the largest host 2002). 'Molecular epidemiology' is the integration of range within the M. tuberculosis complex, infecting these techniques with conventional epidemiological many mammalian species, including man (O'Reilly approaches for understanding better disease distri- and Daborn 1995), whereas M. tuberculosis is almost bution in populations (Small and van Embden 1994). exclusively a human pathogen. The M. tuberculosis complex genome sequencing Such studies are often designed to allow inference of patterns of disease transmission from similarities projects represent significant landmarks (Cole et al. between genetic patterns generated for infectious 1998). The sequencing projects,M. tuberculosis strain pathogens (Salamon et al. 2000). Using such genetic H37Rv and M. bovis strain AF2122/97 at the Sanger marker-assisted molecular epidemiology, it is now Centre (http://www.sanger.ac.uk. Cambridge, UK) possible to differentiate reproducibly between strains and M. tuberculosis strain CSU93 at The Institute of micro-organisms and to show spatial and temporal for Genome Research (http://www.tigr.org) have aspects of transmission, for example, between ani- provided a hugely valuable research resource and a mals. Epidemiological typing systems are generally unique insight into the biology of these major pathoused to study population dynamics and the spread gens. This should lead to major advances in diagnosof bacteria that undergo clonal reproduction both in tic, vaccination and chemotherapeutic options. The nature and in the clinical setting and often include M. tuberculosis H37Rv genome is relatively large for studies in bacterial population genetics and patho- an obligate pathogen, reflecting the complex biogenesis, providing 'early warning' through local, chemistry of its intracellular lifestyle and providing regional or national surveillance and in outbreak an insight into its origins. The genome is GC rich and it contains several different mobile genetic elements, investigations (Streulens 1996). Typing systems are applied primarily to assist epi- such as insertion sequences and prophages, as well demiological studies and in generating hypotheses as different classes of repetitive DNA (Gordon et al. 2001). about: Until very recently it was thought that M. tuber• the extent of epidemic spread of microbial culosis evolved from M. bovis, by adaptation of an clone(s) in an exposed population; • the number of clones involved in transmission animal pathogen to the human host. Recent studies have provided compelling genetic evidence to sugand infection; gest that the members of the M. tuberculosis complex it the identity of the source(s) of contamination and shared a common ancestor, which was likely to have vehicles of transmission; • the identification and monitoring of reservoirs of resembled M. tuberculosis or M. canetti and was epidemic clone(s) in the population and/or the probably already a human pathogen (Brosch et al. 2002). Comparative genomics has shown that the environment; M. bovis genome is smaller than M. tuberculosis, G the evaluation of the efficacy of control measures aimed at containing or interrupting the spread of which is intriguing due to its wider host range. This comparative approach has also identified a series of epidemic clone(s).

Molecular Epidemiology of Mycobacterium bovis

insertion and deletion events between members of the complex (Gordon et al. 1999a), whose distribution points to a common ancestor and has been used to derive an entirely new evolutionary scenario. M. bovis now appears to be the final member of a separate lineage that branched from the progenitor of M. tuberculosis and is represented by M. africanum, M. microti and M. bovis isolates having undergone successive loss of DNA segments. This may have contributed to clonal expansion and the selection of more successful pathogens in some hosts. This new data is inconsistent with the view that the proposed M. africanum - M. microti - M. bovis lineage could have spread and adapted to their wide host range within the suggested 15,000-20,000 years of speciation of the M. tuberculosis complex.

6.7

Strain Typing Methodology Phenotypic procedures based on physiological or biochemical characteristics and antibiotic susceptibility are often capable of discriminating between strains of micro-organism. However, this has not been the case for the M. tuberculosis complex (Saunders 1995) and in 1965 a WHO working group was established to facilitate development and standardisation of methods for typing mycobacteria. Phage susceptibility typing rapidly became a valuable epidemiological tool, which yielded data that contributed to the understanding of tuberculosis transmission and pathogenesis and provided the basis for current approaches to human tuberculosis control. However, the method is relatively crude and much greater discrimination can be achieved using molecular methods, which now supersede phage typing. The molecular epidemiology of M. tuberculosis in humans is much more advanced than that of M. bovis in cattle, largely because a robust and standardised strain typing method has been applied widely (van Soolingen 2001). Most M. bovis isolates are not amenable to this technique. Therefore, alternative methods have had to be developed and evaluated. The availability of genome sequences has led to the development of a generation of new molecular markers, which have the potential to offer high-resolution genotyping and high-throughput analysis. Collins and colleagues at AgResearch, Wallaceville, New Zealand pioneered bacterial DNA restriction enzyme fragment analysis, or restriction enzyme analysis (REA), as the earliest typing method applied

79

successfully to the organisms of the M. tuberculosis complex (Collins and de Lisle 1984, 1985). In REA, DNA extracted from batch cultures, using detergent and protease digestion followed by solvent extraction, is digested with each of three restriction enzymes (BstEII, Pvull and Bell), prior to electrophoretic separation (Fig. 6.1). Ethidium bromide staining of DNA fragments generates a complex DNA banding pattern, similar to a bar-code fingerprint, with observable differences in the fragment pattern, especially in the higher molecular weight fragments. This produced a highly discriminating typing system for the M. tuberculosis complex, most notably for M. bovis. Approximately 2000 M. bovis isolates have been REA typed over the last 20 years, and more than 165 stable REA types have been identified (Collins 1998). However, the REA technique is not widely used, due to difficulties in accurately reproducing the complex fingerprint patterns and in naming, recording and databasing them. It is a relatively cumbersome technique and technology transfer and inter-laboratory comparisons have proven particularly difficult. A logical modification of the REA technique is pulsed field gel electrophoresis (PFGE), where rare-cutting restriction enzymes are used to digest genomic DNA immobilised in agarose blocks (Hughes et al. 2001). The resulting large DNA fragments are then separated by electrophoresis in a dedicated apparatus (PFGE Fig.6.1). The smaller number of larger DNA fragments generated significantly simplifies the electrophoretic patterns produced, although the discrimination is considerably less than with REA. PFGE of M. bovis isolates has produced moderate discrimination and has been useful in epidemiological studies (Feizabadi et al. 1996). Significant improvements have been made recently to the culture and preparation of samples for PFGE and this should allow better evaluation of method performance (Hughes et al. 2001). Researchers have also exploited the finding ofrepetitive DNA (Tanaka et al. 2000) within the genomes of M. tuberculosis complex bacteria to develop an array of genotyping techniques, based either on DNA amplification using the PCR or Southern blotting, or a combination of the two. There are basically two types of repetitive DNA in bacterial genomes: dispersed repeats and tandem repeats. The former can include mobile genetic elements, including insertion sequences (ISs) and prophages (Gordon et al. 1999b). M. tuberculosis H37Rv contains 56 such IS elements, belonging to well-defined families. Mobile genetic elements contribute significantly to genetic diversity. Whilst most of these ISs are located in the same genome position

80

R. A. Skuce and S. D. Neill

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Fig.6.1. Schematic representation of the main restriction enzyme digestbased genotyping methods applicable to the M. tuberculosis complex. Actual gel images for M. bovis field isolates are shown for PFGEl, REA2 and RFLP. (PFGE gel reproduced with permission from VM Hughes. REA gel reproduced with permission from DM Collins. PFLP gel images reproduced with permission from M Rogers)

(Heersma et al.1998). The strain typing of M. tuberculosis isolates by IS611O-RFLP is now an internationally accepted part of standard control policies, a tool for detecting point source outbreaks and a method for monitoring the efficacy of human tuberculosis control programmes (van Soolingen 2001). Unfortunately, for M. bovis isolates, the IS6110 copy number is much lower, often occurring singly, especially in isolates from cattle (Collins et al. 1993; Skuce et al. 1996; Cousins et al. 1998b). Interestingly, however, the IS6110 copy number is often higher in M. bovis strains isolated from more 'exotic' animal species (van Soolingen et al. 1994). Therefore additional probes are often required to improve discrimination for low IS611 0 copy number strains. One such probe is the 'polymorphic GC-rich repeat' sequence

Molecular Epidemiology of Mycobacterium bovis

(PGRS), which is found in multiple copies within the genomes of M. tuberculosis complex mycobacteria, although it is not considered complex-specific, unlike IS611O. PGRS-RFLP, using the 'Doran repeat' oligonucleotide probe (Doran et al.1993) to hybridise to AluI-digested genomic DNA, produces relatively complex patterns. Most of the visible band differences are in the higher molecular weight fragments. The M. tuberculosis complex specific Direct Repeat (DR) locus (see below) can also be used as a probe in RFLP analysis (Groenen et al. 1993). DR-RFLP, using a DR oligonucleotide probe to hybridise Aluldigested genomic DNA produces a relatively simple banding pattern. Several studies have used the combined results of IS6110-RFLP, PGRS-RFLP and DRRFLP to produce an overall RFLP typing scheme (Skuce et al. 1996; Costello et al. 1999). Genomic libraries have revealed promising new probes for RFLP analysis, such as pUCD (O'Brien et al. 2000a,b). A bioinformatics search shows that pUCD contains several polymorphic loci, some of which have been found by other investigators using entirely different approaches (Supply et al. 2000). It is widely accepted that the RFLP techniques, although highly discriminating, are again relatively cumbersome, inconvenient and not amenable to high throughput genotyping and inter-laboratory comparisons. Hence, effort has been directed at exploiting the various classes of DNA repeat using DNA amplification procedures. For example, the spacer-oligotyping technique, (spoligotyping) (Kamerbeek et al. 1997) uses the PCR to amplify a region of DNA, the socalled Direct Repeat or DR region, the arrangement and sequence of which is highly specific to members of the M. tuberculosis complex (Fig. 6.2). The order of these spacer sequences is remarkably well conserved, so much so that a phylogeny and common ancestor to the M. tuberculosis complex bacteria can be inferred, with a much larger DR locus containing many more spacer sequences than is presently seen in modern members of the complex (van der Zanden et al. 2002). The DR locus belongs to a recently identified class of repeat sequences found in bacteria, known as 'spacer interspersed direct repeats' (SPIDRs) or 'clustered regularly interspaced short palindromic repeats' (CRISPRs), which are reminiscent of centromere-like structures with a possible role in replication partitioning. CRISPR-mediated variation may provide a bacterial population with the diversity required to be adaptable in changing environments. The DR locus is comprised of multiple 36 bp direct repeats interspersed by non-repetitive 34-41 bp DNA spacer sequences. Spoligotyping involves amplification of the

81

entire CRISPR locus using the DR as a target for PCR, followed by hybridisation of the amplified DNA to a set of spacer oligonucleotides derived from M. tuberculosis and M. bovis BCG strain P3. This reverse-cross blot hybridisation (Kaufhold et al. 1994) records the presence, or absence, of spacer DNA sequences and produces a simple digital pattern, which is readily named and databased. Spoligotyping is particularly attractive because the patterns generated may be a presumptive indicator of the M. tuberculosis complex species amplified. For example, M. bovis isolates generally lack spacers 39-43 inclusive, as well as spacers 6,9 and 16 (van Soolingen 200l). Spoligotype patterns are also useful for identifying M. microti (van Soolingen et al. 1998) and have proved extremely valuable for typing some emerging epidemic strains, such as M. tuberculosis WBeijing (Glynn et al. 2002). Differences in spoligotypes are due to deletions of DRs in the CRISPR locus,mediated by transposition ofIS611O, homologous recombination or replication slippage. Strain-specific differences in spoligotype are the result of a sequential loss of single spacers or blocks of contiguous spacers within the CRISPR locus. It has been possible, therefore, to infer a sequence of genetic events separating M. bovis of different spoligotypes. It appears that ST140 is a recent progenitor of several different M. bovis spoligotypes, all of which are represented in current field isolates. The molecular clock for the CRISPR locus appears to be very slow. For example, all M. bovis BCG daughter strains share the same spoligotype, a spoligotype still seen in French M. bovis field strains (Haddad et al. 2001). Current phylogenetic clustering tools consider the gain and loss of individual or contiguous spacers as an equal event. Due to the proposed mechanism of CRISPR evolution, this may misrepresent the relationship between strains. Spoligotyping is relatively easy to perform and can be used to detect and type M. tuberculosis complex bacteria directly in a range of clinical samples (Kamerbeek et al. 1997). However, a major problem with the current configuration of spoligotyping is its relatively limited discriminatory power. Even for M. bovis isolates, spoligotyping is only moderately discriminating, compared to REA and RFLP techniques (Aranaz et al. 1996; Cousins et al. 1998a). More extensive sequencing of M. tuberculosis complex isolates has disclosed additional spacer sequences (van Embden et al. 2000; Caimi et al. 200l), which have been incorporated into the second generation spoligotyping technique. The discrimination and reproducibility of spoligotyping using these new spacer sequences is currently being evaluated on

82

R. A. Skuce and S. D. Neill

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representative panels of M. tuberculosis complex bacteria (van der Zanden et al. 2002). Attempts have also been made to unify and simplify spoligotype pattern nomenclature in order to facilitate inter-laboratory studies of the transmission of strains between and within different countries (Dale et al. 2000) and relatively large databases of spoligotypes are being curated (Sola et al. 2000, 2001). Genomics and bioinformatics have revealed several different classes of repetitive DNA within the genomes of M. tuberculosis H37Rv and M. bovis AF2122/97, which can now be exploited to develop convenient and

discriminating strain typing tools (Brosch et al. 2000). Many tuberculosis genes were shown to be comprised of tandem repeats. The Tandem Repeats Finder software programme (Benson 1999) has been used to predict a number of repeats varying from 9-351 bp. Fifty-three PE_PGRS genes, 27 PPE proteins and 59 unrelated proteins contained such tandem repeats. This could represent a major source of genetic diversity and antige'lic v?riation in a pathogen with a striking lack of neutral, single nucleotide polymorphisms in key house-keeping genes and antigens (Sreevatsan t al. 1997; Musser et al. 2000). One such class of repeat,

Molecular Epidemiology of Mycobacterium bovis

83

which is generating considerable interest at present, was described, although clinical isolates were not is the so-called mycobacterial interspersed repetitive characterised in the study. Analysis of larger numbers unit (MIRU) (Supply et al. 2000). MIRUs range in size of M. tuberculosis complex bacteria allowed the comfrom 46-101 bp and fall into three classes depending pilation of allele naming tables, which form the basis on their length, sequence and organisation. MIRUs of the intuitive MIRU-VNTR nomenclature. Further, occur in 41 loci, mostly intergenic, in M. tuberculosis novel VNTR-type loci have been described recently in H37Rv. Most MIRUs contain an ORF and could poten- the M. tuberculosis H37Rv genome (Skuce et al. 2002) tially encode small peptides. MIRUs often occur as and were evaluated on a reference panel of M. bovis tandem repeats and can be exploited as strain typing isolates compared to existing VNTRs (Frothingham targets. Specific PCR primers are designed to flank and Meeker-O'Connell 1998) and spoligotyping data. such loci and PCR products consequently differ in size Different VNTR-PCRs had different discriminatory capacity and combining VNTR-PCRs produced a relative to the tandem repeat copy number (Fig. 6.3). Other loci, equivalent to MIRUs, known as variable more discriminatory technique. The majority of novel number of tandem repeat loci (VNTR), have also been VNTRs were located within ORFs including several described (Frothingham and Meeker-O'Connell 1998). representatives of the PPE protein family. For examThese MIRU-VNTR loci resemble eukaryotic mini- ple, there were 29 allelic variants of the PPE protein satellite loci, being comprised of tandem repeat units Rv1917c in the test panel of 100 M. bovis isolates. of varying size and copy number (Supply et al. 1997; Further, novel MIRU-VNTR loci have been Frothingham and Meeker-O'Connell 1998; Magdalena subsequently identified in M. tuberculosis genome et al. 1998a,b). Systematic bioinformatic searches of sequences (Roring et al. 2002). Again, their perforavailable genome sequence databases have disclosed mance has been systematically evaluated on a test more such loci within the M. tuberculosis complex panel of M. tuberculosis complex isolates, leading mycobacteria (Smittipat and Palittapongarnpim 2000) to the recommendation that MIRU-VNTR loci be and a simple scheme for naming the MIRU-VNTR loci selected, for genotyping studies, based on their proven

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---IIQUB11a

13451 QUB3232

Fig. 6.3. Schematic representation of PCR-based MIRU-VNTR genotyping of M. tuberculosis complex isolates. a Representation of tandem repeat copy number variation between four hypothetical strains at one MIRV-VNTR locus and sizing of PCR products to deduce copy number. b Hypothetical MIRU-VNTR profiles derived for four strains at five loci. c Gel images for the same six M. bovis field isolates MIRUVNTR typed at three loci (ETR-A, QUBI la and QVB3232)

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performance with a representative test panel of isolates and not just on the convenience of using predetermined sets of markers. For example, the 12 MIRU panel is at least as discriminatory as IS611O-RFLP for M. tuberculosis isolates (Mazars et a1. 2001). However, not all the MIRU loci are informative with the M. bovis isolates comprising the test panel (Roring et a1. 2002). There are now upwards of 30 MIRU-VNTR loci described within the M. tuberculosis complex. Their discriminatory ability will depend on the test panel used. The reproducibility of the MIRU-VNTR PCRs and allele naming is exceptionally high. These MIRU-VNTR loci detect differences between M. bovis BCG daughter strains, entirely consistent with the proposed genealogy (Magdelena et al. 1998a; Behr 2000; Roring et a1. 2002). A major future objective will be to determine the pace of change for each of these loci and to match their properties to specific epidemiological studies. It can be envisaged that a panel of MIRU-VNTR loci, with varying molecular clock speeds, will be used in future epidemiological studies of the M. tuberculosis complex mycobacteria. These MIRU-VNTR loci have many of the most desirable features required to progress rapidly the molecular epidemiology of the M. tuberculosis complex. Several other PCR-based techniques have been developed, based on amplification of DNA fragments between repetitive DNA elements. Some difficulties have been experienced with the reproducibility of such methods on inter-laboratory evaluation (Kremer et a1. 1999).

6.8 Standardisation and Method Performance Evaluation In order that strain-typing results are directly comparable between laboratories, it is important that standard procedures and analyses are performed. Novel strain typing methods are often applied without critical evaluation of their performance characteristics. They often lack standardisation in technical procedures, reference materials and quality assurance, as well as in the criteria used for the interpretation of results. Basic terminology is sometimes used ambiguously by different investigators, compounding the confusion created by variations in methodology (Struelens 1996). Consequently, progress towards performance comparison, or standardisation, has only been achieved for a limited number of bacterial and fungal pathogens (Struelens 1996).

R. A. Skuce and S. D. Neill

Different techniques will have different performance characteristics, e.g. discrimination, reproducibility, epidemiological concordance etc. (see Struelens 1996 for definitions). The most discriminating and the least practical strain-typing technique would be to produce the entire nucleotide sequence for every isolate. Several investigators have recognised the need for a unified approach to the strain typing of members of the M. tuberculosis complex mycobacteria and M. bovis in particular (Kremer et a1. 1999). This would comprise standardisation of procedures, reagents, reference strains, image analysis and nomenclature. Under the auspices of the International Union Against Tuberculosis and Lung Disease (IUATLD), one such study (Cousins et a1. 1998a) recommended IS611O-RFLP to define the copy number in the test population and that IS611O-RFLP was usually adequate for M. bovis strains possessing more than three copies of IS6110. For strains with less than three copies of IS6110, additional typing was often warranted and PGRS-RFLP was the method of choice. Spoligotyping was recommended to replace DR-RFLP for additional typing. The DNA typing of M. bovis specifically was also considered by a multi-centre evaluation of method performance (Skuce et a1. 1998). The candidate methods of IS6110-RFLP, PGRS-RFLP, DR-RFLP, PFGE, spoligotyping, ampliprinting and VNTR typing (Frothingham and Meeker-O'Connell 1998) were evaluated. Methods were optimised by working groups and standard protocols were developed, which detailed procedures, reference strains and reagents, as well as making recommendations for appropriate nomenclature schemes and databasing. The optimised methods were applied to a coded test population of M. bovis isolates and the various performance criteria evaluated were: typability, reproducibility, discrimination, concordance and convenience (Struelens 1996). Methods differed in their performance characteristics. For example, the combined IS611O, PGRS, DR-RFLP approach was found to be highly discriminating and, with care, was adequately reproducible. However, it was by far the least convenient. Spoligotyping was highly reproducible and convenient, but only moderately discriminating in its current configuration with this reference panel. Spoligotyping was recommended as a relatively simple and highly reproducible screening method with moderate discrimination and high concordance. Where further discrimination is required the highly reproducible, convenient and concordant VNTR technique (Frothingham and MeekerO'Connell 1998), or the RFLP and PFGE methods

Molecular Epidemiology of Mycobacterium bovis

were recommended. Further development and evaluation was merited for several methods, most notably the variations on VNTR typing, especially with the imminent release of the genome sequence for the M. bovis isolate AF2122/97. In another study, the discriminatory power and reproducibility of the main candidate DNA fingerprinting methods was assessed recently for M. tuberculosis complex bacteria, including a small number of M. bovis isolates (Kremer et al. 1999). Again the various RFLP-based methods, using IS611 0, IS1081, PGRS, DR and (GTGh as probes were found to be reproducible, although not very convenient. The PCR-based methods of spoligotyping, VNTR typing (Frothingham and Meeker-O'Connell 1998) and mixed-linker PCR were found to be highly reproducible. Subsequently, semi-automated versions ofVNTR-typing (Hughes et al. 2000) and MIRU-typing (Mazars et al. 2001) were developed and have been applied to the same test panel. They were found to be highly reproducible and discriminatory, with MIRU-typing as discriminating as the accepted standard IS611O-RFLP method. Additionally, IS611O-RFLP and MIRU-typing clustered the test panel isolates in a highly concordant manner, making MIRU-typing and possible developments thereof, an exciting, convenient and portable new tool with which to tackle molecular epidemiology of the M. tuberculosis complex. It is anticipated that the best DNA fingerprinting technique will be that which is based on genetic events occurring in synchrony with the time scale of the epidemiological situation. Thus, different epidemiological questions will be best addressed by different techniques. If the genetic events are occurring considerably faster than the epidemiological events, epidemiologically related strains will appear to be unrelated, whereas if the genetic events are occurring more slowly than the epidemiological events, then unrelated strains will appear to be related. A major future challenge of DNA fingerprinting of M. tuberculosis complex bacteria will be to determine the paces of change of the various markers and to match these to study specific epidemiological questions.

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(Kulaga et al. 2002). Epidemiological studies have generally relied on demonstrating plausible opportunities for infection in order to infer transmission. Strain typing of M. tuberculosis isolates by IS611ORFLP analysis is now well developed (van Soolingen 2001) and is being integrated into control policies, as a tool for detecting point source outbreaks and for monitoring the efficacy of tuberculosis control programmes (Small et al. 1994; Alland et al. 1994; van Soolingen et al. 1997aj Bauer et al. 1998). An internationally accepted standard procedure (van Embden et al. 1993) has been devised to facilitate inter-laboratory comparisons (van Embden et al. 1996; Heersma et al. 1998). For M. tuberculosis, strain typing is becoming a standard tool of public health investigators. If there is sufficient genetic diversity in a population, finding a group with the same, or highly related, pattern (cluster) infers epidemiological association, where individuals are either infected from each other or from a common source. Such cluster analysis must be interpreted with caution, especially where the survey has not been sufficiently comprehensive (Glynn et al. 1999a,b). Strain typing has been used to identify clonal transmission, e.g. between neighbours and within prisons, bars, clinics and hospitals. It has also been used to identify epidemiologically unsuspected transmission within groups, or unsuspected ongoing transmission in certain segments of the population, where risk factors, environments and common sources were missed by conventional contact tracing (van HeIden 1998). IS611O-RFLP has surprisingly and repeatedly demonstrated that tuberculosis transmission can occur without close personal contact (Kline et al. 1995). Prompt recognition of such events has helped to arrest such micro-epidemics. Strain typing has also played a role in identifying problematic procedures and laboratory cross-contamination in reference laboratories, where isolation of the organism is often the only basis for diagnosis and intervention.

6.10

Mycobacterium bovis Molecular

6.9

Mycobacterium tuberculosis Molecular Epidemiology: Lessons Learned

The ability to identify transmission events accurately and to intervene in order to prevent further spread is critical in effective tuberculosis control programmes

Epidemiology: Studies and Trends to Date

The REA technique has been used in several epidemiological studies, most notably in New Zealand (Collins 1998). It has provided a new insight into disease dynamics, demonstrating clustering of REA types in defined geographical areas of New Zealand. Possums, other wildlife and farmed animals in the

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same area were often infected with the same REA type (Collins et al. 1986, 1988, 1994). REA typing was used to include or exclude possible sources of infection in specific herds and it has clearly demonstrated whether infection in a farmed animal has come from the infected local wildlife reservoir or from infected cattle or deer brought onto those premises (de Lisle et al. 1995). REA data has been used to influence the level of herd testing or wildlife control in specific areas, e.g. REA and IS6110-RFLP were used to study the M. bovis strain types present in the MacKenzie basin in the South Island of New Zealand, a region that had been free of bovine tuberculosis prior to 1980. The identification of two main groups led to the suggestion that infection was introduced from two distinct, as yet unidentified, sources. Strain typing has, therefore, contributed to determining the extent and spread of infected wildlife in defined areas (de Lisle et al. 1995; Collins et al. 1999) and is now considered an integral component in local bovine tuberculosis control schemes (Collins 1998). Restriction enzyme analysis (REA) was used to type M. bovis isolates from a longitudinal field study of endemically infected possum, cattle, feral pigs and feral ferrets sharing the same habitat (Pfeiffer et al. 1994). A Geographical Information System (GIS) was used to manage the data, which was mapped on a terrain model of the study area. Statistical analysis was used to display the association between such variables as REA type, sex, age, season of detection and terrain covered. Four REA types were described, with two major types each dominating at different times. The same major types were evident in cattle when dominant in possums. Some important inferences regarding potential transmission routes for the wild possum population were possible. Shared REA types between mother and young identified pseudovertical transmission as an effective transmission route. Two successive, major cycles of transmission, showing only limited spatial overlap, were described within the possum population. REA was also used to infer that infected possum, not environmental survival of M. bovis, were responsible for reintroducing tuberculosis to an area following extensive possum depopulation (Corner et al., unpublished). Strain typing has also been used in a targeted fashion to show that domestic cats were usually infected with the same REA types as predominant in other local animal species and that they posed an unsuspected zoonotic risk (de Lisle et al. 1990). The application of molecular epidemiology to bovine tuberculosis is most advanced in New Zealand. However, several other countries have initiated stud-

R. A. Skuce and S. D. Neill

ies on methodology and preliminary epidemiological investigations (Collins 1998; Durr et al. 2000a,b; Skuce and Neill 2001). Despite some similarities, the epidemiology of bovine tuberculosis in other countries may well be very different from the New Zealand situation. For example, in Northern Ireland investigators have favoured the RFLP and spoligotyping techniques to disclose a surprisingly large number of M. bovis strain types in a panel of isolates from different animal species and from different geographical and temporal origins (Skuce et al. 1996; Roring et al. 1998). The RFLP types and spoligotypes identified did not appear to be host restricted, being isolated from cattle, badgers, deer and humans. One strain was over-represented in the panel of isolates, making up approximately 45% of RFLP types and approximately 70% of spoligotypes. Clonal expansion of such a strain is indicative of'success' and this strain is likely to be host-adapted to cattle, although not host-restricted. As with possum and cattle isolates in New Zealand, badger and cattle isolates in Ireland (Costello et al.1999) from the same locality or premises often share the same strain type, suggesting that a common pool of M. bovis strains is circulating between domesticated, wild and feral animals. Without more precise epidemiological data and statistically valid experimental design it is not possible yet to demonstrate, or quantify, the relative extent, if any, of transmission between cattle and wildlife, and vice versa. Mycobacterium bovis genotyping, using spoligotyping, has also shown that, in a significant number of herds for which M. bovis isolates are available for individual animals, multiple spoligotypes exist within an outbreak, usually one predominant spoligotype plus a few isolates of different spoligotypes (Skuce et al. 1996). This suggests that either the DR locus is not sufficiently stable within an outbreak or that such bovine tuberculosis outbreaks are due to multiple sources and that some types may be more transmissible than others. The balance of evidence suggests that such outbreaks are the result of infection from multiple sources, a phenomenon which may be under-reported due to the predominance of some spoligotypes, e.g. ST140. In a spoligotyping study of more than 600 M. bovis isolates in Northern Ireland, ST140 accounted for 70% of isolates, with ST263 accounting for a further 20%. The remaining five spoligotypes accounted for the remaining 10% of isolates (Skuce et al., unpublished). The clonal expansion of M. bovis isolates with the ST140 genotype is indicative of success. It may be speculated that ST140 spoligotype M. bovis possess some selective advantage.

Molecular Epidemiology of Mycobacterium bovis

IS611O-RFLP, PGRS-RFLP, DR-RFLP and spoligotyping were evaluated on a panel of 452 M. bovis isolates recovered from cattle, deer, pigs, sheep and goat in the Republic of Ireland (Costello et al. 1999). RFLP identified 85 strains with one type, the same type as identified in Northern Ireland, accounting for 20%. Spoligotyping identified 20 strains, with ST140 accounting for 52% of isolates. This major type was recovered from all animal species tested and was widely distributed geographically, suggesting that transmission between these animal species was a factor in the epidemiology of bovine tuberculosis in Ireland. However, some strain types were geographically more clustered. Subsequently, IS611O- RFLP, PGRS-RFLP, DR-RFLP and spoligotyping were compared with pUCD-RFLP on a panel of 299 M. bovis isolates (O'Brien et al. 2000a). Using a derived statistical function for discrimination, pUCD-RFLP was found to be more discriminating than the combined RFLP method and spoligotyping. pUCD-RFLP and DR-RFLP combined produced a more discriminating and epidemiologically concordant method. In Great Britain, the majority of isolates from recent outbreaks in cattle have been spoligotyped and mapped using the grid reference of the farm location (Clifton-Hadley et al.I998). Thirty-four spoligotypes were identified, 25 in cattle amongst 2668 isolates collected mainly during 1996 and 1997. In agreement with the Northern Ireland study, the same two spoligotypes (ST140 and ST263) accounted for 70% of all isolates. One spoligotype was detected in 623 herds and 2-5 spoligotypes were detected in the remaining 86 herds, again suggesting multiple source outbreaks. Fifty-three herds had isolates spoligotyped on repeat occasions and in all but five instances, at least one spoligotype was the same as the spoligotype initially detected. This suggests that new sources were responsible for introducing the different spoligotypes to retested herds. Through epidemiological trace-back a source for 426 of the outbreaks was proposed. In situations where badger M. bovis isolates were recovered following an outbreak in cattle, 90 of 99 (91%) isolates were of the same spoligotype. It was concluded that spoligotyping was a useful genotyping method but further discriminatory ability was desirable. A study of M. bovis recovered from a well-characterised badger population suggested that spoligotypes were relatively stable within a location and over a length of time, within a defined population and within individual animals. Using Geographical Information Systems (GISs) to manage the molecular typing data, a marked degree of geographical clustering was demonstrated for several spoligotypes, which can be

87

interpreted as evidence for a stable source of infection for cattle, such as wildlife. In marked contrast to the spoligotyping studies in Northern Ireland, the Republic of Ireland, Great Britain and several other countries, an extensive spoligotyping study of 1,349 M. bovis isolates collected mainly from cattle in France over a 20-year period (1979-2000) demonstrated that the technique had very acceptable and useful discriminatory capacity (Haddad et al' 2001). A large number (161) of spoligotypes were found, relatively more than were found in Great Britain, with two types responsible for 26 and 12% of isolates, respectively. The main spoligotype pattern was described as BCG-like. This may not be surprising, since M. bovis BCG was originally derived from a French M. bovis isolate and was proposed as the progenitor of further spoligotypes, which were linked through the unidirectional loss of CRISPR spacers. Spoligotypes were again mapped and there was marked geographical clustering for several of them. The remarkable diversity in spoligotypes was interpreted as reflecting the very low disease prevalence. Additional factors, such as traditional trading in a large number of different cattle breeds were also cited. It is interesting to note that the 'classical European' M. bovis BCG-like spoligotype pattern now dominates in northern Cameroon and that the introduction of Charolais cattle from France in 1913 is an alleged source. Although a small sample number, the spoligotype patterns in Cameroon appear relatively homogeneous. France is still the main exporter of cattle to Cameroon (Njanpop-Lafourcade et al' 2001). Molecular typing of M. bovis isolates in Tanzania (Kazwala et al' 1998) led to the hypothesis that there were two main categories of strains: autochthonous strains (atypical cultural properties) and strains imported from Europe (with classical cultural properties). Bovine tuberculosis has also become a very significant disease problem of wildlife in the major game reserves of South Africa, severely affecting nature conservation and eco-tourism. The African buffalo (Syncerus caffer) is a valuable big-game species which is susceptible to M. bovis infection, making them a risk for domestic cattle. Tuberculosis-free buffalo are also more valuable, a major driving force in illegal trade. The buffalo populations in Hluluwe-Umfolozi Game Reserve (HUP) and the Kruger National Park (KNP) are infected with M. bovis and act as a maintenance host, responsible for spill-over of infection into local wildlife. IS611 0- RFLP has been used to trace the original source of infection of buffalo populations in the KNP and in tracing the origin of infected animals that were moved to other parts of South Africa. Therefore,

88

R. A. Skuce and S. D. Neill

the identification of the probable origin of animals ogy, evolution and pathogenesis of a major pathogen may be possible by studying the strain types har- such as M. bovis. When integrated with developments boured by animals, where more conventional animal in animal traceability (Houston 2001) and technoloidentification methods have either failed or not been gies such as Global Positioning Systems (GPSs) and applied (Vosloo et al. 2001). Geographical Information Systems (GISs), which IS6110-RFLP and DR-RFLP were used to type are available in developed countries, they should M. bovis isolates from cattle in Mexico and Texas provide powerful and challenging new informa(Perumaalla et al. 1996, 1999). The disclosure of tion with which to inform control strategies better. multi-copy IS6110 strains implicated wildlife res- It is probable however that, as with M. tuberculosis, ervoirs in disease transmission, a theory which has this equivalent of contact tracing may not be very not been proven yet. In Argentina, the disclosure effective at detecting casual contacts and that strain of 'cattle' strain types infecting humans identified typing data will provide alternative explanations for an occupational zoonotic risk (van Soolingen et al. proposed sources and transmission routes. 1994). This contrasts with the current situation in These new tools should also prove valuable for the Netherlands, where bovine tuberculosis has been identifying sources and routes of M. bovis transsuccessfully eradicated. Strain typing of M. bovis mission, thus providing baseline information on isolates from humans showed that they were infected prevalence and distribution of M. bovis strain types with 'multi-copy' IS611 0 strains, which were likely to in animal species. Integration into imaginative and have been due to exposure to infected 'exotic' animals focussed epidemiological studies should help clarify specific issues such as the contributions from interin zoos or animal parks. Australia has succeeded in eradicating bovine bovine transmission and from wildlife. Availability tuberculosis. However, prior to this, M. bovis strain of more precise strain recording should be employed typing was used to propose potential sources and also to investigate: 'persistence' of infection within transmission routes for infection on specific farm a herd; the issue of recrudescence of infection and premises (Cousins et al. 1993, 1998b). Additionally, strain reintroduction, and therefore may ultimately strain typing has been used to investigate other zoo- help to elucidate further the issue of latency in cattle notic risks such as tuberculous captive seals, which referred to by Pollock and Neill (2002) were shown to have infected a seal trainer having the Additionally, it would be of significant value to same strain (Cousins et al. 1990). REA was used in know if particular M. bovis strains may be associated Sweden to show that M. bovis was independently, and with particular epidemiological features observed inadvertently, introduced into Sweden and New Zea- in outbreaks of this disease and if specific strains unusually influence the pathogenesis. Correlation land from Great Britain (Bolske et al. 1995). studies could be devised to compare biological properties of M. bovis isolates from, e.g., non-lesioned cattle, from weak tuberculin-reacting or tuberculinnegative animals exhibiting disease and from large 6.11 multi-reactor outbreaks of tuberculosis. IdentificaConclusions tion of key biological properties that influence strain Obviously, the medical and veterinary pnonties behaviour in such ways could have significant imporbetween developing and developed countries can tance in informing control strategies, particularly at differ significantly and hence their attitudes and the local level. For developing countries, molecular technologies responses to animal tuberculosis and any potential resulting zoonosis. Molecular epidemiology is a could be of equal value in the longer term. Howrelatively new discipline and particularly so when ever, in many instances, their use in surveillance is considering M. bovis. There is now a need to inte- likely to be prohibitively expensive for general and grate these new developments, which until recently widespread application. Nonetheless, collection and have been largely 'technology-driven', with classical collation of standard data could inform on matters of animal and human health, which would be epidemiological studies. Genetic tools to facilitate accurate diagnosis and a significant advance. The findings from molecular high-resolution identification of species and strains epidemiological studies in developed countries will of the M. tuberculosis complex now exist and are eventually yield significant information, which could amenable to high-throughput studies. These should have an impact if extrapolated to developing regions provide important new information about the biol- of the globe.

Molecular Epidemiology of Mycobacterium bovis

Acknowledgements. The authors would like to acknowledge the contributions of colleagues within the bovine tuberculosis statutory and research programme at Veterinary Sciences Division (VSD), Department of Agriculture and Rural Development (Northern Ireland) and the Department of Veterinary Science at the Queen's University of Belfast to some of the work discussed in this chapter. This work was funded by the Department of Agriculture and Rural Development (DARD, Northern Ireland), the Department of Environment, Food and Rural Affairs (DEFRA, Great Britain) and the European Union. The authors wish to thank Malcolm Taylor (VSD, DARD) for his assistance with figures and graphics.

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89 Cheeseman CL, Wilesmith JW, Stuart FA (1989) Tuberculosis: the disease and its epidemiology in the badger, a review. Epidemiol Infect 103:113-125 Clifton-Hadley RS, Inwald J, Archer J, Hughes S, Palmer N, Sayers AR, Sweeney K, van Embden JDA (1998) Recent advances in DNA fingerprinting using spoligotyping: epidemiological applications in bovine TB. Cattle Pract 6:79-82 Cole ST, Brosch R, Parkhill J et al. (1998) Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393:537-544 Collins DM (1998) Molecular epidemiology: Mycobacterium bovis. In: Rutledge C, Dale J (eds) Mycobacteria-molecular biology and virulence. Blackwell Science, Boston Collins DM, de Lisle GW (1984) DNA restriction endonuclease analysis of Mycobacterium tuberculosis and Mycobacterium bovis BCG. J Gen Microbiol 130:1019-1021 Collins DM, de Lisle GW (1985) DNA restriction endonuclease analysis of Mycobacterium bovis and other members of the tuberculosis complex. J Clin Microbiol 21:562-564 Collins DM, de Lisle GW, Gabric DM (1986) Geographic distribution of restriction types of Mycobacterium bovis isolates from brush-tailed possums (Trichosurus vulpecula) in New Zealand. J Hyg 96:431-438 Collins DM, Gabric DM, de Lisle GW (1988) Typing of Mycobacterium bovis isolates from cattle and other animals in the same locality. NZ Vet J 36:45-46 Collins DM, Erasmuson SK, Stephens DM, Yates GF, de Lisle GW (1993) DNA fingerprinting of Mycobacterium bovis strains by restriction fragment analysis and hybridisation with the insertion elements IS1081 and IS6110. J Clin MicrobioI31:1143-1147 Collins DM, Radford AJ, de Lisle GW, Billman-Jacobe H (1994) Diagnosis and epidemiology of bovine tuberculosis using molecular biological approaches. Vet Microbiol 40:83-94 Collins DM et al. (1999) DNA typing of Mycobacterium bovis isolates from the Castlepoint area in New Zealand Cosivi 0, Grange JM,Daborn CJ et al. (1998) Zoonotic tuberculosis due to Mycobacterium bovis in developing countries. Emerg Infect Dis 4(1) CDC URL: http://www.cdc.gov/ ncidodleid/vol4no 11 cosivi.htm Costello E, O'Grady D, Flynn E et ai. (1999) Study of restriction fragment length polymorphism analysis and spoligotyping for epidemiological investigation of Mycobacterium bovis infection. J Clin MicrobioI37:3217-3222 Cousins DV (2001) Mycobacterium bovis infection and control in domestic livestock. Rev Sci Tech Off Int Epiz 20:71-85 Cousins DV, Roberts JL (2001) Australia's campaign to eradicate bovine tuberculosis: the battle for freedom and beyond. Tuberculosis 81:5-15 Cousins DY, Francis BR, Gow BL et al' (1990) Tuberculosis in captive seals. Bacteriological studies on an isolate belonging to the Mycobacterium tuberculosis complex. Res Vet Sci 48:196-200 Cousins DV, Williams SN, Ross BC, Ellis TM (1993) Use of a repetitive element isolated from Mycobacterium tuberculosis in hybridization studies with Mycobacterium bovis as a new tool for epidemiological studies of bovine tuberculosis. Vet MicrobioI37:1-17 Cousins DV, Skuce RA, Kazwala RR, van Embden JD (1998a) Towards a standardized approach to DNA fingerprinting of Mycobacterium bovis. Int J Tuberc Lung Dis 2: 471-478

90 Cousins DV, Williams S, Liebana E et al. (1998b) Evaluation of four DNA typing techniques in epidemiological investigations of bovine tuberculosis. 1Clin Microbiol 36: 168-174 Daborn q, Grange 1M and Kazwala RR (1996) The bovine tuberculosis cycle: and African perspective. 1 Appl Bacteriol81 [Suppl):S27-S32 Dale IW, Brittain D, Cataldi AA et al. (2001) Spacer oligonucleotide typing of bacteria of the Mycobacterium tuberculosis complex: recommendations for standardised nomenclature. Int 1Tuberc Lung Dis 5:216-219 De Lisle GW, Collins DM, Loveday AS, Young WA, Iulian AF (1990) A report of tuberculosis in cats in New Zealand, and the examination of strains of Mycobacterium bovis by DNA restriction endonuclease analysis. NZ Vet 1 38: 10-13 De Lisle GW, Yates GF, Collins DM, MacKenzie RW, Crews KB, Walker R (1995) A study of bovine tuberculosis in domestic animals and wildlife in the MacKenzie Basin and surrounding areas using DNA fingerprinting. NZ Vet 143:266-271 De Lisle GW, Mackintosh CG and Bengis RG (2001) Mycobacterium bovis in free-living and captive wildlife, including farmed deer. Rev Sci Tech Off Int Epiz 20:86-111 Denny GO, Wilesmith IW (1999) Bovine tuberculosis in Northern Ireland: a case-control study of herd risk factors. Vet Rec 144:305-310 Doran TI, Hodgson AL, Davies IK, Radford AI (1993) Characterisation of a highly repeated DNA sequence from Mycobacterium bovis. FEMS Microbiol Lett 111:147-152 Durr PA, Clifton-Hadley RS, Hewinson RG (2000a) Molecular epidemiology of bovine tuberculosis II: applications of genotyping. Rev Sci Tech Off Int Epiz 19:689-701 Durr PA, Hewinson RG, Clifton-Hadley RS (2000b) Molecular epidemiology of bovine tuberculosis I: Mycobacterium bovis genotyping. Rev Sci Tech Off Int Epiz 19:675-688 European Commission Report (1998) Trends and sources of zoonotic agents in animals, feedstuffs, food and man in the European Union in 1997. Document no VI/8495/98-Rev 2 Feizabadi MM, Robertson ID, Cousins DV, Hampson DI (1996) Genomic analysis of Mycobacterium bovis and other members of the Mycobacterium tuberculosis complex by isoenzyme analysis and pulsed-field gel electrophoresis. 1 Clin MicrobioI34:1136-1142 Frothingham R, Meeker-O'Connell WA (1998) Genetic diversity in the Mycobacterium tuberculosis complex based on variable numbers of tandem DNA repeats. Microbiology 144:1189-1196 Gallagher 1, Clifton-Hadley RS (2001) Tuberculosis in badgers: a review of the disease and its significance for other animals. Res Vet Sci 69:203-217 Glynn IR, Bauer 1, de Boer S, Borgdorff MW, Fine PEM, Godfrey-Faussett P, Vynnycky E (1999a ) Interpreting DNA fingerprint clusaters of Mycobacterium tuberculosis. Int 1 Tuberc Lung Dis 3:1055-1060 Glynn IR, Vynnycky E, Fine PEM (1999b ) Influence of sampling on estimates of clustering and recent transmission of Mycobacterium tuberculosis derived from DNA fingerprint techniques. Am 1 EpidemioI149:366-371 Glynn IR, Whiteley 1, Bifani PI et al. (2002) CDC-worldwide occurrence of Beijing/W strains of Mycobacterium tuberculosis: a systematic review. CDC URL:http://www.cdc.gov/ ncidod/EID/voI8n08/02-0002-G.htm Goodchild AV, Clifton-Hadley RS (2001) Cattle-to-cattle transmission of Mycobacterium bovis. Tuberculosis 81:23-41

R. A. Skuce and S. D. Neill Gordon SV, Brosch R, Billault A, Garnier T, Eiglmeier K, Cole ST (1999a) Identification of variable regions in the genome of tubercle bacilli using artificial chromosome arrays. Mol Microbiol 32:643-655 Gordon SV, Heym B, Parkhill J, Barrell B, Cole ST (1999b) New insertion sequences and a novel repeated sequence in the genome of Mycobacterium tuberculosis H37 Rv. Microbiology 145:881-892 Gordon SV, Eiglmeier K, Garnier T, Brosch R, Parkhill 1, Barrell B, Cole ST, Hewinson RG (2001) Genomics of Mycobacterium bovis. Tuberculosis 81:157-163 Grange 1M (2001) Mycobacterium bovis infection in human beings. Tuberculosis 81:71-77 Groenen PMA, Bunschoten AE, van Soolingen D and van Embden IDA (1993) Nature of DNA polymorphisms in the direct repeat cluster of Mycobacterium tuberculosis: application for strain differentiation by a novel typing method. Mol Microbioll0:1057-1085 Guerrero A, Cobo 1, Fortun 1et al. (1997) Nosocomial transmission of Mycobacterium bovis resistant to 11 drugs in people with advanced HIV-l infection. Lancet 350:1738-1742 Haddad N, Ostyn A, Karoni C, Masselot M, Thorel MF, Hughes SL, Inwald 1, Hewinson RG, Durand B (2001) Spoligotype diversity of Mycobacterium bovis strains isolated in France from 1979-2000.1 Clin MicrobioI39:3623-3632 Heersma HF, Kremer K, van Embden ID (1998) Computer analysis of IS611 0 RFLP patterns of Mycobacterium tuberculosis. Methods Mol Bioi 101:395-422 Houston R (2001) A computerised database system for bovine traceability Hughes MS and Rogers M (1994) Vaccination of the badger (Meles meles) against Mycobacterium bovis. Vet Microbiol 51:363-379 Hughes SL, Frothingham R, Inwald 1 et al. (2000) The development of semi-automated fluorescent techniques for improved molecular typing of Mycobacterium bovis. Abstract of the 5th international meeting on bacterial epidemiological markers (IMBEM), Noordwijkerhout, Netherlands, Sept 2000 Hughes VM, Stevenson K, Sharp 1M (2001) Improved preparation of high molecular weight DNA for pulsed-field gel electrophoresis from mycobacteria. 1 Microbiol Methods 44:209-215 Kallenius G, Koivula T, Ghebremichael S et al. (1999) Evolution and clonal traits of Mycobacterium tuberculosis complex in Guinea-Bissau. 1Clin MicrobioI37:3872-3878 Kamerbeek 1, Schouls LM, Kolk A et al. (1997) Simultaneous detection and strain differentiation of Mycobacterium tuberculosis for diagnosis and epidemiology. J Clin Microbioi 35:907-914 Kaufhold A, Podbielski A, Baumgarten G, Blokpoel M, Top 1, Schouls L (1994) Rapid typing of group A Streptococci by the use of DNA amplification and non-radioactive allele specific oligonucleotide probes. FEMS Microbiol Lett 119:19-26 Kazwala RR, Daborn q, Kusiluka LIM, Iiwa SFH, Sharp 1M, Kambarage DM (1998) Isolation of Mycobacterium species from raw milk of pastoral cattle of the Southern HigWands of Tanzania. Trop Anim Health Prod 30:233-239 Kazwala RR, Daborn q, Sharp 1M et al. (2001a) Isolation of Mycobacterium bovis from human cases of cervical adenitis in Tanzania: a cause for concern? lnt J Tuberc Lung Dis 5:87-91 Kazwala RR, Kambarage DM, Daborn q et al. (2001b) Risk factors associated with the occurrence of bovine tubercu-

Molecular Epidemiology of Mycobacterium bovis losis in cattle in the Southern Highlands of Tanzania. Vet Res Commun 25:609-614 Kline SE, Hedemark LL, Davies SF (1995) Outbreak of tuberculosis among regular patrons of a neighbourhood bar. N Engl J Med 333:222-227 Kremer K, van Soolingen D, Frothingham R et al. (1999) Comparison of methods based on different molecular epidemiological markers for typing of Mycobacterium tuberculosis complex strains: interlaboratory study of discriminatory power and reproducibility. J Clin MicrobioI37:2607-2618 Kulaga S, Behr M, Musana K et al. (2002) Molecular epidemiology of tuberculosis in Montreal. Can Med Assoc J 167:353-354 Livingstone PG (1992) Tuberculosis in New Zealand-current status and control policies. Surveillance 19:14-18 Magdalena J, Vachee A, Supply P, Locht C (1998a) Identification of a new DNA region specific for members of Mycobacterium tuberculosis complex. J Clin MicrobioI36:937-943 Magdalena J, Supply P, Locht C (1998b) Specific differentiation between Mycobacterium bovis BCG and virulent strains of the Mycobacterium tuberculosis complex. J Clin Microbiol 36:2471-2476 Mazars E, Lesjean S, Banuls A-L, Gilbert M, Vincent V, Gicquel B, Tibayrenc M, Locht C, Supply P (2001) High-resolution minisatellit-based typing as a portable approach to global analysis of Mycobacterium tuberculosis molecular epidemiology. Proc Natl Acad Sci USA 98:1901-1906 Morris RS, Pfeiffer DU, Jackson R (1994) The epidemiology of Mycobacterium bovis infections. Vet MicrobioI40:153-177 Musser JM, Amin A, Ramaswamy S (2000) Negligible genetic diversity of Mycobacterium tuberculosis host immune system protein targets: evidence of limited selective pressure. Genetics 155:7-16 Neill SD (1994) Pathogenesis of Mycobacterium bovis infection in cattle. Vet MicrobioI40:41-52 Neill SD, Cassidy J,Hanna J, Mackie DP, Pollock JM, Clements A, Walton E, Bryson DG (1994) Detection of Mycobacterium bovis infection in skin test-negative cattle with an assay for bovine interferon-gamma. Vet Rec 50:229-232 Njanpop-Lafourcade BM, Inwald J, Ostyn A, Durand B, Hughes S, Thorel M-F, Hewinson G, Haddad N (2001) Molecular typing of Mycobacterium bovis isolates from Cameroon. J Clin Microbiol 39:222-227 O'Brien R, Flynn 0, Costello E, O'Grady D, Rogers M (2000a) Identification of a novel DNA probe for strain typing Mycobacterium bovis by restriction fragment length polymorphism analysis. J Clin MicrobioI38:1723-1730 O'Brien R, Danilowiez BS, Bailey L et al. (2000b) Characterization of the Mycobacterium bovis restriction frament length polymorphism DNA probe pUCD and performance comparison with standard methods. J Clin Microbiol 38: 3362-3369 O'Reilly LM, Daborn CJ (1995) The epidemiology of Mycobacterium bovis infections in animals and man: a review. Tuberc Lung Dis 76 [SuppI1]:1-46 Perumaalla VS,Adams LG,Payeur J et al. (1996) Molecular epidemiology of Mycobacterium bovis in Texas and mexico. J Clin Microbiol 34:2066-2071 Perumaalla VS, Adams LG, Payeur J et al. (1999) Molecular fingerprinting confirms extensive cow-to-cow intra-herd transmission of a single Mycobacterium bovis strain. Vet Microbiol 70:269-276 Pollock JM, Neill SD (2002) Review: Mycobacterium bovis infection and tuberculosis in cattle. Vet J 163:115-127

91 Pfeiffer DU, Jackson R, de Lisle GW, Collins DM, Morris RS (1994) The use of genetic markers to clarify tuberculosis epidemiology. Kenya Vet 18:293-295 Rastogi N, Legrand E, Sola C (2001) The mycobacteria: an introduction to nomenclature and pathogenesis. Rev Sci Tech OffInt Epi 20:21-54 Roring S, Brittain D, Bunschoten AE et al. (1998) Spacer oligonucleotide typing of Mycobacterium bovis isolates compared to typing by restriction fragment length polymorphism analysis using PGRS, DR and IS611 0 probes. Vet MicrobioI61:111-120 Roring S, Scott A, Brittain D, Walker I, Hewinson G, Neill S, Skuce R (2002) Development of variable-number tandem repeat typing of Mycobacterium bovis: comparison of results with those obtained by using existing exact tandem repeats and spoligotyping. J Clin MicrobioI40:2126-2133 Salamon H, Behr MA, Rhee JT, Small PM (2000) Genetic distances for the study of infectious disease epidemiology. Am J EpidemioI151:324-334 Saunders NA (1995) State of the art typing of Mycobacterium tuberculosis. J Hosp Inf 29:169-176 Skuce RA, Neill SD (2001) Molecular epidemiology of Mycobacterium bovis: exploiting molecular data. Tuberculosis 81:169-175 Skuce RA, Brittain D, Hughes MS, Neill SD (1996) Differentiation of Mycobacterium bovis isolates from animals by DNA typing. J Clin MicrobioI34:2469-2474 Skuce RA, Brittain D, van Embden JD, Smith T, Sharp M, Hewinson G, Rogers M, Garcia Marin J-F, Neill SD (1998) Development of novel standardised methodology and nomenclature for the identification of Mycobacterium bovis strains. EU Contract SMT4 CT96 2097 Final Report (EU Commission) Skuce RA, McCorry TP, McCarroll JF, Roring SM, Scott AN, Brittain D, Hughes SL, Hewinson RG and Neill SD (2002) Discrimination of Mycobacterium tuberculosis complex bacteria using novel VNTR-PCR targets. MicrobioI148:519-528 Small PM, van Embden JD (1994) Molecular epidemiology of tuberculosis. In: Bloom BR (ed) Tuberculosis: pathogenesis, protection and control. American Society for Microbiology Small PM, Hopewell PC, Singh SP et al. (1994) The epidemiology of tuberculosis in San Francisco. A population-based study using conventional and molecular methods. N Engl J Med 330:1703-1709 Smittipat N, Palittapongarnpim P (2000) Identification of possible loci of variable number of tandem repeats in Mycobacterium tuberculosis. Tubercle Lung Dis 80:69-74 Sola C, Filliol I, Legrand E, Rastogi N (2000) Recent developments of spoligotyping as applied to the study of epidemiology, biodiversity and molecular phylogeny of the Mycobacterium tuberculosis complex. Path Bioi 48:921-932 Sola C, Filliol I, Gutierrez M C et al. (2001) Spoligotype database of Mycobacterium tuberculosis: biogeographic distribution of shared types and epidemiologic and phylogenetic perspectives. Emerg Inf Dis http://www.cdc.gov?ncidod/ eid.vol7n03/solaGl.htm Sreevatsan S, Pan X, Musser JM (1997) Restricted structural gene polymorphism in the Mycobacterium tuberculosis complex indicates evolutionarily recent global dissemination. Proc Natl Acad Sci USA 94:9869-9874 Struelens MJ (1996) Consensus guidelines for the appropriate use and evaluation of microbial epidemiologic typing systems. Clin Microbiol Infect 2:2-11

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Supply P, Magdalena J, Himpens S, Locht C (1997) Identification of novel intergenic repetitive units in a mycobacterial twocomponent system operon. Mol MicrobioI26:991-1003 Supply P, Mazars E, Lesjean S, Vincent V, Gicquel Band Locht C (2000) Variable human minisatellite-like regions in the Mycobacterium tuberculosis genome. Mol MicrobioI36:762-771 Tanaka MM, Small PM, Salamon H, Feldman MW (2000) The dynamics of repeated elements: applications to the epidemiology of tuberculosis. Proc Natl Acad Sci USA 97:3532-3537 Van Belkum A (2002) Molecular typing of micro-organisms: at the centre of diagnostics, genomics and pathogenesis of infectious diseases? J Med MicrobioI51:7-10 Van Belkum A, Struelens M, de Visser A, Verbrugh H, Tibayrenc M (2001) Role of genomic typing in taxonomy, evolutionary genetics and microbial epidemiology. Clin Microbiol Rev 14:547 Van der Zanden AG, Kremer K, Schouls LM, Caimi K, Cataldi A, Hulteman A, Nageikerke NJ, van Soolingen D (2002) Improvement of differentiation and interpretability of spoligotyping for Mycobacterium tuberculosis complex isolates by introduction of new spacer oligonucleotides. J Clin Microbiol 40:4628-4639 Van Embden JD, Cave MD, Crawford JT et al. (1993) Strain identification of Mycobacterium tuberculosis by DNA fingerprinting: recommendations for a standardized methodology. J Clin MicrobioI31:406-409 Van Embden JD, van Soolingen D, Heersma HF et al. (1996) Establishment of a European Network for the surveillance of Mycobacterium tuberculosis, MRSA and penicillin-

R. A. Skuce and S. D. Neill resistant pneumococci (letter; comment). J Antimicrob Chemother 38:905-907 Van Embden JDA, van Gorkom T, Kremer K et al. (2000) Genetic variation and evolutionary origin of the direct repeat locus of Mycobacterium tuberculosis complex bacteria. J BacterioI182:2393-2401 Van Heiden P (1998) Molecular epidemiology: human tuberculosis. In: Rutledge C, Dale J (eds) Mycobacteria-molecular biology and virulence. Blackwell Science, Boston Van Soolingen D (2001) Review: molecular epidemiology of tuberculosis and other mycobacterial infections: main methodologies and achievements. J Intern Med 249:1-26 Van Soolingen D, de Haas PEW, Haagsma J et al. (1994) Use of various genetic markers in differentiation of Mycobacterium bovis strains from animals and humans and for studying epidemiology of bovine tuberculosis. J Clin Microbiol 32:2425-2433 Van Soolingen D, Borgdorff MW, de Haas PEW et al. (1997a) Molecular epidemiology of tuberculosis in The Netherlands: a nationwide study from 1993 through 1997. J Infect Dis 180:726-736 Van Soolingen D, Hoogenboezem T, de Haas PE et al. (1997b) A novel pathogenic taxon of the Mycobacterium tuberculosis complex, Canetti: characterisation of an exceptional isolate from Africa. Int J Syst BacterioI47:1236-1245 Van Soolingen D, van der Zanden AG, de Haas PW et al. (1998) Daignosis of Mycobacterium microti infections among humans by using novel genetic markers. J Clin Microbiol 36: 1840-1845

7 Tuberculosis in Special Groups and Occupational Hazards JAIME ESTEBAN

CONTENTS 7.1 7.2 7.3 7.4 7.5 7.6

7.7 7.8 7.9

7.10 7.11 7.12

Special Groups (1). Diabetics 93 Special Groups (2). Transplantation 94 Special Groups (3). Malignant Diseases 96 Special Groups (4). Drug Abusers 97 Special Groups (5). Correctional Facilities 98 Special Groups (6). Shelters 100 Special Groups (7). Immigrants 100 Occupational Hazards (1). Health Care Workers 101 Occupational Hazards (2). Laboratory Workers 104 Occupational Hazards (3). Silicosis 106 Occupational Hazards (4). Other Workers 106 Conclusion 107 References 108

host against the pathogen, some population groups, such as closed communities (correctional facilities, shelters, jails, hospitals, miners and others) seem to present unique characteristics. This is also the case in patients with underlying conditions that make the risk of active tuberculosis higher, either by immunosuppression or by local factors (silicosis, transplantation, diabetes, malignancies, drug abuse). The following pages describe the special characteristics of tuberculous diseases in these groups, with a special emphasis on protective measures.

7.1 Special Groups (1). Diabetics At the beginning of the last quarter of the twentieth century, tuberculosis seemed to be a disease in decay in the developed world. The image was that of a slow but progressive decrease in the prevalence of the disease due to the availability of a very effective therapy and the increasing development of hygienic measures. However, some years later, an increase in the number of cases of tuberculosis was detected in the USA. This fact, together with the appearance of cases of multidrug-resistant tuberculosis, which were very difficult to treat, increased the interest of the scientific community in this half-forgotten disease. In 1993, the WHO declared tuberculosis a global emergency because of the increasing number of cases throughout the world, and more measures were taken in the fight against the disease. The fact that tuberculosis is mainly a respiratory disease that can be transmitted airborne or by droplets makes any person in contact with a patient who suffers from active respiratory tuberculosis susceptible to infection. However, because of the nature of transmission and the immune response of the

J. ESTEBAN, MD Department of Medical Microbiology, Fundaci6n Jimenez Diaz, Av. Reyes Cat6licos 2, 28040 Madrid, Spain

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

Diabetes is a well-known risk factor for tuberculosis. Diabetics have higher rates of tuberculosis than nondiabetics (2-5 times higher) (Opsald et al.1961; Small and Fujiwara 2001; Turner 1951). Although the reason for this is not well known, there are several hypotheses which try to explain this phenomenon. They include alterations in pulmonary immune cell function (including altered polymorphonuclear cell function, reduced activity of monocyte-macrophages, in particular impaired phagocytosis of intracellular organisms and depressed lymphocyte function) and the effect of diabetic microangiopathy in the capillaries of the alveolar septa and alveolar arterioles. The latter may affect local response to infection (Koziel and Koziel 1995). Tuberculous diabetics have the same symptoms and signs as non-diabetic patients, and their evolution seems to be similar. However, several reports describe atypical radiographic findings in diabetics, such as a higher prevalence of cavitations and tuberculous lesions in lower lobes. These data have been reported in several studies, which have in common small sample sizes, the results being statistically non conclusive (Morris et al. 1992). Two other reports with a higher number of patients gave different results. One of them supports the idea of a higher

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incidence of lower lobe disease in diabetics of all age groups (Perez-Guzman et al. 2000). The other report showed no statistical difference between all the groups, although a more detailed statistical analysis suggested an association between lower lobe disease and female gender. Another finding was that lower lobe disease in patients older than 40 years was more frequent in diabetics, whereas the frequency of cavitations seemed to be higher in patients with insulin-dependent diabetes (Bacakoglu et al. 2001). This report also showed a lower frequency of smear-positive patients in diabetics compared to non-diabetics. Given the higher incidence of tuberculosis in diabetics, tuberculin testing should be carried out in these patients. However, because of the risk of anergy, appropriate controls must be done in poorly controlled diabetics for a proper evaluation of the results. Prophylactic isoniazid is indicated in patients with a positive PPD skin test because of the high risk of reactivation of the disease. Treatment regimens are otherwise similar to those of non-diabetics. As peripheral neuropathy is a secondary effect of isoniazid, pyridoxine should be given with the antibiotic and all these patients should be carefully monitored for clinical symptoms of both neuropathy and hepatic disease (Koziel and Koziel 1995). Therapy of tuberculosis is the same as for nondiabetic patients. However, there are data suggesting higher relapse rates among diabetics, so longer courses of therapy may be indicated in order to minimise relapse incidence (Kameda et al. 1990). Moreover, a recent report establishes a higher incidence of multidrug-resistant tuberculosis among diabetics (Bashar et al. 2001). However, no other reports have confirmed this finding, so changes in therapeutic protocols are not currently indicated unless specific epidemiological data suggests a high rate of multidrug-resistant tuberculosis in the area. In this case, specific measures for proper management of the cases must be implemented and, probably, antimicrobial susceptibility testing would be indicated for all the isolates of M. tuberculosis from these patients.

7.2 Special Groups (2). Transplantation Transplantation is a therapeutic procedure that is increasingly being employed worldwide for numerous diseases. However, it implies several procedures to minimise the risk of rejection and most of them produce an alteration in the immunity of the patient.

J. Esteban The impairment of immune function is a circumstance that must be taken into account in all these patients because it increases the risk of infections, caused by both common and rare organisms. The degree of immunosuppression and other complications is quite different between bone marrow transplants and solid organ transplants and so is the risk of infection, which is higher for bone marrow transplantation. This is so because immunosuppressive therapy is given before and after the transplant; the risk is higher in allogeneic transplants than in autotransplants. In the pretransplantation period the presence of neutropenia and altered anatomical barriers are the main risk factors for development of infection. In the pre-engraftment period, aplasia due to the conditioning regimen employed, represents the major immune defect. In the third phase, neutropenia abates and the anatomic barriers are restored, although immune alterations persist. The presence of graft-versus-host disease and its therapy in this period represents further complications that increase the risk of infection. Later, in a fourth period, chronic graft-versus-host disease represents almost the only risk factor for the development of infection (Sable and Donowitz 1994). Tuberculosis (a disease that is closely related to immune function) was expected to be more frequent among transplanted patients due to the broad impairment of host immunity that they suffer. However, initial reports showed lower rates than those expected, although they were higher than those for the general population (Kurzrock et al.1984). An initial explanation for this finding was that these studies were done in countries with low global rates for tuberculosis (Roy and Weisdorf 1997). However, recent reports from countries with higher prevalence rates suggest that the initial findings should be reviewed and that tuberculosis rates in this group of patients are in fact similar to the rates of the general population (Aljurf et al. 1999; Budak-Alpdogan et al. 2000; George et al. 2001; Ip et al. 1998). Despite these data on incidence, tuberculosis in patients that underwent bone marrow transplantation had special characteristics compared to those of general population, perhaps due to the immune impairment that these patients suffer. There is a high number of cases of extrapulmonary or disseminated disease in many reports (Aljurf et al. 1999; George et al. 2001), although in others respiratory disease is the most frequent form of the disease (Ip et al. 1998; Kurzrock et al. 1984). However, even respiratory cases can have atypical presentations (Kurzrock et al. 1984). These facts, together with the relatively low

Tuberculosis in Special Groups and Occupational Hazards

incidence of the disease can often mislead the physician, and in many cases therapy is delayed. Some cases are diagnosed after the patient's death. Because of the severity of the disease in these cases, an aggressive approach should be used to diagnose the disease as soon as possible. Common therapeutic regimens can be used for these patients. These regimens, however, must be started as soon as possible, as diagnostic tests are not always available on time. A recent official report establishes the measures for prevention of tuberculosis in this group (Centers for Disease Control 2000). Measures include screening of candidates by careful medical history and tuberculin skin testing by the Mantoux method. For immunocompromised patients, a positive test is defined as 5 mm or more of induration. Persons with a positive test or a history of positive test must be evaluated for detection of active tuberculosis. If no disease is detected, a full 9month course of isoniazid chemoprophylaxis must be performed. This regimen is also indicated for patients who have been in close contact with an active tuberculosis case, regardless of skin test status. Routine anergy testing is not indicated in these patients. An alternative for isoniazid therapy is a 2-month course of daily pyrazinamide/rifampin, although there are only limited data about the safety and efficacy of this. It must also be taken into account that rifampin interacts with many drugs, such as cyclosporine or corticosteroids, so routine use of this regimen is not recommended. BCG vaccination is also contraindicated in these patients, because the BCG strain might cause severe (even fatal) disease in immunocompromised patients (Abramowsky et al.1993). Solid organ transplantation includes a broad range of procedures with variable degrees of immunosuppression that depends on the organ to be transplanted. Prevalence of tuberculosis among transplanted patients in developed countries is as high as 1% (Patel and Paya 1997), which is higher than that for the general population in these countries (Singh and Paterson 1998). Most cases of tuberculosis have been reported in renal transplant recipients, although cases have also been reported in liver, heart and lung transplanted patients (Singh and Paterson 1998). Unlike other infections, tuberculosis in these patients is not related to the time since the transplantation procedure (Patel and Paya 1997). However, the disease appeared earlier in heart, liver and lung transplant recipients than in renal ones. Although transmission of tuberculosis through the graft has been reported (Graham et al. 2001;

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Mourad et al. 1985), this mechanism of infection is rare, and reactivation and primary infection are the most common mechanisms of acquisition of the disease. There have also been reports of outbreaks of tuberculosis in transplantation programmes (Sundbery et al.199l). The clinical aspects of the disease include a high number of cases of extrapulmonary or disseminated tuberculosis (49%) (Singh and Paterson 1998). Transplantation of organs that imply a high level of immunosuppression, such as heart transplant, show an even higher proportion of extrapulmonary cases (Munoz et al. 1995). Among extrapulmonary cases, presentations include gastrointestinal, hepatic, skin, muscle, osteoarticular, genitourinary, ganglial, central nervous system and other more uncommon sites of disease such as larynx, tonsils or eye (Patel and Paya 1997; Singh and Paterson 1998). Clinical data from these patients were similar to those from the general population. Mortality of tuberculosis in transplanted patients is 30%. Disseminated disease, prior rejection and treatment with OKT3 or anti-T cell antibodies are significant predictors of mortality in these patients. Clinicians should suspect tuberculosis in patients who present with fever and radiographic infiltrates or symptoms of extrapulmonary disease. Smears for acid-fast stains and mycobacterial cultures should be performed on appropriate specimens. Pulmonary cases require an aggressive approach if the results of sputum testing are inconclusive because these patients have a high mortality risk. Procedures to be performed include bronchoscopy, including bronchoalveolar lavage or transbronchial biopsy, or even open lung biopsy (Patel and Paya 1997). Other techniques (bone marrow biopsy, liver or other organ biopsies, blood cultures for mycobacteria) are also useful when extrapulmonary or disseminated tuberculosis is suspected, although the results of some of these (for example, blood cultures) can take a long time (Esteban et al. 200lb). Samples should also be sent for pathological evaluation, looking for suggestive lesions such as granuloma formation. The treatment of transplanted patients with tuberculosis must be performed with at least two bactericidal drugs and during a longer period of time (l2 months) than that for common regimens (Patel and Paya 1997). Hepatotoxicity is a side effect of great importance in the context of liver transplantation, so these patients must be monitored carefully, including the performance of biopsies to detect hepatitis or graft rejection. Published data has shown that hepatotoxicity requiring discontinuation

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of isoniazid therapy occurs in 41 % of liver transplant patients. The percentages of hepatotoxicity for other patients were lower (Singh and Paterson 1998). It is also of interest to note that antimycobacterial therapy has important drug interactions. Rifampin can induce hepatic enzymes and accelerate metabolism of drugs such as cyclosporine or corticoids, so close monitoring of drug levels must be performed (Patel and Paya 1997). Tuberculin skin testing is indicated both in transplant recipients and, if possible, in donors. A history of tuberculosis exposure or past disease must also be recorded. Although no study has demonstrated the efficacy of isoniazid prophylaxis in tuberculin skin test positive transplanted patients, this therapy has been reported to minimise the risk of developing tuberculosis in renal patients (John et al. 1994). However, the indication of chemoprophylaxis must be balanced against the risk of hepatotoxicity. If possible, isoniazid should be given several months prior to transplantation. Other patients that should be considered as candidates for chemoprophylaxis include those with skin test conversion, a history of inadequately treated tuberculosis, close contacts with active tuberculosis cases, patients with chest radiograph abnormalities or the immunocompromised host. Prophylaxis should also be considered for patients who receive grafts from donors with a history of tuberculous infection or disease (Lichtenstein and MacGregor 1983; Qunibi et al. 1991).

J. Esteban

Patients with leukaemia have a higher risk of developing disseminated or extrapulmonary disease compared to those with other haematological tumours (Libshitz et al. 1997; Morii and Narita 1998). Another report mentions a high incidence of tuberculosis in hairy cell leukaemia (Advani and Banavali 1989), with incidences as high as 50% for patients suffering from this disease. The incidence of these manifestations is also higher in patients with lymphomas than in the general population, especially in Hodgkin lymphoma. However, in these diseases extrapulmonary tuberculosis is usually a focal disease and not a disseminated one (Melero et al. 1992). In bone marrow transplanted patients (a group of patients that often suffer from malignancies as well) the disease has unique characteristics that make diagnosis very difficult, such as involvement of extrapulmonary organs or atypical signs and symptoms. Atypical radiographic signs can also appear in pneumonia (Libshitz et al. 1997). Some of these presentations can go unrecognised until the death of the patient (Libshitz et al. 1997; Morii and Narita 1998; Muller et al. 1980; Rosenthal et al. 1975). An aggressive approach must be taken for an early diagnosis of these patients, including the taking of biopsies or the performance of bronchoscopic procedures. Proper therapy must then be performed using common schemes. Screening using the Mantoux technique must be done in patients who are going to receive aggressive chemotherapy, as the latter can induce severe immunosuppression (Morii and Narita 1998). In patients with a positive skin test, chemotherapy with isoniazid is indicated. 7.3 In solid organ cancers, tuberculosis is mainly pulmonary, and extrapulmonary or disseminated Special Groups (3). Malignant Diseases disease is less common (Libshitz et al. 1997). The Tuberculosis in cancer patients does not seem to have highest incidence is seen in head and neck cancer, very different characteristics to that in the general lung cancer and gastrointestinal cancer (Kumar et population, despite an increased incidence of the dis- al. 1999; Libshitz et al.I997). Pulmonary tuberculosis ease (Libshitz et al. 1997). However, some neoplastic and lung cancer can appear simultaneously, and in diseases have special characteristics that can affect some series the relation between these diagnoses is more frequent than other associations (Libshitz et the course of the disease. Haematological malignancies have a higher al. 1997). Nevertheless, in other series the incidence incidence of tuberculosis than solid organ cancers of simultaneous diseases and sequential diseases is (Libshitz et al. 1997; Melero et al. 1992). Among similar (Tamura et al. 1999). The location of tubercuthese malignancies, acute leukaemia and Hodgkin losis and lung cancer can be the same (in one series lymphoma have an even higher incidence than other M. tuberculosis was cultured from collapsed lobes in diseases (Advani and Banavali 1989; Libshitz et al. patients with lung cancer (Libshitz et al. 1997» or 1997; Melero et al.I992). The patients with these hae- different (Tamura et al. 1999). A normal radiographic matological disorders have impaired immunity. This pattern can appear if HIV infection is associated with is due to the disease itself and to cancer treatments, cancer and tuberculosis (Libshitz et al.I997). Because which can include radiotherapy, chemotherapy, of the risk of simultaneous infection and neoplastic corticosteroids and even bone marrow transplant. disease, samples for diagnosis should be sent to both

Tuberculosis in Special Groups and Occupational Hazards

microbiology and pathology laboratories. If cancer and tuberculosis appear in a sequential pattern, the disease seems to be more severe. This could be due to a greater debilitation of the patients during cancer therapy (Libshitz et al. 1997).

7.4 Special Groups (4). Drug Abusers Drug abusers have distinct characteristics that affect the course and management of concurrent tuberculosis. Many of them are outcasts and have antisocial behaviours, such as criminality or erratic behaviour (including auto-medication or even trading with the pills to obtain money or drugs), which are a serious hazard to the correct treatment of any disease. An important number of them also have other important risk factors, such as HIV infection, malnutrition or bad hygienic practices. The close association between HIV infection and intravenous drug abuse makes it difficult to differentiate between the role of the two factors in the development of the disease. Relatively little is known about the immune system in drug abusers. In the case of HIV-infected patients, the effects on the immune system of the HIV are so important that they minimise other possible defects. However, in HIV-non-infected patients, immune defects can also be found. In this group of intravenous drug abusers serum IgM and IgG levels are frequently elevated (Brown et al. 1974), and this elevation is usually accompanied by autoantibodies. The repeated injection of antigens is a possible explanation for the hypergammaglobulinaemia. Tcell function is also altered, as several in vitro studies with T-Iymphocytes have shown (Levine and Brown 2001). Delayed hypersensitivity skin test reactions are sometimes diminished or absent. Both increases and decreases in the T-Iymphocyte cell count have been reported. Morphine depresses several monocyte functions affecting antiviral defence and it also inhibits the monocyte response to activating stimuli (Stoll-Keller et al. 1997). Some studies describe the effects of morphine and, to a lesser degree, methadone on the neutrophil-monocyte system. The clinical implications of these in vitro findings are, however, unknown (Levine and Brown 2001). The relation between tuberculosis and intravenous drug abuse has been well known for many years (Perlman et al. 1995). Recent reports show rates of 44% positive Mantoux test for HIV-negative intravenous drug users (Daley et al.1998) and a 6.8% rate for

97

tuberculous disease among intravenous drug abusers (Friedman et al. 1996). Other studies have described drug abuse as a statistically significant risk factor for tuberculosis in the general population (Iftigo-Martinez et al. 2000; Moro et al. 2002). Drug abuse is linked to unemployment and low socio-economic status. In these population groups tuberculosis is a prevalent disease. Many intravenous drug users also have a previous history of imprisonment or homelessness. These circumstances increase the risk of tuberculosis, as will be explained further in the chapter. The AIDS epidemic has also affected the relation between drugs and tuberculosis. AIDS patients have a high risk for development of tuberculosis, both when they are positive for the tuberculin skin test and when they are anergic (Selwyn et al. 1992). In these patients, "atypical" presentations of the disease are also found, including a higher percentage of extrapulmonary or disseminated disease (Havlir and Barnes 1999; Hill et al. 1991; Small and Fujiwara 2001). In recent years, outbreaks of multidrug-resistant tuberculosis with extremely high mortality have been reported (Perlman et al. 1995). In these outbreaks, primary progressive disease has been described and many of the patients in these outbreaks were also intravenous drug abusers. Diagnosis of tuberculosis in intravenous drug abusers is affected by the presence of concomitant HIV infection and also by the association of other infections at the moment of diagnosis. This can mask clinical data, so clinicians should rule out tuberculosis in any drug abuser who presents with fever (Hamburg and Frieden 1994). Screening of tuberculous infection is also difficult in these patients as HIVinfected patients are generally anergic. In this setting a single skin test does not predict the development of tuberculosis (Friedman et al. 1996; Perlman et al. 1995; Selwyn et al. 1992). Moreover, recent data suggest that anergy tests are not reproducible, so it is not recommended to perform these tests in HIV patients anymore (Havlir and Barnes 1999). The use of chemoprophylaxis in infected patients has been proved to be effective in preventing the development of active disease (Gourevitch et al.1998; Selwyn et al.1992; Snyder et al.I999). However, recent studies have shown that chemoprophylaxis does not reduce the incidence of disease in HIV anergic patients, so in these cases it is not currently indicated (Daley et al.1998; Havlir and Barnes 1999). Treatment of the active disease has also been shown to be effective (Small and Fujiwara 2001), although in HIV patients some modifications should be made. In these patients, therapy with protease

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98

inhibitors and reverse-transcriptase inhibitors for the treatment of HIV infection complicates the therapy of tuberculosis because they interact with rifampin. The administration of this antibiotic can result in sub-therapeutic levels of antiretroviral drugs. In these cases, rifabutin, a rifampin derivative, can be used with efficacy instead of rifampin in the common regimens (Havlir and Barnes 1999; Small and Fujiwara 2001). However, the main problem in performing a proper anti-tuberculous therapy remains in the low compliance of these patients. A great number of intravenous drug abusers abandon therapy, and the sequels of this include therapeutic failure, prolonged infectivity, increased rates of transmission and the development of drug-resistant strains (Perlman et al. 1995). Several mechanisms have been developed in order to increase compliance among these patients. Directly observed therapy (DOT) is a strategy that has proved useful for the treatment of low compliance patients (Gasner et al. 1999; Perlman et al. 1995). However, some patients refuse any therapy. Legal measures have been developed for these cases, including the arrest of these patients during the treatment period (Gasner et al. 1999). These measures, however, must be restricted to only a few "impossible" patients who refuse any therapeutic measure (including DOTs), so arrest should remain only as the last resort to cure patients in tuberculous programmes.

7.5

Special Groups (5). Correctional Facilities

Prisons and other correctional facilities, such as jails, penal colonies and prisoner of war camps, represent a very special community for different reasons. Prisoners are often young males from socio-economically disadvantaged groups, poor educational backgrounds and ethnic minorities, including illegal immigrants. Prison conditions frequently include overcrowding, high incidence of HIV-infected individuals and low standards of hygiene. In addition, several behaviours, such as drug abuse and sex between men, often promote illness. Many of these circumstances, for example overcrowding, increase the risk of transmission of airborne infectious diseases, and HIV infection is considered the strongest known risk factor for the development of tuberculosis (Centers for Disease Control 1996). Moreover, correctional facilities are not closed environments; so many people circulate between the prison and the open society (Fig. 7.1).

These include liberated prisoners, but also workers and visitors. A history of previous imprisonment is one of the statistically significant risk factors for tuberculosis in some reports (Inigo-Martinez et al. 2000; Moro et al. 2002). Prisons are among the communities with the highest incidence of tuberculosis. Many reports have published annual case notification rates as high as 7200 cases/l00,000 (Coninx et al. 2000; Koffi et al. 1997; Wares and Clowes 1997) and even in developed countries, rates are several times higher than those of the general populations (Jones and Schaffner 2001; Fernandez-Martin et al. 2000; Centers for Disease Control 1996) (Table 7.1). An obvious consequence of this is the high risk of becoming infected for all the people who dwell in these institutions, especially when the period of imprisonment is long. Molecular epidemiology analysis confirmed internal transmission of tuberculosis inside correctional facilities, with more then 25% of the patients appearing in clusters (Fernandez-Martin et al. 2000; Laniado-Laborin 2001). This is true even if the time that the prisoner spends in the correctional facility is shorter than in prisons (Jones et aI.1999). Other problems include delay in the diagnosis of sputum smear-positive cases, failures in medical services, transfer of infectious patients inside and between prisons, and patients with low compliance for therapy. The diagnosis of these patients can be difficult because of the concomitant existence of other factors, such as HIV infection, that can increase the possibility of extrapulmonary, disseminated or even atypical forms of the disease. Other factors that could affect the diagnosis are of another nature: in some prisons, patients with disease sell smear-positive sputa to other prisoners so that they can avoid hard labour (Drobniewski 1995) or have access to better living conditions Non-infected Prisoners

i

__________

Infected"Prisoners ----------. Prisoners with active tuberculosis

Non-infeited prison workers

t Infected prison workers

~

Prison workers with active disease _

/

Outer Society

: Risk of contagion

-+ : Possible evolution of the patients

Fig.7.1. Relation between different kinds of patients in the correctional setting

Tuberculosis in Special Groups and Occupational Hazards Table 7.1. Incidence of tuberculosis in correctional facilities Location of correctional facility (year)

Annual rate (per 100,000)

Tomsk, Russia (1996) Azerbaijan (1994) Bouake, Cote d'ivoire (1990-1995) Madrid, Spain (1997-1998) Memphis, USA (1995-1997) New York, USA (1993)

7,000 4,667 7,200 693 274 139.3

in the prison hospital. Power structures in prisons also have direct implications in the management of tuberculosis, affecting detection and treatment of patients (Reyes and Coninx 1997). The therapy of diagnosed cases is also problematic. Some patients use the pills for trading with other prisoners or even correctional workers. Other prisoners manage to obtain the pills and take the drugs without proper medical and control. This inadequate therapy can lead to the development of resistant strains. This risk must be added to the bad compliance of many patients that implies the abandonment of therapy after a few weeks, especially if the prisoner is liberated and no specific programme exists to co-ordinate the correctional medical structure efforts with the open society structures. Sometimes, when anti-tuberculous drugs are scarce, a black market for these drugs can appear, especially if tuberculosis is an important problem in the facility (Coninx et al. 2000). This fact can be of extreme importance in the prisons of developing countries, where drug are not always available. Mobility of prisoners is another factor that can extend the disease between prisons, as prisoners can be transferred when they are still infectious (Reyes and Coninx 1997). This contributes to the transmission of multidrug-resistant strains, as in New York in 1991 (Drobniewski 1995). Proper measures must be implemented to minimise the problem of tuberculosis inside correctional facilities. These measures are based in a few clear points: rapid detection of patients with tuberculous disease, isolation and therapy for these cases, detection of infected patients and the institution of chemoprophylaxis when indicated. The pivotal measure for tuberculosis control is the active detection of infectious cases. This detection must be done using screening tests, such as symptom screening, tuberculin skin test or chest radiograph screening (Centers for Disease Control 1996). The selection of the initial screening test must be done according to the individual characteristics of each centre.

99

Symptom screening is useful in areas where tuberculosis prevalence is high. The presence of prolonged productive cough, fever, haemoptysis and other systemic symptoms (malaise, weight loss, etc.) suggest the possibility of active tuberculosis. In these cases, proper diagnostic measures must be performed, including radiological and microbiological tests, and also a careful medical history taken about previous episodes or treatments. The performance of chest radiographs for all symptomatic patients is always indicated. There are also studies showing cost-effective use of chest radiographs for all the prisoners in areas with high prevalence (Jones and Schaffner 2001). The results of chest radiography must be interpreted together with a careful medical history, and other diagnostic tests are indicated if there is suspicion of active tuberculosis. The Mantoux test is the preferred tuberculin skin test. However, its interpretation must be cautious in this setting, because there are areas where BCG vaccination is currently used. The high prevalence of HIV-infected patients can also affect the results, as severely immunocompromised patients have negative test results. All patients with positive skin test should be medically evaluated and other tests (like radiographs or sputum analysis) must be performed if indicated. Negative skin test individuals without anergy should be tested again periodically. Screening tests should be done both for correctional inmates and for correctional workers, because both groups have a high risk of infection. The earlier the detection of these patients, the less is the risk of infection for other people, as diagnosis must lead to proper isolation measures and initiation of therapy. Isolation measures are recommended for patients with respiratory tuberculosis. They will need transport to hospital if the prison lacks proper isolation measures. Therapy must be performed according to common protocols. It must be directed observed therapy (DOT), as there is a low level of compliance in many patients. DOT assures therapy of the patients and minimises the risk of developing resistances. Preventive therapy with isoniazid (6-12 months) is recommended also for infected individuals without active disease. Anergic HIV-infected patients should also receive prophylaxis because of the high risk of development of active tuberculosis in these patients (Selwyn et al. 1992). Co-ordination between correctional administrations and health programmes outside correctional facilities is essential, as many patients abandon therapy

J. Esteban

100

when they are liberated. Active searching and followup of these patients by tuberculosis programmes in the different communities should ensure the proper therapy of these patients and minimise the risk of relapse, therapeutic failures or development or resistances (Maher 1998; Centers for Disease Control 2000).

7.6 Special Groups (6). Shelters Homelessness is one of the risk factors for the development of tuberculosis, with estimated prevalences from 1.6% to 6.8% (Centers for Disease Control 1992a). Among these individuals, other risk factors for tuberculosis are found, such as malnutrition, poor hygiene, immigration from countries with high prevalence of the disease, substance abuse (both alcohol and/or intravenous drugs) and, in recent years, HIV infection (Centers for Disease Control 1992a; Moss et al. 2000). It is difficult to determine the true role of each of these factors, as they all playa role. However, an important fact is the recent finding of a high proportion of clustering when molecular epidemiology studies are applied to this population (Gutierrez et al. 1998; Moss et al. 2000). These data suggest a high proportion of transmission of tuberculosis in this population. Shelters and other provisional dwellings are considered as foci where transmission of the disease occurs and shelter-associated tuberculosis outbreaks have been described (Nardell et al. 1986). Because of the difficulties of establishing an adequate prevention programme in shelters, measures should be directed at rapid diagnosis and treatment of infectious cases (Stead 1989). Clinical characteristics of tuberculosis in this group are similar to the general population and variations in them are due to the presence of other concomitant factors, such as HIV infection. Thus, people with symptoms and signs of pulmonary tuberculosis should be studied with chest radiographs and, if available, proper microbiological studies. When the diagnosis of tuberculosis is made, therapy should be started using common therapeutic regimens (Centers for Disease Control 1992a). The most important variable in the outcome of these patients is the low compliance that many of them have. Directly observed therapy is indicated for these difficult cases, and even hospitalisation throughout all the treatment is indicated in individuals that have mental diseases that incapacitate them to follow the therapy. Several incentives have been recommended to increase the adherence to therapy, such as travel

tickets, food, clothes or even money. These incentives have proven to be effective in increasing the compliance of these patients (Centers for Disease Control 1992a; Moss et al. 2000). Contact study of the infective cases is more difficult. The mobility of this population makes them difficult to study. Other troublesome factors are the use of aliases by the patient or the potentially infected persons. Tuberculin skin test positive patients who were treated with isoniazid are not entirely free of risk, as shown by one of the first studies to describe an outbreak among these populations (Nardell et al. 1986). The frequent description of clustering supports this finding, even in populations with high prevalence of latent infection (Moss et al. 2000). However, if tuberculin skin testing is performed, the concomitant presence of factors such as HIV infection among these patients must be taken into account (Centers for Disease Control 1992a). Structural measures in the shelters have also been considered as useful to prevent transmission of the disease. The use of ultraviolet lamps has been recommended to disinfect the air. These lamps, however, must be installed appropriately to minimise the risk of eye and skin lesions. Enhanced ventilation systems could also help to reduce the airborne transmission of the disease (Centers for Disease Control 1992a).

7.7 Special Groups (7). Immigrants In the early years of the twenty-first century, immigration from many countries to more developed ones has become a problem of great importance. The migratory movements of populations between countries have become more frequent, and this represents an easy route for transmission of infectious diseases from one place to another. Tuberculosis prevalence is higher in countries from Africa and Asia, according to the WHO data (World Health Organization 2001). Movements affecting people from these high prevalence areas are of great interest because they can affect the control programmes of other countries. As a matter of fact, they have been considered the cause of resurgence of the disease in Western countries (Rieder et al. 1994). In our hospital, the relative percentage of immigrants with tuberculosis has gone from 5.05% in 1995 to 21.8% in 2000. This data probably explains the maintenance of tuberculosis rates in our area, despite the decreasing incidence in the local population (Dr. M.C. Alvarez-Castillo, personal

101

Tuberculosis in Special Groups and Occupational Hazards

communication, and Epidemiological Bulletins from grants and transmission between them (Lillebaek et al. 2001).A possible explanation is the low social conthe Comunidad de Madrid) (Figs. 7.2 and 7.3). Illegal immigration adds more problems to the tact that exists between the two communities. Other control of the potentially infected population. A reports suggest that tuberculosis in immigrants is the study from Spain, a country frequently crossed by result of reactivation and not of primary disease due immigrants en route to other European countries, to recent infection (Chin et al. 1998; Moro et al. 2002; detected that 78% of the immigrants with active Samper et al. 1998). tuberculosis were illegal ones (Huerga et al. 2000). Drug resistance among these patients is also a risk This population involves more factors that compli- to be taken into account. Resistance rates in many cate the management of patients, such as overcrowd- countries from which immigrants go to Western states ing, language difficulties, poverty, fear to go to health are high (The WHO/IUATLD Global Project on Anticare facilities and frequent imprisonment. All these tuberculosis Drug Resistance Surveillance 1994-1997, factors probably affect the therapy compliance in 1997). When these patients develop tuberculous disthese patients, and compliance is even lower for che- ease this data is of great importance in the planning moprophylaxis of infected patients without active of proper therapeutic regimens. Multidrug-resistance disease (Duran et al. 1996). However, strict follow-up is also important in these patients (Fig. 7.4). Antimiand other complementary measures, such as the use crobial susceptibility testing is indicated in patients of the patient's language for examinations, made it who come from world areas with high resistance rates possible to increase the compliance of tuberculous against anti-tuberculous drugs, as these rates are carried on by this group of patients (Huerga et al. 2000). patients to 78% (Huerga et al. 2000). The potential transmission of tuberculosis from immigrants to local population is a theoretical risk. However, a Danish study showed only minor transmission between these populations. This study 7.8 performed a molecular epidemiology analysis Occupational Hazards (1). using both RFLP and spoligotyping, and found only Health Care Workers nine minor clusters in both Danish and immigrant patients. Many other clusters were found, suggesting Among the different professions, health care workers the existence of predominant strains between immi- are at this time almost unanimously considered a spe-

50

45 40

35 30 25

20

15 10

District 7

5

o

1996

1997

1998

1999

Fig. 7.2. Incidence of tuberculosis (No. cases/lOO,OOO inhabitants). Comunidad de Madrid and District 7. 1996-1999

Fundaci6n Jimenez Diaz 5L--~-­

o

1996

1997

1998

1999

Fig. 7.3. Percentage of tuberculosis in immigrants. Fundaci6n Jimenez Diaz, Comunidad de Madrid and District 7Madrid (District 7 includes Fundaci6n Jimenez Diaz) 1996-1999

102

Fig.7.4. Multidrug-resistant tuberculosis in an immigrant patient

cial kind of worker with a higher risk of tuberculous infection than other workers or the general population. However, this common idea has not always been considered an unquestionable fact. It was not until the decade of 1950s that the increased risk for health care workers was recognised, in the years before that there were even several authors that considered the health care worker a profession with a lower risk of being infected than other people (Sepkowitz 1994). Nowadays, at least in developed countries, health care facilities are institutions where contact between workers and tuberculous patients is a frequent matter, chiefly in those hospitals where the number of tuberculous patients is high. In our experience, the majority of diagnoses of tuberculosis were made in the hospitals, where patients go when they are acutely (or even moderate chronically) sick. These are also the institutions where tuberculous patients spent at least the first days of their therapy. In some cases, the patients could spend several days undiagnosed, until a proper diagnosis was made after performing several tests of different kinds in different areas of the hospital. Even in a few cases death occurred and the diagnosis was delayed until autopsy or cultures gave the final results (Esteban et al. 2001bj Flora et al. 1990; Kramer et al.1990; Rosenthal et al.I975). Delay in diagnosis is a problem common in those hospitals or institutions where tuberculosis prevalence is low

J. Esteban and it affects only a minority among all the patients. However, this delay could have very important consequences. Health care workers could be infected because no proper preventive measures were taken before the diagnosis, as has been demonstrated in epidemic outbreaks (Frampton 1992; Griffith et al. 1995; Pearson et al. 1992) and, recently, in an environment where there was no outbreak (Greenaway et al. 2002). However, it is important to discriminate between the risk of infection and the risk of developing the active disease. Historical data concerning the last topic showed an increased incidence in nurses that could be as high as 500 times higher than in the general population (Sepkowitz 1994). Recent reports, however, have shown incidences analogous to that of the overall population (Capewell et al. 1988) or even lower (Raitio and Tala 2000). The low prevalence of tuberculosis and other risk factors for developing disease (such as HIV infection), together with BCG vaccination, has been considered in one of these reports as the explanation for this phenomenon (Raitio and Tala 2000). Speed in the detection of infectious cases and, again, BCG vaccination, are the reasons shown in the other article (Capewell et al.1988). Moreover, it must be taken into account that health care workers are usually healthy young people, without clear risk factors for developing tuberculosis, except for a few individuals (the healthy worker effect; Menzies et al. 1995). Probably the reasons for these data are difficult to find and possibly they are multifactorial. However, the risk of developing tuberculosis has been clearly recognised in several reports of outbreaks, including some due to multidrug-resistant strains (Griffith et al. 1995; Menzies et al.1995), so it must still be considered, mainly in some special circumstances. The risk of infection has also been considered another hazard of work in health care workers since the same time that the risk of tuberculous disease was acknowledged. Historical data documented conversions as high as 100% among health care workers (Sepkowitz 1994). More recent data indicate a high risk of infection among these workers (Louther et al. 1997; Menzies et al. 1995; Schwartzman et al. 1996), although clearly lower than the previous reports. Global annual infection risk has been reported between 0.2-10% (Menzies et al.1995). This risk could be even higher in outbreaks (Griffith et al.1995; Pearson et al. 1992; Wenger et al. 1995). However, not all health care workers, or even all health care facilities, had identical risks. More detailed studies indicated that the risk of infection is related to the number of tuberculous patients admitted by the hospital,

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Tuberculosis in Special Groups and Occupational Hazards

the contact between these patients and the different workers and other factors such as inadequate ventilation or delay in the diagnosis (Boudreau et al. 1997; Greenaway et al. 2002; Louther et al. 1997; Menzies et al. 1995,2000; Schwartzman et al. 1996). Hospitals with fewer than ten tuberculous patients/year of less than one patient with active disease/l00 workers per year had fewer Mantoux conversions than those with a higher number of admissions due to tuberculosis (Menzies et al.1995; Schwartzman et al.I996). Nurses are among those categories of workers with high conversion rates in many studies (Boudreau et al. 1997; Griffith et al. 1995; Ktsanes et al. 1986; Louther et al. 1997; Schwartzman et al. 1996), even when they are still students (Esteban et al. 2001a; Lainez et al. 1999; Sepkowitz 1994; Weiss 1973). However, other conditions such as housekeeping, ward clerks and workers in a bronchoscopy department have been documented as having high risk of infection (Boudreau et al. 1997; Louther et al. 1997; Schwartzman et al. 1996). Preventive measures has also been described for health care workers since the decade of 1930 (Sepkowitz 1994). Nowadays, several guidelines have been published where the measures for protecting the workers against infection are clearly specified (Centers for Disease Control 1994; Joint Tuberculosis Committee of the British Thoracic Society 2000; Moreno-Guillen et al. 1997), although these are not always adequately implemented in daily routine (Sutton et al. 2000). These measures have obviously been developed for respiratory disease, which is considered as contagious because tuberculosis is transmitted through respiratory secretions in most cases, although there are reports of infection due to extrapulmonary tuberculosis (Frampton 1992; Hutton et al.I990). Two important groups of measures could be defined: proper isolation measures and a programme of tuberculin screening for the workers. Isolation measures (Table 7.2) include both structural and personal protective measures. Structural interventions include the isolation of infectious patients in individual rooms with proper ventilation. Several reports of outbreaks defined poor ventilation as the cause, at least in part, of the contagion (Menzies et al. 1995). Another report also described poor ventilation as an important risk factor for infection in a non-outbreak setting (Menzies et al. 2000). Rooms with negative pressure are therefore recommended for isolation (Centers for Disease Control 1994). These rooms must have the door closed and at least six changes of air per hour (Centers for Disease ControI1994). Other structural measures, such as the use

Table 7.2. Recommended isolation measures for patients with tuberculosis Subject

Specific measure

Patient lodgings

Private room with negative pressure. Door must be closed Biosafety respirators (N95) Limited to strictly necessary. The patient wears a surgical mask during transportation Hand washing Gloves when necessary Face protection when necessary Clean, non-sterile gown Proper management of sharp devices Minimise aerosols or other exposures to samples

Respiratory protection Patient transport

Standard precautions

of ultraviolet lamps, have also been recommended as useful and cheaper than the negative pressure isolation rooms (Hannan et al. 2000; Menzies et al.I995). Protective measures for individuals are directed at blocking the access of infectious particles to the lower respiratory tract. For this purpose, wearing a mask is the measure recommended. However, not all the masks offer similar protection. Classical surgical masks are designed to avoid contamination from the person who wears it. However, they are not designed to protect that person, and there are reports where failure of these masks to protect health care workers has been documented (Sokolove et al.I994). Because of this fact, surgical masks are only recommended to be worn by the infectious patients when they are outside the isolation room (Centers for Disease Control 1994; Moreno-Guillen et al. 1997). Dust and HEPA respirators are designed to minimise the risk of a particle of a minimal size (l fl) reaching the alveolus. Because there are differences in the percentage of filtration efficacy, Centers for Disease Control and other protocols recommend the wearing of respirators with at least 95% of efficiency and the capacity to filter particles of 1 fl. These recommendations have been adopted by other guidelines (Centers for Disease Control 1994; Moreno-Guillen et al. 1997). However, there are reports where the efficacy of the different kinds of respiratory protection is similar (Catanzaro 1995). Another difficulty is how to evaluate one single measure if other additional isolation measures have been taken, and it is impossible to estimate the degree of protection that is due to each single measure. Because of all these data, it seems wise to use the recommended respirators if possible, but when they are not available, wearing a surgical mask probably offers a certain degree of protection that is better than nothing.

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The other great pillar in the measures for protection of health care workers is the programme for detection of recent infections and treating them through tuberculin skin testing and proper isoniazid chemotherapy (Bolyard et al. 1998; Centers for Disease Control 1994; Joint Tuberculosis Committee of the British Thoracic Society 2000; Moreno-Guillen et al. 1997). The programme is based on the performance of a two-step initial test for those workers who are negative in the first test to minimise the risk of a booster reaction that could be considered as a conversion, and the periodical re-testing of those workers that were negative in the previous test (Bolyard et al. 1998). However, in our experience and also the experience of others (Clague et al. 1991), it could be very difficult to develop a tuberculin programme in hospital. The tuberculin skin test is different from other tests performed in a protocol of health control because it must be performed on one day and read on another. This fact seems to be of great importance, and there are many workers that do not go to the reading of the test because they estimate that the result "is negative". Moreover, if it is difficult to convince the workers to perform one test, the two-step test for negative ones is even more difficult to perform, so, in some guidelines, this two-step test is not recommended for all the workers and must be individually evaluated (Moreno-Guillen et al. 1997). The periodicity to perform the test is another problem, because if it is performed too frequently (according to the worker's idea), the worker will not go to have the test the next time. BCG vaccination is recommended in some guidelines (Joint Tuberculosis Committee of the British Thoracic Society 2000), although many others do not recommend it for all workers (Centers for Disease Control 1994). However, the use of BCG vaccination could be indicated for some health care workers in some special conditions, such as outbreaks of multidrug-resistant tuberculosis (Bolyard et al. 1998). As in the case of the use of respiratory protections, in these cases a certain degree of protection is better than nothing.

7.9 Occupational Hazards (2). Laboratory Workers Laboratory workers are a special category among health workers because their risk has special characteristics. Laboratory workers are not usually exposed

J. Esteban to contagion by the usual route (contact with a patient with active respiratory tuberculosis), but they are exposed to infection through manipulation of clinical samples or cultures. Because tuberculosis is a disease mainly airborne transmitted, procedures that imply aerosol formation have infection risk. In a laboratory, aerosol-producing activities include subculturing and streaking cultures, cooling and flaming loops, pipetting for mixing microbial suspensions, needle and syringe manipulations, centrifugation of samples and cultures, mixing and homogenising procedures (use of shakers, homogenisers, blenders, sonicators and other mixing instruments such as vortex) pouring fluids, open culture containers (including plates or tubers), spillage of infectious material, lyophilisation and filtration under vacuum and even egg inoculation and harvesting (Sewell 1995). Other risk procedures include manipulation of samples or tissues from infected patients for processing, as done in microbiology and pathology departments. Even direct inoculation of cultures has also been reported as the cause of tuberculosis in a laboratory and must be taken into account when working with pure cultures of the organism (Peerbooms et al. 1995). The recent introduction of automated liquid cultures for rapid detection of mycobacteria introduces another potential risk, because inoculation of samples and extraction of liquid from positive cultures are done using syringes and this manipulation has the risk of creating aerosols (Richmond et al. 1996). Several reports have stated that laboratory workers have a risk of infection two to nine times higher than the general population (Grist and Emslie 1994; Harrington and Shannon 1976; Sewell 1995) There is a report in which incidence of infection was as high as 100 times the frequency observed in the general population (MUller 1988). The progressive lowering of the incidence of tuberculosis has been claimed as the cause of the decrease in the number of these infections. This is seen in pathology laboratories rather than in microbiology ones (Grist and Emslie 1994). In a recent report, laboratory personnel did not have the highest rates of infection among health care workers, and their rate was even lower than the global rate (4.4 conversions per 100 person/year versus 5.2 conversions per 100 person/year) (Louther et al. 1997). Probably, all these data suggest the efficacy of the safety measures implemented in the laboratories. Mycobacterium tuberculosis is an organism included in the biosafety level III in most guidelines for laboratory safety when manipulation of cultures is performed (Anonymous 1997; Richmond et al. 1996; Richmond and McKinney 1999), although procedures such as

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preparation of smears for acid-fast stains only require biosafety level II measures (Richmond and McKinney 1999). The organism is considered as an agent with potential for aerosol transmission and the disease that it produces may have serious or even lethal consequences, but the risk of infection is only individual, and the population as a whole has only a minimal risk (Richmond and McKinney 1999; World Health Organization 1994). Measures to minimise this risk include a broad spectrum that goes from rooms with negative pressure that must be away from the common laboratory to the use of biosafety cabinets, protective masks, gloves and other protective clothes (Table 7.3). The biosafety level III laboratory must have special design features. A double door access to the laboratory is recommended. The mycobacteria laboratory must also be separated from the laboratory and the ventilation must be balanced to provide directional airflow into the working room (negative pressure), although in some legislation this measure is only recommended and not obligatory (Anonymous 1997). In others this measure is always considered as necessary (Richmond and McKinney 1999; World Health Organization 1994). In the era of multidrug-resistant tuberculosis, and because of the risk of dissemination of these organisms, negative pressure is a desirable objective to be achieved for all the laboratories that perform manipulation of mycobacteria cultures. However, this measure is far from being available in many laboratories. In a recent survey performed by the Sociedad Madrileiia de Microbiologia Clinica (Society for Clinical Microbiology of Madrid), in the year 2001 only 4 out of 15 mycobacteriology laboratories from the Madrid Com-

munity had negative pressure (data reported in the 2002 congress of the SMMC). Biosafety cabinets (BSCs) are a measure included as necessary in all the legislation and recommendations (Anonymous 1997; Richmond et al. 1996; Richmond and McKinney 1999; World Health Organization 1994). The design of these containment devices differs in significant ways, although both BSC classes II and I protect the laboratory worker and the environment (Richmond et al. 1996). Class II devices are also designed for protecting samples and cultures from contamination. In the case of mycobacterial laboratories, both BSC classes I and II are adequate for biosafety level II measures, but when biosafety level III measures are required (manipulation of cultures for identification or susceptibility testing, for example) a BSC class II or even class III is recommended as necessary (Richmond and McKinney 1999). Protective clothing for working is another important protective measure for workers. Wearing gloves, solid-front gowns, scrub suits or coveralls is recommended, and this equipment should not be used outside the biosafety level III laboratory. Reusable equipment must be disinfected before been laundered. Frequent hand washing is also recommended (Richmond and McKinney 1999) and in some guidelines foot-operated lavatories are also suggested as necessary (World Health Organization 1994). Respiratory protection is recommended only when BSCs are not available (Richmond and McKinney 1999). However, because of the risk of accidents due to compromise of the containment capacity of BSCs or other potential accidents (Richmond et al. 1996),

Table 7.3. Recommended laboratory facilities for working with Mycobacterium tuberculosis complex organisms in laboratories (Richmond and McKinney 1999; Anonymous 1997; World Health Organization 1994) Measures

USA

European Union

W.H.O.

Physical separation from other working areas or corridors Filtration of air through HEPA filters

Yes

Desirable

Yes

Yes, for exhausted air from cabinets Yes Yes Yes

Yes, for exhausted air

Recommended Yes Yes Yes

Yes Yes Not stated Not stated Not stated Yes

Yes Desirable Yes, for workbench, floor, walls and ceilings Desirable Yes Yes Yes Yes Yes

Yes Yes

Yes Not stated

Yes Yes

Restricted access Negative airflow into laboratory Surfaces easily disinfected The working area should be sealed for disinfection Surfaces resistant to chemicals Security storage of biological agents Window or other system for control of the workers Laboratory with full exclusive equipment Use of biosafety cabinets for manipulation of specimens and cultures Autoclave or incinerator available Self-closing, double-door access

Yes Yes Not stated Not stated Not stated Yes

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respiratory protection for working at biosafety level III is recommended, even if a BSC is currently used. Together with the biosafety level II or III measures, periodic tuberculin skin testing is recommended for laboratory workers (Richmond and McKinney 1999). This procedure should be repeated at least annually for all the workers who are Mantoux negative, and probably the frequency of re-testing should be higher for those who work in high risk areas. If an accident with a high level of exposure potential occurs, all negative tuberculin skin test workers should be retested, and then re-tested again at 3 month intervals until no new conversions are detected (Richmond et al. 1996). Chemotherapy for infected workers should be performed according to the general criteria.

7.10 Occupational Hazards (3). Silicosis The relation between tuberculosis and silicosis has been known for many centuries. In the past century many reports established high rates of tuberculosis for silicotic patients throughout the world (Rosenman et al. 1997; Small and Fujiwara 2001; Snider 1978). Local alterations of the lung, the favourable conditions for contagion in the mines, the difficulties for a rapid diagnosis and the high prevalence of tuberculosis in the population may explain the high rates of tuberculous disease among these patients. Important local alterations include the impairment of macrophage function, a cell that plays a significant role in the pathogenesis of the disease. Small particles of silica dust are ingested by macrophages. Then, the ingested particles disrupt the phagosomal membranes and their enzymes are released, causing the death of the affected cells. The lysed cells stimulate the migration of more macrophages, the proliferation of fibroblasts and the production of collagen. Sublethal doses of silica dust also affect the ability of macrophages to inhibit the growth of Mycobacterium tuberculosis (Snider 1978). The diagnosis of tuberculosis in silicotic patients may be a difficult matter. Symptoms are usually non-specific and could be due to other conditions or diseases. Acid-fast stains from the sputa of these patients are negative in many cases, probably because the tuberculous bacilli hardly reach the bronchial tree due to silicotic fibrosis. Chest roentgenogram is considered of great value in the diagnosis (Barras 1970). The appearance of new infiltrates, cavities, pleural effusion, coalescence

J. Esteban of nodules and the development of bronchial stenosis are radiographic criteria that strongly suggest the diagnosis of tuberculosis (Snider 1978), even in the presence of negative microbiological diagnosis techniques results. Accordingly, clinical and radiological data should be used to establish a diagnosis and begin adequate therapeutic regimens in these patients. Therapy of tuberculosis among these patients includes longer therapeutic regimens with the same drugs as for non-silicotic patients. Longer regimens are necessary due to the lower penetration of the drugs in the silicotic nodules. A study in Hong-Kong showed that the standard 6-month short course therapy is inadequate for these patients, as 22% of patients had bacteriological relapses in the 6-month therapy group compared to 7% of bacteriological relapses in the 8-month therapy group (Hong Kong Chest Service/Tuberculosis Research Centre and Madras/British Medical Research Council 1991). As a general recommendation, in the silicotic patient the sterilising phase must be prolonged and patients should be treated for at least 9 months. If pyrazinamide is not included in the regimen, therapy with isoniazid and rifampin must be prolonged for a minimum of 12 months (Snider 1978). Retreatment regimens must also be prolonged as much as 12 months and the follow-up of these patients should also be prolonged for 5 years. Preventive chemoprophylaxis with isoniazid has also been considered of great value in diminishing the rates of active disease. A study that compared the treatment of 825 silicotic patients with 2,408 untreated silicotic patients showed that preventive therapy with isoniazid decreases the risk of developing active disease from 2.66% to 0.32% (annual rates) (Snider 1978). Shorter courses of chemoprophylaxis with several drugs have also achieved lower rates of tuberculosis than in non-treated patients, despite its efficacy being unacceptably lower (Cowie 1996). Other studies have shown the efficacy of isoniazid chemotherapy. However, the difficulties are the same as for the therapy of tuberculous disease and longer regimens are indicated for these patients.

7.11 Occupational Hazards (4). Other Workers Other groups of workers also have high rates of tuberculous diseases. Farm workers and other workers involved in animal management are considered a

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group with high risk for tuberculosis (McKenna et al. 1996). Specific measures for the prevention of the disease in these groups have been established. Among these, it has been reported that disease rates are even higher in migrant farm workers (Centers for Disease Control 1992b; Ciesielski et al. 1991; Garcia et al. 1996; Hibbs et al. 1989; McCurdy et al. 1997; Schulte et al. 2001). This population has unique characteristics, such as overcrowding, close contact between individuals and high rates of immigrants from countries with a high prevalence of tuberculosis (Centers for Disease Control 1992b; World Health Organization 2001). Prevention and control of tuberculosis among these workers includes the following measures: rapid diagnosis and therapy of tuberculous patients, contact investigation (Mantoux test) and chemoprophylaxis of infected persons, and screening and proper therapy in immunosuppressed workers, including HIV-infected ones. Diagnosis causes no difficulties, as these patients suffer from a similar disease to that suffered among the general population. Therapy should not be performed with short-course standard schemes and, if needed, should include directly observed therapy (Centers for Disease Control 1992b). In some cases, the disease can be caused by Mycobacterium bovis rather than Mycobacterium tuberculosis in workers in contact with animals (Dalovisio et al. 1992; Fanning and Edwards 1991; Pillai et al. 2000; Thompson et al.1993). In these cases, therapy schemes should consider that M. bovis strains are intrinsically pyrazinamide-resistant, so this drug cannot be used. Proper veterinary control measures, such as detection and management of tuberculous animals, could also be useful in the control of the infection. Workers with pneumoconiosis other than silicosis also have high rates of tuberculous disease (Mosquera et al. 1994; Taguchi et al. 2000). However, in these patients the characteristics differ from those of silicotic patients, probably because of the implications of silica particles in the pathogenesis of the disease, as has been previously explained (Snider 1978). Differences in the incidence of tuberculosis can also be found between the different kinds of pneumoconiosis, depending on the material inhaled (Starzynski et al. 1996). The rates of tuberculosis are higher in workers of the metallurgical industry than in those from refractory material manufacturing plants (such as ceramics). Nine-month therapeutic regimens (2 months of daily streptomycin, isoniazid, rifampin and pyrazinamide followed by 7 months of daily isoniazid and rifampin) have proven effective in these patients with only a 5% relapse rate and an identical amount of therapeutic failures (Lin et al. 1987).

Another profession that has been reported to have unusually high rates of tuberculosis is that of funeral director (McKenna et al.1996). Tuberculous infection has also been reported to be very frequent in other funeral home employees (Gershon et al.1998).A possible explanation is the contact with infected corpses, in which the tuberculous bacilli can be cultured even if they have been embalmed (Weed and Boggenstoss 1951). This theory has been recently demonstrated in a case of tuberculosis acquired by a funeral director, which was confirmed by both conventional and molecular epidemiology (Lauzardo et al. 2001). Periodic tuberculin skin testing and the use of respiratory protection has been advised for these workers because of the high incidence rates of disease and infection (Gershon et al. 1998). Another study has reported a higher risk of tuberculosis in unemployed people (McKenna et al. 1996). This is probably linked to neglect and other risk factors that are found among unemployed people and that are different to the mere occupational ones.

7.12 Conclusion Tuberculosis is perhaps one of the oldest known human diseases. However, in the beginning of the twenty-first century, and despite the existence of a very effective therapy, this disease is still affecting humans as one of the most frequent and lethal ones. Airborne transmission favours infection in those circumstances where a concentration of tuberculous patients occurs especially if there is overcrowding, poor hygiene and bad ventilation. Moreover, recently developed aggressive therapies that are used for other diseases favour the development of active disease through alterations in the normal defences of the organism. The knowledge of these facts must lead to the development of effective measures to control the expansion of the disease. However, we must not forget that the most effective measure for the control of the infection is early diagnosis and therapy of patients with active disease. Continuous efforts must be made in this direction in order to minimise the risk of healthy people acquiring this disease that has been called "captain among these men of Death" (Daniel 1997).

Acknowledgements. I want to acknowledge Dr. Francisco G. Santos-O'Connor for his help with the English language of this document.

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110 comial de la tuberculosis. Programa regional de prevenci6n y control de la tuberculosis en la Comunidad de Madrid. Direcci6n General de Prevenci6n y Promoci6n de la Salud. Consejeria de Sanidad y Servicios Sociales, Comunidad de Madrid, Madrid, pp 65-79 Morii T, Narita N (1998) Mycobacterial infection in patients with hematologic disorders. Nippon Rinsho 56:3209-3211 Moro ML et al. (2002) Two-year population-based molecular epidemiological study of tuberculosis transmission in the Metropolitan Area of Milan, Italy. Eur J Clin Microbiol Infect Dis 21:114-122 Morris JT, Seaworth BJ, McAllister CK (1992) Pulmonary tuberculosis in diabetics. Chest 102:539-541 Mosquera JA, Rodrigo L, Gonzalvez F (1994) The evolution of pulmonary tuberculosis in coal miners in Asturias, northern Spain. An attempt to reduce the rate over a 15-year period, 1971-1985. Eur J Epidemioll0:291-297 Moss AR et al. (2000) Tuberculosis in the homeless. A prospective study. Am J Respir Crit Care Med 162:460-464 Mourad G et al. (1985) Transmission of Mycobacterium tuberculosis with renal allografts. Nephron 41:82-85 Muller HE (1988) Laboratory-acquired mycobacterial infection. Lancet ii:331 Muller K, Fopp M, Senn HJ (1980) Unrecognized atypical tuberculosepsis in generalized hematologic neoplasms. Schweiz Med Wochenschr 110:1815-1817 Munoz P et al. (1995) Tuberculosis in heart transplant recipients. Clin Infect Dis 21:398-402 Nardell E, McInnis B, Thomas B, Weidhaas S (1986) Exogenous reinfection with tuberculosis in a shelter for the homeless. N Engl J Med 315:1570-1575 Opsald R, Riddervald HO, Aas TW (1961) Pulmonary tuberculosis in mitral stenosis and diabetes. Acta Tuberc Scand 4:290 Patel R, Paya CV (1997) Infections in solid-organ transplant recipients. Clin Microbiol Rev 10:86-124 Pearson ML et al. (1992) Nosocomial transmission of multidrug-resistant Mycobacterium tuberculosis. A risk to patients and health care workers. Ann Intern Med 117: 191-196 Peerbooms PGH et al. (1995) Laboratory-acquired tuberculosis. Lancet 345:1311-1312 Perez-Guzman C, Torres-Cruz A, Villarreal-Velarde H, Vargas MH (2000) Progressive age-related changes in pulmonary tuberculosis images and the effect of diabetes. Am J Respir Crit Care Med 162:1738-1740 Perlman DC et al. (1995) Tuberculosis in drug users. Clin Infect Dis 21:1253-1264 Pillai SD et al. (2000) Failure to identify non-bovine reservoirs of Mycobacterium bovis in a region with a history of infected dairy-cattle herds. Prev Vet Med 43:53-62 Qunibi WY et al. (1991) Mycobacterial infection after renal transplantation-report of 14 cases and review of the literature. Quart J Med 77:1039-1060 Raitio M, Tala E (2000) Tuberculosis among health care workers during three recent decades. Eur Respir J 15:304-307 Reyes H, Coninx R (1997) Pitfalls of tuberculosis programmes in prisons. Br Med J 315:1447-1450 Richmond JY, McKinney RW (1999) Biosafety in Microbiological and Biomedical Laboratories. US Government Printing Office, Washington DC Richmond JY, Knudsen RC, Good RC (1996) Biosafety in the clinical mycobacteriology laboratory. Clin Lab Med 16:527-550

J. Esteban Rieder HL et al. (1994) Tuberculosis control in Europe and international migration. Eur Respir J 7:1545-1553 Rosenman KD, Reilly MJ, Kalinowski DJ, Watt FC (1997) Silicosis in the 1990 s. Chest 111 :779-786 Rosenthal T, Pitlik S, Michaeli D (1975) Fatal undiagnosed tuberculosis in hospitalized patients. J Infect Dis 131 [Suppl]:S51-S56 Roy V, Weisdorf D (1997) Mycobacterial infections following bone marrow transplantation: a 20 year retrospective review. Bone Marrow Transplant 19:467-470 Sable CA, Donowitz GR (1994) Infections in bone marrow transplant recipients. Clin Infect Dis 18:273-284 Samper S et al. (1998) The molecular epidemiology of tuberculosis in Zaragoza, Spain: a retrospective epidemiological study in 1993. Int J Tuberc Lung Dis 2:281-287 Schulte JM, Valway SE, McCray E, Onorato 1M (2001) Tuberculosis cases reported among migrant farm workers in the United States, 1993-1997. J Health Care Poor Underserved 12:311-322 Schwartzman K, Loo V, Pasztor 1, Menzies D (1996) Tuberculosis infection among Health Care Workers in Montreal. Am J Respir Crit Care Med 154:1006-1012 Selwyn PA et al. (1992) High risk of active tuberculosis in HIV-infected drug users with cutaneous anergy. JAMA 268:504-509 Sepkowitz KA (1994) Tuberculosis and the health care worker: a historical perspective. Ann Intern Med 120:71-79 Sewell DL (1995) Laboratory-associated infections and biosafety. Clin Microbiol Rev 8:389-405 Singh N, Paterson DL (1998) Mycobacterium tuberculosis infection in solid-organ transplant recipients: impact and implications for management. Clin Infect Dis 27: 1266-1277 Small PM, Fujiwara PI (2001) Management of tuberculosis in the United States. N Engl J Med 345:189-200 Snider DE (1978) The relationship between tuberculosis and silicosis. Am Rev Respir Dis 118:455-460 Snyder DC et al. (1999) Tuberculosis prevention in methadone maintenance dinics. Effectiveness and cost-effectiveness. Am J Respir Crit Care Med 160:178-185 Sokolove PE, Mackey D, Wiles J, Lewis RJ (1994) Exposure of emergency department personnel to tuberculosis: PPD testing during an epidemic in the community. Ann Emerg Med 24(3):418-421 Starzynski Z, Marek K, Kujawska A, Szymczak W (1996) Mortality among different occupational groups of workers with pneumoconiosis: results from a register-based cohort study. Am J Indust Med 30:718-725 Stead WW (1989) Special problems in tuberculosis. Clin Chest Med 10:397-405 Stoll-Keller F et al. (1997) Effects of morphine on purified human blood monocytes: modifications of properties involved in antiviral defenses. Int J Immunopharmacol 19:95-100 Sundbery R et al. (1991) A tuberculosis outbreak in a renal transplant program. Transplant Proc 23:3091-3092 Sutton PM, Nicas M, Harrison RJ (2000) Tuberculosis isolation: comparison of written procedures and actual practices in three California hospitals. Infect Contr Hosp EpidemioI21:28-32 Taguchi 0 et al. (2000) Mixed dust fibrosis and tuberculosis in comparison with silicosis and macular pneumoconiosis. Am J Indust Med 37:260-264

Tuberculosis in Special Groups and Occupational Hazards Tamura A et al. (1999) Active pulmonary tuberculosis in patients with lung cancer. Kekkaku 74:797-802 The WHO/IUATLD Global Project on Anti-tuberculosis Drug Resistance Surveillance 1994-1997 (1997) Anti-tuberculosis drug resistance in the world. World Health Organization, Geneva Thompson PJ et al. (1993) Seals, seal trainers, and mycobacterial infecion. Am Rev Respir Dis 147:164-167 Turner WM (1951) Pulmonary tuberculosis and diabetes mellitus. Quart J Med 26:31 Wares DF, Clowes CI (1997) Tuberculosis in Russia. Lancet 350:957

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Weiss W (1973) Tuberculosis in student nurses at Philadelphia General Hospital. Am Rev Respir Dis 107:136-139 Wenger PN et al. (1995) Control of nosocomial transmission of multidrug-resistant Mycobacterium tuberculosis among healthcare workers and HIV-infected patients. Lancet 345:235-240 World Health Organization (1994) Manual de bioseguridad en ellaboratorio. World Health Organization, Geneve World Health Organization (2001) Global tuberculosis control. WHO report 2001. WHO/CDS/TBI2001.287. World Health Organization, Geneva

Microbiology, Immunology, Pathogenesis and Pathology

8

Microbiology of Tuberculosis A. Ow OSOBA

CONTENTS 8.1 8.2 8.3 8.3.1 8.3.2 8.3.2.1 8.3.2.2 8.3.2.3 8.3.3 8.3.3.1 8.3.3.2 8.3.3.3 8.3.4 8.4 8.4.1 8.4.2 8.4.3 8.4.4 8.4.5 8.4.6 8.4.7 8.5 8.5.1 8.5.2 8.5.3 8.5.4 8.5.5 8.5.6 8.5.6.1 8.5.7

Aetiology and Morphology 115 Characteristics of Mycobacteria 116 Laboratory Diagnosis of Mycobacteria 117 Specimen Collection 117 Microscopic Examination 118 New AFB Detection Methods 119 Specimen Preparation and Culture 119 Liquefaction and Decontamination 119 Culture Media for the Isolation of Mycobacteria 120 Solid Media 120 Liquid Automated Culture Systems 122 Inoculation and Incubation Procedure 123 Identification of Mycobacteria Species 123 Molecular Techniques for Identification of Mycobacteria 123 Nucleic Acid Probes for Actively Growing Mycobacteria 123 The Accuprobe System 124 The BDProbe Tec ET 124 The Amplified Mycobacterium Tuberculosis Direct (MTD) Test 124 Amplicor M. Tuberculosis (PCR) Test 125 Ligase Chain Reaction (LCR) 125 Other Molecular Techniques 125 Antimicrobial Susceptibility Testing 126 Conventional Methods of Susceptibility Testing 126 Radiometric Method of Drug Susceptibility Testing 126 Non-Radiometric Methods of Drug Susceptibility Testing 127 The Mycobacterial Growth Indicator Tube (MGIT) System 127 The MB/BacT Microbial Detection System 127 Genetic Approach to the Detection of Drug Resistance by M. tuberculosis 127 Line Probe Assay (LIPA) 128 Newer Techniques of Drug Susceptibility Testing 128

A. O. OSOBA, MD, FRCPath (UK), FFPath (Ireland), FWACP Consultant & Head of Microbiology, King Khalid National Guard Hospital, P.O. Box 9515, Jeddah 2143, Saudi Arabia

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

8.5.7.1 8.5.7.2 8.5.7.3 8.6 8.6.1 8.6.1.1 8.6.1.2 8.6.2 8.6.2.1 8.6.2.2 8.6.2.3

Luciferase-based Reporter Phage 128 Epsilometer (E-) test 128 Hybridisation Protection Assay (HPA) 128 Serological Diagnosis of Tuberculosis 129 Immunochromatographic Tests 130 ICT Tuberculosis Test 130 Rapid Test TB 130 Enzyme-linked Immunosorbent Assays 130 Tuberculosis IgA EIA 130 The Pathozyme TB Complex Test 130 PATHOZYME-MYCO IgG, IgA, and IgM Tests 130 References 131

8.1

Aetiology and Morphology

Tuberculosis is caused by Mycobacterium tuberculosis. The word tuberculosis is derived from the word tubercle, meaning a small lump or nodule (Wolinsky 1988). The disease was first described by Jean-Antoine Villemin, a French military doctor in 1868, when he successfully transmitted the infection to rabbits by inoculating them with material from man and cattle. He later showed that scrofula (tuberculous cervical lymphadenitis) and pulmonary tuberculosis were different manifestations of the same disease (Grange 1984). The organism was first isolated in pure culture by Robert Koch in 1882. The characterisation of the isolate led to the famous Koch's postulates, providing concrete evidence of M. tuberculosis as the causative agent of tuberculosis. In 1896, Lehmann and Neumann described the genus of Mycobacterium, which included M. tuberculosis and M. leprae, the leprosy bacillus. Mycobacterium tuberculosis has been classified in the genus of Mycobacterium, which belongs to the family of Mycobacteriaceae of the order of Actinomycetales. In this order are the families of Actinomycetaceae and Streptomycetaceae. In the order of Actinomycetaceae are the genera of Actinomyces and Nocardia, while the order of Streptomycetaceae includes the genus of Streptomyces.

116

A.O.Osoha

8.2 Characteristics of Mycobacteria Mycobacteria are primarily slow-growing intracellular curved bacilli. Their main characteristic feature is their distinctive staining properties. When stained with carbolfuchsin or other fluorochrome dyes, they resist decolorisation with acid and alcohol. Hence they are sometimes referred to as "acid-fast bacilli" (AFB). Robert Koch not only cultured M. tuberculosis but was also able to stain the organism with alkaline solution of methylene blue for 24 hours. The technique was later improved by Ehrlich using a hot solution of aryl ethylene dye fuchsin. This procedure was later modified by Ziehl and Neelsen (ZN), whose names are still today used to describe the staining technique used for staining Mycobacteria (Grange

Superflcialliplds (Myoosldes. cord lactor and 5ulpholipids)

Peptidoglycan (Murein layer) "'~--f-- Upoarabinomannan

1984).

Another characteristic feature of the Mycobacteria is their unique and complex cell wall. The cell walls are rich in lipid complexes such as peptidoglycolipids (mycosides), cord factor and sulpholipids, which give the organism its shape, rigidity and colonial characteristics (Fig. 8.1). These mycosides are structurally and functionally similar to the 0 antigens of Gram-negative bacteria and determine the seroagglutination and bacteriophage susceptibility of the organism. The cord factor (trehalose dimycolate) and sulpholipids have toxic properties but their contribution to virulence has not been elucidated (Davies et al. 1996). Recently, some workers have provided evidence to suggest that lipoarabinomannan plays a significant role in virulence (Moulding 1999). The unique, lipid-rich outer membrane confers on the organism an effective barrier to prevent entry of antimicrobials into the cell and helps to resist phagocytosis as well as the immune system of the host. (Fig. 8.2 + 8.3) The Mycobacteria are aerobic, non-sporing and non-motile organisms. They appear as thin slightly curved rods and, when stained by the ZN stain, may appear beaded. They measure 0.2-0.6 by 1.0-10.0 11m in size. They are only lightly stained or weakly Grampositive by Gram's stain, which is used to stain most bacteria, due to the high lipid content of their cell wall. They are characteristically slow growing on laboratory media and have a generation time of 12-36 hours. Mammalian tuberculosis is caused by M. tuberculosis (human tubercle bacillus), M. bovis (the bovine tubercle bacillus), M. africanum, found in equatorial Africa and intermediate between the above two species, and M. microti, a rare pathogen of voles and

Fig. 8.1. A diagrammatic representation of the mycobacterial cell wall

Fig. 8.2. False electron micrograph of the surface of Mycobacterium tuberculosis (After Medicine Digest, February, 1996, Cover page)

lower mammals. They are collectively referred to as M. tuberculosis complex. M. tuberculosis grows very slowly at 35°C and may take 3-6 weeks to produce visible colonies, which are buff-coloured, rough and friable.

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Microbiology of Tuberculosis

Human infections may also be produced by Mycobacteria other than the M. tuberculosis complex. These have been referred to as atypical, anonymous or MOTT (Mycobacterium other than typical tuberculosis). However the preferred terminology nowadays is non-tuberculous Mycobacteria (NTM) (Grange 1984). The most widely used classification of Mycobacteria is that of Runyon, which is based on clinical and microbiological features of the organisms, such as rate of growth, ability to grow and produce pigment in the presence or absence of light. These features provide an important method of differentiating between the various species in a clinical laboratory (Table 8.1) (Hopewell and Bloom 1994). The characteristic features of the NTM are shown in Table 8.1.

8.3 Laboratory Diagnosis of Mycobacteria The confirmation of the clinical diagnosis of mycobacterial infection depends on the identification of the mycobacteria in smears, isolation on laboratory media, identification of the species and susceptibility testing of the isolate.

8.3.1 Specimen Collection In order to make an accurate diagnosis of mycobacterial infection, adequate and proper collection of specimens submitted for examination must be made.

Table 8.1. Runyon's Classification of Non-tuberculous Mycobacteria Runyon's group and pigment production

Species

Rate of growth (days)

Clinical features and site of lesion

M. kansasii

10-21 7-14 7-14 7-14

Rare contaminant; lung disease Rare contaminant; skin and soft tissue Rare human pathogen; lung Rarely pathogenic

M.szulgae M.gordonae

10-28 12-28 10-28

M. flavescens

7-10

Rare human pathogen; lymphadenitis Rare human pathogen; lung disease Rarely pathogenic; environmental contaminant Rarely pathogenic; environmental contaminant

Group I Photochromogens Yellow/orange pigment after exposure to light

M. marinum M.simiae M. asiaticum

Group II Scotochromogens Orange/red pigment in the dark

M. scrofulaceum

Group III Nonphotochromogens

M. avium-

(Smooth and cream coloured colonies)

M. ulcerans

10-21

Lung disease in immunocompromised patients

28-60 14-28

Buruli ulcer (Africa) Optimal growth at 42°C; lung disease Environmental contaminant Rare human pathogen; lung disease

intracellulare (MAC) M. xenopi M. malmoense

M. haemophilum

}

18-84

10-21

Optimal growth at 20-32°C; skin and soft tissue disease in immunocompromised host Rarely pathogenic; environmental contaminant Rarely pathogenic; environmental contaminant Rarely pathogenic Environmental contaminant

3-7 3-7 3-7 3-7

Environmental contaminants; ulcers Environmental contaminant; ulcers Rarely pathogenic Rarely pathogenic

M. terrae-complex

10-21

M. gastri

10-21

M. flavescens M. triviale

Group IV M. fortuitum

Rapid growers (Growth in few days)

M. chelonae M. smegmatis M.phlei

118

In addition, the specimens must be submitted in the correct containers, held in the appropriate conditions and sent to the laboratory for processing as soon as possible, in leak-proof universal containers. If there is going to be a delay in culture, the sample must be refrigerated. Swabs are not recommended for isolation of mycobacteria. a) Pulmonary specimens - 5-10 ml of early morning sample of sputum collected on three consecutive days in a sterile container will be adequate. Deep coughing must be encouraged so that exudative material is obtained from the lungs. If the patient is unable to expectorate a satisfactory sample, deep coughing may be induced by inhalation of an aerosol of warm, hypertonic (5-10%) saline. The specimen should be properly labelled as ,induced sputum' so that it will not be rejected by the laboratory as saliva. Saliva and nasal drainage are unsatisfactory samples. Similarly 5-10 ml bronchoalveolar lavage submitted in a sterile container will be adequate for processing. b) Extrapulmonary specimens - For urine samples at least 40 ml of early morning samples collected on three consecutive days in a sterile container is recommended. Two millilitres of cerebrospinal fluid and 5-10 ml of gastric aspirates are usually required. Gastric lavage is particularly useful in children who do not produce adequate sputum specimens and who usually swallow coughed secretions. Hospitalisation of the child may be necessary so that the lavage can be collected very early in the morning. Synovial and pleural fluid require at least 5 ml of the sample in a sterile container. Tissues, fine needle aspirates and bone marrow samples can also be processed for mycobacteria, if submitted in sterile containers or inoculated at the bedside in liquid culture media (Shinnick and Good 1999).

8.3.2 Microscopic Examination After decontamination and concentration of the samples, two staining procedures are commonly used for the identification of mycobacteria in specimens. These are the ZieW-Neelsen stain and the aurarninerhodamine stain. Ziehl-Neelsen Stain. The smears are heat-fixed

and then flooded with carbolfuchsin and heated intermittently for 1 minute. The smears are then rinsed with tap water and then decolourised with

A. O. Osoba

Fig. 8.3. ZieW Neelsen stain of sputum sample showing slender acid-fast bacilli stained red against a blue background

acid alcohol, rinsed again with tap water and then counter-stained with methylene blue or malachite green for 2 minutes. The Mycobacteria are stained red against a blue background. This so-called "acid-fast" staining procedure is based on the fact that Mycobacteria are capable of retaining the red colour of the carbolfuchsin despite treatment with acid alcohol (Fig. 8.3). The smears are then examined under a light microscope with a 100x objective oil immersion. At the higher magnification, the smear should be read in three parallel sweeps of the long axis, with a minimum of 300 fields being examined or for a duration of 15 minutes. Usually, 5,000-10,000 organisms per millilitre of sample are required before they can be detected under the microscope. This makes the ZN stain less sensitive than cultures, although a properly performed smear has a positive predictive value of over 90% and specificity of over 90% in pulmonary tuberculosis (Shinnick and Good 1999; Marshall and Shaw 1997). Usually, 40 -70% of patients with M. tuberculosis isolated in culture will give a positive ZN stain reaction, while the rest will be ZN-negative. The advantage of the ZN stain is that it is cheap, the result can be made available in

119

Microbiology of Tuberculosis

a few hours and, more importantly, it can be used to determine the infectivity of a patient suspected of pulmonary open tuberculosis, based on clinical findings or chest radiography. (Fig. 8.6).

Auramine-rhodamine Stain. This is a fluorochrome stain employing auramine-rhodamine fluorescent dyes. The smear is flooded with auramine stain for 10 minutes and then rinsed with tap water. It is then decolourised with 5% acid alcohol for 2 minutes, rinsed again with tap water and then counter-stained for 5 minutes with potassium permanganate. The slide is allowed to air-dry and is then examined under fluorescent microscopy with 25x and 40x objectives. At lower magnification, the smear should be read in three parallel sweeps of the long axis, with a minimum of 30 fields of view. Acidfast bacilli appear as bright luminous yellow bacilli approximately 1-10 flm long, most typically in the form of slender rods but may appear curved or bent. Individual bacteria may display beaded and uneven staining. Some mycobacteria other than M. tuberculosis may appear pleomorphic, ranging from long rods to coccoid forms, with more uniform distribution of staining properties. A positive fluorochrome stain requires confirmation by over-staining the same slide with ZN stain. The fluorochrome stain is more sensitive and rapid than the ZN stain since the examiner is looking for yellowish-green fluorescing bacteria against a dark background and scanning of the smears is usually at a lower magnification.

8.3.2.1 New Acid-Fast Bacilli (AFBJ Detection Methods

Improved AFB detection methods in clinical specimens have been described, in order to increase the efficiency of standard microscopic procedures. One of these tests is the immunomagnetic separation strategy for capturing and concentrating mycobacteria from processed specimens. Magnetic polystyrene beads are coated with antibody to mycobacteria and then mixed with the sputum sample. The beads now covered with organisms are then recovered using a magnet. The organisms are washed off and stained and examined by fluorescent microscopy. The detection of M. tuberculosis by the immunocapture technique has been improved by the use of magnetic beads coated with rabbit IgG polyclonal antibody to lipoarabinomannan, a constituent of the mycobacterial cell wall (Fig. 8.1). The preliminary evaluation is very impressive but more clinical laboratory evaluation is still required (Shinnick and Good 1999).

B.3.2.2 Specimen Preparation and Culture

The definitive diagnosis of mycobacterial infection depends on the detection and recovery of AFB in clinical specimens. Since mycobacteria are often present in situations where there is resident bacterial flora (e.g. sputum) or are present in small numbers (e.g. CSF), specimens submitted for examination must be specially prepared for culture. Three main steps are usually required for processing specimens: a) Bacterial flora present in the specimens must be removed or reduced in numbers before inoculation in special media, since these are faster growing than mycobacteria; b) Mycobacteria trapped in mucin must be released by a liquefaction process without killing the mycobacteria, for easy identification and culture; c) Specimens with low bacterial load must be concentrated to enable detection by microscopy and culture; d) Suitable media (solid and/or liquid media) and appropriate incubation environment must be chosen to ensure optimum recovery of mycobacteria.

8.3.2.3 Liquefaction and Decontamination

The selection of a liquefaction and decontamination process that maintains the viability of the mycobacteria, eliminates the present bacterial flora and liquefies the mucin in the sample is desirable (Roberts et al. 1991). The three most widely used digestion methods are NaOH, the Zephiran-trisodium phosphate method and the NALC-NaOH method (Roberts et al. 1991). The NALC-NaOH method utilises a mucolytic agent, NALC for digestion and NaOH for decontamination and it is the most commonly used method in clinical laboratories. The advantage of this method is that a large number of specimens can be processed in a short time; concentrated smears can be ready for staining immediately and it has been shown to give a high rate of recovery of mycobacteria (Roberts et al. 1991) (Figs. 8.4, 8.5). Specimens collected aseptically from sterile body sites such as CSF, ascitic fluid and synovial fluids may be inoculated directly into appropriate media. Specimens other than sputum do not usually require digestion and decontamination. Urine specimens can be inoculated directly or treated with 10% CaCl and then centrifuged for 30 minutes at 2,500xg and the

A. O. Osoba

120

Fig. 8.4. Mycobacterium tuberculosis showing serpentine cords (Ziehl Neelsen stain. (After Meylan, 1993)

Fig. 8.6. Ziehl Neelsen stain of sputum showing a mass of acidfast bacilli in a patient with open tuberculosis

SMEAR Staining: Microscopy Ziehl-Neelsen Auramine-Rhodanine

deposit inoculated into appropriate media. For stool samples, the specimen can be processed by the NaOH sputum digestion method and then inoculated into appropriate media. After suitable treatment of the specimens, the suspension should be centrifuged for at least 15 minutes at 2,200-2,500xg or higher and the deposit inoculated into appropriate media. All centrifugation should be carried out in sealed safety cups.

CULTURE/ Inoculation of Media

SOLID

U Middlebrook

TB confirmation of +vesmears by PCR,LCR

LIQUID 12B Septi-Check BacT/Alert BAaEC MGIT 960

8.3.3 Culture Media for the Isolation of Mycobacteria 8.3.3.1 Solid Media

Three types of solid media have been described for the isolation of Mycobacteria and each has its advantages (Table 8.2).

* AST =Antimicrobial

susceptibility Testing

Fig. 8.5. Processing of clinical specimens for mycobacteria identification and susceptibility testing

a) Egg-based media - The most widely known media is the Lowenstein-Jensen (LJ) medium, which is an egg-based non-selective medium. LJ medium has a long shelf life, up to 1 year when refrigerated and is very cheap to prepare; it is used widely in developing countries. Its disadvantages are that it may be difficult to distinguish artefacts from true colonies on this medium and the fact that heat is required for solidification, which along with

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the presence of albumin inactivates some antituberculous drugs. On the whole it is good for the recovery of M. tuberculosis but not so much for the non-tuberculous mycobacteria (Table 8.2). It is generally regarded as the ,gold standard' as it results in a very high recovery rate of mycobacteria (Hopewell and Bloom 1994; Garcia et al. 1998; Palacios et al. 1999) (Fig. 8.7). The other types of egg-based media are the American Thoracic Society medium and a modified LJ medium by Petragnani, which contains a different concentration of malachite green used in the medium. Conventional culture on solid media, although inexpensive but specific, requires 1-5 x 102 bacilli per millilitre for reliable positive results and may take 6-8 weeks, since the growth of M. tuberculosis species is rarely visible to the naked eye until after 18 days of incubation. (Fig. 8.7) (Garcia et al. 1998; Palacios et al. 1999). b) Agar-based media - the agar-based selective media are the Middlebrook 7H1O and 7Hll media, which contain defined salts, vitamins, cofactors, oleic acid, glycerol, glucose as enrichment, catalase and biotin, to stimulate the regrowth of damaged bacilli, and albumin to promote growth by combining with the toxic products in the media (Table 8.2).

Fig. 8.7. Mycobacterium tuberculosis growing on LowensteinJensen's medium. Note buff-coloured colonies produced after 4 weeks incubation

c) Biphasic media - Another media used for the culture of Mycobacteria in some laboratories is the BBL-Septic-Chek AFB system, which is a biphasic system, containing both agar and broth. It uses the Middlebrook 7H9 broth in its lower chamber and agar slope of Middlebrook 7H 11 in the upper part. Mycobacteria grow readily in this medium

Table 8.2. Different Media used for the Isolation of Mycobacteria Medium

Composition

Malachite green present/absent (gllOO ml)

Inhibitory agents for non-mycobacterial contaminants

Egg-based (non-selective) Lowenstein-Jensen

Fresh whole eggs, defined salts, glycerol, potato flour

0.025

None

Egg-Based (liquid -selective) Middlebrook 7H12

7H9 broth base, bovine serum albumin, casein hydrolysate, catalase, 14C-labelled palmitic acid

None

Polymyxin B, amphotericin B, nalidixic acid, trimethoprim, azlocillin

Agar-based medium Defined salts, vitamins, cofactors, oleic acid, albumin, catalase, glycerol, glucose (selective) Middlebrook 7H10

0.00025

Cycloheximide, lincomycin, nalidixic acid

Agar-based medium Defined salts, vitamins, cofactors, oleic (selective) acid, albumin, catalase, glycerol, glucose, Middlebrook 7H11 casein hydrolysate

0.0025

Carbenicillin, amphotericin B, polymyxin B, trimethoprim lactate

Liquid culture Bactec (Middlebrook 7H12)

Same as Middlebrook 7H12 above

None

Same as in 7H12 above

Liquid culture MB/BacT (Middlebrook 7H9 broth)

Middlebrook 7H9 broth supplemented with growth factors

None

Amphotericin B, azlocillin, nalidixic acid, polymyxin B, trimethoprim

* Modified from Roberts et al' (1991)

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and at 2 or 3 days intervals during incubation the broth is made to run over the agar. Colonies are formed on the agar if they contain mycobacteria. The incorporation of NAP in the agar in a second tube will suppress the growth of M. tuberculosis and allow quick identification of MBT (Jenkins 1998). Agar-based media are expensive and have a relatively short shelf life, hence are not widely used in developing countries. However, they have the advantage of easy identification of microcolonies and accurate drug concentrations can be achieved for susceptibility testing. 8.3.3.2 Liquid Automated Culture Systems

1) The Bactec 460 TB instrument was the first automated instrument developed by Becton Dickinson, Sparks, Md. for the recovery of Mycobacteria from clinical specimens, using a radiometric detection system. The liquid medium is an enriched Middlebrook 7H9 base supplemented with bovine serum, albumin (fraction V) catalase, casein hydrolysate and 14 C-labelled substrate. The medium is used for the isolation, differentiation of M. tuberculosis complex from non-tuberculous mycobacteria and drug susceptibility testing. Although it is capable of recovering Mycobacteria in 7-14 days, it has several disadvantages, such as the inability to observe colonial morphology and mixed cultures and high costs. It is labour-intensive and uses radioactive reagents and needles, which could lead to cross-contamination. In view of these limitations, it is now less commonly used. 2) The MB/BacT system (Organon Teknika, Turnhout, Belgium) is the first fully automated nonradiometric system for the culture of Mycobacteria, approved by the FDA in 1996 (Fig. 8.8). It relies on a continuous colorimetric CO 2 detection to indicate Mycobacterial growth in a closed system. The measured values are transmitted continuouslyevery 10 minutes to a computer, which indicates vials with Mycobacterial growth based on a sophisticated algorithm. The system will recover Mycobacteria in 10-14 days. In the MB/BacT system the process bottles contain Middlebrook 7H9 broth, Tween 80, amaranth and an antibiotic supplement containing amphotericin B, azlocillin nalidixic acid, polymyxin Band trimethoprim. The MB/BacT cabinet holds 240 process bottles, which are continuously monitored for up to

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8 weeks (Garcia et al. 1998; Palacios et al. 1999). 3) BACTEC MGIT 960 - The MGIT (Mycobacterium growth indicator tube) system (Becton Dickinson, Sparks, Md.) uses tubes in which a fluorescent compound is embedded in silicone on the bottom of tubes. This fluorescent compound is sensitive to the presence of oxygen dissolved in the broth. Initially, the large amount of dissolved oxygen quenches emissions from the compound and little fluorescence can be detected. Later, actively respiring Mycobacteria consume the oxygen and allow the fluorescence to be detected. The mean time to detection (TTD) is about 15.4 days (range 4-47 days (Flanagan et al. 1999). It has the advantage of accommodating 960 tubes, which is suitable for large volume laboratories (Fig. 8.9). Both the MB/BacT and MGIT systems have the same limitations of failure to detect mixed cultures, the inability to identify colonial morphology and high cost of media and equipment. These preclude their Widespread use in developing countries. These liquid culture systems increase the recovery of mycobacteria while at the same time decreasing the time of recovery, since the mycobacterial growth is detected more rapidly in liquid media. Many clinicallaboratories now use a combination of solid media and liquid selective media in primary isolation of mycobacteria since most species grow in 7-14 days in liquid media as opposed to 6-8 weeks with solid media.

Fig.8.8. MB/BacT instrument for automated mycobacterial culture, identification and susceptibility testing (Organon Teknika)

Microbiology of Tuberculosis

Fig. 8.9. BACTEC MGIT 960 instrument for automated culture and susceptibility testing (Becton Dickinson)

8.3.3.3 Inoculation and Incubation Procedure

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niacin test, nitrate reduction, susceptibility to T2H, catalase test, urease test, arylsulphatase test, iron uptake test, growth on MacConkey agar without crystal violet, sodium chloride tolerance test, deamination of pyrazinamide, tel1urite reduction and Tween 80 hydrolysis. Mycobacterium tuberculosis can be identified by its slow growth on solid media,non-photochromogenicity, strongly positive niacin test, negative catalase test and positive nitrate reduction test. The p-nitro- -acetylamino-beta-hydroxypropiophenone (NAP) test is an intermediate compound in the synthesis of chloramphenicol and inhibits species of the Mycobacterium complex (i.e. M. tuberculosis, M. bovis, M. africanum, M. microti and bacilli Calmette-Guerin). This compound does not inhibit other mycobacteria. This test can be used to identify M. tuberculosis in positive cultures in the liquid automated culture systems in 4-6 days (Siddiqi 1999). However, although the NAP test has been recommended by the Centers for Disease Control and Prevention and widely used for the identification of M. tuberculosis, it is not to be used alone as a confirmatory test because of some reports of false-positive results (Rau and Libman 1999) (Fig. 8.5).

Solid Media

Egg-based Medium. After the decontamination and digestion of the samples, the sediment is inoculated into Lowenstein-Jensen slope and incubated in the dark at 35-37°C for 8 weeks, in an atmosphere of 5-10% CO 2 for the first 7 days, with the screw caps left loose. The cultures are visually inspected each week for evidence of growth (Fig. 8.7).

Liquid Automated Culture Systems. The supplements are reconstituted and inoculated into culture process bottles. The processed sample from the specimen is inoculated into the culture bottles. They are loaded into the incubator cabinet, which monitors the growth for 8 weeks. Bottles flagged positive are checked for purity and presence of acid-fast bacilli and then subjected to identification tests and susceptibility testing (Figs. 8.8, 8.9).

8.3.4 Identification of Mycobacteria Species

Conventional methods for the identification of Mycobacteria are (1) growth rate at different temperatures, (2) colonial morphology, (3) pigmentation in dark or light, and (4) biochemical tests. The biochemical tests commonly used to differentiate Mycobacteria are

8.4 Molecular Techniques for Identification of Mycobacteria Since conventional methods for the identification of Mycobacteria take 2-3 weeks, there has been increased effort to develop rapid identification techniques, especially in the wake of the resurgence of tuberculosis as a result of the HIV/AIDS pandemic. Molecular techniques have been developed in the last decade with the aim of achieving faster commencement of appropriate treatment, shortening time to detection of anti-mycobacterial drug resistance, and instituting appropriate control measures.

8.4.1 Nucleic Acid Probes for Actively Growing Mycobacteria

Actively growing mycobacteria may be identified by using commercial DNA probes, which detect specific DNA or ribonucleic acid (RNA) fragments by nucleic acid hybridisation. These tests require some amplification of the bacterial DNA. These methods include target, probe and signal amplification tech-

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niques, where ribosomal RNA or different parts of genomic DNA are selected as targets. The specificity of the tests is nearly 100%, but their sensitivity is still relatively lower compared with culture, especially in smear-negative specimens. The tests are cumbersome and expensive, which preclude their use in many developing countries. Probes are now available for the identification of M. tuberculosis complex, M. avium complex, M kansasii and M. gordonae isolated either on solid or liquid media.

8.4.2 The Accuprobe System In the Accuprobe system (Gen-Probe, San Diego, Calif.) the bacterial culture is sonicated to break up the bacterial cells, the lysate is incubated with an acridinium-Iabelled oligonucleotide probe. This hybridises to mycobacterial ribosomal RNA. The unbound oligonucleotide is removed and the bound probe is measured using a luminescence detection system. The Accuprobe can identify M. tuberculosis is under 2 hours. The test has been reported to be specific and when combined with the Bactec system can provide speciation of an isolate from a clinical sample in 14 days. However, false positives have been reported with M. avium-intercellulare complex strains (Marshall and Shaw 1997).

8.4.3 The BDProbe Tec ET The BDProbe Tec (Becton Dickinson, Sparks, Md.) is a nucleic amplification technique, which is based on homogeneous strand displacement amplification (SDA) and fluorescent energy transfer detection in an instrument system. SDA is an isothermal enzymatic process that amplifies nucleic acid exponentially. The process is based on the nicking of a modified recognition sequence by the restriction endonuclease BsoBl and the extension and repair of that site by the DNA polymerase Bst, which synthesises a new strand of DNA while displacing the existing strand. The displaced strand can then serve as a template for further amplification. The process takes place at a temperature of 52.5°C. An internal amplification control system is run with each sample and is

complex, M. avium complex and M. kansasii, performed on isolates grown in liquid or solid media. The test consists of three main steps: sample processing, priming and warming, and simultaneous amplification and detection. The whole procedure takes about 2 hours. While the sensitivity and specificity of the test is about 100% for smear-positive samples, however for smear-negative specimens the sensitivity and specificity are about 85% and 97%, respectively (Bergmann et al. 2000). Current probe technology, however, cannot distinguish live from dead mycobacteria, which indicates that while molecular techniques will achieve great usefulness in the primary diagnosis of mycobacterial infections, cultural methods will be required for monitoring the response to therapy. Most clinical laboratories now combine both molecular techniques and cultural methods in the laboratory diagnosis and susceptibility testing of Mycobacteria and this practice is likely to continue in the foreseeable future.

8.4.4 The Amplified Mycobacterium Tuberculosis Direct (MTD) Test The MTD test uses a transcription-mediated amplification (TMA) principle to detect M. tuberculosis complex directly from respiratory specimens and provides a billion-fold amplification of the rRNA targets (MTD, Gen-Probe, San Diego, Calif.). The amplification process uses a single temperature throughout the test. The target is 16s RNA. The mycobacterial cells are sonicated and the nucleic acids are released. The specimens are then heated to 42°C and multiple copies of the mycobacterial RNA are generated. In the test system, ampIicons are created through DNA intermediates by a reverse transcriptase. M. tuberculosis complex-specific sequences are then detected by the Gen-probe chemiluminescentlabelled DNA probes and the results are measured in a luminometer. The test is recommended for use only with smear-positive concentrated specimens such as bronchoalveolar lavages, bronchial aspirates and tracheal aspirates. The specificity of the test is 97-99%, while the sensitivity is 82-97%. The advantage of the test is that it uses a single temperature and a single tube format. The detection of rRNA accounts for its high sensitivity. The high reliability of the test makes

designed to verify the SDA reaction. The assay con-

it an ideal tool for diagnosing tuberculosis with low

sists of direct M. tuberculosis complex (DTB) assay performed on clinical respiratory specimens and the culture identification (ID) assays for M. tuberculosis

bacterial count. Since the test has a negative predictive value close to almost 100%, it can quickly help in ruling out tuberculosis from the differential diag-

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Microbiology of Tuberculosis

nosis, alternatively, if the smear is ZN positive, it suggests the presence of non-tuberculous mycobacteria if MTD negative (Pfyffer 1994).

working hours of a clinical diagnostic laboratory (Beavis et al. 1995).

8.4.6 8.4.5

Ligase Chain Reaction (LCR)

Amplicor M. Tuberculosis (PCR) Test

The Amplicor M. tuberculosis test by Roche Diagnostic Systems (Branchburg, N.J.) is based on a polymerase chain reaction (PCR), nucleic acid hybridisation for the detection of M. tuberculosis complex in digested, decontaminated sputum and bronchial alveolar lavage samples. The test is based on three major processes: PCR, target amplification, hybridisation of the amplified product to a specific nucleic acid probe and the detection of the amplified product by colour formation. In the test, gene-specific primers located in a highly conserved region of the 14S ribosomal RNA (rRNA) gene of M. tuberculosis are used to amplify a 584 base-pair sequence. The DNA-containing sample and reagent mixture are heated to separate the double-stranded helix and expose the primer target sequences. As the mixture cools, the biotinylated primers anneal to their targets. The thermostable DNA polymerase, in the presence of excess of deoxynucleoside triphosphates (dNTPs), extends the annealed primers along the target templates to produce amplicons. This process is repeated for a number of cycles, each cycle effectively doubling the amount of target DNA. After 37 cycles, over a billion copies can be produced from a single copy of DNA. The ampIicons are then chemically denatured to form single strands that are added to a microwell plate containing a bound, amplicon-specific oligonucleotide probe. The biotin-labelled amplicons will then bind (hybridise) to the amplicon specific probe and thus be captured on to the plate. The detection of the amplicons is carried out by an enzyme immunoassay technique by the addition of Av-HRP conjugate and the optical density of the mixture is measured in an automated microwell plate reader. In smearpositive samples the sensitivity was found to be 95% and the specificity to be 98% in one report, while in smear-negative samples the sensitivity was 75% and the specificity was 99% (Rau and Libman 1999; Gilpin et al. 1999; Carpenter et al. 1995). However there are reports of some current commercial kits having a sensitivity range of up to 70% for smearnegative M. tuberculosis samples (Rau and Libman 1999). The assay is rapid and easy to perform, taking about 8 hours and can be fitted into the normal

Ligase chain reaction is a probe amplification technique incorporating a DNA polymerase and it is based on sequential rounds of template-dependent ligation of two adjacent oligonucleotide probes. When a pair of probes has hybridised to the target sequence on a single strand of DNA, there is a gap of a few nucleotides between the probes. The addition of a DNA polymerase into the reaction acts to fill in this gap by incorporating nucleotides. Once the gap is filled ligase can covalently join the pair of probes to form an amplification product that is complimentary to the original target sequence and can itself serve as a target in subsequent cycles of amplification. The target nucleic acid sequence for LCR assay for M. tuberculosis (Abbott LCX probe system, Abbott Diagnostics, Chicago, Ill.) is found within the single copy chromosomal gene of M. tuberculosis which encodes for protein antigen b. This gene sequence is specific to the M. tuberculosis complex and has been detected in all M. tuberculosis complex strains. In the assay sediments from a clinical sample or culture material are sonicated and amplified in a thermocycler. The amplicons were detected in an LCX analyser (LCX probe system). In smear-positive samples the sensitivity was found to be 100% and the specificity to be 98% in one report, while in smearnegative samples the sensitivity was 89% and the specificity was 98% (Gilpin et al. 1999).

8.4.7 Other Molecular Techniques

A number ofmolecular techniques have been described for the rapid identification of mycobacteria growing on solid media. These are (1) thin-layer chromatography, (2) high-performance liquid chromatography, (3) gasliquid chromatography, (4) analysis with DNA probes. Although these procedures can produce rapid identification of mycobacteria growing on solid media, they are too insensitive for the identification of isolates in liquid media, due to the relatively low cell mass often produced, or they are only capable of identifying a limited number of species (Taylor et al. 1997). In summary, these newer techniques will have to be used to supplement the conventional methods and need to be interpreted in conjunction with the

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patient's clinical features, such as medical history, physical examination, chest radiograph, tuberculin test and therapeutic response to anti-tuberculous agents (Pfyffer 1994).

8.5 Antimicrobial Susceptibility Testing Antimicrobial susceptibility testing (AST) of isolated Mycobacteria is very important not only for appropriate therapy but also for control of the disease and the identification of resistant strains. Conventional methods are still the method of choice but these take 3-8 weeks, while the Bactec 460 TB and the liquid culture systems take 8-12 days (Siddiqi 1999). The newer methods of susceptibility testing have distinct advantages and improvements over the older methods (Inderlied 1994).

8.5.1 Conventional Methods of Susceptibility Testing There are three methods of conventional susceptibility testing of M. tuberculosis and these are based on its growth on solid medium containing a fixed amount of the drug. (Hawkins IE et al.1991; Vareldzis et al. 1994). a) Absolute concentration method: medium containing known concentrations of antimicrobial agents and control medium without drugs are inoculated with standardised suspension of M. tuberculosis. A preliminary reading is made at 2 weeks and a final reading at 4 weeks. The strain is regarded as resistant if there is growth greater than 20 colonyforming units (CPU) at a specific drug concentration. The method is highly sensitive to variations in inoculum size. b) Resistance ratio method: this method is similar to the absolute concentration method in that both the drug-free media and the drug-containing media are inoculated with both the test strain and a standard strain of M. tuberculosis ( H37Rv). Resistance is expressed as the ratio of the MIC of the test strain divided by the MIC of the control organism used in the test. If the test strain has a ratio of 8 or more it is considered as resistant, while a resistance ratio of 2 or less is defined as sensitive. A resistance ratio of 2 or less is equivalent to the presence of less than 20

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colonies growing on 0.2 mgtl of isoniazid in the absolute concentration method. In this method, it is important that the inoculum be properly standardised. Variations in the inoculum size are difficult to prevent (Vareldzis et al. 1994). c) Proportion method: this is the most widely used method and it involves the inoculation of both drug-free media and drug-containing media in duplicate with various dilutions of the test organism and the plates incubated. The media used are the Middlebrook 7HlO or 7H11. The dilutions are made to produce between 50 and 100 colonies on at least one of the control media. The CPU on the drug-containing media is then compared with that of the drug-free media. Resistance is defined as Mycobacteria with greater than 1% of the population exhibiting growth in the presence of the lowest concentration of the drug tested. Results can be available in 14-21 days (Hawkins et al. 1991). The proportion method is the most widely used method in the USA, as it provides fairly accurate and reproducible results for primary and secondary anti-mycobacterial drugs. However the drawback of the method is the difficulty of standardisation of the inoculum and quality control. In addition, it has not been validated for testing new agents such as ciprofloxacin, ofloxacin and rifabutin (Hawkins et al. 1991; Vareldzis et al. 1994).

8.5.2 Radiometric Method of Drug Susceptibility Testing

Bactec 460 TB System. In 1980, Gardner Middlebrook introduced the Middlebrook 7H12 liquid medium, an automatable radiometric detection system for the growth of Mycobacteria in a liquid selective medium using the Bactec 460 TB system (Becton Dickinson Diagnostic Instruments Systems, Towson, Md.). The system revolutionised the isolation and susceptibility testing of Mycobacteria. The system is far superior to the conventional solid media in that it recovers more positive cultures in a significantly shorter period (2 weeks instead of 6-8 weeks) (Marshall and Shaw 1997; Siddiqi 1999). The medium contains 14 C_ labelled palmitic acid and the growth of Mycobacteria is detected by metabolic release of radio-labelled carbon dioxide from the palmitic acid. Radioactivity of the labelled CO 2 is determined quantitatively and is a measure of the rate and amount of growth in the vial. These numbers are designated the "growth index»

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(GI). By daily monitoring of the culture vials, detection 8.5.5 times have been shortened in this system to 7-14 days. The MB/BacT Microbial Detection System By the addition of anti-mycobacterial drugs into the vials, inhibition of growth results in a reduction in This is also a non-radiometric, automated colorithe amount of 14C produced and a reduction of the metric system consisting of a culture bottle with a GI, compared with the drug-free vial (control). The growth sensor for detecting mycobacterial growth. Bactec system allows the drug susceptibility testing to The instrument incubates and scans the bottles for be performed in 12-14 days after isolation and identi- positivity and a computerised data management fication, with excellent correlation with conventionally system records and reports results. The MB/BacT determined susceptibility testing (Marshall and Shaw susceptibility test is performed using the MB/BacT 1997). It can be used to test all primary drugs, i.e. process bottles, MB/BacT antibiotic supplement isoniazid, rifampicin, streptomycin, ethambutol and (MAS) reconstitution fluid and antimicrobial drugs. pyrazinamide as well as secondary drugs including The drugs are added to the new MB/BacT process quinolones and rifabutin. The main drawback of the bottles (one drug per bottle and one concentration method is the reporting of false susceptibility or resis- per drug). These bottles with drugs are inoculated tance due to testing of mixed populations of M. tuber- with broth from a positive MB/BacT bottle. Next to culosis and non-tuberculous mycobacteria. However, these bottles with drugs a process bottle without the critical concentrations have not been established drugs is inoculated with broth from the positive MB/BacT bottle. This bottle is considered the growth for the newer agents (Inderlied 1994). control. Growth of the M. tuberculosis isolate in the bottles with drugs is compared to the growth control 8.5.3 to decide if the isolate is resistant or susceptible. The Non-Radiometric Methods of Drug Susceptibility M. tuberculosis isolate is considered resistant if the Testing bottle containing the drug is flagged positive before or at the same time as the growth control. An isolate The worldwide resurgence of tuberculosis has under- is considered susceptible if the bottle containing the scored the necessity to develop rapid methods for drug remains negative during the test period or when isolation and susceptibility testing of mycobacteria. flagged positive after the growth control. The conBecause of the concerns for radioactive materials, centration at which the drugs are tested are streptosome governments placed restrictions on the Bactec mycin 1 Ilg/ml, isoniazid 1 Ilg/ml, rifampicin 1 Ilg/ml, 460 system culture bottles. This led to the develop- ethambutol 2 Ilg/ml and pyrazinamide 50 Ilg/ml. The ment ofnon-radiometric culture systems such as the test is concluded in 12 days. The MB/BacT cabinet Mycobacterial Growth Indicator Tube (MGIT) Bactec holds 240 process bottles, which are continuously MGIT 960 (Becton Dickinson) and the MB/BacT monitored for up to 8 weeks (Fig. 8.8). (Organon Teknika, Durham, N.C.).

8.5.6 8.5.4 The Mycobacterial Growth Indicator Tube (MGIT) System

It is an automated non-radiometric culture system using Middlebrook 7H9 broth and an oxygen sensitive fluorescence sensor to indicate microbial growth in a vial. It is similar to the Bactec 460 system. By the addition of anti-mycobacterial drugs, the actively respiring mycobacteria consume the oxygen and allow fluorescence to be detected by the instrument, indicating resistance. Control bottle without any drug is included with each run. The cabinet has a capacity to accommodate 960 bottles (Fig. 8.9). The mean time to determination of susceptibility or resistance is 10-12 days (Flanagan et al. 1999).

Genetic Approach to the Detection of Drug Resistance by Mycobacterium tuberculosis

Recent major advances have been made in uncovering the molecular basis of the resistance of M. tuberculosis to various antimicrobials, viz. isoniazid (Zhang et al. 1992; Banerjee et al. 1994), streptomycin (Finken et al.1993), quinolones (Takiff et al.1994), rifampicin (Telenti 1993a,b, 1997). For example, the mechanism of rifampicin resistance by M. tuberculosis has been associated with point mutations and small insertions or deletions in a limited region of the gene encoding for the B-subunit of the RNA polymerase (rpoB). In the case of isoniazid, mutations in the kat G, inh AI mab A, ahp C and oxy R genes confer resistance on M. tuberculosis. Based on this approach, commercial

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128

tests have become available for use in clinical diagnostic laboratories.

8.5.6.1 Line Probe Assay (UPA)

This test is based on the detection of mutations by hybridisation in the rpo B gene, which confers resistance on M. tuberculosis. Telenti (1993a,b; Cole and Telenti 1995) developed a screening method using PCR and single strand conformation polymorphism analysis and Williams (1994) used the PCR and heteroduplex formation to detect rifampicin resistance in M. tuberculosis cultures. In the LIPA test, oligonucleotide probes are immobilised as parallel lines at known locations on a nitrocellulose strip (Beenhower et al. 1995). The amplified material is denatured and incubated with a LIPA strip in a shaking water bath for 1 hour at 50°C in 1 ml of hybridisation mixture. The hybrids formed are revealed by an immunoenzymatic procedure, resulting in a coloured precipitate that enables visual reading of the results. If a mutation is present in one of the probe target regions, the mismatch created will prevent the corresponding probe from hybridising. The test is fast and easy to perform and allows the simultaneous detection of M. tuberculosis and the discrimination between rifampicin-sensitive strains and rifampicin-resistant strains of M. tuberculosis in clinical samples. The test can be completed in 2 days and when performed on cultures it takes about 8 hours. In one report, (Beenhower et al. 1995) the susceptibility of M. tuberculosis strains can be correctly determined in up to 97% of the strains tested. However, the test will fail to determine the susceptibility of strains utilising a different mechanism of resistance from the rpo B gene (Beenhower et al. 1995; Drobniewski and Pozniak 1996).

8.5.7 Newer Techniques of Drug Susceptibility Testing

8.5.7.1 Luciferase-based Reporter Phage

This is a molecular technique which has recently been described to provide a rapid drug susceptibility testing of M. tuberculosis. In this test, the gene encoding a luciferase enzyme from fireflies was inserted into a bacteriophage. When the bacteriophage infects M. tuberculosis, the luciferase enzyme is synthesised and emits light. Following the exposure of the organism to anti-mycobacterial agent, the organism dies and no light is emitted, indicating susceptibility to the drug.

Between 500 and 5,000 mycobacteria infected by this bacteriophage will produce a clear positive signal and the test can be completed in 3 hours (Marshall and Shaw 1997; Roth et al. 1997; Jacobs et al. 1993). This is a promising test, which will find useful application in clinical laboratories in the future.

8.5.7.2 Epsilometer (E-) test

The E-test has been used very recently to determine the Minimum Inhibitory Concentration (MIC) of many organisms. More recently the technique has been modified to determine the susceptibility of M. tuberculosis and M. avium-intercellulare to both first-line and second-line anti-mycobacterial agents (Flynn et al. 1997; Koontz et al. 1994; Wanger and Mills 1994). The E-test ( AB Biodisk, Solna, Sweden) is based on a stable-gradient strip impregnated with an antimicrobial drug placed on Middlebrook 7Hll media which has been inoculated with the test organism, and then incubated for 5 days. The results are interpreted by applying National Committee for Clinical Laboratory Standards (NCCLS) criteria. Four strips can be placed on a 150-mm diameter plate. The method produces MICs within 1 week of primary isolation, thus allowing early modification of therapy.

8.5.7.3 Hybridisation Protection Assay (HPA)

This is a simple and fast M. tuberculosis drug susceptibility test, which is now commercially available. After isolation of the organism from clinical specimen, it is grown on Middlebrook 7H9 broth and incubated at 37°C for 5-7 days. The inocula are standardised to McFarland no. 0.5 standard and then mixed with an anti-mycobacterial drug solution to give a final concentration of 0.1 and 1.0 Ilg/ml for isoniazid and 1.0 and 10.0 Ilg/ml for rifampicin. The resulting bacterial suspension with or without the test drug, is cultured on an agitating plate at 37°C for up to 5 days. At 0-, 1-,3- and 5-day intervals each sample is removed and subjected to the HPA test with acridinium ester (AE)labelled DNA probe{ AccuProbe; Gen-Probe, Inc. San Diego, Calif.). The assay results are read in a luminometer and expressed as relative light units (RLU). The statistical significance of the RLU between tubes with and without drugs is calculated (Miyamoto et al. 1996). In this test, drug-resistant strains of M. tuberculosis can be accurately detected after 1 day of incubation with the drug. The HPA test is safe, simple and fast. It can be incorporated into the routine of

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a clinical diagnostic laboratory. However, it is more serological diagnosis of tuberculosis have been expensive than the radiometric or conventional agar handicapped by the fact that the pattern of antibody methods. It may have useful application in some situ- response after M. tuberculosis infection varies from ations such as testing immunocompromised patients one lesion to another and from patient to patient. In many patients the antibody response is weak and is infected with multidrug-resistant M. tuberculosis. In general, a handicap of both genetic and phe- frequently directed predominantly against non-spenotypic tests for susceptibility of M. tuberculosis is cific mycobacterial antigens (Woodhead 1992). Antigen preparations have contained moieties that they cannot precisely distinguish between mixed cultures that contain 1% to 10% of resistant cells and present in many microbial species that lead to serocultures that contain only susceptible organisms. This logical cross-reactivity. Assays with crude antigens distinction is of clinical importance since the patient have had poor specificity because of the presence with a mixed culture would be regarded as having of cross-reacting epitopes between M. tuberculosis a drug-resistant M. tuberculosis and would be given and other mycobacteria. By means of chemical and immunological methods, several purified antigens, appropriate treatment (Shinnick and Good 1999). In conclusion, conventional methods based on such as A60 antigen (Amicosante et al. 1993; Alifano ZN microscopy and culture on LJ medium with et al. 1994; Charpin et al. 1990) and 38 kDa antigen biochemical tests to identify the isolates are the (Simonney et al. 1996; Young et al. 1986; Bothamley et most widely used for the diagnosis of tuberculosis al.1992; Harboe and Wiker 1992) have been prepared and are still considered the "gold standard" . These which have improved the enzyme-linked immunomethods are cost-effective but are rather slow for sorbent assay (ELISA) test chatacteristics (Wilkins the effective control of tuberculosis. The new tech- and Ivanyi 1990; Jackett et al. 1988). Recently, mouse niques of nucleic acid amplification offer the pros- monoclonal antibodies (Mabs) to specific epitopes pect of more rapid diagnosis, susceptibility testing on antigens of M. tuberculosis have been used in a and improved and accurate epidemiological infor- solid-phase antibody competition test to measure mation (Marshall and Shaw 1997). The resurgence antibody titres to these determinants in human sera of tuberculosis has necessitated the development (Jackett et al. 1988; Cocito 1991; Bothamley et al. of more rapid methods of diagnosis. The objec- 1992). The application of Mabs into the serological tive of clinical laboratories should be to report the tests for the diagnosis of tuberculosis is a significant isolation of M. tuberculosis within 10-14 days of the advance because they can be readily prepared in a receipt of the sample and the result of drug suscep- standard form and are usually free from problems tibility tests within the next 14 days (Shinnick and of cross-reactivity. They also allow the estimation of Good 1999; Rau and Libman 1999). both IgG and IgM in a single assay, thereby obviating the need to purify antigens from M. tuberculosis. The interest to develop serological tests for the diagnosis of tuberculosis stems from the fact that 8.6 blood is readily available in any form of the disease for serological testing. Therefore the measurement Serological Diagnosis of Tuberculosis of titres of antibody to M. tuberculosis specific Since 40-60% of patients with pulmonary disease antigens may be of value in the diagnosis of both and up to 75% of patients with extrapulmonary smear-positive and smear-negative pulmonary diseases are smear-negative, a number of alternative tuberculosis. Antibody titres may also help to diagnostic methods using molecular, chromato- identify those patients who should be treated in a graphic and immunological methods have been hospital, those who require observed chemotherdeveloped. While these tests are very specific and apy as well as those who might require additional only moderately sensitive, they rely on the provision drugs to the standard regimen for the therapy of of adequate material from the site of the lesion. This their infection. is often difficult, especially in children, and in most In order to meet these objectives, a number of cases of extrapulmonary tuberculosis, such as cere- serological tests developed for the diagnosis of bral tuberculoma or tuberculous osteomyelitis and tuberculosis have now become commercially availabdominal tuberculosis (Wilkins and Ivanyi 1990; able. These tests can be divided into two groups, viz.: Pottumarthy et al. 2000). Previous investigations into (a) Immunochromatographic tests and (b) Enzymetuberculous serology have been faced with problems linked immunosorbent Assay. Some of these will be of both sensitivity and specificity. These studies on briefly described.

A.O.Osoba

130

8.6.1 Immunochromatographic Tests 8.6.1.1

8.6.2.3 PATHOZYME-MYCO IgG, IgA, and IgM Tests

The three assays measure the levels in serum of IgG, IgA and IgM antibodies, respectively, to two antigens lipoarabinomannan (LAM) and recombinant 38 kDa This is a immunochromatographic test in which five antigen. These kits detect infection due to Mycobachighly purified antigens (including one of 38 kDa) terium species. secreted by M. tuberculosis during active infection In a study evaluating the performances of these are immobilised in four lines on the test strip (ICT tests in various categories of patients (Pottumarthy Diagnostics, Balgowish, New South Wales, Australia). et al. 2000), it was found that the ICT Tuberculosis The test detects the presence of immunoglobulin G test followed by PATHOZYME-MYCO IgG had the best performance characteristics with sensitivi(IgG) antibodies to these antigens. ties of 41 % and 55%, respectively, with sera from patients with acute tuberculosis and specificities 8.6.1.2 of 96% and 89%, respectively, with sera from the Rapid Test TB Mantoux test controls, and 88% and 90%, respecIt is a one-step coloured immunochromatographic tively, with sera from anonymous controls. In a assay (Quorum Diagnostics, Vancouver, British study in the United Arab Emirates (Nsanze et al. Columbia, Canada). It detects antibodies to the recom- 1997) on a population of patients with tuberculosis binant 38 kDa antigen from M. tuberculosis expressed and leprosy, using a combination of PATHOZYME TB-Complex test and PATHOZYME-MYCO IgG and purified in E coli (Pottumarthy et al. 2000). test, it was found that the tests showed a significant difference in antibody levels between the patients with active pulmonary disease, extrapulmonary 8.6.2 tuberculosis and leprosy in comparison with the Enzyme-linked Immunosorbent Assays control group. The sensitivity of the two tests combined for proven pulmonary tuberculosis was 8.6.2.1 about 95% using a higher EIA cut-off of 1.6, while Tuberculosis IgA EIA the specificities were 100%. The sensitivity for This test detects the IgA antibody to a mycobacterial extrapulmonary tuberculosis at the higher cutKp90 immuno-cross-reactive antigenic compound off was 51 %. The authors conclude that while the (ImCRAC). tests may be of some value in decision making in extrapulmonary tuberculosis, they may be useful in serological screening of populations at high risk in 8.6.2.2 The Pathozyme TB Complex Test endemic areas (Nsanze et al. 1997). Although a negative result by any of these tests This test detects serum IgG antibody to a recombi- would be useful in helping to exclude disease in a nant 38 kDa antigen from M. tuberculosis expressed population with a low prevalence of tuberculosis, a and purified from E coli, permitting the isolation of positive result may aid in clinical decision making significant quantities of protein (OMEGA DIAG- when applied to symptomatic patients being evaluNOSTICS LTD, Alloa, Scotland). This antigen has ated for active tuberculosis (Pottumarthy et al. 2000). been reported as the single most important antigen The tests now commercially available confirm a more for the serological diagnosis of tuberculosis. It is a limited antibody response in smear-negative pulmounique disease-associated protein, which appears to nary disease, but suggest that a battery of monoclobe completely specific to the M. tuberculosis complex, nal antibodies, with differing specificities, produces i.e. M. tuberculosis, M. bovis and M africanum. The better results than single monoclonal antibody kit is specific for the diagnosis of disease due to M. (Woodhead 1992). However they have the advantage tuberculosis complex. In this test the test sera are that they are rapid and relatively inexpensive. Overdiluted 1:50 and standards were provided to gener- all, more research is still required to produce better ate a semi logarithmic reference curve. The results tests with increased sensitivities in extrapulmonary tuberculosis which can be readily incorporated into are expressed as sero-units. clinical diagnostic laboratories. ICT Tuberculosis Test

Microbiology of Tuberculosis

References Alifano M et al. (1994) ELISA method for evaluation of anti-A 60 IgG in patients with pulmonary and extrapulmonary tuberculosis. Microbiologica 17:37-44 Amicosante M et al. (1993) Antibody repertoire against the A60 antigen complex during the course of pulmonary tuberculosis. Eur Respir J 6:816-822 Banerjee A et al. (1994) InhA, a gene encoding a target for Isoniazid and Ethionamide in Mycobacterium tuberculosis. Science 263:227-230 Beavis KG et al. (1995) Evaluation of amplicor PCR for direct detection of Mycobacterium tuberculosis from sputum specimens. J Clin MicrobioI33:2582-2586 Beenhower HD et al. (1995) Rapid detection of rifampicin resistance in sputum and biopsy specimens from tuberculosis patients by PCR and line probe assay. Tuberc Lung Dis 76:425-430 Bergmann JS, Keating WE, Woods GL (2000) Clinical evaluation of the BDProbeTec ET system for rapid detection of Mycobacterium tuberculosis. J Clin Microbiol 38:863-865 Bothamiey GH et al. (1992a) Clinical value of the measurement of M. tuberculosis-specific antibody in pulmonary tuberculosis. Thorax 47:9-14 Bothamley GH et al. (1992b) Clinical value of the measurement of Mycobacterium tuberculosis specific antibody in pulmonary tuberculosis. Thorax 47:270-275 Carpenter E et al. (1995) Diagnosis of tuberculosis by amplicor Mycobacterium tuberculosis test: a multicenter study. J Clin MicrobioI33:3106-3110 Charpin D et al. (1990) Value of ELISA using A60 antigen in the diagnosis of active pulmonary tuberculosis. Am Rev Respir Dis 142:380-384 Cocito CG (1991) Properties of the mycobacterial antigen complex A60 and its applications to the diagnosis and prognosis of tuberculosis. Chest 100:1687-1693 Cole ST, Telenti A (1995) Drug resistance in Mycobacterium tuberculosis. Eur Respir J B SuppI20:701s-713s Davies PDO, Girling DJ, Grange JM (1996) Tuberculosis. In: Weatherall DJ, Ledingham JGG, Warrell DA (eds) Oxford textbook of medicine. Oxford University Press, Oxford, pp 638-655 Drobniewski FA, Pozniak AL (1996) Molecular diagnosis, detection of drug resistance and epidemiology of tuberculosis. Br J Hosp Med 56:204-208 Finken M et al. (1993) Molecular basis of streptomycin resistance in Mycobacterium tuberculosis: Alteration of the ribosomal protein S 12 gene and point mutations within a functional16S ribosomal RNA pseudoknot. Mol Microbiol 9: 1239-1246 Flanagan PG, Williams R, Paull A (1999) Comparison of two automated systems for the isolation of mycobacteria from clinical specimens. Eur J Clin Microbiol Infect Dis 18: 912-914 Flynn et al. (1997) Application of the E test to the antimicrobial susceptibility testing of Mycobacterium marinum clinical isolates. J Clin 35:2083-2086 Garcia FG et al. (1998) Evaluation of the MB/BACT automated mycobacteria culture system versus culture on Lowenstein medium. Clin Microbiol Infect 4:339-343 Gilpin CM et al. (1999) Comparative study of Amplicor polymerase chain reaction and Ligase chain reaction for direct

131 detection of M. tuberculosis in clinical specimens. Saudi Med J 20:79-84 Grange JM (1984) Tuberculosis. In: Wilson G, Miles A, Parker MT (eds) Topley and Wison's principles of bacteriology, virology and immunity, 7th edn. Arnold, London, pp 32-35 Harboe M, Wiker HG (1992) The 38-kDa Protein of Mycobacterium tuberculosis.: a review. J Infect Dis 166:874-884 Hawkins JE, Wallace RJ, Brown BA (1991) Antibacterial susceptibility tests: Mycobacteria. In: Balows A, Hausler WJ, Herrmann KL, Shadomy HJ (eds) Manual of clinical microbiology, 5th edn, chap 114. American Society for Microbiology, Washington DC, pp 1138-1152 Hopewell PC, Bloom BR (1994) Tuberculosis and other mycobacterial diseases, 2nd edn. In: Murray JF, Nadel JA (eds) Textbook of respiratory medicine. Saunders, Philadelphia, pp 1094-1117 Inderlied CB (1994) Antimycobacterial susceptibility testing: present practices and future trends. Eur J Clin Microbiol Infect Dis 13:980-993 Jackett PS et al. (1988) Specificity of antibodies to immunodominant mycobacterial antigens in pulmonary tuberculosis. J Clin MicrobioI26(11):2313-2318 Jacobs WR et al. (1993) Rapid assessment of drug susceptibilities of Mycobacterium tuberculosis by means of luciferase reporter phages. Science 260:819-822 Jenkins PA (1998) The microbiology of tuberculosis. In: Davies PO (ed) Clinical tuberculosis. Chapman and Hall, London, pp 69-79 Koontz FP et al. (1994) Etest for routine clinical antimicrobial susceptibility testing of rapid growing mycobacteria isolates. Diagn Microbiol Infect Dis 19:183-186 Marshall BG, Shaw RJ (1997) Diagnostic techniques: old and new. Eur Respir Mon 4:30-50 Meylan PR ASM News vol 59(12), 1993 (Cover page) Miyamoto J et al. (1996) New drug susceptibility test for Mycobacterium tuberculosis using the hybridization protection assay. J. Clin Microb. 34:1323-1326 Moulding T (1999) Tuberculosis and non nontuberculous mycobacterial infections, 4th edn. In: Schlossberg D (ed) Pathogenesis, pathophysiology, and immunology: clinical orientations. Saunders, Philiadelphia, pp 48-64 Nsanze H et al. (1997) Serodiagnosis of tuberculosis and leprosy by enzyme immunoassay. Clin Microb and Infection. 3:236-239 Palacios JJ et al. (1999) Fully automated liquid culture system compared with lowenstein-Jensen solid medium for rapid recovery of mycobacteria from clinical samples. Eur J Clin Microbiol Infect Dis 18:265-273 Pfyffer GE (1994) Amplification techniques: hope or illusion in the direct detection of tuberculosis. Med Microbiol Lett 3:335-347 Pottumarthy S, Wells VC, Morris AJ (2000) A comparison of seven tests for serological diagnosis of tuberculosis. J Clin MicrobioI38:2227-2231 Rau NV, Libman (1999) Laboratory implementation of the polymerase chain reaction for confirmation of pulmonary tuberculosis. Eur J Clin Microbiol Infect Dis 18:35-41 Roberts GD, Koneman EW, Kim YK (1991) Mycobacterium. In: Balows A, Hausler WJ, Herrmann KL, Shadomy HJ (eds) Manual of clinical microbiology, 5th edn, chap 34. American Society for Microbiology, Washington DC, pp 304-318 Roth A, Schaberg T, Mauch H (1997) Molecular diagnosis of

132 tuberculosis: current clinical validity and future perspectives. Eur Respir J 10:1877-1891 Shinnick TM, Good RC (1999) Diagnostic mycobacteriology laboratory practices. Clin Infect Dis 21 :291-299 Siddiqi SH (1999) Recent advances in the diagnosis of tuberculosis: an overview. J King Abdulaziz Univ Med Sci 7:31-35 Simonney N et al. (1996) Comparison of A60 and three glycolipid antigens in an ELISA test for tuberculosis. Clin Microbiol Infect 2:214-222 Takiff HE et al. (1994) Cloning and nucleotide sequence of the Mycobacterium tuberculosis gyrA and gyrB genes and characterization of quinolone resistance mutations. Antimicrobial Agents Chemother 38:773-780 Taylor TB et al. (1997) Routine use of PCR-restriction fragment length polymorphism analysis for identification of mycobacteria growing in liquid media. J Clin Microbiol 35(1):79-85 Telenti A (1993a) Detection of rifampicin-resistance mutations in Mycobacterium tuberculosis. Lancet 341: 647-650 Telenti A (1993b) Direct automated detection of Rifampicin-resistant Mycobacterium tuberculosis by polymerase chain reaction and single-strand conformation polymorphism analysis. Antimicrob Agents Chemother 37:2054-2058 Telenti A (1997) Genetics of drug resistance in tuberculosis. Clin Chest Med 18:55-64

A. O. Osoba Tuberculosis. In: Wyngaarden JB, Smith LH (eds) Cecil textbook of medicine. Saunders I Harcourt Brace Jovanovich, Philadelphia, pp 1682-1696 Vareldzis BP et al. (1994) Drug-resistant tuberculosis: laboratory issues. World Health Organization recommendations. Tubercle Lung Dis 75:1-7 Wanger A, Mills K (1994) Etest for susceptibility testing of Mycobacterium tuberculosis and Mycobacterium aviumintracellulare. Diagn Microbiol Infect Dis 19:179-181 Wilkins EGL, Ivanyi J (1990) Potential value of serology for diagnosis of extrapulmonary tuberculosis. Lancet 336: 641-644 Williams DL (1994) Characterization of rifampicin resistance in pathogenic mycobacteria. Antimicrob Agents Chemother 38:2380-2386 Wolinsky E (1988) Tuberculosis. In: Wyngaarden JB, Smith LH (Eds.) Cecil Textbook of Medicine. Pp 1682-1696. WB Sounders Co., Harcourt Brace Javonovich, Inc., Philadelphia Woodhead M (1992) New approaches to the rapid diagnosis of tuberculosis. Thorax 47:264 Young D et al. (1986) Immunological activity of a 38-Kilodalton protein purified from Mycobacterium tuberculosis. Infect Immun 54(1):177-183 Zhang Y et al. (1992) The catalase-peroxidase gene and isoniazid reisstance of Mycobacterium tuberculosis. Nature 358:591-593

9

The Immunology and Pathogenesis of Tuberculosis GRAHAM

A. W.

ROOK

CONTENTS 9.1 9.1.1 9.1.2 9.1.3

9.2 9.2.1 9.2.2 9.2.2.1 9.2.2.2 9.2.3 9.2.4 9.2.4.1 9.2.4.2 9.2.5 9.2.5.1 9.2.5.2 9.2.5.3 9.2.5.4 9.2.6 9.2.7 9.2.8 9.2.8.1 9.2.9 9.2.9.1 9.2.9.2 9.2.9.3 9.2.9.4

Introduction 133 Latent Tuberculosis and Its Relationship to Persisters After Chemotherapy 134 Protection Versus Immunopathology 134 The Objectives of the Immunologist 135 Immunity to Tuberculosis 135 The Crucial Role of the Type 1 Response for Immunity to Tuberculosis in Mice 135 The Possible Role of Other Types of T Lymphocyte 135 The Detrimental Role of Type 2 Responses 135 Variability of Tuberculosis in Different Mouse Strains 135 The Protective Role of Tumour Necrosis Factor (TNF-a) 136 Immunity to Tuberculosis in Man 136 Genetics of Susceptibility to Tuberculosis 136 Natural Human Gene Knockouts; Proof of the Role of IFN-y and IL-12 136 Other T Cell Types That May Be Involved in Immunity 136 CD8+ IFN-y-secreting T Cells 136 CD-I-restricted T Cells 137 Gammaldelta (y/'6) T Cells 137 Regulatory T Cells 138 The Role of TNF-a in Human Tuberculosis 138 Type 2 Responses in Human Tuberculosis 138 The Causes of the Controversy over Expression ofIL-4 in Human Tuberculosis 139 The Mechanisms of the Shift Towards a Type 2 Cytokine Profile 139 Macrophage Function and M. tuberculosis 139 Uptake of Mycobacteria 139 Toll-like Receptors 140 Mycobactericidal Mechanisms Within Macrophages 140 Reactive Oxygen and Nitrogen Intermediates 140

9.2.9.5 Macrophage Apoptosis and the Death of Bacteria 141 9.2.10 Evasion of the Antimicrobial Functions of Macrophages 141 9.2.11 Bacterial Genetics and Mechanisms of Avoidance of Destruction by the Type 1 Response 142 Immunopathology 142 9.3 The Koch Phenomenon; the Response 9.3.1 Characteristic of Disease 142 9.3.2 Tuberculin Response and Protection 142 9.3.3 The Relationship Between the Koch Phenomenon and the Shwartzman Reaction 143 9.3.4 A Hypothesis to Explain the Koch Phenomenon 143 9.3.5 Detrimental Roles of Tumour Necrosis Factor-a in Human Tuberculosis 144 9.3.6 Fibrosis 144 9.4 Endocrinology 144 9.4.1 Vitamin D3 Metabolism in Tuberculosis Lesions 144 9.4.2 Adrenal Steroids in Tuberculosis 145 9.4.2.1 The Effects of Stress 145 9.4.2.2 The Hypothalamo-Pituitary-Adrenal Axis in Human Tuberculosis 145 9.4.2.3 Dysregulation of the Cortisol-Cortisone Shuttle 145 Vaccination 145 9.5 9.5.1 Interference by Exposure to Environmental Mycobacteria 145 9.5.2 Concurrent Parasite Infections 146 9.5.3 Vaccine Dose 146 9.5.4 A Possible Novel Approach to Vaccine Design 146 9.5.6 Immunotherapy 146 References 147

9.1

Introduction

G. A. W. ROOK, BA, MB Bchir, MD Professor, Department Medical Microbiology, Royal Free and University College Medical School, Windeyer Institute of Medical Sciences, 46 Cleveland Street, London WIT 4JF, UK

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

Tuberculosis is a global emergency, currently aggravated by HIV, the break-down of health care systems and increases in drug resistance (Espinal et al. 2001). There are now more cases of tuberculosis than ever before in the history of mankind. The current failure to control tuberculosis is attributable to several factors that must be taken into consideration in any account of the immunology of the disease. These factors are:

134

1. The inadequacy of the current vaccine, Bacillus

2.

3.

4.

5.

Calmette-Guerin. The protection given varies from zero to about 80% (Fine 1995). Inadequate understanding of the biology of the organism itself. Mycobacterium tuberculosis can remain viable within the tissues without causing symptoms for the life of the individual (Wayne 1994) and, at least in countries with low or moderate tuberculosis endemicity, many cases of tuberculosis result from reactivation of latent infection (van Rie et al. 1999). The best available chemotherapy must be continued for at least 6 months. This treatment regimen is not a realistic proposition in most developing countries, or even in the inner cities of rich ones, because the patients feel well after a few weeks and stop taking the drugs. WHO now admits that directly observed therapy short-course (DOTS), in which the patient is supervised while taking every dose of therapy, helps but does not solve the problem (Butler 2000). Our inadequate understanding of the mechanism of protective immunity, which hampers efforts to design better vaccines, and the extraordinary problem of knowing how to select and test the best vaccine candidates. Inadequate understanding of how to implement immunotherapy. Immunological manipulations that correct the patients' failing immune responses may be the only way to shorten treatment regimens.

G.A,W.Rook

sites of fibrosis or calcification, where oxygen availability may be low. However, in a forgotten paper published in 1927, Opie and Aronson reported that 80% of tuberculous lesions were already sterile (as determined by culture in guinea-pigs) 5 years after the primary infection, whereas live bacilli could be found in macroscopically normal lung tissue (Opie and Aronson 1927). A major recent advance is the detection, by in situ polymerase chain reaction of DNA, of M. tuberculosis in lung tissue from victims of accidental death with no history or post mortem signs of tuberculosis (Hernandez-Pando et al. 2000a). When such samples were taken from countries with endemic tuberculosis (Ethiopia and Mexico), 30-40% of samples were positive. In contrast, no DNA of M. tuberculosis was found in samples from Norway, where transmission within the community ceased several decades ago. In the positive Ethiopian and Mexican samples, the DNA was seen in histopathologically normal tissue and was not confined to macrophages. Cell types containing M. tuberculosis DNA included type II pneumocytes, endothelial cells and fibroblasts (Hernandez-Pando et al. 2000a). These observations raise the possibility that by entering cells that are not "professional antigen-presenting cells",M. tuberculosis is able to escape detection and perhaps subvert the immune response.

9.1.2 Protection Versus Immunopathology 9.1.1 Latent Tuberculosis and Its Relationship to Persisters After Chemotherapy There are two interrelated reasons for the requirement for 6-month regimens. The first is obvious and often discussed. The chemotherapy kills the vast majority of the bacteria within a few days, but there are subpopulations of "persisters" (Grange 1992). It is not clear whether these organisms are in true stationary phase (Siegele and Kolter 1992) or merely replicating extremely slowly. Nor is it clear whether these persisters, defined as organisms that survive chemotherapy, are the same as "latent" or "dormant" bacilli that remain in the tissues of the approximately 90% of individuals who show no clinical disease after infection. These bacteria are evidently controlled by the immune response, but not killed by it. Most research has addressed dormant rather than persister bacilli, though they are likely to be similar populations. It was assumed that latent bacilli are in old lesions or

The second reason for the need for prolonged treatment is usually overlooked. Most tuberculosis patients have a necrotising pattern of response to M. tuberculosis, analogous to the phenomenon first noted by Koch in guinea-pigs (Koch 1891). There is overwhelming evidence that the Koch phenomenon is not a correlate of optimal protective immunity to tuberculosis. Indeed, pre-immunisation of animals so that they have a Koch phenomenon before they are challenged with virulent M. tuberculosis results in a clear and reproducible increase in susceptibility to the disease, compared to unimmunised controls (Wilson et al. 1940). This and other aspects of the Koch phenomenon are discussed in detail later. Its relevance at this point is that this inappropriate pattern of response may not correct itself rapidly during treatment. Therefore, if chemotherapy is stopped at 3 months, relapse rates are high even when the chemotherapy was an optimal rifampicin-containing one that achieved sputum negativity well before

135

The Immunology and Pathogenesis of Tuberculosis

3 months, and in spite of the fact that there are very few live organisms in the patients' tissues at this time (Balasubramanian et al. 1990).

9.2.2 The Possible Role of Other Types ofT Lymphocyte

In addition to conventional CD4+ a/~, Class II MHC9.1.3 The Objectives of the Immunologist The immunologist, therefore, needs to understand the differences between protective immunity and the Koch phenomenon, and the factors that determine which response pattern is present. The ultimate objectives are better prophylactic vaccines, and also therapeutic vaccines that can replace the pathological response with a protective one very early during treatment, using immunotherapeutic strategies that also cause recognition and clearance of persisters and dormant bacilli.

9.2 Immunity to Tuberculosis 9.2.1 The Crucial Role of the Type 1 Response for Immunity to Tuberculosis in Mice The ability to manipulate the immune system of mice with neutralising antibodies or gene knockout (KO) has provided strong evidence that, in this species, immunity to tuberculosis correlates with a Type 1 response. In vivo CD4+ lymphocytes act in concert with CD8+ cells and with numerous other cell types including macrophages, B cells and some stromal cells. Collectively these give rise to two patterns of cytokine release known as Type I (dominated by IL-12 from antigen-presenting cells, and by IL2, and IFN-y from Thl lymphocytes) and Type 2 (dominated by IL-4, 5 and 13 from Th2lymphocytes) (Clerici and Shearer 1994; Salgame et al. 1991). Disruption of the major histocompatibility (MHC) class II genes or of the gene for the ~ chain of the a/~ T cell receptor (Ladel et al. 1995), resulting in a deficiency of CD4+ a/~ T cells, render mice susceptible even to the avirulent Bacillus Calmette Guerin (BCG). Similarly, disruption of the gene for IFN-y makes mice very susceptible to M. tuberculosis (death within 3 weeks) and such mice may even die after many weeks from challenge with BCG (Flynn et al. 1993). A major inducer of the Type 1 pathway is IL-12, and IL-12 KO mice are more susceptible to tuberculosis (Wakeham et al. 1998).

restricted T cells, several other T cell types are also involved in the response to mycobacteria, including CD8+ cells, gamma/delta (y/o) T cells, CDl-restricted T cells and regulatory T cells. These are discussed later in relation to the immunology of the disease in man.

9.2.2.1 The Detrimental Role of Type 2 Responses

These data emphasise the crucial role of the Type 1 response. In agreement with this, other data indicate that the Type 2 response is not only unable to protect mice but can seriously undermine the efficacy of the Type 1 response. If a weak Type 2 response to the shared mycobacterial antigens is deliberately induced before challenge, mice are found to be strikingly more susceptible to tuberculosis than are unimmunised control animals (Hernandez-Pando et al.1997b; Lindblad et al. 1997). Similarly, in the Balb/c mouse model of pulmonary TB infection, the appearance of IL-4 in the lung lesions (as seen by immunohistochemistry and RT-PCR) coincides temporally and spatially with the appearance of areas of pneumonia and necrosis, leading to rapid clinical deterioration and death (Hernandez-Pando et al. 1996). These observations are not contradicted by a claim that, in IL-4 gene-disrupted mice, there is no evidence of increased resistance to the infection (North 1998). The animals used were resistant anyway and had controlled growth of the bacteria by 21 days, which is the optimum that can be achieved (North 1998). In contrast, Balb/c mice control the infection briefly at 21 days, and then relapse with progressive disease. This late phase is accompanied by a switch to Type 2 cytokine production (HernandezPando et al. 1996, 1997b), but progression is greatly attenuated if the IL-4 gene is knocked out (HernandezPando et al., in preparation).

9.2.2.2 Variability of Tuberculosis in Different Mouse Strains

As outlined above, the nature of the disease caused by M. tuberculosis in mice depends on the mouse strain used. For instance,A/J mice develop progressive interstitial pneumonitis, while C57BL/6 mice can develop massive granulomas mediated by a Type 1 response and so "drown" in Thl lymphocytes (Watson et al. 2000). Balb/c mice start with a Type 1 response and

G.A. W. Rook

136

control the infection at 21 days, but then switch to a Type 2 response and die with an increasing bacterial load and immunopathology (Hernandez-Pando et al. 1996, 1997b). Therefore, we cannot be sure which model is most similar to human tuberculosis without first studying the human disease.

9.2.3 The Protective Role ofTumour Necrosis Factor (TNF-a) This pro-inflammatory cytokine can have either protective or detrimental effects in murine disease, and the same is likely to be true in man, as discussed below in relation to immunopathology. Its effects appear to depend upon the other cytokines present. In the mouse, TNF-a is protective early in infection. TNF-a levels are elevated early (day 3) in mice infected via the intratracheal route and reach a second peak in the third week, coinciding with mature granuloma formation (Hernandez-Pando et al. 1997a). TNF-a receptor KO mice succumb faster to M. tuberculosis infection than control mice (Flynn et al.1995), and a disruption of the granulomatous response and increase in mycobacterial load is noted in M. tuberculosis-infected mice when TNF-a bioactivity is blocked (Adams et al. 1995).

culosis in man has come from the study of children with genetic defects of the Type 1 cytokine system. Vaccination with Bacille Calmette-Guerin (BCG), an avirulent derivative of the organism responsible for bovine tuberculosis, occasionally causes disseminated infection. The gene for the IFN-yRI gene in such a child had a single nucleotide deletion that resulted in the creation of a premature stop codon near the N-terminus (Jouanguy et al. 1996). Another study (Newport et al. 1996) involved four children from the same small town in Malta who presented with disseminated mycobacterial infections. The mycobacterial species isolated were M. fortuitum, M. avium (two strains) and M. chelonei. One child also had prolonged salmonellosis. These children had a single nucleotide substitution (A for C) rather than a deletion (Newport et al. 1996). It allowed normal levels of expression of the mRNA, but again introduced a premature stop codon. Interleukin-12 (IL-12) receptor deficiency has also been found in otherwise healthy individuals with mycobacterial infections. Unlike the children with IFNyR deficiency these patients are able to form mature granulomata, but their NK cells and T cells secrete little IFN-y. Thus, IL-12-dependent IFN-gamma secretion in humans seems essential in the control of mycobacterial infections, despite the formation of mature granulomas (Altare et al.1998; de Jong et al. 1998).

9.2.4 Immunity to Tuberculosis in Man

9.2.5

9.2.4.1

Other T Cell Types That May Be Involved in Immunity

Genetics of Susceptibility to Tuberculosis

Conventional genetic studies of tuberculosis patients showed that polymorphisms in genes encoding naturalresistance-associated macrophage protein (NRAMP1), the IL-l gene cluster, the vitamin D receptor and mannose-binding lectin were associated with susceptibility (Bellamy 2000). The relevance of vitamin D receptor polymorphisms is increased when there is also vitamin D deficiency as in the Gujarati population in London (Wilkinson et al. 2000). However, the effects on disease susceptibility are small, and so far studies of this type have cast little light on the mechanisms of immunity.

9.2.4.2 Natural Human Gene Knockouts; Proof of the Role of IFN-y and IL-12

On the other hand definitive evidence that, as in mice, the Type 1 response is crucial for immunity to tuber-

In addition to conventional CD4+ aJ~, Class II MHCrestricted T cells, several other T cell types are also involved in the response to mycobacteria. These are particularly fascinating because many of them recognise non-peptide antigens. Fig. 9.1 summarises the lymphocyte types involved, and some of their functions.

9.2.5.1 CD8+ IFN-y-secreting T Cells

There may be a high frequency of IFN-y-secreting CD8+ cytotoxic T cells in the peripheral blood of healthy individuals who have been exposed to tuberculosis (Pathan et al. 2000). This response was maintained in an asymptomatic contact over 2 years, so such cytotoxic T cells can clearly persist in individuals without active tuberculosis. These CD8 cells recognised a peptide from ESAT-6 (an immunogenic peptide released very early into cultures of M. tubercu-

137

The Immunology and Pathogenesis of Tuberculosis Various cell types thai recognise lipids, glycolipids, Isoprenoids

CD·1

1-1.

IL-12 Class I MHC Class II

COB

:-J

04

=

IFN'r

Activation - - - - - - ,

ltl- ' - - - - - - - - - - Suppression

Antigen· presenting cells

~IL-10 T re TGF·~

IL-10 Class II MHC Class I

Tc1 11----+----+ Cytotoxicity - - - - - - ,

fr'L~

IL·402

-

Tc

COB

' - - - - Fibrosis

Fig.9.1. Multiple lymphocyte types are involved in immunity to mycobacteria. IFN -r, the major activator of macrophages, may be released by CD4+ Thl cells, but also by CD8+ cytotoxic T cells and a variety of CD-I-restricted T cells that recognise unconventional antigens such as lipids and glycolipids (see main text). Macrophage activation and macrophage killing by cytotoxic cells can both lead to bacterial death. If the antigen-presenting cells are secreting IL-IO, rather than IL-12, the T cells generated will tend to be regulatory T cells (Treg ) or IL-4 (IL-402) secreting CD8+ cells and CD4+ Th2 cells. The presence of all of these in TB patients is well documented and, together with TNF·a (not shown), they will impair immunity and cause suppression, macrophage deactivation, fibrosis and immunopathology. The reality is still more complex, because TB patients also have T cells that make both IFN and lL-lO

-r

losis), and other peptides recognised by this cell type have been defined using cells from patients recovering from tuberculosis (Cho et al. 2000). These observations are important since both in mice (Silva and Lowrie 2000) and in man (Cho et al. 2000) CD8+ cytotoxic T cells that use the granule-mediated pathway of killing (as opposed to the Fas-FasL pathway) lead to killing of the contained mycobacteria, too. The role of the granule contents, particularly granulysin, has been reviewed (Krensky 2000). 9.2.5.2 CD-l-restricted T Cells

In humans and other large long-lived animals there are several types of T cell (including a~ T lymphocytes negative for both CD4 and CD8 molecules (socalled double-negative T cells), rb T cells and certain CD4+, CD8+, CD8a/a+ and NK lymphocytes) that recognise mycobacteriallipoarabinomannan (LAM) or mycolic acids presented by the MHC class I-like molecules of the CDI family (Beckman et al. 1994; Moody et al. 1997; Sieling et al. 1995). Similar T cells have been detected that recognise an evolutionarily conserved family of isoprenoid glycolipids that include essential components of protein glycosyl-

ation and cell wall synthesis pathways (Moody et al. 2000). The role of the CD-l restricted T cells remains unclear because rodents have a homologue of CDId, but have lost the genes for CD-la, b or c which are the forms that present mycobacterial lipids and glycolipids. Thus, their protective role will need to be tested in guinea-pigs or in large long-lived animals that have these genes, though it is reported that some types of human CD-I-restricted T cell not only produce significant amounts of IFN -y but also appear able to lyse infected cells and directly kill intracellular mycobacteria (Sieling et al. 1995; Stenger et al. 1998). It is fascinating that the different forms of CD-l "survey" different intracellular compartments, and so will encounter products of M. tuberculosis in different ways (Schaible et al. 2000; Sugita et al. 2000).

9.2.5.3 Gamma/delta (r/o) TCells

rio

Like CD8+ T cells, T cells can also kill infected cells by the granule pathway, and can reduce the viability of the contained bacteria (Dieli et al. 2000b). These cells are activated during pulmonary tuberculosis and

138

increase in frequency (Behr Perst et al.1999), but they decline after treatment (Dieli et al. 2000).

G.A.W.Rook

IL-12 provide definitive evidence of the importance of Type 1 cytokines, and suggest a close parallel with the mouse models. Recently the negative role 9.2.5.4 of Type 2 cytokines in human TB, again paralleling Regulatory T Cells the murine models, has been established (Marchant et al. 2001; Seah et al. 2000; van Crevel et al. 2000). A dominant theme in other domains of immunol- Expression of IL-4, whether measured by flow ogy is the regulatory T cell or "T reg" though they cytometry or by sensitive quantitative RT-PCR have received little attention in the context of on non-stimulated peripheral blood T cells (Seah tuberculosis. Treg characteristically release IL-lO and Rook 1999), is increased and correlates with and TGF-p, and suppress inflammation in models severity of disease and with cavitation (Seah et al. of allergy, inflammatory bowel disease and auto- 2000; van Crevel et al. 2000). The IL-4 mRNA copy immunity (Maloy and Powrie 2001). It has been number also correlates with total IgE (Seah et al. claimed that T cells cloned from the bronchoalveo- 2000) and with levels of soluble CD30 (Seah and lar lavage of human TB patients make both IFN-y Rook 2000). Thus, although it is true that actual and IL-l 0, and so may be a form of Treg (Gerosa et al. cytokine levels and mRNA copy numbers are 1999). Other authors have also noted the increased higher for Th-l than for Th-2 cytokines in tubersecretion of TGFp and IL-I0, though some of the culosis, the major change in cytokine expression IL-lO may come from macrophages rather than Treg compared to healthy donors is not, as previously (Ellner 1997). Inappropriate premature activation of stated, the small decrease in expression of Thl Treg is clearly a possible mechanism of failure of the cytokines, but rather a massive (80-100x) increase in expression of Th2 cytokines (Seah et al. 2000). immune response. Similarly, M. tuberculosis-responding T cells cloned from the peripheral blood of untreated tuberculosis patients, whether from Africa or Italy, secrete 9.2.6 The Role ofTNF-a. in Human Tuberculosis abundant IL-4 in response to M. tuberculosis. After treatment, the cytokine profile returns to Type 1 The other cytokine that is clearly implicated in man, (Marchant et al. 2001). Interestingly, many of the which again shows a parallel with data from the IL-4-secreting cells in TB patients are, in fact, mouse models discussed above, is tumour necrosis CD8+ (Gerosa et al. 1999; van Crevel et al. 2000). factor alpha (TNF-a.). Absolute proof of its role in Actually, it is likely that they are in reality secreting man is available only in relation to latent tubercu- IL-402, the splice variant of IL-4 that drives fibrosis losis. An antibody that neutralises TNF-a. has been (Atamas et al. 1999; Seah and Rook 1999). Finally, achieving some success as a treatment for rheu- it has emerged that M. tuberculosis contains commatoid arthritis, but a clear consequence in some ponents that drive striking expression of IL-4 in individuals is the reactivation of latent tuberculosis normal peripheral blood mononuclear cell cultures (Keane et al. 2001). It is therefore interesting that the in vitro (Seah and Rook 2001). DNA from M. tuberculosis detected by in situ PCR is These data have resolved a long-running controfrequently found in cells situated in tissues devoid versy which deserves explanation. That there is an of lymphocyte infiltration (Hernandez-Pando et al. IL-4 component in the response of human tubercu2000a), so that lymphocyte-derived cytokines may losis patients to M. tuberculosis ought to have been be at very low levels. On the other hand, numerous accepted 10 years ago, because there is no other components of M. tuberculosis may directly trigger known explanation for the presence of specific IgE TNF-a. release from macrophages and other non- antibody (Yong et al. 1989). Interestingly, the other lymphoid cell types, and this local release of TNF-a. largely Type 2 cytokine-dependent antibody, IgG4, is also reported to be increased in patients (Wilsher may maintain latency. et al. 1999). Similarly, immunohistochemistry reveals IL-4-expressing cells in the lymphoid tissue of tuberculosis patients (but not in tissue from patients with 9.2.7 sarcoidosis) (Bergeron et al. 1997). Type 2 Responses in Human Tuberculosis These observations and, above all, the susceptibility of children with defective receptors for IFN-y or

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139

9.2.8

Increasing antigen load is likely to be one factor, since the Thl/Th2 balance is strikingly linked to dose when immunising with particulate antigens such as mycobacteria (Hernandez-Pando and Rook 1994), or Why, then, has the matter been controversial? Firstly, leishmania (Bretscher et al. 1992). IL-4 is biologically active at much lower concentraThere are now conclusive data showing that M. tions than IFN-y and has a correspondingly lower tuberculosis contains components that drive IL-4 mRNA copy number, so methods that reliably pick expression and secretion in vitro when cultured with up IFN-yor its messenger RNA fail to detect biologi- human peripheral blood mononuclear cells (Seah cally significant levels of IL-4. Moreover the mRNA and Rook 2001). The nature and importance of these for IL-4 has a very short half-life, so it has often components is currently under investigation. disappeared from clinical specimens collected in In some populations excessive or inappropriate the field before they reach the laboratory. Workers contact with environmental mycobacteria may have who failed to detect IL-4 in either normal donors primed a Type 2 response to the crucial common or TB patients assumed, with no logical justifica- antigens. This mechanism is clearly demonstrable tion, that it was not increased in the latter. Secondly, in mice, in which it can massively increase susceptiattempts to increase cytokine expression by stimu- bility (Hernandez-Pando et al. 1997b) and has been lation of the cells in vitro do not yield an accurate suggested, but not conclusively proven, in man (Fine reflection of the cytokine balance present in vivo, 1995; Stanford et al.I981). and rapid early production of IFN-y can suppress During active infection, selective apoptosis of ThlTh2 cytokine release, as repeatedly demonstrated like T cells may be a factor (Das et al. 1999;Varadhachary by workers in the field of allergy. Finally, previous and Salgame 1998), as may prostaglandin release studies failed to take into account the presence of (Hilkens et al.1995; van-der-Pouw-Kraan et al.1995). the IL-4 splice variant (IL-482). This variant of lL-4 Finally there are now strong reasons for suggesting may be an inhibitor of IL-4 activity and is always that endocrine interactions with the immune system co-expressed with IL-4 at about the same level are important. Vitamin D3, cortisol metabolism and (Arinobu et al. 1999). In lung cells it may be dehydroepiandrosterone levels are discussed in the expressed at higher levels than IL-4 itself. However, endocrinology section below. almost every study of IL-4 mRNA levels used primers that would amplify mRNA for both lL-4 and the splice variant (Seah and Rook 1999). 9.2.9 Macrophage Function and M. tuberculosis 9.2.8.1 The Mechanisms of the Shift Towards a Type 2 9.2.9.1 Cytokine Profile Uptake of Mycobacteria

The Causes of the Controversy over Expression of IL-4 in Human Tuberculosis

What are the likely causes of this shift in cytokine profile? Several possibilities are shown in Fig. 9.2.

Mycobacteria are taken up by multiple pathways including complement receptors and mannose recep-

Fig. 9.2. Mechanisms that may lead to excessive activation of Type 2 cytokines and immunoregulation in human tuberculosis. These can impair mycobactericidal functions of macrophages and, in concert with TNF-a, contribute to immunopathology. Additional factors not shown are prostaglandins, and also prior induction of Th2 response to cross-reactive components of environmental mycobacteria

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tors (Kang and Schlesinger 1998; Schlesinger 1998). However, this is clearly not the whole story because in vitro M. tuberculosis can enter a variety of cell types that do not express these receptors (Filley and Rook 1991; Shepard 1958). The exact mode of uptake must affect the subsequent fate within the cell (AstarieDequeker et al. 1999).

9.2.9.2 Toll-like Receptors

Much of the initial activation and cytokine response of macrophages to mycobacteria may be mediated by interaction with the Toll-like receptors (TLR). These are members of the interleukin 1 (IL-1) receptor family, related to Toll, a molecule involved in innate microbial resistance mechanisms in Drosophila. Both virulent and attenuated strains of M. tuberculosis can activate in a TLR-dependent manner. TLR2, but not TLR4, could confer responsiveness to LAM isolated from rapidly growing mycobacteria. In contrast, LAM isolated from M. tuberculosis or Bacillus Calmette-Guerin failed to induce TLR-dependent activation. However, other soluble and cell wall-associated components of M. tuberculosis are involved. A soluble heat-stable and protease-resistant factor was found to mediate TLR2-dependent activation, whereas a heat-sensitive cell-associated mycobacterial factor mediated TLR4dependent activation (Means et al. 1999). Lipoproteins can activate via TLR, and several from M. tuberculosis will drive IL-12 production in this way (Brightbill et al. 1999), perhaps explaining the latter result. 9.2.9.3

Mycobactericidal Mechanisms Within Macrophages

Inhibition or killing ofM. tuberculosis is easily induced in murine macrophages by exposure to IFN-y but such

effects are extremely difficult to demonstrate convincingly in human cells (Rook et al. 1985, 1986). Success has been reported using human alveolar lavage macrophages exposed to TNF-a in vitro (Hirsch et al.1994). It is possible that the major killing mechanism is not a direct effect of activated macrophages, but rather an event that occurs during certain types of apoptosis (see below) or during killing of the macrophage by cytotoxic T cells that "inject" granulysin and perforin (see section on CD8+ effector cells above) (Fig. 9.3).

9.2.9.4 Reactive Oxygen and Nitrogen Intermediates

If macrophages do themselves kill M. tuberculosis, these are likely candidate killing mechanisms (Fig. 9.3) (Chan et a1.1992, 1995). The mechanism of action of the nitric oxide (NO) is uncertain, because it has important signalling and second messenger functions that may be as important as direct toxicity for the organisms (Roach et a1. 1994). However, KO mice unable to make NO or other reactive nitrogen intermediates (RNI) showed no increase in proliferation of M. tuberculosis in the lungs until very late in the infection, but there was increased growth in the spleen. In contrast, KO mice unable to make reactive oxygen intermediates (ROI) had increased growth of bacilli in the lungs. Interestingly, activation of macrophages by IFN-y in vitro to control proliferation of M. tuberculosis was dependent upon RNI rather than ROI, and so appeared to parallel immunity in the spleen rather than in the lungs (Adams et a1. 1997). The role of NO in man remains unclear. It probably is made by appropriately activated human macrophages (Nicholson et a1. 1996), but never in the very large quantities that murine macrophages can release. There is not universal agreement about the antimycobacterial relevance

MACROPHAGE

1) Activation

Acidification of phagosomes Maturation to hydrolytic vesicle

IFN-y lNF-a

Reactive oxygen and nitrogen derivatives ------l

2) Cytotoxic T cells

~ 'YJ 3) Induction of apoptosis

Perlorin Granulysin - - - - - +

Fas

-----A--------"

ATP ~ Death of some bacteria and H20 2 uptake of apoptotic bodies Fas Ligand by fresh macrophages

Multiple mechanisms attempt to kill M. tuberculosis within macrophages

Fig. 9.3. It is still not clear which are the most important mechanisms leading to killing of M. tuberculosis, particularly in human cells where killing is very difficult to achieve in vitro. Candidate pathways are shown and all are referenced and discussed in the text. Note that only some inducers of apoptosis result in reduced viability of the contained bacteria. Further macrophage activation must occur via the Toll-like receptors but their role in killing is not yet known

141

The Immunology and Pathogenesis of Tuberculosis

9.2.10

of this mechanism (Aston et al. 1998). There is some evidence that l,25(OHhD3 may be involved in the activation of iNOS in a human monocyte cell line (Rockett et al. 1998), so this could explain the antimycobacterial effect of this material in vitro (Rook et al. 1986).

Evasion of the Antimicrobial Functions of Macrophages

Apoptosis (programmed cell death) is a major regulator ofthe immune system,byproviding differential removal of different lymphocyte and macrophage subsets. Some human peripheral blood T cells undergo apoptosis in 9.2.9.5 the presence of antigen from M. tuberculosis (Das et Macrophage Apoptosis and the Death of Bacteria al. 1999; Hirsch et al. 1999). In contrast, several groups Large numbers of apoptotic T cells and macrophages report that M. tuberculosis actively inhibits apoptosis are seen in caseous foci. Immunohistochemistry and of macrophages (Fig. 9.4). Mannose-capped lipoarabiin situ hybridisation showed that the macrophages nomannan (Man-LAM) stimulates phosphorylation of surrounding caseous foci are negative for the anti- Bad, a pro-apoptotic protein, and so inhibits apoptoapoptotic protein bel2, but positive for the pro-apop- sis (Maiti et al. 2000). Another group has shown that totic protein bax, while the associated T cells express Man-LAM inhibits apoptosis by a mechanism involvIFN-y and FasL (Fayyazi et al. 2000). Macrophage ing calcium-dependent signalling (Rojas et al. 2000). apoptosis may be beneficial to the host, because Moreover cells containing M. tuberculosis are markedly death of the infected macrophage can be associated more sensitive to killing by TNF-a (Filley and Rook with death of the contained mycobacteria (Fig. 9.3). 1991), but infected cells secrete soluble TNF receptors Moreover, it has been suggested that reduction in (sTNF-R2) that can block their destruction by TNF-a bacillary numbers is only achieved by apoptosis of (Fratazzi et al. 1999). Thus it might be suggested that infected monocytes, not by the necrotic mode of M. tuberculosis causes death of a subset of T cells, while death (Molloy et al. 1994; Oddo et al. 1998). Apopto- preserving some macrophages as hiding places with sis induced by ATP promotes the killing of virulent reduced microbicidal and antigen-presenting funcM. tuberculosis within human macrophages (Kusner tion. A point against this hypothesis is that infected and Adams 2000; Lammas et al. 1997) as does apop- macrophages may also have down-regulated mRNA tosis induced by Fas ligand (Oddo et al. 1998), and expression of bcl-2, an inhibitor of apoptosis (Klingler hydrogen peroxide-induced apoptosis also causes et al. 1997). It may be that the organism is preferentially mycobactericidal effects (Lauchumroonvorapong et inducing forms of apoptosis that leave the organisms al.1996). Thus, perhaps M. tuberculosis has strategies unharmed. In addition to opposing apoptosis, mycobacteria that oppose macrophage apoptosis in order to limit have numerous other strategies for avoiding being the bacterial killing that can accompany this event.

M. tuberculosis avoids being killed by macrophages 1) Mechanisms during uptake Uptake via Mannose receptor Block Ca++ signalling by complement receptor Mannose receptor

Macrophage

Cell not activated

I Blocked function

2) Resistance to killing Tough cell w

SuperoXJde dismu1aSe

Free radlClll scavengers

H~"C?~ 8

3) Alterations to vesicles Failed maluratJon Allered fUSlOtl panern Blocked proton pump

4) Control cell signalling .....

S) Increased release soluble TNFf11 IL·l0

TGF·p IL-6

6) Decreased release or expression

Faa SHP-l

TNF-C

Actrvate phosphotyroslne phosphalase Block signalling via IFN-y receplOfS Illock an1Jgetl presa
Peptide + Class II MHC

9

Fig. 9.4. This figure should be compared with Fig. 3. Each of the killing pathways in Fig. 3 is opposed by some mechanisms in Fig. 4. Short thick lines indicate blocked pathways. Most of the figure is self-explanatory. Uptake via mannose receptors may avoid triggering killing mechanisms. The vacuoles containing mycobacteria lie within the sorting/recycling endosomal machinery of the macrophage and fail to acidify and fuse with acidic lysosomes. But they do fuse with LAMP-I-containing endosomes and they release vesicles containing LAM. Thus their fusion pattern is altered by the pathogen. (LAM lipoarabinomannan, LAMP-I lysosome-associated protein 1) SHP-I is a phosphotyrosine phosphatase

142

killed by phagocytes (Fig. 9.4) (Chan et al. 1991), M. tuberculosis may be taken up via mannose receptors that fail to trigger killing events (Astarie-Dequeker et al. 1999). It also inhibits complement-receptormediated Ca++ signalling, which may contribute to the failure of killing mechanisms (Malik et al. 2000). Mycobacteria can inhibit acidification of the phagosome (Sturgill-Koszycki et al. 1994) and modify intracellular trafficking of vacuoles so they behave like part of the endosomal recycling compartment rather than as toxic phagolysosomes (Xu et al. 1994). These vacuoles release quantities of lipoarabinomannan (LAM) which insert into glycosylphosphatidylinositol (GPI)-rich domains in the cell membrane (Ilangumaran et al. 1995). LAM is itself a GPI of unusual glycan structure, with the ability to modify numerous macrophage functions including the ability to respond to IFN -y and the ability to present antigen (reviewed in Ilangumaran et al. 1995). The last point may be relevant to the apparent inability of long-term mycobacterium-infected macrophages to present antigen to CD4+ T cells (Pancholi et al.1993). Thus the organisms may hide, undetected, in modified macrophages. The pattern of cytokine release from infected macrophages changes so that macrophage activation is diminished and T cell recruitment impaired (Fig. 9.4). Recruitment of Thl lymphocytes requires IL-12 production, which is inhibited by increased production of TGF-~ and IL-IO (Ellner 1997; Fulton et al.1998; Toossi et al.1997) and IL-6 release may also be a factor. TGF-~ and IL-I0 also impair macrophage microbicidal function and the IL-I0 contributes to increased release of TNF receptor-2, which blocks the activating role of TNF-a (Balcewicz-Sablinska et aI.1998).

9.2.11 Bacterial Genetics and Mechanisms of Avoidance of Destruction by the Type 1 Response There is intense interest in the bacterial factors that allow M. tuberculosis to resist destruction by the immune system in mice after the development of the full Type 1 response at about 21 days. The recent publication of the entire sequence of the M. tuberculosis genome has allowed a variety of genetic techniques to be applied. Mutations that inactivate mycolic acid cyclopropane synthase (Glickman et al. 2000) or isocitrate lyase, which is required for the metabolism of fatty acids (McKinney et al. 2000), both result in decreased ability to persist. Others have expressed candidate virulence genes,

G.A. W. Rook

or plasmid libraries of M. tuberculosis DNA in the avirulent organism M. smegmatis and then looked for increased ability to survive inside macrophages (Miller and Shinnick 2000; Wei et al. 2000). A review of the comparative genomics of mycobacteria gives an overview of the techniques used and the results obtained (Brosch et al. 2000).

9.3 Immunopathology 9.3.1 The Koch Phenomenon; the Response Characteristic of Disease As outlined in the introduction, Koch noted that 4-6 weeks after establishment of infection in guineapigs, intradermal challenge with whole organisms or culture filtrate resulted in necrosis locally and in the original tuberculous lesion (Koch 1891). Similar phenomena occur in humans. The tuberculin test is frequently necrotic in subjects who are, or have been, tuberculous, whereas necrosis does not occur when positive skin-tests to tuberculin are elicited in normal BCG recipients or in tuberculoid leprosy patients. Koch sought to exploit this phenomenon for the treatment of tuberculosis and found that injection of larger quantities of culture filtrate (Old Tuberculin) subcutaneously into tuberculosis patients would evoke necrosis in established tuberculous lesions at distant sites (Anderson 1891). This resulted in necrosis, sloughing and "cure" of the lesions of skin tuberculosis (Lupus vulgaris, usually caused by bovine strains), but when similar necrosis was evoked in deep lesions in the spine or lungs, the results were disastrous and merely provided further necrotic tissue in which the bacteria could proliferate (Fig. 9.5). This treatment was therefore abandoned, but it provided crucial clues as to the nature of the immunopathology of tuberculosis.

9.3.2 Tuberculin Response and Protection The error in Koch's thinking was highlighted in the 1940s. When guinea-pigs were pre-immunised so that they had powerful Koch phenomena in response to small doses of tuberculin, they became more susceptible to tuberculosis than were unimmunised control animals (Wilson et al.1940). Obviously this was seen

The Immunology and Pathogenesis of Tuberculosis

143

Fever, rigors. necrosis and sloug/ling 01 the skln lesion, and dangerous necrosis of other lesions In lUngs or spine.

24-48hrs

~

.~

only if the challenge infection was into the lungs or by deep intramuscular injection, so that necrosis could not result in shedding of the infected tissue. Optimal protection was seen in animals with moderate positive responses. This experiment is illustrated in Fig. 9.6 (Wilson et al.I940),and makes the point, also apparent from human epidemiology (Fine 1993), that the most protective response correlates with a small positive induration in the Mantoux test (delayed type hypersensitivity or DTH) rather than with the massive necrotic Koch phenomenon.

9.3.3 The Relationship Between the Koch Phenomenon and the Shwartzman Reaction Koch's discovery that soluble bacterial material could trigger necrosis in a distant tuberculous site (in addition to the site of injection) has some parallels with the Shwartzman reaction (Shwartzman 1937), and subsequent experiments strengthen the parallel still further. For instance injections of endotoxin-rich material into a distant site (instead of the tuberculin used by Koch) will also trigger necrosis in tuberculous lesions (Bordet 1931; Debonera et al.1932; Shands and Senterfitt 1972). These observations are compatible with the view that tuberculous lesions are susceptible to superimposed cytokine-mediated damage.

Fig. 9.5. Koch's failed immunotherapeutic treatment for tuberculosis, similar to the phenomenon he had previously described in guinea-pigs. It achieved necrosis and sloughing of the chronic lesions of cutaneous tuberculosis (Lupus vulgaris), but the simultaneous necrosis and liquefaction of cryptic lesions in deep tissues was disastrous and the treatment was abandoned

9.3.4 A Hypothesis to Explain the Koch Phenomenon There is increasing evidence for increased susceptibility to cytokine-mediated tissue necrosis of tissues undergoing inflammation mediated simultaneously by Type 1 and Type 2 cytokines. This is easily demonstrated in Balblc mice with pulmonary tuberculosis (HernandezPando et al. 1995). During the first 3 weeks, DTH sites were not sensitive to local injection of as much as 1 ~g of recombinant TNF-a. This is the period of Type 1 response (Orme et al.1993). After 50 days, the animals enter a phase of slowly progressive disease accompanied by increasing Th2 cytokine production, seen as IL-4 positive cells in the lesions. In these animals DTH sites become TNF-a-sensitive (Hernandez-Pando et al. 1997b; Hernandez-Pando and Rook 1994). Recently we have found that this state of TNF-a-sensitivity of the DTH sites does not occur in tuberculous IL-4 KO mice, but is restored if the IL-4 KO mice receive an intravenous injection of a persistent form of IL-4 (Hernandez-Pando et al., in preparation). This propensity for TNF-a toxicity in the presence of IL-4 is supported by several examples in non-mycobacterial models. Lawrence and co-workers, studying Trichinella spiralis infection in mice, have found that the enteropathy caused by TNF-a is dependent upon IL-4 (Lawrence et al. 1998). Other murine studies have also revealed that, in certain mouse strains, DTH caused by Th2 cells cor-

Result of inlramuscular infecllon with 18

~

~

I

Immunise with killed M. tuberculosis by various protocols \

W

•

, . . . . . - - - - - - - . . . , MORE susceptible ... 'Koch" than unimmunised

r-

ooMro~ Rank according to ~ Positive tuberculin ~

~ response

.. Negative Unimmunised controls

R' t t es,s an

~+----_Negative

Susceptible Susceptible

Fig.9.6. Large numbers of outbred guinea-pigs were immunised with killed M. tuberculosis by a variety of protocols an d then tested with a range of dilutions of tuberculin, before they were challenged by the intramuscular route with a very small does of M. tuberculosis. The most protected animals were those with small positive tuberculin responses, whereas animals with exquisite tuberculin sensitivity (Koch phenomenon) were more susceptible to the infection that were unimmunised controls (Wilson et al. 1940)

G.A. W. Rook

144

relates with TNF-a production by the cells (Muller et al. 1994). Finally, if an important component of the Koch phenomenon is cytokine-mediated damage in a site of mixed Type l/Type 2 inflammation, then the toxicity of Koch's "treatment" for tuberculosis is easily explained (Figs. 9.5, 9.2) (Anderson 1891).

9.3.5 Detrimental Roles ofTNF-a in Human Tuberculosis The previous section suggests that a component of the immunopathological state in human tuberculosis may result from the simultaneous presence of Type 1 and Type 2 cytokines and TNF-a. An increase in plasma TNF-a levels has been associated with clinical deterioration in patients with severe tuberculosis (Bekker et al. 1998). Both thalidomide and pentoxifylline, as inhibitors of TNF-a release, have been tried as treatments for the cachexia of chronic disease (Haslett 1998). Thalidomide, which reduces IL-6, IL-lO as well as TNF-a levels, and reduced lung pathology in a murine model (Moreira et al. 1993), was clearly clinically beneficial in the human disease (Tramontana et al. 1995).

9.3.6 Fibrosis The fibrosis is another aspect of the immunopathology of human tuberculosis that requires explanation. The dominant cytokine in tuberculosis, IFN-y, opposes fibrosis, so why does fibrosis occur? In fact, in all human diseases characterised by marked pulmonary fibrosis there is expression of Type 2 cytokines (systemic sclerosis, idiopathic pulmonary fibrosis, radiation-induced pulmonary fibrosis, chronic lung allograft rejection [reviewed in Lee et al. 2001]) and the same is true in the mouse in the bleomycin model (Lee et al. 2001) and in schistosomiasis, where fibrosis and tissue remodelling do not occur if induction of Type 2 cytokines by the ova is blocked by preimmunisation with ova+IL-12. These observations have led to the "Type 2 cytokine hypothesis offibrosis" (Lee et al. 2001). Type 2 cytokines such as IL-4, IL-482 and IL-13 activate fibroblasts and promote collagen formation. IL-13 also drives formation of TGF-~ and, by increasing release of the enzymes that activate TGF-~ (such as MMP-9) while down-regulating latent TGF-~-binding protein (LTBP), it also activates the TGF-~ (Lee et al. 2001). Significantly, the increase in expression of Type 2 cytokines in human TB extends to IL-13 which, like IL-4 and IL-482, is increased 80-100

fold compared to controls matched for age, race and gender (Seah et al. 2000).

9.4 Endocrinology There are several endocrine and metabolic changes in tuberculosis that may contribute to the failure of the Type 1 immune response to control the infection, and to the increasing level of Type 2 cytokine expression.

9.4.1 Vitamin D3 Metabolism in Tuberculosis Lesions The macrophages of tuberculosis patients, following activation by IFN-y, express an active la-hydroxylase, and rapidly convert 25(OH)-vitamin-D3 to calcitriol (Rook 1988; Rook et al. 1986). This is a potent phenomenon, leading occasionally to leakage of calcitriol into the periphery and to hypercalcaemia, though it has in the past been difficult to understand its role in the disease (Rook 1988). It now seems possible that this is a feed-back mechanism that tends to down-regulate Th1 and enhance Th2 responses, because calcitriol inhibits production of IFN-y and IL-2, and increases production ofIL-4 and IL-5 (Daynes et al. 1991; Rigby et al. 1987). This may well be related to the ability of calcitriol to inhibit release of IL-12 (Lemire 1995). In the 1940s attempts were made to treat tuberculosis with vitamin D. When patients with skin tuberculosis (Lupus vulgaris, often due to M. bovis) were treated with this vitamin, the chronic non-healing granulomatous lesions often underwent necrosis followed by resolution (Macrae 1947). However necrosis and liquefaction also occurred in deep lesions in the spine and lungs (Brincourt 1967), so the result was as disastrous as the use of Koch's immunotherapy described above (Anderson 1891). The mechanism of this effect remains unknown, but an increase in Type 2 cytokine expression in granulomata rich in Type 1 cytokines and TNF-a would be expected to cause necrotising immunopathology as discussed earlier.

The Immunology and Pathogenesis of Tuberculosis

9.4.2 Adrenal Steroids in Tuberculosis

9.4.2.1 The Effects of Stress

Glucocorticoids cause a switch to Type 2 cytokine production (Brinkmann and Kristofic 1995; Ramirez et al. 1996), probably because of effects on dendritic cells, which secrete less IL-12 and more IL-1O in their presence (Vieira et al. 1998; Visser et al.1998), but glucocorticoids also down-regulate the antimycobacterial effects of macrophages (Rook et al. 1987). It is therefore not surprising that reactivation or progression of infection with tuberculosis is sensitive to glucocorticoid therapy and to activation of the hypothalamopituitary-adrenal axis. Exposing humans to the stress of war or poverty (Spence et al. 1993), or cattle to the stress of transportation are enough to cause reactivation of disease. The disease-promoting effect of stress (Brown et al.1993; Tobach and Bloch 1956) and excessive activation of the hypothalamo-pituitary-adrenal axis (Hernandez-Pando et al.1998a,b) have been demonstrated under more controlled conditions in mice.

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that the site of abnormal conversion of inactive cortisone to active cortisol in the patients is the infected lung itself (Baker et al. 2000; Rook et al. 2000). This may be explained by the observation that TNF-a and IL1~ both increased the expression levels and reductase activity of ll~-HSD-l in a cell line in vitro (Escher et al. 1997). The result is a local increase in cortisol levels that is not apparent from measurements of serum cortisol. This cortisol excess will cause a shift towards Type 2 cytokine expression, deactivation of the antimycobacterial effects of macrophages, increased IL10 and increased TGF-~, so it may contribute to the changes seen in the human disease.

9.5

Vaccination The protective efficacy of BCG vaccination varies from 80% protection to no protection at all in different populations (reviewed in Fine 1993). The need to understand this variability before undertaking long and expensive trials of novel vaccines in man is obvious. Several hypotheses are currently under investigation.

9.4.2.2 The Hypothalamo-Pituitary-Adrenal Axis in Human Tuberculosis

In tuberculosis patients who are rested and acclimatised to hospital, the cortisol diurnal rhythm is normal and so are the responses of the adrenals to CRH and to very low doses (i.e. physiological) of ACTH (Rook et al. 2000). The total 24-hour cortisol output may be normal or modestly raised. However, there is a change in the pattern of metabolism of cortisol indicating a large alteration in the equilibrium point of the cortisol-cortisone shuttle, as discussed below (Rook et al' 1996).

9.4.2.3 Dysregulation of the Cortisol-Cortisone Shuttle

A major mechanism for the regulation of local tissue cortisol levels is the inter-conversion of active cortisol (II-hydroxy) and inactive cortisone (II-keto). Thus, effective cortisol concentrations in different organs can be very different from the values found in the serum. Gas chromatography and mass spectrometry revealed a striking excess of metabolites of cortisol relative to metabolites of cortisone in 24-hour urine collections from tuberculosis patients (Rook et al. 1996). Subsequent analysis of alveolar lavage samples from tuberculosis patients and controls has revealed

9.5.1 Interference by Exposure to Environmental Mycobacteria This hypothesis assumes that the common antigens, shared by all mycobacterial species, are relevant to protection. We have known for many years that the Bacillus Calmette-Guerin (BCG) is as effective a vaccine against leprosy as it is against tuberculosis, although M. leprae is an entirely different species (Fine et aI. 1986). BeG must therefore be able to work through common epitopes. Similarly, there is evidence that contact with an environmental organism leading to mycobacterial skin-test positivity is protecting the population of Malawi from both tuberculosis and leprosy (Fine et aI. 1994). In mice powerful protective or "anti-protective" effects can be induced with an environmental mycobacterial saprophyte, simply by altering the immunisation protocol so as to induce Type 1or Type 2 response (Hernandez-Pando et al. 1997b). These effects are obviously due to the common antigens. It is also significant that tuberculosis patients who still maintain necrotising skin-test positivity to antigens of M. tuberculosis itself, have diminished or absent skin-test responses to environmental saprophytes (Kardjito et al. 1986), whereas these do evoke responses in protected

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populations. The heat shock proteins (hsp), which are very highly conserved across species, are important examples of this concept. Indeed, the 65 kDa heat shock protein of M. leprae can protect mice against M. tuberculosis (Silva and Lowrie 1994), as can DNA vaccines based on its sequence. It is, therefore, logical to suggest that an apparent reduction in the efficacy of BCG could occur either because the environmental saprophytes were themselves protecting, or because they were priming deleterious patterns of response (e.g. Type 2) to the common antigens and so blocking the efficacy of the BCG. These two effects were suggested to be occurring in different countries (Stanford et al. 1981) and both effects are easily demonstrated experimentally (Hernandez-Pando et al. 1997b).

9.5.2 Concurrent Parasite Infections Some authors suggest that the presence of concomitant parasite infections may cause a systemic bias towards Th2 responses that undermines the ability of BCG to induce a Thl response to mycobacterial antigens.

9.5.3

then used as recombinant vaccinia or salmonella or as the purified protein plus adjuvant, or as DNA vaccines. The problem is that almost all such vaccines show some efficacy in mouse models, but rarely work as well as BCG, a vaccine already known to fail in man. This approach might be flawed. Virtually all patients develop a strong Type 1 response, so that a vaccine that merely accelerates the establishment of this Type 1 response provides marginal benefit. It may be that the solution is to identify the antigens and epitopes of M. tuberculosis shown to drive the "subversive"Type 2 component (Seah and Rook 2001), by screening for IL-4 induction, and then incorporate these in a vaccine with a potent Type 1 adjuvant, such as IL-12, or with an adjuvant capable of activating regulatory T cells that suppress Type 2 responses (Zuany-Amorim et al. 2002). The aim would be to suppress the Type 2 response to these antigens, or to force the establishment of a Type 1 response to them, even if they prove to be common mycobacterial antigens to which there is a pre-existing Type 2 response evoked by environmental species. Then if the individual were subsequently exposed to M. tuberculosis, the organism would be unable to activate the subversive IL-4secreting component. This novel approach is under investigation and should, moreover, provide a vaccine suitable for use as an immunotherapeutic.

Vaccine Dose Another suggestion is that BCG would be more reliable if used at a very low dose, because the dose at which the vaccine starts to evoke a deleterious Type 2 component may be much lower in some individuals than in others. This idea is derived from vaccination studies with Leishmania in different mouse strains, where a dose that evokes a Type 1 response in some strains is too high, and so Type 2-inducing, in others (Bretscher et al. 1992). Because BCG is a live vaccine it should still be effective at very low doses. In each individual it should proliferate to the level at which a mycobactericidal Thl response is induced (Power et al. 1998). In deer 5XI04 or 5xl07 is protective but 5x108 is less effective, so there might be some truth in this idea (Griffin et al. 1999).

9.5.4 A Possible Novel Approach to Vaccine Design Enormous effort has gone into testing purified or recombinant antigens and seeking those that evoke the most potent Type 1 response, with maximal output of IFN-yfrom human or murine cells. These antigens are

9.5.6 Immunotherapy This is perhaps the most important issue facing workers in the field of tuberculosis. As outlined in the introduction, DOTS helps but fails to solve the problem, and multi-drug-resistant disease is an increasing threat. Immunotherapy is the only solution, and the need for this approach has been recognised since the time of Robert Koch (Stanford et al. 1993). One potential approach to immunotherapy is the direct use of cytokines in patients, either systemically or given by aerosol. IL-2, IFN-y, IL-12 and GM-CSF have all been investigated (reviewed in Holland 2000). Their potential roles in therapy, other than as a potential adjunct to drug treatment in multi-resistant cases, have yet to be elucidated. Another approach that gives striking results in mice is the use of dehydroepiandrosterone or of the very similar androstenediol. These compounds oppose a subset of the effects of glucocorticoids, and can reverse the switch towards Type 2 cytokine profile in Balblc mice, but this has not been tested in man (Hernandez-Pando et al.I998ab).

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Immunotherapy is unlikely to be achieved by References simple antigen preparations, because there needs to be an immunoregulatory component with Abou-Zeid C et al. (1997) Induction of a Type 1 immune responses to a recombinant antigen from Mycobacterium down-regulation of pre-existing Type 2 cytokine tuberculosis expressed in Mycobacterium vaccae. Infect production. This may explain why antigen prepaImmun 65:1856-1862 rations that can protect against tuberculosis when Adams LB et al. (1995) Exacerbation of acute and chronic murine used as vaccines before challenge can fail to act tuberculosis by administration of a tumour necrosis factor receptor-expressing adenovirus. J Infect Dis 171:400-405 as therapeutics in mouse models (Turner et al. 2000). Interestingly, the only preparations shown Adams LB et al. (1997) Comparison of the roles of reactive oxygen and nitrogen intermediates in the host response to be effective immunotherapeutics in tuberculous to Mycobacterium tuberculosis using transgenic mice. mice are killed Mycobacterium vaccae (HernandezTubercle Lung Dis 78:237-246 Pando et al. 2000b; Rook and Hernandez-Pando Altare F et al. (1998) Impairment of mycobacterial immunity in human interleukin-12 receptor deficiency. Science 280: 1996; Zhang et al. 2000) and more recently DNA 1432-1435 vaccines encoding common mycobacterial antigens (Lowrie et al. 1999). Attempts at immunotherapy Anderson MC (1891) On Koch's treatment. Lancet i:651-652 Arinobu Y et al. (1999) Antagonistic effects of an alternative using the environmental saprophyte, M. vaccae, splice variant of human IL-4, IL-4 delta 2, on IL-4 activifollowed studies of the influence of such organisms ties in human monocytes and B cells. Cell Immunol 191: 161-167 on disease susceptibility and on the efficacy of BCG vaccination (Stanford et al. 1981), a concept that Arkwright PD, David TJ (2001) Intradermal administration of a killed Mycobacterium vaccae suspension (SRL 172) is now widely accepted (Fine 1995). Two studies is associated with improvement in atopic dermatitis in of single injections of heat-killed M. vaccae have children with moderate-to-severe disease. J Allergy Clin been carried out to Good Clinical Practice (GCP) in Immunol107:531-534 human tuberculosis patients also receiving DOTS. Astarie-Dequeker C et al. (1999) The mannose receptor mediates uptake of pathogenic and nonpathogenic mycobacteThe results are conflicting (Group 1999; Johnson ria and bypasses bactericidal responses in human macroet al. 2000), though the striking success of recent phages. Infect Immun 67:469-477 studies in retreatment cases (National Cooperation Aston C et al. (1998) Early inhibition of mycobacterial growth Group on Clinical Study of Mycobacterium vaccae by human alveolar macrophages is not due to nitric oxide. Am J Respir Crit Care Med 157:1943-1950 and Luo 2001) and multi-drug-resistant (MDR) TB (Luo et al. 2000) in China suggest that further trials Atamas SP et al. (1999) Production of Type 2 cytokines by CD8+ lung cells is associated with greater decline in of multiple doses should be undertaken. In view of pulmonary function in patients with systemic sclerosis. the inevitable difficulty of demonstrating an effect Arthritis Rheum 42: 1168-1179 when a single dose is superimposed upon DOTS Baker RW et al. (2000) Increased cortisol-cortisone ratio in acute pulmonary tuberculosis. Am J Respir Crit Care Med under clinical trial conditions in patients with 162:1641-1647 drug-sensitive infections, there is a clear need for Balasubramanian R et al. 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(1999) Phenotypically activated gammadelta T lymphocytes in the peripheral blood of patients with and in clinical trials in human patients with asthma tuberculosis. J Infect Dis 180: 141-149 or eczema (Arkwright and David 2001; Camporota Bekker L et al. (1998) Selective increase in plasma tumour et al. 2000). Interestingly, it is now clear that the necrosis factor-a and concomitant clinical deterioration mode of action of M. vaccae is mainly the induction after initiating therapy in patients with severe tuberculosis. J Infect Dis 178:580-584 of regulatory T cells that suppress Type 2 responses Bellamy R (2000) Identifying genetic susceptibility factors (Zuany-Amorim et al. 2002). It can also induce Thl for tuberculosis in africans: a combined approach using a recognition of common mycobacterial antigens in candidate gene study and a genome-wide screen. 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terium tuberculosis in a human macrophge-like cell line. Infect Immun 66:5314-5321 Rojas M et al. (2000) Mannosylated lipoarabinomannan antagonizes Mycobacterium tuberculosis-induced macrophage apoptosis by altering Ca+2-dependent cell signaling. I Infect Dis 182:240-25 I Rook G (1988) The role of vitamin D in tuberculosis (editorial). Am Rev Respir Dis 138:768-770 Rook G, Hernandez-Pando R (1996) The pathogenesis of tuberculosis. Annu Rev Microbiol 50:259-284 Rook G et al. (1985) I-A restricted activation by T cell lines of anti-tuberculosis activity in murine macrophages. Clin Exp ImmunoI59:414-420 Rook G et al. (1986) Vitamin D3, gamma interferon, and control of proliferation of Mycobacterium tuberculosis by human monocytes. Immunology 57:159-163 Rook G et al. (1987) A direct effect of glucocorticoid hormones on the ability of human and murine macrophages to control the growth of M. tuberculosis. Eur I Respir Dis 71:286-291 Rook G et al. (1996) Urinary steroid metabolites in tuberculosis; a new clue to pathogenesis. Quart I Med 89:333-341 Rook Get al. (2000) Local regulation of glucocorticoid activity in sites of inflammation; insights from the study of tuberculosis. Ann NY Acad Sci 917:913-922 Salgame PR et al. (1991) Differing Iymphokine profiles of functional subsets of human CD4 and CD8 T cell clones. Science 254:279-282 Schaible UE et al. (2000) Intersection of group I CDI molecules and mycobacteria in different intracellular compartments of dendritic cells. I ImmunoI164:4843-4852 Schlesinger LS (1998) Mycobacterium tuberculosis and the complement system. Trends MicrobioI6:47-49; discussion 49-50 Seah GT, Rook GA (1999) A sensitive, non-radioactive quantitative method for measuring IL-4 and IL-4delta2 mRNA in unstimulated cells from multiple clinical samples, using nested RT-PCR. J Immunol Methods 228:139-149 Seah GT, Rook GAW (2000) High levels of mRNA encoding IL-4 in unstimulated peripheral blood mononuclear cells from tuberculosis patients revealed by quantitative nested RT-PCR; correlations with serum IgE levels. Scand J Infect Dis 33:106-109 Seah GT, Rook GAW (2001) IL-4 influences apoptosis of mycobacterium-reactive lymphocytes in the presence of TNF-a. J ImmunoI167:1230-1237 Seah GT, Scott GM, Rook GA (2000) Type 2 cytokine gene activation and its relationship to extent of disease in patients with tuberculosis. J Infect Dis 181:385-389 Shands IW, Senterfitt VC (1972) Endotoxin-induced hepatic damage in BCG-infected mice. Am J Pathol 67:23-40 Shepard CC (1958) A comparison of the growth of selected mycobacteria in HeLa, monkey kidney, and human amnion cells in tissue culture. I Exp Med 107:237-246 Shwartzman G (1937) Phenomenon of local tissue reactivity and its immunological, pathological, and clinical significance. Hoeber, New York Siegele DA, Kolter R (1992) Life after log. I Bacteriol 174: 345-348 Sieling PA et al. (1995) CD I-restricted T cell recognition of microbial Iipoglycan antigens. Science 269:227-230 Silva CL, Lowrie DB (1994) Asingle mycobacterial protein (hsp65) expressed by a transgenic antigen-presenting cell vaccinates mice against tuberculosis. Immunology 82:244-248

The Immunology and Pathogenesis of Tuberculosis Silva CL, Lowrie DB (2000) Identification and characterization of murine cytotoxic T cells that kill Mycobacterium tuberculosis. Infect Immun 68:3269-3274 Skinner MA et al. (1997) Immunization with heat-killed Mycobacterium vaccae stimulates CD8+ cytotoxic T cells specific for macrophages infected with Mycobacterium tuberculosis. Infect Immun 65:4525-4530 Spence DP et al. (1993) Tuberculosis and poverty. Br Med J 307:759-761 Stanford JL, Shield MJ, Rook GAW (198l) How environmental mycobacteria may predetermine the protective efficacy of BCG. Tubercle 62:55-62 Stanford JL et al. (1993) Old plague, new plague and a treatment for both? AIDS 7:1275-1277 Stenger S et al. (1998) An antimicrobial activity of cytolytic T cells mediated by granulysin. Science 282:121-125 Sturgill-Koszycki S et al. (1994) Lack of acidification in Mycobacterium phagosomes produced by exclusion of the vesicular proton-ATPase. Science 263:678-681 Sugita M et al. (2000) CDlc molecules broadly survey the endocytic system. Proc Natl Acad Sci USA 97:8445-8450 Tobach E, Bloch H (1956) Effect of stress by crowding prior to and following tuberculous infection. Am J Physiol 187: 399-402 Toossi Z et al. (1997) Modulation of IL-12 by transforming growth factor-beta (TGF-beta) in Mycobacterium tuberculosis-infected mononuclear phagocytes and in patients with active tuberculosis. J Clin Lab Immunol 49:59-75 Tramontana JM et al. (1995) Thalidomide treatment reduces tumor necrosis factor alpha production and enhances weight gain in patients with pulmonary tuberculosis. Mol Med 1:384-397 Turner J et al. (2000) Effective preexposure tuberculosis vaccines fail to protect when they are given in an immunotherapeutic mode. Infect Immun 68:1706-1709 Van Crevel R et al. (2000) Increased production of interleukin 4 by CD4+ and CD8+ T cells from patients with tuberculosis is related to the presence of pulmonary cavities. J Infect Dis 181:1194-1197 Van Rie A et al. (1999) Exogenous reinfection as a cause of recurrent tuberculosis after curative treatment. N Engl J Med 341:1174-1179 Van-der-Pouw-Kraan TC et al. (1995) Prostaglandin-E2 is a potent inhibitor of human interleukin 12 production. J Exp Med 181:775-779 Varadhachary AS, Salgame P (1998) CD95 mediated T cell apoptosis and its relevance to immune deviation. Oncogene 17:3271-3276 Vieira PL et al. (1998) Glucocorticoids inhibit bioactive IL-

151 12p70 production by in vitro- generated human dendritic cells without affecting their T cell stimulatory potential. J ImmunoI161:5245-5251 Visser J et al. (1998) Differential regulation of interleukin-1O (IL-I0) and IL-12 by glucocorticoids in vitro. Blood 91: 4255-4264 Waddell RD et al. (2000) Safety and immunogenicity of a fivedose series of inactivated Mycobacterium vaccae vaccine for the prevention of HIV-associated tuberculosis. Clin Infect Dis 30 [SuppI3]:S309-S315 Wakeham J et al. (1998) Lack of both types 1 and 2 cytokines, tissue inflammatory responses, and immune protection during pulmonary infection by Mycobacterium bovis bacille Calmette-Guerin in IL-12-deficient mice. J Immunol 160:6101-6111 Wang CC, Rook GAW (1998) Inhibition of an established allergic response to ovalbumin in Balblc mice by killed Mycobacterium vaccae. Immunology 93:307-313 Watson VE et al. (2000) Apoptosis in Mycobacterium tuberculosis infection in mice exhibiting varied immunopathology. Journal of Pathology 190,211-20 Wayne LG (1994) Dormancy of Mycobacterium tuberculosis and latency of disease. Eur J Clin Microbiol Infect Dis 13: 908-914 Wei J et al. (2000) Identification of a Mycobacterium tuberculosis gene that enhances mycobacterial survival in macrophages. J Bacteriol 182:377-384 Wilkinson RJ et al. (2000) Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis among Gujarati Asians in west London: a case-control study. Lancet 355:618-621 Wilsher ML et al. (1999) Human in vitro immune responses to Mycobacterium tuberculosis. Tubercle Lung Dis 79: 371-377 Wilson GS, Schwabacher H, Maier I (1940) The effect of the desensitisation of tuberculous guinea-pigs. J Pathol Bacteriol 50:89-109 Xu S et al. (1994) Intracellular trafficking in Mycobacterium tuberculosis and Mycobacterium avium-infected macrophages. J Immunol 153:2568-2578 Yong AJ et al. (1989) Total and antimycobacterial IgE levels in serum from patients with tuberculosis and leprosy. Tubercle 70:273-279 Zhang L, Ma W, Da J (2000) Mycobacterium vaccae influences the kinetics of Thl/Th2 cells and expression of iNOS in a marine model of experimental tuberculosis. Zhonghua Jie He He Hu Xi Za Zhi 23:43-46 Zuany-Amorim C et al' (2002) Suppression of airway eosinophilia by killed Mycobacterium vaccae-induced allergenspecific regulatory T-cells. Nat Medicine 8:625-629

10 Pathology of Tuberculosis MOHAMMED AKHTAR

and

HADEEL AL MANA

CONTENTS 10.1 10.2 10.3

Pathobiology of Tuberculosis 153 Microscopic Pathology 154 Identification of Mycobacteria in Tissue Section 155 Macroscopic Pathology 156 Lung 156 Lymph Nodes 157 Intestine 157 Urinary Tract 157 Male Genital Tract 158 Female Genital Tract 158 Central Nervous System 159 Miliary Tuberculosis 159 Disseminated Bacille Calmette-Guerin (BCG) 160 Role of Fine-Needle Aspiration Biopsy in the Diagnosis of Tuberculosis 160 References 161

10.1

Pathobiology of Tuberculosis

Following inhalation, the droplet nuclei usually implant in the bronchioles and alveoli. The tubercu10.4 lous bacilli first elicit a polymorphonuclear leukocyte 10.4.1 reaction. Later the bacilli are ingested by pulmonary 10.4.2 macrophages. If the organisms are virulent or if the 10.4.3 inhaled dose is large, the bacilli may multiply within 10.4.4 the phagocytic vacuoles of the macrophages. The 10.4.5 10.4.6 resulting lesion may grow due to influx of additional 10.4.7 monocytes/ macrophages from the blood stream. At 10.5 this stage, this immune response is mainly due to a 10.6 tissue-damaging delayed hypersensitivity response, which kills the bacilli-laden macrophages thus pro10.7 ducing a solid caseating center containing extracellular bacilli. The next stage of the lesion depends upon the quality and intensity of cell mediated immunity. If only poor cell mediated immunity response develops, Tuberculosis is caused by Mycobacterium tuberculo- the bacilli escape from the periphery of the caseatsis, a slender, acid-fast aerobic organism which can ing center and are ingested by macrophages. Again be transmitted by inhalation, by ingestion or, rarely, the delayed hypersensitivity response kills these by direct implantation. A fetus can be infected in macrophages causing enlargement of the caseous utero transplacentally. Patients with active pulmo- center and progression of the disease. If, on the other nary tuberculosis are the major source of infection hand, an effective cell-mediated immunity response and inhalation is overwhelmingly the most frequent is mounted, the lesion is surrounded by highly actiroute. Droplet nuclei containing a few organisms vated macrophages, i.e. epithelioid cells, which ingest become airborne during coughing, speaking or even and destroy the bacilli often arresting the lesion at singing and may remain suspended in the room air the subclinical stage. for hours. In many cases, however, the bacilli continue to multiply extracellularly. Additional delayed hypersensitivity reaction may cause local tissue damage, thus resulting in progressive enlargement of the lesion with extension into surrounding tissues. With the passage of time, the areas of caseation undergo liquefaction. The cause of liquefaction is not known. Possibly hydrolytic enzymes released from the dead M. AKHTAR, MD, FCAP, FRCPA, FRCPath Chairman, Department of Pathology and Laboratory Medi- inflammatory cells and products of cell wall of the cine, King Faisal Specialist Hospital and Research Centre, P.O. bacilli may playa role. Liquefaction plays an imporBox 3354, MBCIO, Riyadh 11211, Saudi Arabia tant role in the progression of the disease in two H. AL MANA, MD important ways. First, the liquidized caseous mateFellow, Department of Pathology ad Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, P.O. Box rial is frequently, but not always, an excellent growth 3354, Riyadh 11211, Saudi Arabia medium for tubercle bacilli. Second, the liquidized M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

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material causes further tissue damage and may easily erode into adjacent structures, such as blood vessels and bronchi, thus spreading the disease to other locations. Excessive localized tissue damage may also result in cavitation (Allison et al. 1962; Shima et al. 1972; Dannenberg 1993,1999; Dannenberg and Rook 1994; Fayyazi et al. 2000).

10.2 Microscopic Pathology

M. Akhtar and H. Al Mana

cells are believed to be formed by the fusion of several epithelioid cells. The granulomas are surrounded by a zone of lymphocytic cells, which are an integral part of the cell-mediated immunity against mycobacterial infection. Several subtypes of lymphocytes have been identified including natural killer cells, cytotoxic T cells and type I and type II T helper cells among others (Dannenberg 1999). Most of the granulomas in mycobacterial infections are characterized by the presence of central areas of caseation necrosis and are termed as caseating granulomas. (Figs. 10.2-1004) In these granulomas, the epithelioid cells form a palisading arrangement around the caseating center. Other granulomas may lack central caseation and are called non-caseating granulomas. (Fig. 10.1) Histologically, caseation necrosis consists of amorphous, coarsely granular, acellular debris. Liquefaction of the caseat-

The morphologic hallmark of tissue response to mycobacterial infection is inflammation which is composed of nodular microscopic lesions called granulomas. Granulomas are usually small «2 mm) and are composed of aggregates of epithelioid cells surrounded by a rim of lymphocytes (Fig. 10.1). The epithelioid cells are highly activated macrophages which are characterized by abundant slightly eosinophilic granular cytoplasm and a relatively small, usually eccentric, nucleus. The epithelioid cells may superficially mimic epithelial cells. At ultrastructural level, these cells lack junctional complexes and their cytoplasm is rich in lysosomes and abundant rough endoplasmic reticulum. These cells are less actively phagocytic than the typical macrophages, but have potent bactericidal function due to the abundant lysosomal content. A striking morphologic feature of granulomas is the presence of multinucleated giant cells. Some of the multinucleated cells, which have nuclei evenly dispersed through the cytoplasm, are called foreign body giant cells. Others have nuclei disposed in a horse-shoe arrangement and are termed Langhans giant cells. Both types of giant

Fig. 10.2. Granulomas in a lymph node composed of epithelioid cells and a few giant cells. The granulomas are noncaseating, except for one on the left which reveals extensive caseation. Hematoxylin and eosin stain magnification IOOx

Fig. IO.I. Photomicrograph featuring a lymph node with granulomas composed of epithelioid cells. No caseation is present. Hematoxylin and eosin stain magnification 200x

Fig. 10.3. A large caseating granuloma with palisading epithelioid cells and multinucleated giant cells. Hematoxylin and eosin stain magnification 200x

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ing centers may result in cavitation. As the granuloma matures, it becomes surrounded by a layer of fibrosis which may gradually extend towards the center of the granuloma. (Fig.IO.S) Healed granulomas are virtually completely replaced by fibrous tissue although occasional epithelioid cells or giant cells may be preserved. These fibrosed granulomas usually lack any organisms. Cavitary lesions heal by fibrosis and calcification, both of which may be quite extensive in longstanding lesions.

Fig. lOA. A caseating granuloma with a Langhans giant cell. Hematoxylin and eosin stain magnification 300x

Fig. 10.5. A non-caseating granuloma undergoing fibrosis

Fig. 10.6. Acid-fast bacilli stained by Ziehl-Neelsen stain. DiffQuik stain 400x

10.3 Identification of Mycobacteria in Tissue Section Histopathologic diagnosis of tuberculosis depends on the demonstration of granulomatous inflammation with caseation. However, similar morphologic changes may also be encountered in association with other infections, especially fungal organisms. Therefore, demonstration of the offending organism may be crucial for arriving at a definitive diagnosis of tuberculosis. If the tissue is received in a fresh state, part of the material may be submitted for microbiologic cultures. In addition, histologic sections of the tissue may be stained using special staining procedures for the demonstration of tubercle bacilli. Ziehl-Neelsen stain is the most commonly used stain for identification of tubercle bacilli in tissue sections. Owing to the waxy nature of the cell wall component, mycobacteria stain with the red dye carbolfuchsin and retain the stain after washing with acid alcohol (Stevens and Frances 1996). This indicates that the mycobacteria are acid-fast as compared to other bacilli, which are usually not acid-fast. When acidfast bacilli (AFB) are detected in the granulomatous area, it is highly specific for mycobacterial infection. In Ziehl-Neelsen stain, tubercle bacilli are identified as a straight or curved rod 0.2-0.sx2-S 11m, that stain uniformly bright red but often have a beaded appearance. (Fig. 10.6) The organisms are usually located at the junction of viable tissue with the necrotic zone. Ziehl-Neelsen stain, however, is relatively insensitive. It has been estimated that between 105_10 6 bacteria per milliliter of tissue is required before they can be visualized in a section stain by Ziehl-Neelsen stain (Jagirdar and Zagzag 1996). Auramine-rhodamine stain is a more sensitive stain for mycobacteria, but it may not be so specific. Furthermore, it requires a fluorescent microscope for detection of the organisms (Stevens and Frances 1996).

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Monoclonal antibodies directed to different proteins of M. tuberculosis have been employed by some workers for identification of these organisms. However, several technical problems remain to be addressed (Barbolini et al. 1989). Recently polymerase chain reaction (PCR) for identification of mycobacterium tuberculosis complex DNA has been employed successfully on formalin-fixed paraffin-embedded material as well as lesion material obtained by fine needle aspiration biopsy. These studies have provided evidence for higher sensitivity and specificity of PCR amplification for identification of M. tuberculosis in biopsy material (Vago et al. 2000). Ligase chain reaction (LCR) is another diagnostic alternative for detection of tubercle bacilli. This technique uses a combination of polymerase and ligase for amplification of target DNA sequences in the chromosome of M. tuberculosis. This technique may be applied in body fluids as well as material from tissue biopsies. It is commercially available as a semi-automatic assay which is rapid, sensitive and is claimed to be quite specific. However, additional studies are required to determine the usefulness of this technique for identification of tuberculous bacilli in material derived from paraffin embedded tissue sections (Ruiz-Serrano et al. 1998).

M. Akhtar and H. Al Mana

node component. The parenchymal lesion can occur anywhere in the lung but is usually seen in the middle and lower lobes. On gross examination, it is a well circumscribed, often subpleural, nodule. (Fig. 1O.7) Initially, these lesions are centrally necrotic but later they became fibrotic and calcified. The lymph node component of Ghon complex is found in the draining hilar or intrapulmonary nodes (Allen 1995). Post primary tuberculosis represents recurrence of pulmonary tuberculosis after previous sensitization to M. tuberculosis during primary infection. These lesions usually involve apical and posterior segments of the lungs and are grossly characterized by fibrotic and caseous areas, frequently with cavitation. (Figs. 10.8, 1O.9) These cavities may be quite extensive and fibrosis and calcification of their walls may prevent collapse. In severe cases, cavities may replace the entire lobe and may extend to the other parts of the lung. In

10.4 Macroscopic Pathology The macroscopic appearance of an organ or tissue involved by tuberculosis has several important clues which raise suspicion of tuberculosis. The presence of caseation necrosis, cavitation and enlarged regional lymph nodes with similar areas of caseation necrosis should strongly suggest tuberculosis. However, the macroscopic appearance may be somewhat modified according to the location and the organ involved.

Fig. 10.7. A localized subpleural nodule in the lower lobe of right lung, probably representing primary tuberculosis in a 20-year-old man

10.4.1 Lung The gross appearance of the lung involved by tuberculosis depends upon whether it is primary tuberculosis, which is encountered in patients who have no previous exposure to M. tuberculosis infection, or whether it is post primary tuberculosis in a patient who has had a previous encounter with tuberculosis infection. The clinical and pathologic manifestation of primary tuberculosis is the Ghon complex, which consists of a parenchymal component and a prominent lymph

Fig. 10.8. Wedge resection of the upper lobe of the right lung featuring multiple cavitary lesions extensively replacing the lung parenchyma

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volume of the diseased tissue in regional lymph nodes than at the original site of infection. Infected lymph nodes commonly become greatly enlarged. On sectioning, the nodes are found to be replaced by light yellow areas of caseation necrosis. (Fig. 10.10) Some of the nodes may be virtually completely replaced by caseating necrosis, which may also extend to adjacent extranodal tissues. Several lymph nodes may be matted together to form a large mass superficially mimicking a neoplasm. Overlying skin may be stretched or ulcerated, resulting in sinus tracts.

Fig. 10.9. Cut surface of left lung showing congestion of the lung parenchyma. Several yellowish areas in the upper part of the lung represent caseating lesions of tuberculous bronchopneumonia

10.4.3 Intestine

The ileocecal region is the most common site for gastrointestinal tuberculosis. The earliest changes occur most frequently in the terminal ileum or cecum in the form of small nodules which project into the intestinal lumen and may show evidence of ulceration. As the inflammatory process progresses, characteristic morphologic changes of ulcerative, ulceratohypertrophic or hypertrophic disease occur. In the ulcerative type, the disease is mostly limited to mucosa and submucosa with transverse ulcers which may involve the intestine circumferentially. Mesenteric lymph nodes are frequently involved by the disease and may show massive enlargement. The hypertrophic form (seen in 10% of patients) is characterized by extensive inflammation and fibrosis of all layers of the bowel wall. Fibrous adhesions involving bowel, mesentery and lymph nodes may result in a mass closely resembling Fig. 10.10. Multiple matted lymph nodes extensively replaced a neoplasm. Stricture of the bowel wall may lead to by caseating tuberculous lesions obstruction. The ulceratohypertrophic type of disease may have features of both ulcerative and hypertrophic the higWy susceptible, highly sensitized individual, the disease (Yangking and Chandrasama 1999). Colonic tuberculous infection may spread rapidly throughout tuberculosis may involve any part of the colon. In the large areas of the lung and produce a diffuse bron- acute phase, localized ulceration of the mucosa occur. chopneumonia or lobe-exudative consolidation. The ulcers tend to be transverse. In the chronic phase, Longstanding cavities may be secondarily infected by extensive caseation and fibrosis may be seen. Anobacteria or fungi (Scully et al. 1990; Anonymous 1970). rectal tuberculosis may be an ulcerative type similar Some of the fungal infections maybe in the form of to that seen in the colon or it may be characterized fungal balls. Rarely, tuberculous lesions may co-exist by complex fistulae. The latter type of involvement with carcinoma (Ting et al. 1976). may be difficult to distinguish from Crohn's disease (Kobayashi and Chandrasama 1999).

10.4.2 Lymph Nodes A nearly uniform event following infection by M. tuberculosis is spread from the primary focus to regional lymph nodes. This often results in a greater

10.4.4 Urinary Tract The renal parenchyma initially becomes infected by hematogenous spread, which may involve both the

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kidneys. The kidney may be enlarged or decreased in size with irregular scarring on the surface (Farrow 1997). The lesions usually start in the medullary region, later leading to papillary necrosis and extension of the disease into the renal pelvis. A cut surface reveals dilation of the renal pelvis and calyxes, which are filled by light yellow caseous material. (Fig.lO.11) Distinction between renal tuberculosis and xanthogranulomatous pyelonephritis may be difficult. In advanced cases, the renal parenchyma is replaced by caseous material leaving a thin rim of atrophic renal tissue at the periphery. (Fig. 10.12) Localized lesions may heal by calcification. In the urinary bladder, early macroscopic changes are typically disposed around the ureteral orifices. There is marked edema and hyperemia, later changing to fine mucosal nodulation and ulceration. The ulcers are sharply demarcated and have undermined edges and a layer of gray soft material on the floor. The ureteral orifice may be deformed by the disease; it may be distorted and nodular or remain rigidly open: the characteristic 'golf hole' ureter. The lesions may extend to the trigone or the rest of the bladder. In the late stages, there is fibrosis and shrinkage of the bladder with reduction of capacity (McClure and Young 1989). Occasionally, there is formation of exuberant granulation tissue forming polypoid masses which may mimic neoplasm. The lesions in the ureter and urinary bladder are always secondary to tuberculosis of the kidney. The most common site of involvement in the ureter is ureterovesical orifice or ureteropelvic junction.

10.4.5 Male Genital Tract

M. Akhtar and H. AI Mana

Fig. 10.11. Cut surface of nephrectomy specimen with marked dilatation of calyxes and the renal pelvis. Some of the calyxes are lined by light yellow caseous material. Renal parenchyma reveals variable atrophy

Fig. 10.12. A nephrectomy specimen showing extensive caseous material filling the dilated calyxes

Testis and epididymis are involved by metastatic spread through the blood stream and are usually associated with tuberculosis in other areas in the genitourinary system. On gross examination, there is enlargement, thickening and fibrosis of the testis and epididymis and there are variable numbers of necrotic and caseous lesions with discharging sinuses. (Figs. 10.13, 1O.14) Tuberculosis of the prostatic urethra and penis have rarely been reported.

10.4.6 Female Genital Tract The most common site for involvement by tuberculosis in the genital tract is the fallopian tubes. In the

Fig.IO.B. Epididymo-orchiectomy specimen in which epididymitis is involved by several caseating lesions. The testis is somewhat atrophic but is not involved

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Fig. 10.14. Cut surface of a testis virtually completely replaced by amorphous light yellow caseous material

Fig. 10.15. A space-occupying lesion (tuberculoma) resected from the posterior fossa in a 30-year-old man. There are cystic areas filled with necrotic caseating material

adhesive ulcerative form of tuberculous salpingitis, there is little distension and enlargement of the tube is mainly interstitial. The surface may show minute gray to yellow nodules and there may be adhesions to adjacent organs and development of fistulae. In the inflammatory exudative form, the tubes are markedly distended by exudates, which may be purulent rather than caseous. The wall is thin and serosa relatively smooth. There is eversion of the fimbria and the abdominal ostium is usually patent. Occasionally, the tube may appear normal at gross inspection. In the uterine cavity the disease is limited to the endometrium, which may be difficult to recognize at gross examination. Vulvovaginal disease takes the form of small shallow ulcers with sinus tracts and fibrosis. Involvement of the ovaries is uncommon but ovarian tissues may show adhesions and inflammatory exudates due to granulomatous inflammation.

reported throughout the cerebral hemispheres, basal ganglia, the brain stem and cerebellum. Tuberculoma is usually a well defined mass separated from the surrounding brain tissue by a zone of fibrosis. The mass is usually solid with areas of necrosis and may reveal focal cystic change. (Fig. 10.15) Distinction from a glioma may not always be possible and correct diagnosis usually requires microscopic examination.

10.4.7 Central Nervous System Involvement of the central nervous system is usually through the blood stream, although the spinal cord may be involved by extension of the disease from adjacent lesions in the vertebral bones. Leptomeningitis due to tuberculosis is characterized by a covering of the surface by a diffuse exudate, which later develops into small nodules. These changes may be more pronounced at the base of the brain. Tuberculous infection may also be present in the form of a space-occupying lesion in the brain or, rarely, in the spinal cord. These masses, called tuberculomas, may be single or multiple and mayor may not be associated with concomitant meningitis. They have been

10.5 Miliary Tuberculosis Miliary tuberculosis results from a massive hematogenous spread of tubercle bacilli, which may occur either at the time of primary infection or at a time remote from primary infection. Lymphohematogenous dissemination following primary infection is the usual mechanism causing miliary tuberculosis in infants and children. Miliary dissemination may also occur when an older tuberculous lesion in the lung or an extrapulmonary site reactivates and discharges massive numbers of tubercle bacilli into the blood stream. Miliary tuberculosis may involve many organs including lung, liver, spleen, bone marrow, kidney, adrenals, eyes and thyroid (Divinagracia and Harris 1999). The involved organs have numerous small, gray to reddish brown, punctate rounded lesions of more or less uniform size. Microscopically, miliary foci reveal tuberculous granulomas with or without central caseation. With appropriate stains, acid-fast bacilli may be found within the macrophages or epithelioid cell of the granulomas or in the areas of caseation.

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10.6 Disseminated Bacille Calmette-Guerin (BCG)

10.7 Role of Fine-Needle Aspiration Biopsy in the Diagnosis of Tuberculosis

Vaccination of the newborn and babies with Bacille Calmette-Guerin has been used widely throughout the world and has been shown to be a safe method for providing some protection against tuberculosis. However, in some cases local ulceration or regional lymph node enlargement due to granulomatous disease may be seen. In patients with congenital or acquired immune deficiency, a more progressive and disseminated BCG infection may develop, which may prove fatal unless treated by anti-tuberculous chemotherapy. In these cases, a biopsy usually reveals diffuse proliferation of histiocytes intermixed with variable numbers of neutrophil without distinct granulomas. (Fig. 10.16) The histiocytes on Ziehl-Neelsen staining usually reveal large numbers of intracytoplasmic acid-fast bacilli (Fig.10.1?) (AI BhlaI2000).

Fine-needle aspiration biopsy is an extremelyeffective technique for the pathologic diagnosis of tuberculosis. The morphologic pattern encountered in smears parallels closely with that seen in histologic preparations. Thus all the components of granulomatous inflammation including lymphocytes, macrophages, epithelioid giant cells and other inflammatory cells are easily recognized. (Fig. 10.18) Caseating necrosis can also be recognized by the presence of amorphous material with scattered polymorphonuclear cells and a few epithelioid cells (Das and Pant 1994; Prasoon 2000; Radhika et al. 1993; Bhattacharya et al. 1998) (Fig. 10.19). Aspirated material may also be used successfully for culturing the tubercle bacilli. In addition, aspiration smears may be stained by special stains to identify tubercle bacilli.

Fig. 10.16. Photomicrograph of a lymph node involved by disseminated BeG infection. The node is replaced by numerous histiocytes with abundant granular cytoplasm. No granulomas are present. Hematoxylin and eosin stain 300x

Fig.IO.IS. Fine-needle aspiration biopsy smear showing an epithelioid granuloma without caseation. Diff-Quik stain 300x

Fig. 10.17. Numerous intracytoplasmic acid-fast bacilli present within the macrophages. Ziehl-Neelsen stain 400x

Fig. 10.19. Aspiration smear featuring an epithelioid granuloma associated with a background of necrosis and inflammatory cells indicating caseation. Diff-Quik stain 200x

Pathology of Tuberculosis

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References AI Bhlal LA (2000) Pathologic findings for Bacille CalmetteGuerin infections in immunocompetent and immunocompromised patients. Am J Clin Pathol 113:703-708 Allen EA (1995) Tuberculosis and other mycobacterial infections of the lung. In: Thurlbeck WM, Churg AM (eds) Pathology of the lung, 2nd edn, pp 299-265 Allison MJ, Zappasodi P, Lurie MB (1962) Host-parasite relationships in natively resistant and susceptible rabbits on quantitative inhalation of tubercle bacilli. Am Rev Respir Dis 85:553-569 Anonymous (1970) Aspergilloma and residual tuberculous cavities - the results of a resurvey. Tubercle 51:227-245 Barbolini G, Bisetti A, Colizzi V, Damiani G, Migaldi M, Vismara D (1989) Immunohistologic analysis of mycobacterial antigens by monoclonal antibodies in tuberculosis and mycobacteriosis. Hum Pathol 20:1078-1083 Bhattacharya S, Raghuveer CV, Adhikari P (1998) FNAC diagnosis of tuberculosis - an eight years study at Mangalore. Indian J Med Sci 52:498-506 Dannenberg AM Jr (1993) Immunopathogenesis of pulmonary tuberculosis. Hosp Pract 28:33-40, 51-58 Dannenberg A (1999) Pathogenesis oftuberculosis. In: Schlossberg D (ed) Tuberculosis and non-tuberculous mycobacterial infections. Saunders, Philadelphia, pp 17-47 Dannenberg AM Jr, Rook GAW (1994) Pathogenesis of pulmonary tuberculosis: an interplay of tissue-damaging and macrophage-activating immune responses - dual mechanisms that control bacillary multiplication. In: Bloom BR (ed) Tuberculosis: pathogenesis, protection, and control. American Society for Microbiology, Washington DC, pp 459-483 Das DK, Pant CS (1994) Fine needle aspiration cytologic diagnosis of gastrointestinal tract lesions. A study of 78 cases. Acta CytoI38:723-729 Divinagracia R, Harris HW (1999) Miliary tuberculosis. In: Schlossberg D (ed) Tuberculosis and non tuberculous mycobacterial infection Saunders, Philadelphia, pp 271-284 Farrow GM (1997) Diseases of the kidney in the urologic pathology (Murphy WM ed). Saunders, Philadelphia, pp 440-442 Fayyazi A, Eichmeyer B, Soruri A, Schweyer S, Herms J, Schwarz P, Radzun HJ (2000) Apoptosis of macrophages and T cells in tuberculosis associated caseous necrosis. J Pathol 191:417-425 Jagirdar J, Zagzag D (1996) Pathology and insight into patho-

genesis of tuberculosis. In: Rom WN, Gary S (eds) Tuberculosis. Little Brown, Boston, pp 467-491 Kobayashi G, Chandrasama P (1999) Non neoplastic lesions of the colon. In: Chandrasama P (ed) Gastrointestinal pathology. Appleton and Lange, Stanford, pp 263-264 McClure J, Young RH (1989) Infectious disease of the urinary bladder, including malakoplakia. In: Young RH (ed) Pathology of urinary bladder Churchill Livingston, New York, pp 351-375 Prasoon D (2000) Acid-fast bacilli in fine needle aspiration smears from tuberculous lymph nodes. Acta Cytol44:297-300 Radhika S, Rajwanshi A, Kochhar R, Kochhar S, Dey P, Roy P (1993) Abdominal tuberculosis. Diagnosis by fine needle aspiration cytology. Acta Cytologica 37:673-678 Ruiz-Serrano MJ, Albadelejo J, Martinez-Sanchez L, Bouza E (1998) LCx: a diagnostic alternative for the early detection of mycobacterium tuberculosis complex. Diagn Microbiol Infect Dis 32:259-264 Scully RE, Mark EJ, Menealy WF, Menealy BU (eds) (1990) Case 45-1990 Case records of Massachusetts General Hospital. N Engl J Med 323:329-336 Shima K, Dannenberg AM Jr, Ando M et al. (1972) Macrophage accumulation, division, maturation, and digestive and microbicidal capacities in tuberculous lesions. 1. Studies involving their incorporation of tritiated thymidine and their content of lysosomal enzymes and bacilli. Am J PathoI67:159-180 Stevens A, Frances RJ (1996) Micro organisms. In: Bancroft JD, Stevens A (eds) Theory and practice of histopathologic techniques, 4th edn. Churchill Livingston, New York, pp 291-308 Thomas JO, Adeyi D, Amanguno H (1999) Fine needle aspiration in the management of peripheral lymphadenopathy in a developing country. Diagn Cytopathol 21:159-162 Ting YM, Church WR, Ravikrishnan KP (1976) Lung carcinoma superimposed on pulmonary tuberculosis 199: 307-312 Vago L, Zervi P, Caldarelli-Stefano R, Cannone M, D'Amico M, Bonetto S, Barberis M (2000) Polymerase chain reaction for mycobacterium tuberculosis complex DNA. Use on negative archival Ziehl-Neelsen cytologic samples. Acta Cytol 44:1023-1028 Yanking M, Chandrasama P (1999) Pathology of small intestine. In: Chandrasama P (ed) Gastrointestinal pathology. Appleton and Lange, Stanford, pp 199-201

11 Nontuberculous Mycobacteria JAE-JOON YIM and STEVEN M. HOLLAND

CONTENTS 11.1 11.2 11.3 11.4 11.5 11.6 11.6.1 11.6.2 11.6.3 11.6.4 11.7

1l.8 11.9 11.10 11.11 11.11.1 11.11.2 11.11.3 11.11.4 11.12 11.12.1 11.12.2 11.13

Introduction 163 Classification of Nontuberculous Mycobacteriosis 163 Epidemiology 164 Host Susceptibility Factors 166 Host Defense Against Mycobacteria 168 Human Immune Defects 169 IFNy Receptor 1 Deficiency 169 IFNy Receptor 2 Deficiency 170 1L-12 Receptor ~ 1 Deficiency 170 IL-12 p40 Deficiency 170 NFKB Essential Modulator (NEMO) or IKB Kinase Defects 170 Familial Syndrome 171 Polymorphisms 171 Body Morphotype 171 Clinical Presentation and Diagnosis 172 Pulmonary Disease 172 Lymphadenitis 173 Skin and Soft-Tissue Infection 173 Disseminated NTM Infection 175 Treatment 175 Chemotherapy 175 Immunotherapy 177 Summary 178 References 178

11.1 Introduction The Norwegian physician G. H. Armauer Hansen described an organism subsequently known as Mycobacterium leprae in the skin of leprosy patients for the first time in 1874 (Hansen 1874). Eight years later, the German physician Robert Koch identified Mycobacterium tuberculosis. In 1885, 3 years after Koch's discovery of M. tuberculosis, a smegma bacillus, erroneously thought to be connected to syphilis but now

J.-J. YIM, MD Respiratory and Critical Care Medicine, Seoul National University College of Medicine, Seoul, South Korea 110744 S. M. HOLLAND, MD Immunopathogenesis Section, Building 10, Room 11N103, 10 Center Dr. MSC 1886, Bethesda, MD 20892 1886, USA

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

known as one of the nontuberculous mycobacteria, M. smegma tis, was identified. Currently, 71 species of Mycobacterium are recognized or have been proposed (Shinnick and Good 1994). Despite the fact that these mycobacteria have occasionally been identified from clinical specimens (Wolinsky 1979), it is only relatively recently that serious attention has been paid to them. A variety of terms have been applied to these nontuberculous mycobacteria, including anonymous, unclassified, unknown, tuberculoid, environmental, opportunist, nyrocine, and mycobacteria other than tuberculosis (MOTT) (Collins et al. 1984; Debrunner et aI.1992). The word 'atypical' has been popular in the USA, while 'anonymous' and 'opportunist' have been preferred in the UK (Collins et al.1984). However, each term has its own limitations: These mycobacteria are certainly not 'anonymous', there is no reason to regard them as 'atypical', and the term 'opportunist mycobacteria' could be equally applied to the more virulent Mycobacterium tuberculosis, especially in the setting of AIDS (Grange 1989). Although the term nontuberculous mycobacteria (NTM) has been widely used and accepted after the American Thoracic Society adopted this term in its official statement about these mycobacteria (ATS 1990), NTM itself is a kind of misnomer. These mycobacteria usually do result in the formation of tubercles in infected tissue; in other words, they are 'tubercle-ous' (Grange 1989). Furthermore, the British Thoracic Society still uses the term 'opportunist mycobacteria'in its official guidelines (BTS 2000). In this chapter, we will review NTM disease in terms of classification, epidemiology, pathogenesis, diagnosis, and treatment. In addition, the state of knowledge of host susceptibility and related cytokine therapy will be underscored.

11.2 Classification of Nontuberculous Mycobacteriosis Growth rates, colony morphologies, and biochemical tests have traditionally been used to differentiate

J.-J. Yim and S. M. Holland

164

NTM from M. tuberculosis. M. tuberculosis takes 3-6 weeks to grow, has white colonies, and gives a positive niacin test result; most NTM are niacinnegative (Wayne 1985). In 1954, Timpe and Runyon classified NTM for the first time (Timpe and Runyon 1954). Their classification was based on NTM growth rates, morphology, and colony pigmentation. According to their scheme, if a mycobacterium took?.7 days to grow, it was a 'slow grower' and fell into groups I, II, or III. If it took <7 days, it was a 'rapid grower' and was classified as group IV. Among the slow growers, if colonies showed yellow pigmentation when grown in the light, they were photochromogens, type I. If they were strongly pigmented, yellow to orange when grown in the dark, they were scotochromogens, type II. If they showed no or shallow pigmentation when grown in the dark, they were classified as type III, nonphotochromogens. In fact, group IV, the rapid growers, shares many similarities with group III, the nonphotochromogens, except that the individual colonies grow in <7 days.

Although this Runyon classification system provided the first basis for a taxonomic understanding of mycobacteria, it has limitations. It is not particularly relevant to the clinical manifestations of NTM diseases, and some bacteria cannot be clearly classified. In fact, Runyon himself proposed that some mycobacterial species from different categories could share similar clinical manifestations (Runyon 1974). Consequently, the classification of NTM according to their predisposition to involve various organs has gained popularity (Table ILl). Over the last decade, the number of new species added to the NTM has increased dramatically (Wayne and Sramek 1992). Correct identification of these newly added NTM species by traditional culture-based and biochemical methods has become more challenging and is sometimes inadequate (Springer et al.I993). The development of new techniques, such as 16S rRNA gene sequencing (Sansila et al. 1998), PCR-RFLP of a 439 bp segment of the heat shock protein 65 (hsp-65) gene (Eriks et al. 1996), or high-performance liquid

Table 11.1. Classification of the nontuberculous mycobacteria recovered from humans Features of the common species Clinical disease species

Common etiologic Geography

Morphologic features species

Unusual etiologic

Pulmonary disease

M. avium complex Worldwide

Usually not pigmented Slow growth (>7 days) Pigmented; often large and beaded on acid-fast stain Rapid growth «7d) not pigmented Slow growth; pigmented Slow growth; not pigmented

M.simiae M.szulgai M. fortuitum M. celatum M. asiaticum M.shimodii M. haemophilum M. smegmatis

Usually not pigmented Pigmented Slow growth

M. fortuitum M. chelonae M. abscessus

M. kansasii

M. abscessus

M. xenopi M.

malmoense

USA, coal mining regions, Europe Worldwide but mostly USA Europe, Canada UK, northern Europe

Lymphadenitis

M. avium complex Worldwide M. scrofulaceum Worldwide M. malmoense UK, northern Europe (especially Scandinavia)

Cutaneous disease

M. marinum

M. fortuitum M. chelonae

M. abscessus M. ulcerans

Worldwide

Photochromogen; requires low temperatures (28-30°C) For isolation Worldwide, mostly USA Rapid growth; not pigmented

From ATS (1997)

M. kansasii M. nonchromogenicum M. smegmatis

M. haemophilum Australia, tropics, Africa, Grows slowly, pigmented SE Asia

Disseminated disease M. avium complex Worldwide

M. kansasii M. chelonae M. haemophilum

M. avium complex

USA USA USA, Australia

Isolates from patients with AIDS usually pigmented (80%) Photochromogen Not pigmented Not pigmented; requires hemin, often low temperatures, and CO 2 to grow

M. abscessus

M.xenopi M. malmoense M. genavense

M.simiae

M. conspicuum

M. marinum M. fortuitum

Nontuberculous Mycobacteria

chromatography (HPLC) mycolic acid fingerprinting (Butler and Kilburn 1990; Butler et al. 1992) have provided identifications and are in part responsible for the recent explosion of new species of NTM. Newly described or emerging human species of NTM are listed in Table 11.2.

11.3

Epidemiology

165

Table 11.2. Newly described or emerging human species of nontuberculous mycobacteria Newly described clinically significant human pathogens Rapid growing mycobacteria: M. mucogenicum M. goodii M. immunogenum M. wolinskyi M. fortuitum third biovariant complex, including M. septicum Slowly growing mycobacteria: M. genavense

M. triplex M. lentiflavum After the first report of disseminated NTM infection M. celatum in an AIDS patient in 1982 (Zakowski et al.1982), the M. interjeetum number of patients with NTM disease dramatically M. intermedium increased in developed countries (Selik et al. 1987; M. conspicuum Horsburgh and Selik 1989), even though the prevaM. branderi M. geidelbergense lence of NTM disease in AIDS patients in Africa is M. heckeshornense still low (Okello et al.1990; Morrissey et al.I992). The M. bohemicum epidemic of AIDS not only increased the number of M. tusciae cases of NTM disease, it also changed its characteris- Newly described potential human pathogens: tics. Before the AIDS epidemic, NTM disease was usuM. confluentis M. mageritense ally confined to the lungs, lymph nodes, or skin; only M. alvei in rare cases was it disseminated (Wolinsky 1979). M. hassiacum However, NTM disease in AIDS patients is usually M. kubicae disseminated. In addition, the most common dissemM. novocastrense inated NTM in AIDS patients is M. avium, (Zakowski M. brumae et al. 1982), whereas infection by M. kansasii and M. Old but emerging pathogens: M. ulcerans intracellulare was more frequent in the era before the M. haemophilum AIDS epidemic (Ahn et al. 1979; Falkinham 1996). M. xenopi Irrespective of the change related to the AIDS M. malmoense epidemic, the NTM which cause lymphadenitis in Adapted from Brown-Elliott et al. (2002) with permission children have also changed: M. scrofulaceum was the most frequent organism causing cervicallymphadenitis in children (Wolinsky 1979), but M. avium has now become the most common (Colville 1993; Wolinsky infection of AIDS patients from the hot water system 1995). This observation raises the possibility that the of hospitals (von Reyn et al. 1994). Although MAC is natural or environmental population of M. avium and one of the major causes of mycobacteriosis in poultry M. scrofulaceum is changing, that there is a change in and swine, recent serologic and molecular studies sugchildren's behavior, or that other factors (e.g., inciden- gest a low possibility of animal-to-human transmission tal antibiotic use) may be involved (Falkinham 1996). (Meissner et al. 1977; Ahrens et al. 1995; Guerrero et al. Water is the major source of infection for numerous 1995). The waterborne M. marinum has been reported NTM species including M. avium complex (MAC), M. to infect persons through aquarium exposure (Adams marinum, M. kansasii, M. xenopi, M. simiae, M. fortui- et al. 1970; Barrow and Hewitt 1971), and M. xenopi has tum, M. chelonei, M. abscessus, and others. MAC grows been suggested to infect humans through an aerosol well in the natural waters ofGermany (Beerwerth 1973), route (Collins and Yates 1984). In addition, the rapidly Japan (Ichiyama et al. 1988), Finland (von Reyn et al. growing mycobacteria M. fortuitum, M. chelonae, and 1993), Uganda (von Reyn et al. 1993), Zaire (von Reyn M. abscessus have been reported to cause nosocomial et al. 1993), the USA (Gruft et al. 1981), and probably outbreaks and pseudo-outbreaks from tap water many other untested regions. MAC can be aerosolized (Lowry et al. 1988; Maloney et al. 1994), ice prepared (Meissner and Falkinham 1986), raising the probability from tap water (Laussucq et al. 1988), processed tap of airborne infection for these mycobacteria. In 1994, water for dialysis (Bolan et al. 1985), and the whirlpool von Reyn et al. suggested the transmission of MAC footbaths of nail salons (Winthrop et al. 2002).

166

J.-J. Yim and S. M. Holland

Even though many mycobacteria including MAC the rapidly growing NTM M. fortuitum, M. chelonae, (Paull 1973; Reznikov and Leggo 1974; Reznikov and and M. abscessus (Wolinsky 1979; Griffith et al. 1993; Dawson 1980; Brooks et al. 1984; Eaton et al. 1995), Hadjiliadis et al. 1999). M. malmoense (Saito et al. 1994), and M. fortuitum Although disseminated M. avium infection has (Wolinsky and Rynearson 1968; Paull 1973) have been been common among patients with advanced HIV isolated from soil, there is no evidence that mycobacte- disease, pulmonary MAC disease has occurred infrequently in these patients. The frequency of MAC lung ria from soil can directly infect human beings. Although the prevalence of NTM disease cannot be disease in patients with disseminated MAC infection estimated easily, it has been suggested that the preva- is low, between 2.5% andlO% (Kalayjian et al. 1995). lence of NTM disease is now increasing in the USA This may reflect differences in organism tropism and (O'Brien et al.1987; Pae et al.1997), Switzerland (Deb- virulence, as bacteremic strains in AIDS patients runner et al. 1992), and Japan (Sakatani 1994). The tend to be M. avium, whereas M. intracellulare is reasons for this increase ofNTM disease are unknown, the more common pulmonary pathogen. Horsburgh but better clinical recognition and improved, increased et al. studied advanced AIDS patients with CD4+ Tamounts of culturing for NTM are felt to play impor- lymphocyte counts <25/mm 3 and found that the contant roles (ATS 1997). MAC is the most prevalent sumption of hard cheese and pate were associated species followed by M. kansasii (O'Brien et al. 1987; with recovery of MAC from stool, whereas consumption of raw shellfish was associated with recovery of Debrunner et al.1992; Sakatani 1994). The NTM are widely thought to be opportunistic. MAC from sputum (Horsburgh et al. 1994). Those patients most commonly afflicted are ones with structural lung disease (e.g., bronchiectasis, pneumoconiosis, chronic obstructive pulmonary disease [COPDj, prior tuberculosis) (Wolinsky 1979; O'Brien et al. 1987; Pae et al. 1999). Bronchiectasis 11.4 and MAC infection often coexist, making causality Host Susceptibility Factors difficult to determine in some cases. Specific morphotypes have been associated with pulmonary NTM In 1964, Engbaek reported the first familial outbreak infection, particularly in women with pectus excava- of fatal MAC infection (Engbaek 1964), suggesting a tum, thoracic scoliosis, and mitral valve prolapse genetic basis for the development of severe disease (Iseman et al. 1991). Pulmonary NTM disease has with these relatively nonpathogenic organisms. In been shown to have a growing female predominance, the 1980s, advanced HIV infection showed the critiincluding a significant number of older women with- cal role of CD4+ T-Iymphocytes as effectors against out clearly recognized predisposing factors (Prince et mycobacteria: NTM infections typically occurred al. 1989; Griffith et al. 1993). The majority of elderly only after the CD4+ T-Iymphocyte number fell below 3 male patients have risk factors such as smoking or 50/mm (Horsburgh and Selik 1989; ATS 1997), sugCOPD (Iseman 1996). In contrast to male smokers gesting that specific T-cell products or activities were with upper lobe cavitary disease who tend to carry required for mycobacterial resistance. The genetic the same single strain of MAC indefinitely, female basis of susceptibility to NTM has been characterized nonsmokers with nodular bronchiectasis tend to through identification of specific mutations involvcarry 3 or more strains over time. This suggests either ing the interferon-y (IFNy) synthesis and response polyclonal infection or recurrent infection with dis- pathways (Table 11.3). These include mutations in tinct strains (Wallace et al.1998). Patients with cystic interferon-y receptor 1 (IFNyR1), interferon-y recepfibrosis, in whom there are both structural lung dis- tor 2 (IFNyR2), interleukin-12 receptor ~1 subunit orders (Olivier et al. 1996) and abnormalities in the (IL12R~1), interleukin-12 p40 (IL12p40), the signal function of defensins, small antibacterial peptides transducer and activator of transcription 1 (STATl), secreted by bronchial epithelium (Goldman et al. and NFKb essential modulator (NEMO), an X-linked 1997), form a special risk group for pulmonary NTM trait that affects IL-12 production (Dorman and Holinfection. Patients with pulmonary alveolar pro- land 2000; Doffinger et al. 2001; Dupuis et al. 2001). teinosis are also at higher risk for pulmonary NTM However, despite the growing number of genetic infections as well as infection with the closely related defects identified in patients with disseminated NTM Nocardia (Witty et al. 1994). Esophageal motility dis- infections, only about one-third of cases without HIV orders such as achalasia have been found to be sig- infection have a genetic diagnosis. Therefore, almost nificantly associated with pulmonary disease due to two-thirds of all disseminated cases to date are still

167

Nontuberculous Mycobacteria

Table 11.3. Human identified immune defects Defect

Location

Zygosity Infections (disseminated mycobacterial disease)

c-IFNJ'RI

Sl16X

Homozygous

131delC 22delC 107ins4; 200+ 1 G~A 561de14; 373+1 G~T

Homozygous Homozygous Homozygous Heterozygous Heterozygous

561 del4

Homozygous

M. avium, Salmonella, M. chelonei, M. fortuitum BCG M. avium M. avium M. smegmatis, BCG? BCG, M. avium, M. kansasii, Listeria monocytogenes BCG

c-IFNJ'R2

278delA,G 791deiG

Homozygous Homozygous

M. avium, M. fortuitum BCG? M. abscessus

AR p-IFNJ'Rl

1871

Homozygous

BCG, S. enteritidis, 1. pneumophilia?, M. tuberculosis?

AR p-IFNJ'R2

R1l4C

Homozygous

BCG, M. abscessus

AD p-IFNJ'RI

818del4

Heterozygous

818delT 817insA

Heterozygous Heterozygous

BCG, M. avium, M. kansas ii, M. spp., H. capsulatum BCG, M. avium M. avium, M. kansasii, M. chelonei

c-IL-12 p40

p40de14.4

Homozygous

BCG, S. enteritidis

c-IL-12RPI

de1409-549 Q32X Q376X K305X 783+1 G~C Q214R

Homozygous Homozygous Homozygous Homozygous Homozygous Homozygous

BCG, S. typhimurium M. avium, S. paratyphi M. avium, S. group B BCG, S. enteritidis BCG M. avium, S. enteritidis

STATl

L706S

Homozygous

BCG, M. avium

NEMO

X420W

X-linked

M. kansasii, M. sp., S. enteritidis, S. pneumoniae, P. carinii M. avium, P. aeruginosa, CMV

201-2A~G

1167insC 1218insA D3l1N nd

H. influenzae, S. pneumoniae M.avium S. pneumoniae S. pneumoniae

R175P L227P C417F C417R A288G Polymorphism: NRAMPI 5'(CA)n 199/other INT4G~C D543NG~A

3'UTR TGTG+/del

S. pneumoniae H. influenzae S. pneumoniae

Heterozygous Heterozygous Heterozygous Heterozygous

Pulmonary tuberculosis Pulmonary tuberculosis Pulmonary tuberculosis Pulmonary tuberculosis

Abbreviations: c-IFNJ'Rl, complete interferon-y receptor 1 deficiency; c-IFNJ'R2, complete IFNJ'R2 deficiency; AR p-IFNJ'Rl, autosomal recessive partial interferon-y receptor 1 deficiency; AR p-IFNJ'R2, autosomal recessive partial IFNJ'R2; AD p-IFNJ'Rl, autosomal dominant partial interferon-y receptor 1; c-IL-12 p40, complete interleukin-12 p40 deficiency; c-IL-12RPl, complete interleukin-12 receptor ~ 1 deficiency; STATl, signal transduction and activation oftranscription factor 1; NEMO, NFKB essential modulator; NRAMPl, natural resistance-associated macrophage protein 1; BCG, bacille Calmette-Guerin. Adapted from Guide and Holland (2002) with permission.

168

syndromic (e.g., sarcoid, CD4+ T-Iymphocytopenia) or idiopathic. Interestingly, an association has been noted between pulmonary NTM infections and body habitus, predominantly in postmenopausal Caucasian women (pectus excavatum, scoliosis, mitral valve prolapse) (Iseman et al. 1991; Pomerantz et al. 1996).

J.-J. Yim and S. M. Holland

and Scott 1999). Binding results in phosphorylation of the associated cytoplasmic kinases, tyrosine kinase 2 (Tyk2) and Janus kinase 2 (Jak2), which in turn phosphorylate STAT4, leading to transcription of IL-12-responsive genes, in particular IFNy. IFNy activates neutrophils and macrophages to produce superoxide and nitric oxide, to increase the surface display of MHC molecules and Fc receptors, to decrease lysosomal pH, and to increase the intracellular concentration of certain antibiotics (Bermudez and Young 1989; Boehm et al. 1997). IFNy signals 11.5 through a membrane-bound receptor composed Host Defense Against Mycobacteria of two chains, IFNyRI and IFNyR2, which are conIn normal hosts, mycobacteria are initially phago- stitutively bound to their respective Janus kinases, cytosed by macrophages, which respond with the Jakl and Jak2. IFNy binding initiates aggregation of production of interleukin-12 (lL-12; see Fig. ILl) IFNyRI and IFNyR2, phosphorylation of Jakl and (Fulton et al. 1996). IL-12 is a complex heterodimer Jak2, and phosphorylation of the IFNyRI cytoplascomposed of p35 (chromosome 3) and p40 (chro- mic domain, which enables docking of STATl. Phosmosome 5) moieties, which together comprise p70. phorylated STATl (STATl-P) then homodimerizes IL-12p70 activates T-Iymphocytes and NK cells and translocates as a complex to the nucleus, where through binding to the IL-12 receptor, composed of it upregulates IFNy-responsive genes such as IL-12, IL-12R~1 and IL-12R~2 (Gately et al. 1998; Trinchieri major histocompatibility complex genes, and TNF . The positive feedback loop between IFNyand IL-12 is pivotal in the immune response to mycobacteria and other intracellular infections. Defects in any of these receptors or cytokine genes negatively affect the production of IFNy and/or IL-12, and consequently enhance mycobacterial susceptibility (Fig. 11.1) IL-12 (Dorman and Holland 2000). In mouse studies, IFNy has been shown to exert a mycobacteriostatic effect, possibly through acidification of mycobacteria-containing vesicles (Appelberg and Orme 1993). Toxic oxygen radicals do not control NTM infection in mice (Doherty and Sher 1997), but they may be important in early tuberculosis infection, TNFa especially in the lungs (Adams et aI. 1997; Cooper et al. 2000). Although in vitro data for IFNy control of NTM using macrophages has been inconsistent (Douvas et al. 1985; Bermudez and Young 1989; Denis et al. 1990), the in vivo data have been persuasive. Fig. ILL Cytokine pathways involved in mycobacterial infecDisruption of IFNy production in mice resulted in tion and host response. Mycobacteria infect macrophages and Widespread tuberculosis with poor granuloma forstimulate production of IL-12. Subsequently, IL-12 leads to T or NK cell production of IFNy. IFNy binds to a specific site on mation and rapid death (Flynn et al. 1993; Cooper IFNyRl, leading to aggregation of IFNyRl and IFNyRZ. Follow- et aI. 2000). Exogenous administration of IFNy did ing this aggregation, the associated cytoplasmic Janus kinases, not restore normal resistance in these animals, sugJakl and Jak2, transphosphorylate each other, leading to phosgesting that IFNy may playa critical developmental phorylation of the intracellular domain of IFNyRl. This phosphorylation creates a binding site for cytosolic STAT!, which is role, or that injecting systemic IFNy does not activate in turn phosphorylated. Phospho-STAT! then homodimerizes local defenses in the same manner as local producand is transported to the nucleus, where it upregulates IFNy- tion. Similar results were seen in IFNyR-deficient responsive genes. IFNy also upregulates TNFa production in mice (Kamijo et al. 1993) and in mice lacking the the setting of endotoxin (lipopolysaccharide). The mechanisms IFNy-induced interferon regulatory factor-l (IRF-l) by which IFNy mediates the killing of mycobacteria are not yet well characterized. *, denotes genes known to predispose to (Kamijo et al. 1994). These models define a critical role for IFNy in tuberculosis resistance and control in mycobacterial infection when mutated

Nontuberculous Mycobacteria

the mouse. Similar findings have been reported with MAC infection in IFNy-deficient mice (Doherty and Sher 1997). In normal mice infected with MAC, exogenously administered IFNy successfully augmented mycobacterial clearance, in part by suppressing the production of prostaglandin E2, an inhibitor of macrophage function (Edwards et al. 1986).

11.6

Human Immune Defects 11.6.1 IFNy Receptor1 Deficiency

In 1994, four children of an extended Maltese family were described with an autosomal recessive pattern of susceptibility to NTM (Levin et al. 1995). These related children had severe disseminated disease with a variety of NTM including M. chelonae, M. fortuitum, and MAC, in addition to recurrent infections with Salmonella. Affected children had impaired TNFa production in response to stimulation by IFNy, while their parents were intermediate between the patients and normals, suggesting a gene dosage effect in heterozygotes. Antigen presentation was also impaired (D'Souza et al.1996). Newport et al. identified a homozygous point mutation in the extracellular domain of IFNyRI in these patients, resulting in a premature stop codon (Newport et al. 1996). Simultaneously, a Tunisian infant was reported with disseminated BCG infection and a more proximal extracellular chain-terminating mutation (131delC) in the IFNyRI gene (Jouanguy et al. 1996). Since then, numerous autosomal recessive mutations in the extracellular domain of IFNyRI have been identified in patients with disseminated mycobacterial infections. Identification of compound heterozygotes in outbred populations indicates that mutations in IFNyRI are not simply the result of remote founder effects (Dorman and Holland 2000). Extracellular mutations leading to disruption of IFNyRI function lead to failure to activate STATl in response to IFNy. This leads to an inability to upregulate IFNy-responsive genes including TNFa. Since IFNy and IL-12 production are co-dependent, both show an impaired response to phytohemagglutinin (PHA) stimulation (Holland et al. 1998). However, complete IFNyRI or IFNyR2 deficiency leads to loss of IFNy removal from the plasma and elevated circulating levels of IFNy, despite low levels of IFNy generation in vitro (Fieschi et al. 2001).

169

Complete IFNyRI deficiency typically presents as disseminated BCG or NTM disease in infancy or childhood. Salmonella infections have occurred in cases from outside North America, probably due to the greater exposure to that organism in those parts of the world. Complete IFNyRI deficiency is associated with a poor prognosis and high mortality due to incomplete clearance of infection despite aggressive antibiotic therapy, as well as continued susceptibility to new infections. Other infections reported in these patients include Listeria monocytogenes, cytomegalovirus (CMV), severe respiratory syncytial virus (RSV), herpes simplex virus (HSV), and varicella zoster virus (VZV). Although these are common viruses prevalent in the general population, these infections are often much more severe in IFNyRI-deficient patients, suggesting that this may be an aspect of the clinical phenotype (Dorman et al. 1999). Two Portuguese siblings with disseminated BCG and presumed tuberculosis were identified with a homozygous mutation in the extracellular domain of IFNyRI (I87T) leading to an alteration in a Nlinked glycosylation site (Jouanguy et al. 1997). They were both cured with antibiotics alone and showed partial IFNy responsiveness in vitro. The formation of intact, tuberculoid granulomas by one child with disseminated BCG further demonstrated residual IFNyactivity. Autosomal dominant (AD) mutations in the IFNyRI gene have been shown to confer only a partialloss of IFNy responsiveness. Jouanguy et al. identified a four-base deletion (818deI4) in 12 unrelated people from around the world (Jouanguy et al. 1999), and another 2 Japanese patients with the same mutation were reported recently (Sasaki et al. 2002). This latter group also identified less common autosomal dominant mutations, 818delT and 818insA. These mutations result in deletions of the Jakl and STATl intracellular binding sites as well as deletion of the receptor recycling domain. These mutations impede signal transduction and receptor removal from the cell surface while preserving the receptor binding capacity. Autosomal dominant IFNyRI disease has a milder phenotype, lower mortality rate (<5%), and is associated with a later onset of infection and less likelihood of dissemination than complete ARIFNyRI mutations. These ADIFNyRl patients often develop mycobacterial osteomyelitis; other identified infections include histoplasmosis, herpesvirus infections, and Salmonella.

I.-I. Yim and S. M. Holland

170

11.6.2 IFNy Receptor 2 Deficiency

11.6.4 IL-12 p40 Deficiency

Complete IFNyR2 deficiency shows similar clinical features, histopathology, and in vitro responses to complete IFNyRI defects. Dorman and Holland (l998, 2000) identified a frameshift mutation in the IFNyR2 gene of a child with disseminated M. fortuitum and M. avium complex (MAC) infections resulting in a premature stop codon which caused IFNy unresponsiveness. A child with an extracellular domain mutation of IFNyR2 causing a partial defect leading to reduced IFNy responsiveness but normal surface IFNyR2 expression was also reported (Doffinger et al. 2000).

IL-12p40 is the first identified cytokine gene defect affecting mycobacterial susceptibility (Altare et al. 1998b). Autosomal recessive inheritance of the IL12p40 defect was demonstrated in a child with consanguineous Pakistani parents. The patient developed postvaccine disseminated BCG infection followed by disseminated Salmonella enteritidis. Both IFNy receptors 1 and 2 were intact along with the IL-12R~1 chain and a functional IL-12R. Similar to patients with IL12R~1 deficiency, this child's cells produced about 10% of normal IFNy but demonstrated normal TNFa and IL-8 production. Aggressive antibiotic therapy and two courses of IFNy (currently still on IFNy) were required for successful control of the Salmonella infection. The father had also had recurrent, severe Salmonella infections in his youth, raising the possibility of haploinsufficiency in heterozygous carriers.

11.6.3 IL-12 Receptor ~1 Deficiency

In 1998, mutations in the IL-12R~1 receptor were identified in several unrelated cohorts (Altare et al. 1998a; de Tong et al. 1998). These patients were infected with BCG, NTM, or Salmonella. In contrast to the patients with disabling mutations in IFNyRI or IFNyR2, patients with mutations in IL-12R~1 showed intact and mature-appearing granulomas, later onset of infections, and much higher rates of survival than did ARIFNyRI-deficient patients. Most of these patients were treated successfully with antibiotics and IFNy. However, despite aggressive therapy, several fatal cases of disseminated BCG in IL-12R~I-deficient patients have been reported from Turkey (Sanal et al. 2000). In vitro, despite a complete lack of expression of IL-12R~I, the cells maintained a normal proliferation to mitogen or antigen (PPD) and normal IFNy responsiveness. However, defective IL-12 signaling was exhibited in terms of NK activity, proliferation, and poor IFNy production (1-10% of normal). To date, most of the reported cases have been homozygous autosomal recessives, even in the absence of reported consanguinity, presumably reflecting founder effects in some populations. No mutations in IL-12R~2 have been found yet, although they are predicted to be similar in severity and theoretically as likely as mutations in IL-12R~1. However, IL-12R~1 is also one of the critical chains for the IL23 receptor, suggesting that IL-12R~1 deficiency also confers IL-23 unresponsiveness.

11.7 NFKB Essential Modulator (NEMO) or IKB Kinase Defects Recently, mutations in one of the proteins required for nuclear factor kappa B (NF-KB) activation have been shown to cause immunodeficiency associated with hypohidrotic ectodermal dysplasia (HED-ID) (Zonana et al. 2000; Doffinger et al. 2001; Orange et al. 2002). The NFKB essential modulator (NEMO) or IKKy encodes the regulatory subunit of the IKB kinase (IKK) complex, which is required for the activation of the NF-KB signaling pathways and immune defense. NF-KB regulates the transcription of genes encoding inflammatory proteins and antiapoptotic factors. Disruptions in NEMO that result in truncation of the protein or alteration of the zinc finger domain result in impaired NF-KB activation and a distinct physical phenotype of conical teeth, poor sweat gland formation, and abnormal hair growth (hypohidrotic ectodermal dysplasia) along with recurrent infections. Gram-positive, gram-negative and mycobacterial infections, bronchiectasis, and poor febrile responses are characteristic features of this disease. The defect in NEMO affects not only the signaling through the ectodysplasin/dysplasin pathway, explaining the ectodermal dysplasia phenotype, but also signaling through the TNFR, IL-IR, IL-18R, CD40, and Toll-like receptors (TLR), thereby explaining the infection susceptibility and lack of fever.

Nontuberculous Mycobacteria

11.8 Familial Syndrome A familial syndrome has been identified in which two generations of previously healthy women developed CD4+ T-Iymphocytopenia, disseminated NTM infection, and subsequent myeloid leukemia (Holland et al. 1994). Affected individuals displayed a similar clinical phenotype consisting of marked monocytopenia, indolent mycobacterial disease, and progressive lymphocytopenia prior to the development of myeloproliferative disease. This suggests an autosomal dominant common genetic defect that controls mycobacterial susceptibility and myeloid regulation. Holland et al. (1994) also reported a family with disseminated MAC infection in males from two generations. This family had abnormal regulation of IL-12, poor IFNy production, and clinical improvement with IFNytreatment (Frucht and Holland 1996; Frucht et al. 1999). These patients have recently been shown to have a novel mutation in NEMO (E315A).

11.9 Polymorphisms Aside from the specific defects described above, there is a growing interest in the role for genetic polymorphisms in mycobacterial susceptibility. In mice, polymorphisms in the natural resistance-associated macrophage protein (NRAMPl) gene were found to influence early, but not late mycobacterial susceptibility (Vidal et al. 1995). NRAMPI is expressed in activated macrophages and is clearly responsible for the higher bacterial burdens found 3 weeks after infection in BCG-susceptible mouse strains. However, by 6 weeks post infection, both susceptible and resistant strains have cleared the infection. The natural occurrence of this dichotomous trait in mice is due to a single amino acid change (Vidal et al. 1995). NRAMPI encodes an ion transporter that localizes to the lysosomal membrane during phagocytosis of mycobacteria as well as other pathogens. It is thought that NRAMPI may restrict organism replication through alteration of the phagolysosomal environment by regulating iron or other divalent cation transport (Supek et al. 1996; Gruenheid et al. 1997). The NRAMPI gene clearly plays a critical role in the early inflammatory response and early control of mycobacteria but may not influence the course of the disease later on, as demonstrated by the similar time to clearance of infection regardless of the NRAMPI

171 status of the strain. A study of the human orthologue of NRAMPI in a West African population with high rates of tuberculosis found significant associations of several polymorphisms with the development of tuberculosis (Bellamy et al.I998). However, in a small study of eight older women with pulmonary MAC infection, none of the described defects or polymorphisms in NRAMPI was found (Huang et al. 1998). A functional polymorphism in an intron of the IFNy gene has been identified that is correlated with decreased IFNy production, but this has not yet been linked to any infection susceptibility (Pravica et al. 1999). However, almost all patients with disseminated MAC infection produce low levels of IFNy in response to in vitro cell stimulation by the nonspecific T-cell mitogen PHA (Holland et al. 1994). No cases of genetic IFNy deficiency have been identified to date. Many more mutations and polymorphisms have been identified in cytokine receptors than in the cytokines themselves, although the reason for this is unclear.

11.10 Body Morphotype Many patients with pulmonary NTM infections appear to have similar clinical characteristics and body type, including scoliosis, pectus excavatum, mitral valve prolapse (MVP), and joint hypermobility (Iseman et al. 1991; Huang et al. 1999). Many of these physical characteristics are reminiscent of individuals with heritable collagen-vascular diseases (Bruno et al. 1984; Pyeritz and McKusick 1979; Grahame and Child 1984; Glesby and Pyeritz 1989; Roman et al.1989; Sponseller et al. 1995) or the hyper-IgE recurrent infection syndrome (Job's syndrome) (Grimbacher et al. 1999). Therefore, patients with pulmonary NTM infections may possess a subtle connective tissue defect. In this context, phenotypic abnormalities may be the consequence of a genetic defect that affects both body morphotype and infection susceptibility. The relationship between immunity and body morphotype has not been well characterized, but certain associations have been noted. Pulmonary abnormalities including spontaneous pneumothoraces, generalized emphysema, cystic lung disease, bronchiectasis, and increased susceptibility to pneumonia have long been noted in patients with Marfan syndrome (Guide and Holland 2002). Patients with cystic fibrosis (CF), who have been noted to develop NTM infections later in life (Olivier et al. 1996), showed an increased incidence of spinal curvature as well (Erkkila et al. 1978).

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J.-J. Yim and S. M. Holland

Patients with Job's syndrome suffer from recurrent more important for the diagnosis of a mycobacterial pulmonary infections and have recently been shown to disease than for routine bacterial infection, since labohave a characteristic phenotype that includes scoliosis, ratories typically do not look for mycobacteria withjoint hypermobility, and a high arched palate (Grim- out a specific request. In untreated cavitary disease, bacher et al. 1999). In a comprehensive phenotype sputum smears and cultures are usually positive. study of Job's patients, Grimbacher et al. found that The placement of mycobacterial skin tests usually 76% of patients had scoliosis, 68% had hyperextensible implies anticipation of M. tuberculosis infection, not joints, and 57% had recurrent fractures (Grimbacher et nontuberculous infection. In studies from the early al. 1999). The paradigm of Job's syndrome, in which a 1980s, about 50% of patients with pulmonary NTM distinct and somewhat similarbody morphotype is rec- infection had positive skin tests with purified protein ognized in the setting of recurrent infections, suggests derivative (PPD), the antigen filtrate derived from that an association between phenotype and immunity MTB (O'Brien et al. 1987). Recently, von Reyn and may also exist in patients with NTM infections. colleagues have revived the use of an antigen derived from M. avium, the M. avium sensitin (MAS), and compared it with testing with PPD in patients with pulmonary MAC or MTB. They looked for dominance of one skin test over the other when both MAS and 11.11 Clinical Presentation and Diagnosis PPD are placed simultaneously (>5 mm reaction and >3 mm larger than the heterologous skin test reac11.11.1 tion). MAS-dominant skin tests were 97% specific for Pulmonary Disease discriminating MAC from MTB disease (von Reyn et al. 1998). MAS is under trial but not yet available in Clinically, pulmonary NTM infection is usually milder the USA; it is used extensively in Scandinavia. than active pulmonary TB, although the destructive The radiographic appearance of NTM disease in the pulmonary changes and chest radiographs can be lung can be similar to TB, with extensive cavity formaindistinguishable. Symptoms can persist for months tion, nodules, and airspace disease (Fig.ll.2). Discrimito years before radiographs are taken or mycobacterial nating aspects of pulmonary MAC disease compared disease emerges in the differential diagnosis. Fatigue with TB are disease limited to the right middle lobe, is usually the most prominent symptom and one that disease limited to either lower lobe, or combined simulis quite troublesome to the patient. Cough productive taneous disease in the right middle lobe and lingula of mildly purulent sputum may be severe, but it is (Table 1104). Diffuse bronchiectasis involving four or usually simply annoying, worse in the morning or on more lobes of the lung is also more common for pulmorecumbency, and tolerated fairly well. Hemoptysis is nary MAC disease, whereas pleural calcification is more not usually serious but may occur in the course of dis- suggestive of MTB (Lynch et al.1995). The combination ease in up to one-third of patients (Griffith et al.1993). of bronchiectasis and lung nodules seen by chest CT Night sweats and fever eventually occur in the major- scanning had a sensitivity of80% for predicting positive ity; weight loss is common but not severe. Concurrent sputum cultures for MAC (Swensen et al.1994). The American Thoracic Society has proposed bacterial infection, especially with Pseudomonas aeruginosa, is not uncommon and may greatly exacerbate formal guidelines for the diagnosis of NTM disease, cough, sputum production, and fatigue. Various sapro- initially in 1990 (ATS 1990) and then revised in 1997 phytic fungi are frequently cultured from the sputum, (Table U.5) (ATS 1997). Although these are valuable but their influence on the pace or severity of disease is guidelines for the diagnosis of NTM disease, cautious undefined. The tempo of the infection is rarely rapid, interpretation of the radiologic or bacteriologic findand changes may be seen on radiographs evolving ings in the context of the clinical setting and follow-up over years if left untreated. Dyspnea is typically seen observation should be underscored. As we recognize only late in disease when extensive destruction has more cases of pulmonary NTM infection, and the relaoccurred. The physical examination is not very infor- tive frequency of pulmonary TB in the USA declines, mative, usually does not reflect the activity or quies- these guidelines may be unnecessarily restrictive in cence of mycobacterial disease, and is often relatively terms of the criteria required for the diagnosis of an active NTM infection. In most cases, if a patient has a normal, despite extensive involvement. The first step toward the diagnosis of pulmonary positive culture for NTM in the context of a compatible nontuberculous mycobacterial infection is to include history and radiograph, it is likely to be pulmonary that entity in the differential diagnosis. This is much NTM infection and not simple colonization.

Nontuberculous Mycobacteria

173

Table 11.4. Radiographic appearance of mycobacterial disease

a

Feature

Nontuberculous mycobacteria

Diffuse bronchiectasis' Focal bronchiectasis b RUL bronchiectasis RML bronchiectasis RML and lingular bronchiectasis RLL bronchiectasis Either RLL or LLL Nodules Diffuse bronchiectasis and well-defined nodules Cavities Airspace disease Pleural calcification

+++

+

+++ +++ +++ ++ +++ +++

Tuberculosis

+++ +++

+

+ +

+++

++ +++ +++

+

+++ +++ ++

RUL, right upper lobe; RML, right middle lobe; RLL, right lower lobe; LLL, left lower lobe; + indicates relative prevalence of radiographic feature in NTM compared with TB, with three plusses (+++) signifying a very common finding and one plus (+) a very uncommon one; - indicates absence of that feature • Diffuse bronchiectasis defined as involving ~4 lobes b Focal bronchiectasis defined as involving only one lobe. Adapted from Guide and Holland (2002) with permission

b Fig. 11.2a,b. Radiographic findings of pulmonary NTM disease. a Chest CT of a 69-year-old woman with pulmonary MAC disease shows characteristic bronchiectasis in the right middle lobe and lingula. b Chest CT of a 56-year-old woman with long-standing M. abscessus pulmonary infection showing extensive left lung destruction with bronchiectasis and consequent chest wall deformity

11.11.2 Lymphadenitis Lymphadenitis caused by NTM most commonly involves the submandibular, submaxillary, cervical, or preauricular lymph nodes of children between the ages of 1 and 5 years (Margileth et al. 1984; Wolinsky 1995). A unilateral, rapidly enlarging lymph node or group of nodes is usually the only presenting complaint, with occasional low-grade fever and malaise. In the USA currently, the majority of infections are due to MAC (80%) (Lai et al. 1984). This predominance of MAC is a change from 30 years ago, when M. scrofulaceum was the most common etiologic mycobacteria (Lincoln and Gilbert 1972). The presumptive diagnosis of NTM lymphadenitis can be made on the basis of caseating granulomata in the pathologic

specimen, with or without positive acid-fast bacillus smears and cultures, in the absence of a positive PPD reaction. Culturing NTM from the involved lymph node can provide a definitive diagnosis, but the yield of positive culture in cervical lymph nodes is only 50%-85% (Schaad et al.I979).Although the tuberculin skin test is helpful in making a diagnosis, it does not distinguish tuberculosis from NTM infection in one-third of cases (Wolinsky 1995). Excisional biopsy of the involved lymph node is recommend both for diagnosis and treatment. The role of fine needle aspiration in the diagnosis of NTM lymphadenitis has been controversial (Bailey et al. 1985; Lau et al. 1991; Gupta et al. 1993), and incisional biopsy may cause fistula formation with chronic drainage (Schaad et aI. 1979). In contrast to other forms of NTM infection, antibiotic therapy is often not needed; excision of the involved lymph node without chemotherapy is currently the best treatment option for isolated NTM lymphadenitis of childhood (Stewart et al. 1994).

11.11.3 Skin and Soft-Tissue Infection Although almost all species have been described as occasional pathogens in cutaneous disease (Wolinsky 1979; Falkinham 1996), M. jortuitum, M. abscessus,

c. Same

For a diagnosis of pulmonary disease, all three criteria - (1) clinical, (2) radiographic, and (3) bacteriologic - must be satisfied From ATS (1997)

c. Tissue biopsy • Any growth from bronchopulmonary tissue biopsy • Granuloma and/or AFB on lung biopsy with one or more positive cultures from sputum/bronchial wash • Any growth from usually sterile extrapulmonary site

I. Local immune suppression II. General severe immune suppression Alcoholism (M. avium complex) Leukemia Bronchiectasis Lymphoma Organ transplantation Cyanotic heart disease Other immunosuppressive therapy Cystic fibrosis Prior mycobacterial disease Pulmonary fibrosis Smokinglchronic obstructive lung disease None 1. Clinical criteria: a. Same a. Compatible signs/symptoms (cough, fatigue most common; fever, weight loss, hemoptysis, dyspnea may be present, particularly in advanced disease) with documented deterioration in clinical status if an underlying condition is present and b. Same b. Reasonable exclusion of other disease (e.g., tuberculosis, cancer, histoplasmosis) to explain condition, or adequate treatment of other condition with increasing signs/symptoms 2. Radiographic criteria: a. Same a. Any of the following chest X-ray abnormalities; if baseline films are more thanl year old, should be evidence of progression • Infiltrates with or without nodules (persistent >2 months or progressive) • Cavitation • Nodules alone (multiple) b. Same b. Any of these HRCT abnormalities • Multiple small nodules • Multifocal bronchiectasis with or without small lung nodules 3. Bacteriologic criteria: a. At least three available sputum/bronchial wash samples within I year a. Same • Three positive cultures with negative AFB smears or • Two positive cultures and one positive AFB smear or b. Same except b. Single available bronchial wash and inability to obtain sputum samples • culture positive with I + • Positive culture with 2+,3+, or 4+ growth or or greater growth • Positive culture with a 2+, 3+, or 4+ AFB smear or

Presumed or confirmed HIV-seropositive potential risk factors

Table 11.5. Criteria for the diagnosis of pulmonary nontuberculous mycobacterial disease

b. Same except • culture positive with I + or greater growth (excludes M. avium complex) c. Same

a. Same

b. Same

a. Same

b. Same

a. Same

CD4 count <200

Presumed or confirmed HIV-seronegative potential risk factors

0..

~

~

~

~

~

~

~ '"0..

,

--

...... ~

175

Nontuberculous Mycobacteria

M. marinum, and M. ulcerans are the most common NTM causes of skin and soft-tissue infection (Wolinsky and Rynearson 1968). Abscess formation and/or drainage at the site of puncture wounds, open traumatic injuries, or fractures are typical manifestations of cutaneous NTM infection. Furunculosis in the lower extremities by M. fortuitum through nail salon pedicure baths (Winthrop et al. 2002) and nosocomial infections involving long-term intravenous or peritoneal catheters have been reported (Wallace et al. 1983; Hoy et al. 1987). The diagnosis can be made by culture of NTM from the drainage material or on tissue biopsy. M. marinum can cause so-called 'swimming pool granuloma' or 'fish tank granuloma'. This bacillus infects abraded skin during the cleaning of freshwater fish tanks or from scratches from salt water fish, shrimp, fins, etc. (Wolinsky 1979). Skin infection by M. marinum commonly presents as a nodular or ulcerative sporotrichoid lesion on the elbows, fingers, hands, or knees. These lesions usually resolve spontaneously within 36 months (Catinella 1978). However, extensive tendonitis can occur. It is imperative to consider M. marinum early in the differential diagnosis of any necrotizing tendonitis, as the antibiotics effective against it are quite distinct, and failure to identify this organism often leads to recurrent operations and procedures with associated tendon destruction and loss of use. M. ulcerans usually causes a painless nodule on the leg without other signs or symptoms in young adults and children (Marston et al. 1995). It can progress to a shallow ulcer with a necrotic base. Spontaneous resolution may occur in 6-9 months, but sometimes the lesion will spread and cause serious deformity (Marston et al. 1995). NTM can cause chronic granulomatous infections of tendon sheaths, bursae, joints, bones, and prostheses inserted during orthopedic procedures (Kelly et al. 1967). M. marinum and MAC are prone to causing tenosynovitis of the hands (Wolinsky 1979; Hellinger et al. 1995; Falkinham 1996). On rare occasions, NTM can infect prosthetic heart valves (M. chelonae) (Repath et al. 1976) or the genitourinary tract (MAC, M. chelonae) (Clark et al. 1989).

11.11.4 Disseminated NTM Infection

Disseminated infection due to NTM usually occurs in the setting of immunosuppression such as AIDS (Horsburgh and Selik 1989), after solid organ transplantation (Lichtenstein and MacGregor 1983),

leukemia (Ingram et al. 1993), lymphoma (Ingram et al. 1993), collagen vascular disease (Ingram et al. 1993), severe combined immunodeficiency syndrome (Stone et al. 1992), and others. Patients with disseminated NTM infection without any apparent underlying disease have also been reported (Lincoln and Gilbert 1972). MAC has been the most common NTM infecting patients with HIV infection (Horsburgh and Selik 1989). However, in the other settings mentioned above, although MAC (Wolinsky 1979; Horsburgh et al. 1985) is most common, M. kansasii (Lichtenstein and MacGregor 1983), M. chelonae (Wallace et al. 1983; Cooper et al. 1989; Ingram et al. 1993),M. scrofulaceum (Wolinsky 1979),M. abscessus (Wolinsky 1979), and M. haemophilum (Kiehn and White 1994) also cause disease. In patients with disseminated NTM infection without AIDS, disease can manifest as a fever of unknown origin (Horsburgh et al.1985) or multiple subcutaneous nodules or abscesses (Wolinsky 1979; Cooper et al.1989; Ingram et al.1993; Kiehn and White 1994). In AIDS patients, prolonged fever accompanied by night sweats and weight loss in the setting of <50 CD4+ Tlymphocytes suggests disseminated NTM infection (ATS 1997). Diagnosis in both settings is confirmed by culture of NTM from bone marrow or blood. A case of disseminated MAC infection without known risk factors is illustrated in Fig. 11.3.

11.12

Treatment 11.12.1 Chemotherapy

Management of these infections is very much still evolving and remains challenging even in the most straightforward cases. Many of the NTM, such as MAC, are typically resistant to many antimycobacterial agents and frequently relapse after therapy. The newer macrolides, azithromycin and clarithromycin, have shown remarkable activity against these infections. Clear and defined roles for immunotherapy and surgery remain to be determined. In the pre-macrolide era, long-term success rates for the treatment of pulmonary MAC infection ranged from 44% to 80% and were not aided by the determination of in vitro susceptibilities. Dutt and Stead reported on 85 cases of pulmonary and 5 cases of extrapulmonary MAC infection from Arkansas in the era before macrolides. Some 65% of their popu-

176

J.-J. Yim and S. M. Holland

Fig. 11.3. a A 7-year-old-boy with extreme splenomegaly had a draining inguinal lymph node (b). Blood and drainage cultures grew MAC. c Bone marrow aspirate showed no granulomatous response, and staining of his bone marrow showed numerous acid-fast bacilli

lation had underlying pulmonary disease, and 31% were women. Although they found a high rate of drug resistance in vitro, they were still successful in treating patients with multiple agents including isoniazid, ethambutol, and streptomycin at least for 12 months. Some 63% of their patients cleared their sputa within 3 months, with an overall medical failure rate of 32%. They found no added benefit to treatment with more than four drugs (Dutt and Stead 1979). Engbaek et al. reported a retrospective study of 37 Danish patients (30% women) with pulmonary MAC disease treated with combinations of isoniazid, ethambutol, PAS, streptomycin, cycloserine, and rifampin. There was a 44% medical success rate despite very high levels of in vitro resistance of the organisms (Engbaek et al. 1981). Ahn et al. treated 46 patients with pulmonary MAC, 67% of whom had predisposing lung disease, and 33% of whom were women. Using a 9-week inpatient induction regimen of isoniazid, ethambutol, rifampin, and twice weekly streptomycin for 6 months, they achieved a 91 % sputum conversion rate. Subsequently, after 18-24 months of therapy, 4 patients relapsed or had recurrent disease (Ahn et al. 1986). Horsburgh et al. reported on 75 patients, 53% of whom were women, and 77% of whom had been treated previously. They started patients on an initial regimen of isoniazid, ethambutol, rifampin, capreomycin, ethionamide, and cycloserine. The overall response rate in 4 months was 66%, with more responders having received more drugs to which their organism was susceptible in vitro (Horsburgh et al. 1987). The existence of multiple case

series in the pre-macrolide era successfully treated without the benefit of in vitro susceptibility testing suggests that we are still fairly ignorant of the critical aspects of therapy and may be relying on inessential components of management currently. However, at least in the USA, the clinical epidemiology of MAC lung disease has changed and is now more female predominant, so the response rates may be changing for reasons other than treatment. Macrolides are now the mainstay of NTM therapy. Wallace et al. gave clarithromycin 500 mg twice daily for 4 months, followed by multidrug therapy, in an effort to determine the activity of the macrolide alone. They showed a 58% apparent cure rate in 20 adults, most of whom were previously untreated, and 40% of whom were women. The drug was fairly well tolerated; 16% of isolates developed clarithromycin resistance (Wallace et al. 1994). Azithromycin 600 mg/ day as monotherapy was studied by the same group in 23 patients. They found similar results except that toxicities such as gastrointestinal effects and altered hearing were more common; there was no development of macrolide resistance (Griffith et al. 1996). The combination of high-dose rifabutin (600 mg/day) with macrolides caused multiple toxicities including leukopenia, gastrointestinal symptoms, abnormal liver functions, diffuse polyarthralgias, and anterior uveitis (Griffith et al. 1995). Huang et al. have treated 27 patients with pulmonary MAC infection (93% were female, 90% Caucasian). After 12 months of multidrug therapy including azithromycin/clarithromycin, rifampin/rifabutin, and ethambutol, they had a 50%

Nontuberculous Mycobacteria

177

treatment failure rate (Huang et al. 1999). Whether counts rebounded. These results were seen in patients these changing rates of success with drug therapy with low CD4+ T-lymphocyte counts, suggesting that reflect changes in the demographics of the patient the IFNyeffect in this setting was not T-cell mediated. group (increasing numbers of Caucasian women) or We have identified a heterogeneous cohort of the organism or loss of potency of the multidrug regi- patients with abnormalities in IFNy generation mens remains to be determined in larger studies. and disseminated MAC infection without HIY. This The rapidly growing mycobacteria, especially has been associated with abnormal IL-12 producM. abscessus, present a special problem. Pulmonary tion (Frucht and Holland 1996) or idiopathic CD4+ disease due to M. abscessus is more likely to occur T-Iymphocytopenia (Holland et al. 1994) We have in Caucasian women who are nonsmokers without used subcutaneous IFNy in a total of 23 patients cavitary disease, more likely to be associated with with disseminated MAC and other NTM infections previous mycobacterial infection, less likely to be with favorable results (Fig. 11.4, unpublished obsermedically curable, and more likely to lead to death vations). Treatment has been used for up to 1 year due to lung destruction than other mycobacterial or longer. These patients have persistent in vitro lung diseases. This infection is a distinct entity that hypoproduction of IFNy, even long after cure. Three requires more intravenous therapy than does MAC patients have relapsed after discontinuation of their infection and may be less responsive (Griffith et al. IFNy, despite continuation of their antimycobacterial 1993). Although surgery is frequently attempted and therapy. may improve the pulmonary symptoms, M. abscessus may cause severe fistulizing disease if there has been contamination of the operative bed. Treatment guidelines from the American Thoracic Society and the British Thoracic Society from 1997 and 1999, respectively, are briefly summarized in Table 11.6 (ATS 1997; BTS 2000).

11.12.2 Immunotherapy It was not long after Koch's discovery of M. tuber-

culosis that he developed an extract of the organism, tuberculin, the forerunner of PPD, as a cure for tuberculosis (Koch 1891). The use of tuberculin and other extracts as a treatment for tuberculosis continued well into the middle part of this century. However, the lack of controlled studies, the requirement for individualization of treatment regimens to avoid complications, and relatively slow results prevented this approach from gaining wide application. Effective multidrug antituberculous therapy made tuberculin therapy obsolete. Animal models and human studies show that IFNy is a critical factor in the control of mycobacteria. Squires et al. (1989, 1992) treated 6 MAC-bacteremic AIDS patients with IFNy with or without concurrent antimycobacterials (Squires et al.1989, 1992). In those patients who received IFNy plus antimycobacterials, there was a clear decline in mycobacteremia. In contrast, when IFNywas used without concurrent antimycobacterials there was no change in bacterial counts. The treatment trial lasted no more than 6 weeks, at the end of which time IFNy was stopped, and bacterial

a

b Fig.l1.4a,b. Abdominal CT scan before (a) and after (a) treatment with subcutaneous IFNg in a 42-year-old man with disseminated MAC infection. Chylous ascites caused by MAC decreased dramatically after 4 months of IFNy treatment (Holland et al. 1994)

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178

Systemic IFNy has been tried in patients with refractory pulmonary MAC infections. These cases usually have severe parenchymal destruction and are difficult to clear, since penetration of antimycobacterials into diseased lung spaces is compromised. The best results have been in patients with noncavitary disease, but still in the 20% range (S.M. Holland, unpublished observations). Aerosolized IFNy has been proposed as a method of delivering organ-specific cytokine therapy, which may reach high levels in diseased airways (Jaffe et al. 1991). Chatte et al. used aerosolized IFNy 500 flg by nebulizer 3 days/week in a 38-year-old man with silicosis and severe refractory cavitary MAC disease (Chatte et al. 1995). His smears converted to negative, but the cultures remained positive; with the cessation of aerosolized IFNy, his smears reverted to positive, his disease progressed, and he died. This was the first report of aerosolized IFNy in the treatment of mycobacterial disease, and rapid conversion of sputum smear in such a long-term refractory patient was remarkable. However, the failure to convert his cultures is a concern for future applications. Similar results of smear but not culture conversion were seen with aerosolized IFNy therapy for multidrug-resistant tuberculosis (Condos et al. 1997). Placebo-controlled, prospective trials are necessary to determine the most appropriate delivery system and the patient groups that are most likely to benefit. To date, the adverse experience profile for IFNy is essentially the same as that seen in chronic granulomatous disease (The International Chronic Granulomatous Disease Cooperative Study Group 1991). The therapeutic use of IL-12 in human infectious diseases is still quite immature. Low dose IL-12 (60 ng/kg subcutaneously twice weekly) in a patient with pulmonary M. abscessus led to sputum conversion and cure despite failure to improve on IFNy (Holland and Dorman 1998). IL-12 has been shown to induce antimycobacterial activity in vitro (Bermudez et a1.1995) and in vivo (Holland and Dorman 1998) beyond the simple increase of IFNy. However, whether IL-12 has important therapeutic activity beyond that of IFNy is not yet clear, and whether there is any role for IL-12 in the setting of IFNy receptor deficiency is unknown. IL-12 toxicities so far have been greater than those of IFNy but can be controlled by careful dosing (Leonard et a1. 1997). Granulocyte macrophage colony-stimulating factor (GM-CSF) is produced by T-cells, NK cells, activated macrophages, and neutrophils. It stimulates myelopoiesis and activates phagocytes for superoxide production and intracellular killing of bacteria, including mycobacteria (Bermudez and

Young 1990). Monocytes and NK cell infection with MAC in vitro led to GM-CSF detection (Blanchard et a1. 1991). Exogenous administration of GM-CSF to MAC-infected beige mice resulted in increased killing of mycobacteria and an enhanced antimycobacterial effect (Bermudez et al. 1994). Kemper et a1. treated 8 MAC bacteremic AIDS patients with high-dose azithromycin alone or azithromycin plus subcutaneous GM-CSF daily for 6 weeks (Kemper et a1. 1998). Monocyte activation was enhanced in the GM-CSF group, and mycobacterial counts in the blood decreased more in the azithromycin plus GMCSF group than in the azithromycin alone group. The drug was well tolerated. Given the broad experience with GM-CSF in cancer patients and in vitro data supporting its efficacy, further evaluation in clinical trials are warranted. Steroids have been used extensively in the treatment of tuberculous meningitis, pleurisy, and pericarditis in an effort to reduce inflammation and subsequent fibrosis. Controlled studies in pleuritis have failed to show much benefit with steroids, although they reduced symptoms faster than medication alone (Wyser et a1. 1996). Wormser et a1. reported that 5 AIDS patients with disseminated MAC who received dexamethasone 1-4 mg daily in addition to antimycobacterial therapy noted improvement in symptoms, nutritional state, and laboratory markers over baseline (Wormser et a1.1994).

11.13 Summary Precisely because of their low virulence, the NTM have taught us much about both innate and acquired immune pathways. They highlight a critical relationship between the physical morphotype and immunity and have been unusually valuable in leading to the discovery of cytokine and receptor defects predisposing to infection. It is hoped that the observations about cytokine therapy developed in the treatment of the NTM will find broader application in the treatment of infectious diseases.

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Diagnosis

12 Serologic Testing for Tuberculosis CHAKRADHAR KOTARU and EDWARD D. CHAN

CONTENTS 12.1 12.2 12.2.1 12.2.2 12.2.3 12.2.4 12.2.5 12.2.6 12.2.7 12.2.8 12.2.9 12.2.10 12.2.11 12.2.12 12.2.13 12.2.14 12.2.15 12.3 12.3.1 12.3.2 12.3.3 12.3.4 12.3.5 12.4

Introduction 187 Specific Serological Tests for TB 187 Antigen 5 (38 kDa Antigen) 188 A60 Antigen 189 30 kDa Antigen 189 Antigen p90 189 19 kDa Antigen 189 16 kDa Antigen 189 45/47 kDa Antigen Complex 190 P32 Antigen 190 Cord Factor 190 Glycolipid Antigens 190 Lipoarabinomannan 191 ICT Tuberculosis Test 192 Dermal Response to MPB64 Antigen 192 Integral Membrane Antigens of M. habana TMC 5135 192 Lipopolysaccharide Antigen 192 Specific Targeted Populations 192 Childhood TB 193 TB in the Elderly 193 HIV-Positive Individuals 193 Extrapulmonary TB 194 Smear-Negative vs Smear-Positive TB 194 Conclusion 194 References 195

12.1 Introduction Tuberculosis (TB) is a leading cause of morbidity and mortality in the world. The World Health Organization (WHO) estimates that one-third of the world's population is latently infected with Mycobacterium tuberculosis. From this pool, roughly 10 million active TB cases emerge annually, resulting in 2 to 3 million deaths. Early identification and proper treatment of individuals with active TB have a great impact on public health. The bacteriologic methods are either not sufficiently efficient and specific (acidfast smear) or require an extended turnaround time from the laboratory (culture isolation). The development of a rapid nonbacteriologic diagnostic test that is both sensitive and specific for active TB continues to be formidable. This difficulty is due, in part, to the inability of many tests to distinguish latent infection from active disease. This chapter focuses on the current serological methods to diagnose TB.

12.2 Specific Serological Tests for T8 Edward D. Chan is supported by the NHLBIHL-66-112, the Parke-Davis Atorvastatin Research Award, and the American Lung Association Career Investigator Award.

C. KOTARU, MD Department of Medicine and Program in Cell Biology, National Jewish Medical and Research Center, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, and Denver Veteran Administration Medical Center, K613e, Goodman Building, 1400 Jackson Street, Denver, CO 80206, USA E. D. CHAN, MD Associate Professor of Medicine, K613e Goodman Bldg., National Jewish Medical and Research Center, Denver, CO, 1400 Jackson St, Denver, CO 80206, USA

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

Although serological assays may not add to the diagnostic yield in those patients in whom sputa examination is possible an accurate serological test to diagnose TB would have considerable advantages in those patients who are unable to provide adequate sputum samples (e.g., in children and the very elderly), who are smear-negative and/or culture-negative, or have suspected extrapulmonary TB (Steele and Daniel 1991). In populations where the prevalence of tuberculin skin test positivity is high, earlier detection and treatment of active TB by blood screening may help prevent further transmission of TB. However, serological testing has been confounded by crossreactivity associated with bacillus Calmette-Guerin (BCG) vaccination or infection with nontuberculous mycobacteria. For example, using the purified protein

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derivative (PPD) status as a gold standard, the ability of immunoblot for the A60 antigen complex to discriminate between TB infection and noninfection was nearly 100% (Rovatti et al. 1996). However, 90% of the study group (n=140) tested positive for antiA60 antibody after BCG vaccination compared with only 1.4% prior to vaccination (Rovatti et al. 1996). Previous seroassays for TB have utilized either a mixture of M. tuberculosis antigens, such as purified extracted glycolipids, adsorbed mycobacterial sonicates, and PPD, or more distinct mycobacterial antigens (Table 12.1) (Chan et al. 2000). Measurement of tuberculostearic acid in clinical specimens was shown to have a high degree of sensitivity and specificity, but the assay required considerable expertise to perform (Brooks et al. 1987). Using mycobacterial sonicates in an enzyme-linked immunosorbent assay (ELISA) on samples of 31 children with clinical TB, Rosen (l990) found a sensitivity of 26% and specificity of 40%. Khomenko et al. (l996) evaluated an ELISA for M. tuberculosis H37Rv antigenic preparation and found the sensitivity to be lower at 72% and specificity to be 100%. Conversely, using affinity-purified H37Rv antibody to detect the antigen, they found the sensitivity and specificity to be similar, 77% and 90%-93%, respectively. Franco et al. (2001) assessed the serological response to four antigenic fractions of H37Rv sonicate by Western blot analysis. Patients with smear-positive pulmonary infection and tuberculous pleurisy had a positivity rate of 50%-60% against all fractions. Interestingly, of the 16 contacts, 3 had a conversion of their tuberculin skin tests, and the same 3 individuals also had a positive serologic response to the 19 kDa antigenic fractions, making it potentially

Table 12.1. Antigens used in the serological diagnosis of tuberculosis Mycobacterial sonicates Extracted glycolipids Purified protein derivative Antigen 5 (38 kDa antigen) A60 antigen 45/47 kDa antigen complex Antigen Kp90 30 kDa antigen P32 antigen Cord factor (trehalose dimycolate) Lipoarabinomannan 16 kDa antigen Integral membrane antigens of M. habana TMC 5135 Lipopolysaccharide antigen

useful in identifying patients who are candidates for the treatment of latent infection. In the following sections, we reviewed studies that examined the presence of specific antibodies directed against mycobacterial antigens.

12.2.1 Antigen 5 (38 kDa Antigen) The use of antigen 5, also known as the 38 kDa antigen, in a microtiter plate ELISA has been evaluated in a number of countries with reasonable sensitivity and high specificity (AIde et al. 1989; Daniel et al. 1985, 1986; Ma et al. 1986). In one of these studies from China, the test was 89% sensitive and 94%100% specific for patients with active pulmonary TB (Ma et al. 1986). Generally, the antibody titer correlated with the extent of pulmonary disease. In another study, detection of IgG against this 38 kDa revealed a sensitivity of 64% and a specificity of 81 % (Chiang et al. 1997). Recently, Cole and coworkers (l996) also used antigen 5 in a serological test but modified it by using a rapid membranebased antibody assay and found the sensitivity to be 89% (54 of 61) in patients with smear-positive, culture-positive TB. In a group of 91 patients who were both smear- and culture-negative, the sensitivity was 74% even though these patients had been on antituberculous therapy from 1 to 6 months at the time of the test. The overall specificity was 93%. In an ELISA using the monoclonal antibody TBn to the 38 kDa antigen, the sensitivity was about 80% for patients with either smear-positive/ culture-positive or smear-negative/culture-positive TB (Bothamley and Rudd 1994). Interestingly, the sensitivity rate was even higher (-90%) for patients successfully treated for presumed TB but without bacteriologic confirmation of disease. Combining an ELISA to detect antibody to both 38 kDa and a 34 kDa M. tuberculosis protein, Amicosante and colleagues (l995) found the overall sensitivity to be 86%. Importantly, the specificity in PPD-negative or PPD-positive control patients (n=30 each) and in 20 patients with nontuberculous bacterial pneumonia was 100%. Nsanze et al. (l997) reported the utility of the enzyme immunoassay (EIA) kit developed by Omega laboratories using the 38 kDa antigen. Depending on the cut-off points used, the sensitivities were >95%, while the specificities were 86%-100%. The test was much less useful for extrapulmonary TB, with sensitivities ranging from 51% to 71%.

Serologic Testing for Tuberculosis

12.2.2 A60Antigen

The A60 antigen, a thermostable component of PPD, has also been used in the serodiagnosis ofTB (Charpin et al. 1990; Cocito 1991; Fadda et al. 1992; Luh et al. 1996; Yu et al.1992; Zou et al.1994). Unfortunately, this molecule is not specific for mycobacteria because it is also present in Nocardia and Corynebacterium species. In 83 patients with smear-negative but culture-positive pulmonary TB, measurement of both IgM and IgG in an ELISA revealed a sensitivity of 68% and specificity of 100% (Charpin et al. 1990). Similarly, an ELISA revealed a sensitivity of 76.2% for patients with active pulmonary TB and 59% for patients with extrapulmonary TB (Luh et al. 1996). In 153 individuals with inactive tuberculous infection, the specificity was only 81.7%, and in over 500 patients with nontuberculous infection, the specificity was 91.3%. Thus, the positive predictive value was only 67.9% (Luh et al. 1996). In a study of 560 Chinese patients with pulmonary and extrapulmonary TB and over 700 controls, the measurement of IgM appeared to be sensitive (80%) for active primary TB and specific (100%) for latent TB (Zou et al. 1994). On the other hand, IgG against the A60 antigen was more predictive of active postprimary TB (sensitivity of 89%). Among 529 healthy persons most of whom were vaccinated with BCG, including 287 who were PPD positive, there was less than 1% false-positives. Anuradha et al. (2001) evaluated the utility of detecting antibodies to A60 for the diagnosis of extrapulmonary TB. In 72 patients with neuro-TB, antibodies were detected in the serum and/ or CSF in almost 80%. The diagnosis of other forms of extrapulmonary TB by anti-A60 antibodies could be made in about 60% of the cases.

12.2.3 30 kDa Antigen

Using a 30 kDa antigen purified from culture filtrates of M. tuberculosis, McDonough and colleagues (1992) compared a dot EIA with the standard ELISA assay on patients with active TB using control patients who had no clinical evidence of TB but whose PPD status was not known. The specificity for dot EIA and plate ELISA were 92% and 97%, respectively; the sensitivity rate for hospitalized patients with TB was 69% and 78%, respectively. Interestingly, the sensitivity rate was -48% for both methods in ambulatory patients with active TB, while in 26 HIV-positive patients with TB, both immunoassays showed extremely poor sensitiv-

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ity (12% for the plate ELISA and 0% for the dot EIA). In assessing the lymphocyte proliferative and humoral responses to patients with active pulmonary TB and of healthy household contacts, the group with active disease had a strong humoral response to the 30 kDa antigen but a poor proliferative response (Torres et al. 1994); the opposite pattern was seen in the exposed control patients. Thus, a humoral response to tuberculous antigen may not only signify active infection but may also indicate a nonprotective immune response. In a study that measured the presence of the 30 kDa antigen in 25 African patients with smear-positive TB using a monoclonal antibody, 20 of them tested positive (sensitivity 80%) (Ng et al. 1995).

12.2.4 Antigen p90

Arikan and co-workers (1997) showed that in 51 patients with active TB, the sensitivity of anti-Kp90 IgA in either sera or body fluids was 82%, while in 71 control patients, the specificity was 90%. In another study of 88 TB patients, comprised of 32 smear-positive and 56 smear-negative individuals, the overall sensitivity was 70% (Alifano et al. 1997). In a control group of 87 individuals with either nontuberculous lung disease, healed TB, or healthy volunteers, the specificity was 92%.

12.2.5 19 kDa Antigen

Although previously promlsmg, antibody titers to the 19 kDa antigen were found to have poor sensitivity (8%) in Indian patients with active TB, but it was higher in patients from the UK (55%-57%) (Bothamley et al. 1992).

12.2.6 16 kDa Antigen

Using a recombinant 16 kDa antigen of M. tuberculosis, Imaz et al. (2001) compared the seroresponse using EIA to detect IgG, IgM, and IgA in 74 children with active TB, in 149 with nonmycobacterial disease, and in 49 healthy contacts. The average levels of antibodies were higher in the healthy contacts when compared with children with nonmycobacterial disease, making it a potentially useful test for predicting patients who require prophylaxis against latent infection; however,

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the low overall sensitivity (34%, 19%,3%, and 43% for IgG, IgA, IgM, and combined IgG IlgM, respectively) prevented the test being useful in the diagnosis of active childhood TB.

controls who were all skin test-positive (Maekura et al. 1993). Interestingly, the cord factor antibody titers declined to normal levels with antituberculous chemotherapy.

12.2.7 45/47 kDa Antigen Complex

12.2.10 Glycolipid Antigens

In a study that evaluated the IgG response to the 451 47 kDa secreted protein ofM. tuberculosis, the specificity of the test was >98% in control subjects, comprised of healthy volunteers who were either PPD-positive or PPD-negative (Diagbouga et al. 1997). However, the sensitivity of the test was only 40% even in smearpositive TB patients.

Detection of IgG against M. tuberculosis glycolipid antigen in 57 patients (27 smear-positive and 30 smear-negative) revealed that the overall sensitivity was 96% and specificity 91 % (Dogan and Aksu 1997). Escamilla and colleagues (1996) used glycolipids from M. fortuitum (di- and tri-O-acylated trehaloses) to detect an antibody response and found the sensitivity for active TB was >80% and the specificity 98%. In a large multicenter study from Japan, Maekura et al. (2001) described the utility of an ELISA for antituberculous glycolipid (anti-TBGL) in the serodiagnosis of TB. Using a cut-off of anti-TBGL antibody titer >2 Ulml, the assay had a sensitivity of 81 % and specificity of 96% in 318 patients with active pulmonary TB (216 smear-positive andlor culture-positive and 102 smear- and culture-negative, but clinically diagnosed). Subgroup analysis revealed greater sensitivity (90%) in patients with smear- and culture-positive TB, as opposed to culture-positive only (70%) or smear- and culture-negative, clinically diagnosed patients (73%). This suggests a correlation between the positivity of the test and the mycobacterial burden. Another interesting observation that has potential implications in judging the response to therapy was the decline in titers in a subgroup of patients with initially high titers (> 10 U/ml) at the beginning of treatment. The test performance characteristics of ELISA to detect antibodies against M. tuberculosis antigenic glycolipids was evaluated in 142 patients with extrapulmonary TB compared with 578 patients with nontuberculous disease (Niculescu et al.1999). The sensitivity and specificity were 82 and 92%, respectively. Simmoney and co-workers (1996) compared the diagnostic utility of ELISA in detecting antibodies against glycolipid to those against A60 antigen in 46 HIV-positive and 50 HIV-negative patients with documented TB. Overall, antibody to A60 was detected in only 37% of the cases, while 85% of the patients had a positive antibody response to glycolipid antigens. When the data were analyzed in the context of HIV status and the associated level of immunosuppression, HIV-positive patients with lower CD4 counts were more likely to have negative antibody responses to A60 than to glycolipids.

12.2.8 P32Antigen

The serological response to purified protein of M. bovis BCG (known as P32 antigen) was also evaluated in patients with active TB (Turneer et al. 1988). Although there was a statistically significant difference in mean IgG and IgA antibody levels between active TB patients and healthy control subjects, the combined sensitivity rate for both immunoglobulin classes was only 47%. Interestingly, neither naturally acquired tuberculin hypersensitivity nor BCG vaccination affected the positive frequencies in healthy subjects. This same group of investigators also utilized a dot-blot assay with BCG cellular extract and found a good correlation between their ELISA assay and the dot-blot assay (van Vooren et al. 1988).

12.2.9 Cord Factor

The IgG antibody response to M. tuberculosis cord factor (trehalose-6,6'-dimycolate) was examined in a group of 99 patients with mycobacterial infection (42 with culture-positive TB, 46 with a clinical diagnosis of TB, and 11 patients with atypical mycobacterial infection), 5 patients with lung cancer, and 100 healthy controls. The overall sensitivity of patients with any bacterial or clinical diagnosis of a mycobacterial infection was 83%, and the specificity was 100% (He et al. 1991). The antibody response to M. tuberculosis cord factor was tested in an ELISA for patients with active TB and produced a sensitivity of 81 % and a specificity of 96% compared with healthy

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that of M. avium complex (the predominant atypical mycobacteria), the fine structural differences between the LAMs (e.g., degree and configuration The cell walls of mycobacterial organisms contain of mannose capping) have not been fully elucidated. complex macromolecules such as lipoarabinoman- Therefore, despite the relatively good specificity rate nan (LAM) (Fig. 12.1). LAM is a lipoglycan known to reported, the degree of antibody cross-reactivity have a number of immunomodulatory effects. LAM is against LAM of M. tuberculosis vs that of atypical comprised of a linear series of ringed mannose sugar mycobacteria remains to be determined. Second, there was a wide range of sensitivity of residues, with occasional branches of single mannose residues. At the proximal end of LAM, a phosphati- anti-LAM IgG among HIV-negative patients with dylinositol group anchors it to the plasma membrane. active TB, while the sensitivity was generally poor Distal to the mannose residues, a series of arabinose in HIV-positive patients. For example, in HIV-negasugar residues is attached. In M. tuberculosis, these tive patients, the sensitivity ranged from 21.5% to arabinose residues are further 'capped' with mannose 89% (del Prete et al. 1998; Julian et al. 1997; Lawn residues. Thus, the LAM of M. tuberculosis is called et al. 1997; Ratanasuwan et al. 1997; Sada et al. 1992, 'ManLAM'. In relatively recent reports, the detection 1999) but was between 7% and 40% in HIV-positive of anti-LAM antibodies has shown great promise in patients (Boggian et al. 1996; Julian et al. 1997; Lawn the serological diagnosis of active TB (Boggian et al. et al. 1997; Ratanasuwan et al. 1997; Sada et al. 1992, 1996; del Prete et al. 1998; Julian et al. 1997; Lawn et 1999). In HIV-negative patients, the sensitivity of the al. 1997; Ratanasuwan et al. 1997; Sada et al. 1990, MycoDot antiLAM IgG test in Tanzania, Ghana, and 1992; Somi et al. 1999). Thailand was 33%,56%, and 63%, respectively (Lawn In general, three important points can be taken et al. 1997; Ratanasuwan et al. 1997; Somi et al.I999). Third, as with most other types of serological tests, from these studies. First, the specificity of the test was excellent, ranging from 84% to 100%. Moreover, the sensitivity of the test fell with negative smears, Julian and co-workers (1997) tested 14 patients with a finding generally attributed to the lower burden atypical mycobacteria, and anti-LAM IgG could not of organisms in smear-negative cases and/or to the be detected in any of them although it is not clear how greater incidence of smear-negativity in patients comany of these patients were co-infected with HIV. infected with HIV. We recently tested the accuracy of Boggian et al. (1996) tested 104 patients with atypical a simplified, visually detectable, colloidal gold-based mycobacteria for anti-LAM IgG, and only 2 patients serological assay to qualitatively detect IgG directed were weakly positive; however, all the patients tested against LAM in a population of individuals largely were HIV-positive. Although the basic structure of comprised of immigrants to the USA from areas with LAM associated with M. tuberculosis is similar to a high prevalence of TB infection (Chan et al. 2000).

12.2.11

Lipoarabinomannan

ManLAM

Fig. 12.1. Cell wall of M. tuberculosis showing the various macromolecules that comprise the complex structure, including the plasma membrane, peptidoglycan, lipoprotein ,and various Iipoglycans such as mannose-capped Iipoarabinomannan, mycolic acid-arabinogaJactan peptidoglycan complexes (mAGP), Iipomannan (LM), and phosphatidylinositol dimannose (PIM z). The fatty acid chains (acyl groups) are attached to the plasma membrane

lipoproteins

mycolic acids

• 0- mannose-p • D-arabinose-f • galaetose-f '

phosphatidylinositol (palmitate, tuberculostearate)

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In patients with active TB, the sensitivity of anti-LAM IgG was 85%-93%. Importantly, in five patients with active TB who were smear-negative, all tested positive for anti-LAM IgG. The specificity of the test depended on the presence of tuberculous infection. In a group of US citizens comprised of young healthy adults and rheumatology patients, the specificity was 100%. In a population at risk for TB infection who were either tuberculin skin test-negative or -positive, the specificity of the test for active TB was 89%. The negative and positive predictive values of the test were 98% and 52%, respectively. The overall accuracy of the test was 81 %. The high negative predictive value of the test in a population at risk for tuberculous infection makes it a potentially valuable screening test for active TE.

12.2.12 ICT Tuberculosis Test

The ICT tuberculosis test is a card test based on the detection of IgG antibodies directed against five M. tuberculosis secreted antigens, using an anti-human IgG labeled with colloidal gold (Rasolofo et al. 2000), a method similar to the one we employed in the antiLAM IgG dot-blot assay (Chan et al. 2000). Rasolofo and colleagues (2000) showed that the ICT test had a sensitivity of only 68.2% for smear-positive TB and 65.2% for extrapulmonary TB in a group of patients from Madagascar. The specificity was 83.3%. Overall, the ICT assay is not sufficiently predictive for clinical application. The choice of a diagnostic test depends on the pretest probability of a positive response, and therefore the prevalence of disease in the population being tested. Such factors are especially important when decisions regarding health care policy and screening of large populations are being considered. McConkey et al. (2002) illustrated this point well by testing the diagnostic yield of a rapid antibody card test in areas of high prevalence of the disease (Cairo, Egypt) and of low prevalence(St. Louis, Missouri, USA). In Egypt, the antibody test was highly sensitive (87%) for smear-positive and -negative pulmonary TB; the specificity was 82%. The sensitivity and specificity in St. Louis were 29% and 79%, respectively.

12.2.13 Dermal Response to MPB64 Antigen

Although not a serological assay, Nakamura and colleagues (1998) recently reported that the MPB64

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mycobacterial antigen delivered transdermally by the patch test method was highly accurate for diagnosing active TB. In this promising study, 52 of 53 patients (98%) with active TB showed a positive reaction to MPB64, while none of the 43 PPD-positive controls were positive. This resulted in an overall sensitivity of the test for active TB of 98.1%, a specificity of 100%, and an accuracy of 98.9%.

12.2.14 Integral Membrane Antigens of M. habana TMC 5135

Chaturvedi and Gupta (2002) evaluated the usefulness of detecting antimycobacterial antibodies to antigens that belong to the integral compartment of the plasma membrane of M. habana in serum and body fluids of patients with mainly extrapulmonary TB (only 4 of 42 patients had exclusively pulmonary TB). The presence of antibodies against M. habana integral membrane antigens (IMAs) was detected in 36 patients, for an overall positivity rate of 86% (36/42). Anti-M. tuberculosis H37RA antibodies were also found in 29 out of 36 anti-M. habana IMA antibody-positive patients.

12.2.15 Lipopolysaccharide Antigen

Meena and co-workers (2002) recently reported the isolation of an immunodominant lipopolysaccharide (LPS) antigen from M. tuberculosis H37Rv for the serodiagnosis of TB. Serum samples obtained from 59 Indian patients (19 patients with active pulmonary TB, 20 with extrapulmonary TB, and 20 with nontuberculous pulmonary disease) and 20 healthy adults were tested for LPS and three other commercially available antigen assays. The presence of IgG against LPS was highly sensitive and specific (84 and 97%, respectively), similar to the test characteristics of A60 IgG and superior to the assays for antibodies to 38 kDa or p90 antigens.

12.3 Specific Targeted Populations In certain individuals, the diagnosis of active TB is particularly challenging. Such persons include young children, the elderly, HIV-positive individuals, and patients with extrapulmonary TE. This is due to the

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greater difficulty in obtaining a sputum sample, the lower incidence of acid-fast bacilli in respiratory samples, and/or the indolent or atypical presentation of TB in such groups of people.

12.3.1 Childhood TB Although childhood TB represents a small percentage of all cases, infected children are a reservoir for many adult cases (Khan and Starke 1995). The bacteriologic diagnosis of TB is particularly difficult in young children because of the greater incidence of disseminated disease and because children often do not produce an adequate amount of sputum. Thus, serological methods to diagnose childhood TB have great potential and relevance. For children with clinical TB, the detection of IgG and IgM against A60 antigen is comparable to that seen in adults. In a study that examined the utility of detecting specific IgM, IgA, and IgG antibodies to A60 antigen in childhood TB on the Indian subcontinent, the overall sensitivity and specificity of the test with combined IgA and IgM testing were 76% and 92%, respectively (Gupta et al. 1997). In children who were acid-fast positive, the sensitivity rose to 95%. For 150 children with extrapulmonary TB, the overall sensitivity was 77%. In a study to detect IgG against an autoclaved suspension of H37Rv in 132 clinical cases of childhood TB, the sensitivity of the test in the culture-positive group (n=35) was 69% (Hussey et al. 1991). Interestingly, there was a positive correlation between the titer level and increasing age. Prior BCG did not affect the ELISA result. However, in another study that examined IgM and/or IgG against A60 antigen in primary TB or TB adenitis in children, the authors concluded that the test was not diagnostically useful (Turneer et al.1994). Levels of antiglycolipid IgG were found to be higher in children with active TB than in nontuberculous controls, leading the authors to conclude that the detection of IgG antibodies against glycolipids was useful as a complementary technique in the serodiagnosis of pulmonary TB in children (Simonneyet al. 2000).

patterns of primary infection in the elderly compared with young adults may lower the health care provider's suspicion ofTB (Morris 1989). In adults, the incidence of active TB cases is higher in the elderly (Dorken et al. 1987). Miliary TB, often presenting without localizing signs or symptoms, is also more common in the elderly person than in young adults, although the diagnosis is frequently not made until autopsy (Korzeniewska et al. 1994). Reactivation is associated with co-morbid diseases that result in waning cell-mediated immunity, disclosed by reduced skin test positivity to PPD with increasing age. For example, in men, PPD reactivity drops from 50% at age 65-74 years to 10% at age 95+, and in women from 40% to about 5%, respectively (Dorken et al. 1987). Because of the high rate of conversion in the absence of symptoms in nursing home residents, a two-step skin test is recommended for residents on admission to the nursing home: an initial test and, if negative or equivocal, a repeat test 1-2 weeks later. A positive booster effect is defined as an increase of 6 mm or more from an induration <10 mm on the first test to 10 mm with the second test. Thus, this information at baseline can help to distinguish newly acquired disease from a prior infection. The bacteriologic diagnosis of TB in the elderly is generally more problematic due to the greater difficulty in obtaining sputum and the greater incidence of disseminated disease. Unfortunately, there has not been a systematic evaluation of the serologic diagnosis of active TB in the elderly. Whether age per se impairs the immune system and thus may affect the antibody response to bacterial antigens is controversial. For example, although a decline in the adaptive immunity has been observed in the elderly, in many cases it is not clear whether the defect is primary or secondary to an underlying systemic disorder such as cancer or diabetes.An age-associated decline in humoral immunity has been observed, as evinced by a lower rate ofseroconversion and decreased antibody titer after vaccination; this effect may largely be due to loss ofT-helper cell effector function (Miller 1996). We believe a prospective study is needed to determine the accuracy of serologic assays in the diagnosis of pulmonary and extrapulmonary TB in the elderly. This issue is especially relevant in the context of nursing home-associated TB, where transmission is not an uncommon occurrence.

12.3.2 TB in the Elderly Despite the fact that the clinical presentation of TB in the elderly shares features with disease in younger people, TB in the aged frequently goes unrecognized (Fulton and McCallioin 1987). Differing radiographic

12.3.3 HIV-Positive Individuals The ability to detect specific antibodies against M. tuberculosis antigens is substantially diminished in

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HIV-positive individuals. As noted above, the sensitivity of anti-LAM IgG in HIV-positive patients was uniformly lower than in HIV-negative patients. In Ugandan patients with TB who were also HIV-positive, the sensitivity of IgG antibody (ELISA) to the 30 kDa antigen of M. tuberculosis was only 28% compared with 62% for patients who were HIV-negative (Daniel et al. 1994). An ELISA and EIA to detect the 30 kDa antigen revealed an extremely low sensitivity (l1 % and 0%, respectively) in HIV-positive patients (McDonough et al. 1992). The level of immunosuppression may also affect the antibody response as evidenced by an earlier study, conducted prior to the inclusion of TB as an AIDS-defining criteria, which showed that anti-PPD IgG was positive in 8 of 22 patients (36%) co-infected with HIV and TB but without another criteria for AIDS vs 1 of 20 patients (5%) with AIDS (Barrera et al.1992). Thus, the generally poor negative predictive value of serologic assays for TB in HIV-positive individuals makes them unreliable and not cost-effective.

12.3.4 Extrapulmonary 18 An ELISA to detect IgG to a 43 kDa antigen of M. tuberculosis in various body fluids found it to be very sensitive (-100%) and highly specific [95.7% for cerebrospinal fluid (CSF) and 98.1% for pleural and ascitic fluid] (Wadee et al.1990).An antibody response to 38 kDa antigen was noted in 73% of patients with extrapulmonary TB, comparable to the 70% sensitivity rate for smear-negative pulmonary TB (Wilkins and Ivanyi 1990). In four groups of patients with various degrees of confirmed neurologic TB (postmortem proved, culture proved, clinically suspected, and tuberculoma), antibody to the 38 kDa antigen was detected in the CSF in 60%,80%,62.5%, and 0% of the patients, respectively (Kadival et al. 1994). Detection of the 30 kDa antigen using a monoclonal antibody was done on the sera of 51 Mrican patients with clinically diagnosed tuberculous pericardial effusion, of whom 25 had confirmation by pericardial fluid cultures. The sensitivity was 61% and specificity 96% (Ng et al. 1995). Zou et al. (l994) showed that IgG against A60 antigen was present in 88.5% with reactivation TB, and 69%-86% of patients with extrapulmonary TB. Similarly, Lub and co-workers (l996) found the sensitivity rate for anti-A60 IgG to be 76% for pulmonary TB and 59% for patients with extrapulmonary TB. Compared with children with pulmonary TB, the IgG antibody response to glycolipid was significantly

lower in patients with extrapulmonary TB (Simonney et al. 2000). Gupta and co-workers (l997) found that the sensitivity of IgA and IgM directed against A60 antigen was 72.4% for patients with pulmonary TB and 76.6% for patients with extrapulmonaryTB. In Indian patients with pulmonary and extrapulmonary TB, the sensitivity rate for IgA and IgG antibody directed against A60 was 98.3% for pulmonary TB, 88% for pleural TB, and 86% for extrapulmonary TB (Gupta et al. 1995). Overall, an assay for antibody against mycobacterial antigens in either serum or body fluids in patients with extrapulmonary TB holds great potential.

12.3.5 Smear-Negative vs Smear-Positive 18 If acid-fast smear of sputum or body fluids is positive, the diagnosis of TB or atypical mycobacteria is rarely questioned. However, -50% of sputum smear in patients with bacteriologic-confirmed pulmonary TB are smear-negative. Thus, an accurate seroassay may be particularly useful in this group of patients. Charpin and colleagues (l990) specifically examined patients with smear-negative, culture-positive TB using a combined IgG and IgM seroassay for the A60 antigen and demonstrated the sensitivity to be 68%, specificity 100%, and positive predictive value 100%. We had previously shown in our immunoblot assay for anti-LAM IgG that five patients with smear-negative, culture-positive TB had a positive seroassay (Chan et al. 2000). Few studies have directly compared the sensitivity rate of TB patients who are smear-negative and culture-positive vs those who are smear- and culture-positive. As shown in Table 12.2, the sensitivity rate for smear-negative patients is either similar or lower than for smear-positive cases. The sensitivity for the MycoDot assay for LAM was especially low for both groups, likely due to the fact that over 50% of the subjects were HIV-positive (Somi et al. 1999). Unfortunately, in those studies that directly compared smear-negative vs smear-positive cases, the majority (Table 12.2) showed suboptimal sensitivity and thus sufficiently low negative predictive value to be unreliable at present in smear-negative cases.

12.4

Conclusion In summary, the appropriate setting for the use of serological tests to diagnose M. tuberculosis dis-

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Serologic Testing for Tuberculosis Table 12.2. Sensitivity of smear-negative vs smear-positive tuberculosis Antibody detection Smear-positive, Smear-negative, Reference to antigen 'X' culture-positive culture-positive Glycolipid antigen 19kDa LAM (MycoDot)" LAM (ELISA) P32 antigen of M. bovis BCG 38kDa

96% 57% 26% 88% IgA 33% IgG 52% 45-89%

97% 55% 7% 67% IgA 24% IgG 35% 16-82%

P90 Glycolipid

75% 90%

68% 70%

a 51%

Dogan and Aksu (1997) Botharnley et al. (1992) Somi et al. (1999) Sada et al. (1992) Turneer et al. (1988) Cole et al. (1996); Botharnley and Rudd (1994); Chan et al. (1990) Alifano et al. (1997) Maekura et al. (2001)

of the patients were HIV-positive

ease remains to be definitively established. Obvious advantages to serologic diagnostic tests are a greater sensitivity compared with acid-fast smear and a more rapid turnaround time than culturing. However, in our opinion, these tests at the current state of their development cannot be considered as an alternative to the conventional methods for the following reasons: • An overall concern is whether any of these tests offers any significant advantage in the clinical setting over the gold standard of cultivation, which is still necessary to obtain the drug-susceptibility pattern. Importantly, whether the application of these tests improves the patient outcome has yet to be determined. • Suboptimal sensitivity of the serologic assays for patients with smear-negative TB diminishes the utility of these tests because this is the group of patients that is considered potentially to derive the most benefit from these nonconventional tests. Similarly, the poor negative predictive value of serologic assays for TB in HIV-positive individuals should, in its current state, preclude its use in AIDS patients. • The tests are associated with relatively high costs and greater personnel training requirements, issues that are of paramount concern especially in developing countries. • The relatively low positive predictive value due to the decreased ability to distinguish between active and latent TB infection. • The difficulty serological tests have distinguishing between M. tuberculosis vs atypical mycobacteria infection.

References Aide SLM et al (1989) Evaluation of an enzyme-linked immunosorbent assay (ELISA) using an IgG antibody to Mycobacterium tuberculosis antigen 5 in the diagnosis of active tuberculosis in children. Am Rev Respir Dis 139:748-751 Alifano M et al (1997) Evaluation of IgA-mediated humoral immune response against the mycobacterial antigen P90 in diagnosis of pulmonary tuberculosis. Chest Ill: 601-605 Amicosante M et al (1995) Evaluation of a novel tuberculosis complex-specific 34 kDa protein in the serological diagnosis of tuberculosis. Eur Respir J 8:2008-2014 Anuradha S et al (2001) Serodiagnosis of extra-pulmonary tuberculosis using A-60 antigen. J Commun Dis 33:12-16 Arikan S et al (1998) Anti-Kp 90 IgA antibodies in the diagnosis of active tuberculosis. Chest 114:1253-1257 Barrera L et al (1992) Humoral response to Mycobacterium tuberculosis in patients with human immunodeficiency virus infection. Tuberc Lung Dis 73:187-191 Boggian K, Fierz W, Vernazza PL (1996) Infrequent detection of lipoarabinomannan antibodies in human immunodeficiency virus-associated mycobacterial disease. J Clin MicrobioI34:1854-1855 Bothamley GH, Rudd RM (1994) Clinical evaluation of a serological assay using a monoclonal antibody (TBn) to the 38 kDa antigen of Mycobacterium tuberculosis. Eur Respir J 7:240-246 Bothamley G et al (1992) Serodiagnostic value of the 19 kilodalton antigen of Mycobacterium tuberculosis in Indian patients. Eur J Clin Microbiol Infect Dis 11:912-915 Brooks JB et al (1987) Selective procedures for detecting femtomole quantities of tuberculostearic acid in serum and cerebrospinal fluid by frequency-pulsed electron capture gas-liquid chromatograph. J Clin MicrobioI25:1201-1206 Chan ED et al (2000) Diagnosis of tuberculosis by a visually detectable immunoassay for lipoarabinomannan. Am J Respir Crit Care Med 161:1713-1719 Chan SL et al (1990) Serodiagnosis of tuberculosis using an ELISA with antigen 5 and a hemagglutination assay with glycolipid antigens. Am Rev Respir Dis 142:385-390 Charpin D et al (1990) Value of ELISA using A60 antigen in the diagnosis of active pulmonary tuberculosis. Am Rev Respir Dis 142:380-384

196 Chaturvedi V, Gupta HP (2002) Evaluation of integral membrane antigens of Mycobacterium habana for serodiagnosis of extrapulmonary tuberculosis: association between levels of antibodies and Mycobacterium tuberculosis antigens. FEMS Immunol Med MicrobioI33:1-7 Chiang 1-H et al (1997) Serodiagnosis of tuberculosis: A study comparing three specific mycobacterial antigens. Am J Respir Crit Care Med 156:906-911 Cocito CG (1991) Properties of the mycobacterial antigen complex A60 and its applications to the diagnosis and prognosis of tuberculosis. Chest 100:1687-1693 Cole RA et al (1996) Clinical evaluation of a rapid immunochromatographic assay based on the 38 kDa antigen of Mycobacterium tuberculosis on patients with pulmonary tuberculosis in China. Tuberc Lung Dis 77:363-368 Daniel TM, Debanne SM, van der Kuyp F (1985) Enzymelinked immunosorbent assay using Mycobacterium tuberculosis antigen 5 and PPD for the serodiagnosis of tuberculosis. Chest 88:388-392 Daniel TM et al (1986) Field evaluation of enzyme-linked immunosorbent assay for the serodiagnosis of tuberculosis. Am Rev Respir Dis 134:662-665 Daniel TM et al (1994) Reduced sensitivity of tuberculosis serodiagnosis in patients with AIDS in Uganda. Tuberc Lung Dis 75:33-37 Del Prete R et al (1998) Detection of anti-lipoarabinomannan antibodies for the diagnosis of active tuberculosis. Int J Tuberc Lung Dis 2:160-63 Diagbouga S et al (1997) Immunoblot analysis for serodiagnosis of tuberculosis using a 45/47-kilodalton antigen complex of Mycobacterium tuberculosis. Clin Diag Lab ImmunoI4:334-338 Dogan UB, Aksu HSZ (1997) Serodiagnostic value of ELISA in pulmonary tuberculosis in Turkey where tuberculosis is highly prevalent. Respiration 64:73-75 Dorken E, Grzybowski S, Allen EA (1987) Significance of the tuberculin test in the elderly. Chest 92:237-40 Escamilla L et al (1996) Mycobacterium fortuitum glycolipids for the serodiagnosis of pulmonary tuberculosis. Am J Respir Crit Care Med 154:1864-1867 Fadda G et al (1992) Serodiagnosis and follow up of patients with pulmonary tuberculosis by enzyme-linked immunosorbent assay. Eur J Epidemiol 8:81-87 Franco J et al (2001) Serological response (Western blot) to fractions of Mycobacterium tuberculosis sonicate antigen in tuberculosis patients and contacts. Int J Tuberc Lung Dis 5:958-962 Fulton JD, McCallioin J (1987) Tuberculosis - diagnostic difficulty in the elderly. J Clin Exp Gerontol 9:303-11 Gupta S, Bhatia R, Datta KK (1997) Serological diagnosis of childhood tuberculosis by estimation of mycobacterial antigen 6O-specific immunoglobulins in the serum. Tuberc Lung Dis 78:21-27 Gupta S et al (1995) Diagnostic utility of the estimation of mycobacterial antigen A60 specific immunoglobulins IgM, IgA, and IgG in the sera of cases of adult human tuberculosis. Tuberc Lung Dis 76:418-24 He H et al (1991) Rapid serodiagnosis of human mycobacteriosis by ELISA using cord factor (trahalose-6,6'-dimycolate) purified from Mycobacterium tuberculosis as antigen. FEMS Microbiol ImmunoI3:201-204 Hussey G, Kibei M, and Dempster W (1991) The serodiagnosis of tuberculosis in children: an evaluation of an ELISA test

C. Kotaru and E. D. Chan using IgG antibodies to M. tuberculosis, strain H37Rv. Ann Trop Paediatr 11:113-118 Imaz MS et al (2001) Evaluation of the diagnostic value of measuring IgG, IgM and IgA antibodies to the recombinant 16-kilodalton antigen of Mycobacterium tuberculosis in childhood tuberculosis. Int J Tuberc Lung Dis 5: 1036-1043 Julian E et al (1997) Detection of lipoarabinomannan antibodies in patients with newly acquired tuberculosis and patients with relapse tuberculosis. J Clin Microbiol 35: 2663-2664 Kadival GV et al (1994) Detection of antibodies to defined M. tuberculosis antigen (38 kDa) in cerebrospinal fluids of patients with tuberculous meningitis. Zentralblatt BakterioI281:95-101 Khan EA, Starke JR (1995) Diagnosis of tuberculosis in children: Increased need for better methods. Emerg Infect Dis 1:115-123 Khomenko AG et al (1996) Serodiagnosis of tuberculosis: detection of mycobacterial antibodies and antigens. Tuberc Lung Dis 77:510-515 Korzeniewska M et al (1994) Tuberculosis in young adults and the elderly. Chest 106:28-32 Lawn SD, Frimpong EH, Nyarko E (1997) Evaluation of a commercial immunodiagnostic kit incorporating lipoarabinomannan in the serodiagnosis of pulmonary tuberculosis in Ghana. Trop Med Int Health 2:978-981 Luh KT et al (1996) Tuberculosis antigen A60 serodiagnosis in tuberculous infection: application in extrapulmonary and smear-negative pulmonary tuberculosis. Respirology 1:145-151 Ma Y, Wang YM, Daniel TM (1986) Enzyme-linked immunosorbent assay using Mycobacterium tuberculosis antigen 5 for the diagnosis of pulmonary tuberculosis in China. Am Rev Respir Dis 134:1273-1275 Maekura R et al (1993) Clinical evaluation of rapid serodiagnosis of pulmonary tuberculosis by ELISA with cord factor (trehalose-6,6'-dimycolate) as antigen purified from Mycobacterium tuberculosis. Am Rev Respir Dis 148:997-1001 Maekura R et al (2001) Clinical evaluation of anti-tuberculous glycolipid immunoglobulin G antibody assay for rapid serodiagnosis of pulmonary tuberculosis. J Clin Microbiol 39:3603-3608 McConkey SJ et al (2002) Evaluation of a rapid-format antibody test and the tuberculin skin test for diagnosis of tuberculosis in two contrasting endemic settings. Int J Tuberc Lung Dis 6:246-252 McDonough JA et al (1992) Microplate and dot immunoassays for the serodiagnosis of tuberculosis. J Lab Clin Med 120: 318-322 Meena LS et al (2002) Comparative study of three different mycobacterial antigens with a novel lipopolysaccharide antigen for the serodiagnosis of tuberculosis. J Clin Lab Anal 16:151-155 Miller RA (1996) The aging immune system: primer and prospectus. Science 273:70-74 Morris CDW (1989) The radiology, haematology, and biochemistry of pulmonary tuberculosis in the aged. Q J Med 71:529-535 Nakamura RM et al (1998) MPB64 mycobacterial antigen: a new skin-test reagent through patch method for rapid diagnosis of active tuberculosis. Int J Tuberc Lung Dis 2: 541-546

Serologic Testing for Tuberculosis Ng TT, Strang JI, Wilkins EG (1995) Serodiagnosis of pericardial tuberculosis. Quart J Med 88:317-320 Niculescu D et al (1999) Serodiagnosis of extrapulmonary tuberculosis by enzyme-linked immunosorbent assay (ELISA). Roum Arch Microbiol Immunol 58: 111-119 Nsanze H et al (1997) Serodiagnosis of tuberculosis and leprosy by enzyme immunoassay. Clin Microbiol Infect 3:236-239 Rasolofo V et al (2000) Predictive values of the ICT Tuberculosis test for the routine diagnosis of tuberculosis in Madagascar. Int J Tuberc Lung Dis 4:184-185 Ratanasuwan W et al (1997) Evaluation of the MycoDot test for the diagnosis of tuberculosis in HIV seropositive and seronegative patients. Int J Tuberc Lung Dis 1:259-264 Rosen EU (1990) The diagnostic value of an enzyme-linked immunosorbent assay using adsorbed mycobacterial sonicates in children. Tubercle 71:127-130 Rovatti E et al (1996) Evaluation of a western blot serum test for the diagnosis of Mycobacterium tuberculosis infection. Eur Respir J 9:288-292 Sada E et al (1990) Evaluation of lipoarabinomannan for the serological diagnosis of tuberculosis. J Clin Microbiol 28: 2587-2590 Sada E et al (1992) Detection oflipoarabinomannan as a diagnostic test for tuberculosis. J Clin Microbiol 30:2415-2418 Simonney N, Bourrillon A, Lagrange PH (2000) Analysis of circulating immune complexes (CICs) in childhood tuberculosis: levels of specific antibodies to glycolipid antigens and relationship with serum antibodies. Int J Tuberc Lung Dis 4:152-160 Simonney N et al (1996) Comparison of A60 and three glycolipid antigens in an ELISA test for tuberculosis. Clin Microbiol Infect 2:214-222 Somi GR et al (1999) Evaluation of the MycoDot test in

197 patients with suspected tuberculosis in a field setting in Tanzania. Int J Tuberc Lung Dis 3:231-238 Steele BA, Daniel TM (1991) Evaluation of the potential role of serodiagnosis of tuberculosis in a clinic in Bolivia by decision analysis. Am Rev Respir Dis 143:713-716 Torres M et al (1994) Comparison of the immune response against Mycobacterium tuberculosis antigens between a group of patients with active pulmonary tuberculosis and healthy household contacts. Clin Exp ImmunoI96:75-78 Turneer M et al (1988) Humoral immune response in human tuberculosis: Immunoglobulins G, A, and M directed against the purified P32 protein antigen of Mycobacterium bovis bacillus Calmette-Guerin. J Clin Microbiol 26: 1714-1719 Turneer M et al (1994) Determination of humoral immunoglobulins M and G directed against mycobacterial antigen 60 failed to diagnose primary tuberculosis and mycobacterial adenitis in children. Am J Respir Crit Care Med 150: 1508-1512 Van Vooren JP et al (1988) A multiblot immunobinding assay for the serodiagnosis of tuberculosis. J Immunological Methods 113:45-49 Wadee AA, Boling L, Reddy SG (1990) Antigen capture assay for detection of a 43-kilodalton Mycobacterium tuberculosis antigen. J Clin MicrobioI28:2786-2791 Wilkins EGL, Ivanyi J (1990) Potential value of serology for diagnosis of extrapulmonary tuberculosis. Lancet 336: 641-644 Yu CJ et al (1992) Evaluation of the A-60 IgG ELISA serodiagnostic test for tuberculosis in Taiwan. J Formosan Med Assoc 91:614-619 Zou YL et al (1994) Serological analysis of pulmonary and extrapulmonary tuberculosis with enzyme-linked immunosorbent assays for anti-A60 immunoglobulins. Clin Infect Dis 19:1084-1091

13 peR and Diagnosis of Tuberculosis DIANA

L. WILLIAMS

CONTENTS 13.1 13.2 13.3 13.4 13.5 13.6

Polymerase Chain Reaction 199 PCR of M. tuberculosis 200 Drug Resistance in M. tuberculosis 202 PCR Detection of Drug Resistance 204 Impact of PCR Diagnosis on Patient Care Summary 207 References 208

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The current 'gold standard' for the identification of M. tuberculosis in clinical specimens is based on acid-fast microscopy of sputum sediments or other specimens (AFB smears), followed by culture confirmation using definitive biochemical or DNA probe analyses. Although AFB smear results can be available within 1 day, they are only 50%-70% sensitive and do not distinguish between M. tuberculosis and other nontuberculosis mycobacteria that may be present in specimens. Traditional culture-based methodologies for the detection of M. tuberculosis require between 1 and 8 weeks to perform and often have low sensitivity when small numbers of organisms are analyzed (AFB smear-negative). In addition, culture-based drug-susceptibility testing requires several additional weeks to identify drug-resistant M. tuberculosis. These factors make patient diagnosis extremely difficult, and therefore, many patients are routinely started on treatment with minimal diagnostic information. This potentially results in postponing appropriate treatment and the failure to identify rapidly those patients who need to be isolated from the general population because they are harboring drug-resistant organisms. Therefore, the rapid and specific diagnosis of tuberculosis is one of the most pressing needs in the effort to control and eventually eradicate this disease. D. 1. WILLIAMS, PhD Molecular Biology Research Department, Laboratory Research Branch, National Hansen's Disease Programs at LSU-SVM, Rm 3517W, Skip Bertman Dr., Baton Rouge, LA 70803, USA

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

Molecular approaches to aid the diagnosis of human disease have begun to have a major influence on the current clinical management of various diseases. A major goal of tuberculosis research over the last decade has been to apply molecular approaches to develop rapid, reliable procedures that can detect M. tuberculosis directly from clinical specimens and thereby avoid the many weeks required for culture amplification. The result has been the development of numerous nucleic acid-based assays, including ones based on strand displacement amplification (Walker et al. 1992), transcription-mediated amplification (Jonas et al. 1993), oligonucleotide ligation amplification (Iovannisci and Winn-Deen 1993), Q-beta replicase amplification (Shah et al. 1995), and polymerase chain reaction (PCR) (Mullis and Faloona 1987) methodologies. Among them, PCRbased assays have been tested on thousands of clinical specimens and isolates in laboratories around the world. The purpose of this chapter is to summarize the progress that has been made in the past few years in the development and characterization of PCRbased assays for the rapid diagnosis of tuberculosis and drug-resistant tuberculosis, to highlight several critical differences between PCR-based testing and conventional microbiology, and to discuss the impact that PCR analysis can potentially have on patient care and the control of tuberculosis.

13.1 Polymerase Chain Reaction PCR is a nucleic acid-based methodology, originally described in 1987, that uses short oligonucleotide primers to direct the amplification of specific segments of target DNA sequences (template) by repeated cycles of denaturation of the template DNA, primer annealing to this DNA, and primer extension (Mullis and Faloona 1987). This allows exponential multiplication of the specified template, so that beginning with as few as one copy of this sequence,

D. L. Williams

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as many as one billion copies (amplicons) can be produced within 2-4 h of specimen processing. In addition, because of the designed specificity, PCR is a powerful technique for the detection of small numbers of bacterial DNA in crude biological specimens without the necessity of culture. PCR requires: (1) specifically selected primers; (2) an appropriately prepared sample; (3) a thermostable DNA polymerase, buffer, and dNTPs; (4) appropriate positive and negative controls; (5) a thermocycler; and (6) a detection assay. The specificity of PCR lies in the selection of oligonucleotide primers used in this assay. Therefore, primers are typically selected from specific regions of the chromosome not found in other bacterial or eukaryote DNA. Once identified, primers can be synthetically manufactured and used specifically to amplify template from crude biological specimens. In addition, since the primers are incorporated in the amplicon during the PCR reaction, primers can be labeled with biotin or specific Buors for subsequent amplicon detection as discussed below.

13.2 peR of M. tuberculosis Numerous PCR-based assays have been developed for the detection of M. tuberculosis, and several of them are summarized in Table 13.1. All of these assays use specific procedures to recover DNA efficiently from low numbers of M. tuberculosis from clinical specimens and to remove potential contaminants that may inhibit PCR. Sputum specimens are typically used for the PCR detection of M. tuberculosis, but bronchial alveolar washes, skin biopsies, cerebrospinal fluid, blood, gastric lavage fluid, fecal specimens, and tissue biopsy specimens have also been used. The standard protocol for preparing sputum for PCR uses N-acetyl-L-cysteine sodium hydroxide (NALC-NaOH) treatment to digest and decontaminate specimens (Kent and Kubica 1985). The next step is the efficient lysis of the bacteria. This can be accomplished by sonication, treatment with sodium dodecyl sulfate (SDS) plus lysozyme plus heat, protease treatment, and chaeotropic salts followed by a nucleic acid purification step. This insures that the majority of potential inhibitors of the PCR are removed. However, one easy and commonly used procedure for the preparation of sputum sediments for PCR is the fixation of a portion (100-250 Ill) of these sediments in a final concentration of 70% ethanol for at least 2 h (Williams et al. 1995). This

procedure kills M. tuberculosis and preserves bacterial DNA. The fixed sediments can be stored at room temperature indefinitely or can be pelleted, resuspended in sterile H20, and placed in a boiling water bath for 10 min. These crude celllysates serve as an excellent template for PCR or can be stored at -20°C for later use. PCR cycling parameters vary primarily because of the melting temperature of the primers selected for amplification. However, a standard protocol involves an initial denaturation step of 94°C for 5 min followed by a 30-45 cycle program consisting of: 30 s at 94°C; 30 s at the optimal primer annealing temperature; and 30 s at noc, the optimal extension temperature. This program is followed by a final 5-10 min hold at n°e. Once the template is amplified, many methods are available for the detection of PCR amplicons. One of the most commonly used and inexpensive methods is the electrophoretic separation of amplicons on agarose or polyacrylamide slab gels with subsequent visualization of ampIicons in ethidium

Table 13.1. PCR-based assays for detection of M. tuberculosis in clinical specimens Assay

Target

Reference(s)

'In-house' Eisenach et aI. (1990, 1991) Brisson-Noel et aI. (1991) Kent et aI. (1995) Mulcahy et aI. (1996) DesJardin et aI. (1998) Almeda et aI. (2000) Borun et aI. (2001) Williams et aI. (1 998b) rpoB Brisson-Noel et aI. (1991) hsp65 Shinnick and Jonas (1994) MPB70 Cousins et aI. (1992) MTB40 DelPortilio et aI. (1991) 32 kDa antigen Soini et aI. (1992) 65 kDa/IS611O Yeboah-Manu et aI. (2001) (multiplex) 16S rRNA gene Bottger et aI. (1989) Boddinghaus et aI. (1990) IS6110

Commercial: Roche Amplicor 16S rRNA gene www.roche-diagnostics.com Bergmann and Woods (1996) MTB Bennedsen et aI. (1996) Dalovisio et aI. (1996) Soini et aI. (1996) Forbes (1997) Mitarai et aI. (2001) Gomez-Pastrana et aI. (2001) RocheCOBAS 16S rRNA gene www.roche-diagnostics.com Eing et aI. (1998) Amplicor MTB Bogard et aI. (2001) Oh et aI. (2001)

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Because of the large number of copies of this elebromide-stained gels using UV-light transillumination. Documentation of results can be accomplished ment in most strains (1-25) and the random inserusing a standard or Polaroid camera fitted with the tion of this element in different strains of M. tuberappropriate orange filter or by using a computerized culosis, the IS6110 PCR assay has been modified to image acquisition and analysis instrument, such as a produce a DNA fingerprint of a strain (Thierry et al. GelDoc 2000 (BioRad Laboratories, Hercules, CA). 1990; Cave et al.1991). This analysis and others based To increase the sensitivity of amplicon detection, on repeated insertion elements in the genome of M. amplicons can be transferred from gels to nitrocellu- tuberculosis have been used to type clinical isolates lose or nylon membranes using a simple capillary dif- for epidemiological studies (Thierry et al.1990; Cave fusion-based nucleic acid transfer technique or South- et al. 1991; Plikaytis et al. 1993; van Embden et al. ern blotting (Southern 1975). PCR products can then 1993; van Soolingen et al. 1994; Otal et al. 1997). be visualized using one of many hybridization-based Other 'in-house' PCR assays target many different detection techniques with radiolabeled, chemilumines- genes and repeated sequences within the M. tubercucent, or fluorescent-labeled probes. Some protocols use losis genome (Table 13.1). Even though these assays reverse hybridization of amplicons to probes bound on rely on the amplification of different targets, they nitrocellulose filters (de Beenhouwer et al. 1995) or to all have similar specimen preparation and specificthe wells of microtiter plates (Amplicor MTB, Roche ity for smear-positive specimens. However, because Molecular Systems, Emery, CA, USA). In addition, one the majority of these assays are based on single copy commercially available assay provides amplification genes, they are not as sensitive as the IS6110 assay. and detection in a semiautomated system (COBAS In addition to these M. tuberculosis-specific PCR Amplicor MTB, Roche Molecular Systems). assays, another 'in-house' PCR assay has been develThe majority of the assays developed for the detec- oped which identifies the presence of M. tuberculosis tion of M. tuberculosis are referred to as 'in-house' or other mycobacteria in clinical specimens. This PCRs because they have been developed and charac- assay uses mycobacterial genus-specific primers terized by individual laboratories. While these assays which flank a hypervariable region of the 16S rRNA offer the potential for diagnosing tuberculosis with gene in which species-specific differences have been a high degree of sensitivity and specificity in a few characterized (Bottger et al. 1989). The PCR amplihours, only a few have been successfully transferred cons are then subjected to DNA sequencing to disto the clinical laboratory. The IS611 0 'in-house' PCR criminate between mycobacterial species (Bottger et assay, originally developed by Eisenach et al. in 1990, al. 1989; Boddinghaus et al. 1990). This analysis has targets the multicopy IS611 0 insertion element of M. proven to be a rapid and reliable method for the identuberculosis. This assay, or variations of it, have been tification of mycobacteria in the clinical laboratory successfully used in many clinical laboratories to (Kirschner et al. 1993). detect M. tuberculosis (Table 13.1). Presently, there are only a few commercially availWhen the IS6110 PCR assay was evaluated for its able nucleic acid amplification assays for the direct ability to detect M. tuberculosis in sputum specimens detection of tuberculosis from clinical specimens routinely processed in several clinical laboratories, the (Table 13.1). An example of one of these assays is the following conclusions were made: (1) this PCR was Amplicor MTB assay, which is based on PCR amplieasy to fit into the daily routine of a clinicallabora- fication of the 16S rRNA gene and a colorimetric tory with a turnaround time of 24-36 h from time of detection system. This assay is recommended for the specimen collection; (2) existing laboratory personnel detection of M. tuberculosis in liquefied, decontamicould perform these assays; and (3) false-positives, due nated, and concentrated human respiratory specito amplicon contamination of specimens, were rare mens, including expectorated and induced sputum, when personnel strictly adhered to specific laboratory bronchial washings, and bronchial alveolar lavages procedures (Clarridge et al. 1993; Shalwar et al. 1993; (www.roche-diagnostics.com). Nolte et al. 1993). In addition, when the results of this Clinical trials to evaluate the reliability of this study were compared with culture-based detection for assay for the diagnosis of pulmonary tuberculosis the same specimens, there was 100% specificity for M. have concluded that this assay has excellent sensitivtuberculosis and 95% sensitivity with smear-positive, ity, specificity, and positive and negative predictive culture-positive specimens. However, the PCR-based values for smear-positive, culture-positive specimens assay had a lower sensitivity for smear-negative, cul- when compared with other 'in-house' assays (Bergture-positive specimens, thus being of lesser value for mann and Woods 1996; Eing et al. 1998). One such the early detection of disease development. trial evaluated 956 respiratory specimens from 502

202

patients and compared the results of the Amplicor MTB assay with those of culture. For 135 specimens that were culture-positive for mycobacteria, the sensitivity, specificity, and positive and negative predictive values of the Amplicor MTB assay were 79.4%,99.6%, 92.6%, and 98.6%, respectively. For AFB smear-positive specimens, the sensitivity, specificity, and positive and negative predictive values of Amplicor MTB were 97.6%, 100%, 100%, and 90.9%, respectively. For AFB smear-negative specimens, the sensitivity, specificity, and positive and negative predictive values were 40.0%,99.5%,69.2%, and 98.7%, respectively. In another study, the sensitivity was ~95% and specificity 100% in smear-positive specimens (Woods 2001). Another commercially available PCR assay is the Roche COBAS Amplicor MTB assay. This assay is a semiautomated version of the manually performed Roche Amplicor MTB test (www.rochediagnostics.com). When compared with culture and an IS611O-based 'in-house' PCR protocol, the sensitivity, specificity, and positive and negative predictive values for this assay were 66.33%, 99.71 %, 94.36%, and 97.66%, respectively (Eing et al. 1998). The corresponding values for the 'in-house' PCR were 91.08%, 99.85%, 97.87%, and 99.37%, respectively. Another study showed similar results, giving an overall specificity of 99.7% and sensitivities ranging from 85.7% to 90.9% (Bogard et al. 2001). Therefore, it appears that these commercially available assays have good sensitivity, specificity, and predictive values for the detection of M. tuberculosis in smear-positive and culture-positive specimens (EI-Hajj et al. 2001). However, many laboratories, particularly in developing countries, continue to use methods developed 'in house'. This is primarily due to a lack of funding required for the expensive reagents and equipment used to perform these assays. In this environment, great care should be taken in the validation of these 'in-house' assays and in maintaining proper quality control. In summary, many PCR-based assays have been developed for the detection ofM. tuberculosis directly from clinical specimens. Several of these assays have been shown to be extremely sensitive for the direct detection of M. tuberculosis from clinical specimens.

13.3 Drug Resistance in M. tuberculosis Treating tuberculosis with combinations of effective antibiotics is a proven method for limiting the

D. L. Williams

emergence and spread of existing antibiotic-resistant strains of M. tuberculosis. In most areas of the world, current short-course multidrug therapy formulated for tuberculosis (MDT-TB) includes a 2-month daily combination of isoniazid (INH), rifampin (RMP), and pyrazinamide (PZA) and either streptomycin (STM) or ethambutol (EMB) followed by daily therapy with INH and one of the other primary drugs for the next 4 months (Stratton and Reed 1986). However, because of the length of MDT-TB, patient noncompliance often occurs, particularly when direct observation of therapy is not instituted (Frieden et al. 1993; Bradford et al. 1996). Since drug-resistant strains often emerge during intermittent or inadequate chemotherapy (Frieden et al. 1993; Bradford et al. 1996), clusters of disease caused by drug-resistant strains are still reported globally (Cohn et al. 1997; Moore et al. 1997). Therefore, there is a great need for rapid drug-susceptibility testing to monitor the evolution of drug resistance and track the spread of multidrug-resistant tuberculosis (MDR-TB). Conventional drug-susceptibility testing for tuberculosis relies on the cumbersome and time-consuming culture-based assays which can take up to 2 months to obtain results (Kent and Kubica 1985; Heifets 1991). Accordingly, drug-susceptibility testing is not a routine component of tuberculosis control programs in many parts of the world. This limits the ability to monitor the evolution of drug resistance and to establish the success of a treatment strategy like MDT-TB. Recently, substantial progress has been made in our understanding of the molecular basis of M. tuberculosis drug resistance as summarized by Musser (1995), Blanchard (1996), Ramaswamy and Musser (1998) and Cockerill (1999). Drug resistance in M. tuberculosis is primarily attributed to chromosomal mutations in genes encoding drug targets. These mutations occur spontaneously as a result of errors in DNA replication. For example, the frequency of drug-resistant mutants in a population of M. tuberculosis is estimated at 10-6 for INHR mutants and 10-7 for RMp R mutants. These frequencies suggest that one organism in a population of 106 is resistant to INH and one organism in 107 is resistant to RMP. Since it has been estimated that some untreated, smear-positive tuberculosis patients can harbor >109 viable M. tuberculosis/gram of lung tissue, the population of M. tuberculosis in such a patient could contain thousands of drug-resistant organisms. Inappropriate therapy for patients with such large bacterial loads selects for these subpopulations of drugresistant bacteria, resulting in the development of drug-resistant tuberculosis and leading to the spread of one or more resistant phenotypes.

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Isoniazid. INH is an effective, synthetic bactericidal agent for M. tuberculosis that requires the bacterial catalase peroxidase to convert it to its active form. Resistance to INH in the majority of isolates correlates with changes in the catalase enzyme as a result of missense mutations, deletions, or insertions within the katG which encodes the catalase of M. tuberculosis (Zhang et al. 1992; Musser 1995). In addition, INH and ethionamide (ETH), a structural analogue of INH, interfere with new cell wall synthesis in M. tuberculosis (Winder et al. 1971). Resistance to these drugs also develops as a result of defined mutations within the inhA locus encoding the enoyl-ACP reductase and the 3-ketoacyl-ACP reductase involved with mycolic acid biosynthesis (Banerjee et al. 1994; Musser et al. 1996; Ramaswamy and Musser 1998). Additional mechanisms have been described for the development of INH resistance in M. tuberculosis, but all targets and modes of action of this drug in M. tuberculosis are still unknown (Table 13.2).

Rifampin. RMP [3,4-(methylpiperazinyl-iminomethylidene-rifamycin)J, a semisynthetic derivative of rifamycin, has been a key bactericidal component in most antituberculosis chemotherapeutic regimens since the early 1970s. RMP appears to exert its potent

bactericidal activity by binding to the DNA-dependent RNA polymerase complex and uncoupling transcription (Winder 1982). The target for RMP in M. tuberculosis is the ~-subunit of the DNA-dependent RNA polymerase encoded by rpoB (Telenti et al. 1993a; Williams et al. 1994, 1998a). Resistance to RMP in virtually all resistant isolates of M. tuberculosis correlates with changes in the structure of the ~-subunit of the DNA-dependent RNA polymerase as a result of missense mutations, small deletions, and insertions within an 81-base pair region of the rpoB referred to as the RMP resistance-determining region (RRDR) (Telenti et al. 1993a; Williams et al. 1994; Musser 1995; Ramaswamy and Musser 1998). The resultant ~-subunit is still functional, but it is refractory to the effects of RMP or requires much higher levels of the drug to produce bacterial cell death (Williams et al. 1998a).

Pyrazinamide. PZA is a structural analogue of nicotinamide that is used as a first-line tuberculosis drug. The mode of action of this drug is not understood, but it is thought that PZA is converted to the bioactive form of the drug by pyrazinamidase, an enzyme produced by M. tuberculosis (Konno et al. 1967). PZAR isolates lose some or all pyrazinamidase

Table 13.2. PCR-based assays for detection of drug-resistant M. tuberculosis Reference(s)

Assay

Drug

Target

'In-house': PCR-DNA sequencing

INH

EMB FQs RMP INH RMP

Marttila et aI. (1996); Musser et aI. (1996) Musser et aI. (1996) Sreevatsan et aI. (1997c) Telenti et aI. (1993b); Kapur et aI. (1994) Williams et aI. (1994); Nachamkin et aI. (1997) Rossau et aI. (1997); Bartfai et aI. (2001) pncA Sreevatsan et aI. (1997a) Sreevatsan et aI. (1 997b) embB Takiff et aI. (1994) gyrA rrs, rpls Sreevatsan et aI. (1996); Nachamkin et al. (1997) katG Heym et aI. (1995); Rouse et aI. (1995) Victor et aI. (1996); Telenti et aI. (1993a, 1997b) Temesgen et aI. (1997) inhA Rouse et aI. (1995); Telenti et aI. (1997) Telenti et aI. (1997a) ahpC rpoB Telenti et al. (1993a,b, 1997a,b) Felmlee et aI. (1995); Whelen et aI. (1995) Selvakumar et aI. (1997); Kim et aI. (2001) embB Sreevatsan et aI. (1 997b) gyrA Takiff et aI. (1994); Delgado and Telenti (1996) rpoB Williams et aI. (1996, 1998b); Thomas et aI. (2001) katG Piatek et aI. (2000) rpoB Piatek et aI. (1998,2000); EI-Hajj et aI. (2001)

RMP

rpoB

RMP

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katG inhA ahpC rpoB

de Beenhouwer et aI. (1995); Rossau et aI. (1997) Bartfai et aI. (2001)

204

activity (Butler and Kilburn 1983). This occurs as a result of defined missense mutations within pncA which encodes this enzyme (Sreevatsan et al. 1997a; Ramaswamy and Musser 1998; Cockerill 1999).

Streptomycin. STR is an aminocyclitol glycoside antibiotic that appears to function by binding to the 16S rRNA of M. tuberculosis to inhibit translational initiation and detrimentally affects translation fidelity, which results in protein production termination (Douglass and Steyn 1993; Finken et al. 1993; Ramaswamy and Musser 1998; Cockerill 1999). Specific mutations within the 16S rRNA gene (rrs) and rpsi gene encoding the ribosomal protein S12 in M. tuberculosis are responsible for the development of resistance to this drug (Douglass and Steyn 1993; Finken et al. 1993; Sreevatsan et al. 1996; Ramaswamy and Musser 1998; Cockerill 1999). However, not all resistant isolates have mutations in these genes. Ethambutol. EMB ([ S,S']- 2,2'-[ethylenedimino]di-lbutanol) is a bactericidal drug that targets M. tuberculosis cell wall synthesis by inhibiting incorporation of mycolic acids into the cell wall (Takayama et al. 1979; Takayama and Kilburn 1989). This appears to be a function of three genes organized into an operon designated as embCAB (Telenti et al.1997b). Mutations in a single codon of emb are associated with the development of EMB resistance in M. tuberculosis (Telenti et al. 1997; Ramaswamy and Musser 1998; Cockerill 1999). Fluoroquinolones. Ciprofloxacin, ofloxacin, and levofloxacin are fluorinated derivatives of quinolones (FQs) (Hooper and Wolfson 1989) used primarily as second-line drugs in the treatment of drug-resistant tuberculosis (Cambau et al. 1994; Sullivan et al. 1995; Takiff et al.1994; Ramaswamy and Musser 1998). The target for this drug class is the DNA gyrase, an enzyme that catalyzes negative supercoiling of DNA (Hooper and Wolfson 1989). Specific missense mutations within the quinolone resistance-determining region (QRDR) of the gyrA, encoding the GyrA subunit of the gyrase, are responsible for the development of resistance in M. tuberculosis (Cambau et al. 1994; Sullivan et al. 1995; Takiff et al. 1994; Ramaswamy and Musser 1998).

D. L. Williams

has been used to develop a variety of rapid, PCR-based assays for the detection of drug-resistant M. tuberculosis directly from clinical specimens (Table 13.2). These assays are based on the specific genotypic identification of mutations associated with the drug-resistant phenotype within amplicons derived from drug target genes. Some of these assays include: direct PCR-DNA sequencing, PCR single-strand conformation polymorphism (SSCP), PCR heteroduplex formation analysis (PCR-HDA), PCR line probe assay (LiPA), and molecular beacon sequence analysis (Table 13.2).All of these assays can be performed on sputum specimens or clinical isolates within 24 h of sample acquisition, are highly specific and sensitive, and, therefore, have the capability to significantly reduce the time needed for determining drug resistance.

PCR-DNA Sequencing. Direct DNA sequencing of PCR amplicons is the most definitive method to detect mutations associated with drug resistance. This analysis can be performed in a well-equipped diagnostic laboratory and requires approximately 1-2 days to obtain results from clinical specimens. As a result, numerous PCR-DNA sequencing assays have been developed to identify M. tuberculosis (Kapur et al. 1995; Kirschner et al. 1993) and the presence of drug-resistant mutant strains (Table 13.2). These assays are based on PCR amplification of the respective target gene directly from crude celllysates of processed sputum specimens using oligonucleotide primers which flank these regions of the chromosome of M. tuberculosis, purification of the amplicons using commercial reagents, such as QIAquick PCR Purification Kit (QIAGEN, Valencia, CA, www.qiagen.com). and dideoxy DNA sequencing of the amplicons using either manual or automated DNA sequencing strategies. Figure 13.1 shows representative DNA electropherograms of a small fragment of the RRDR of RMp s and RMp R strains of M. tuberculosis obtained by automated DNA sequencing. In the resistant strain, a single missense mutation (TCG-"7TTG) in codon 531 is identified. This results in a substitution of a serine amino acid residue with a leucine residue in the ~-subunit of the RNA polymerase of this mutant and results in the development of highlevel RMP resistance (MIC >64 Ilg/ml) (Williams et al. 1998a).

13.4

PCR-SSCP. PCR single-strand conformation polymor-

Knowledge of the specific mechanisms that result in the development of antituberculosis drug resistance

phism analysis assays have been developed and used to detect drug-resistant mutants of M. tuberculosis directly from patient specimens or clinical isolates (Telenti et al. 1993a,b; Kim et al. 2001) (Table 13.2).

peR Detection of Drug Resistance

205

PCR and Diagnosis of Tuberculosis

This is accomplished using the same basic approach taken to produce PCR arnplicons for DNA sequencing for gene targets. These double-stranded amplicons are then dissociated into single strands by heat denaturation and separated very slowly by gel electrophoresis under stringently controlled temperature conditions. Gels are stained to observe ssDNA fragment mobility patterns called SSCP profiles. A schematic representation of the SSCP assay is shown in Fig. 13.2. DNA strands from a RMp R strain demonstrate a unique mobility pattern compared with RMPS, reflecting the change in nucleotide composition. Numerous studies have used this analysis to study drug resistance in M. tuberculosis (Table 13.2).

affect the mobility of the resultant DNA fragments (Fig. 13.3). Therefore, when the heteroduplexes are separated by gel electrophoresis on polyacrylamide gels and stained with ethidium bromide, unique heteroduplex profiles are observed for susceptible and resistant genotypes (Williams et al. 1998b). The PCR-UHG requires approximately 6 h to complete and uses precast minigels and a nonradioactive detection format.

RRDR rpoB PCR amplieon RMP,Strain

111111111111111 j --u'--

PCR-HDA. PCR heteroduplex assay is another gel electrophoresis-based assay which has been developed to detect simultaneously the presence of M. tuberculosis and its susceptibility to RMP directly from clinical isolates (Williams et al.1994). This assay has been modified to reduce the time taken and technical complexity and can be used directly on clinical specimens with the use of a universal heteroduplex generator (UHG) (Williams et al. 1996, 1998a). The UHG contains several base pair mismatches, insertions, and deletions within the RRDR region of M. tuberculosis rpoB (Williams et al. 1996). When the UHG is heat-denatured and slowly annealed to these denatured amplicons, it provides enhanced mutation detection. Enhanced mutation detection occurs because large areas of unmatched nucleotides (bubbles) in the newly formed duplexes greatly

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Fig. 13.2. Schematic representation of the PCR single-strand conformation polymorphism (PCR-SSCP) assay for detection of rifampin susceptibility of M. tuberculosis

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Fig. 13.3. Schematic representation of the PCR universal heteroduplex generator (PCR-UHG-Rif) assay for detection of rifampin susceptibility of M. tuberculosis

206

D. L. Williams

PCR-LiPA. The line probe assay is a PeR-based reverse hybridization assay that has been developed for the rapid detection of RMP susceptibility of M. tuberculosis (de Beenhouwer et al. 1995; Rossau et al. 1997). LiPA uses PCR to amplify the RRDR region of rpoB and, at the same time, label the fragment with biotin. Denatured PCR amplicons are hybridized with a set of DNA probes immobilized on a membrane strip at specific sites (Fig. 13.4). The immobilized probes are small DNA fragments that are either homologous with short segments of the RRDR of rpoB from a RMp s strain or contain mutations in the RRDR associated with RMp R M. tuberculosis mutants. The stringency of the hybridization reaction is designed so that the single-stranded PCR amplicons will bind only to probes with 100% sequence homology. The resultant hybrids are detected by immunoenzymatic staining, and the results are read visually. An example of LiPA for RMP susceptibility testing is shown in Fig. 13.4. The genotype of the test organism is determined by which lines test positive. Therefore, the presence or absence of a RMp R strain of M. tuberculosis can be determined from the pattern obtained. This assay is commercially available in certain areas of the world (Rossau et al. 1997).

probes contain homologous sequences to either the susceptible or resistant genotype. In addition, they contain a fluorophore on one end and a molecule that quenches fluorescence when it is in close proximity to a fluorophore on the other end. When no PCR amplicons are present, the probe remains in its hairpin shape, and the fluorescence is quenched. However, after these probes bind to their intended targets, they undergo a conformational change that restores thefiuorescence of the internally quenched fluorophore. Therefore, the more amplicons produced, the more fluorescence. The specificity for drug resistance detection is in the short sequence that binds to the amplicon. In summary, there are several PCR-based mutational detection assays to identify drug-resistant mutants of M. tuberculosis. These assays can be performed within days of specimen acquisition or isolation of strains from specimens and, therefore, can be useful for the early detection of drug-resistant tuberculosis. Early detection of drug-resistant tuberculosis can potentially improve patient care and reduce the transmission of drug-resistant tuberculosis by effective isolation of infected individuals.

Molecular Beacons. PCR molecular beacon sequence

13.5 Impact of PCR Diagnosis on Patient Care

analysis has been developed to detect mutations in the rpoB that are associated with RMP resistance (Piatek et al. 1998,2000; EI-Hajj et al. 2001) and INH resistance (Piatek et al. 2000) in M. tuberculosis. Molecular beacons are small hairpin-shaped DNA probes that report the presence of specific nucleic acids (Fig. 13.5). These

BiotioylatedRRDR rpoD PCR Amplicoo RMP.

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Because of the specificity of PCR assays for the detection of M. tuberculosis, a smear-positive, PCR-positive specimen would indicate that the acid-fast bacilli in the sputum of a particular patient are M. tuber-

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Fig. 13.4. Schematic representation of the PCR line probe assay (PCR-LiPA) for detection of rifampin susceptibility of M. tuberculosis

207

peR and Diagnosis of Tuberculosis

~+ Qumched Targd DNA Molecular Beaooo (ss AqJIicoo)

Fig. 13.5. Schematic representation of molecular beacon sequence analysis. The black circle represent the quenching molecule. The open circle represents the fluorophore

developed to monitor drug therapy (DesJardin et al. 1996; Hellyer et al. 1999a) and has been shown to be very useful for rapidly determining the efficacy of therapeutic regimens directly from sputum specimens (DesJardin et al.1996; Hellyer et al. 1999a,b).

13.6

Summary

culosis (Kaul 2001). Therefore, the patient should be appropriately retained in isolation and treated until their sputum becomes smear-negative. A PCR-negative specimen would indicate the presence of a nontuberculosis mycobacterial infection, and the patient could be released from isolation and treated more appropriately. In addition, because of the availability of PCR-based assays for the detection of mutations associated with antituberculosis drug resistance, a smear-positive, PCR-resistant specimen would indicate that this patient is also harboring drug-resistant tuberculosis. Therefore, the patient should be appropriately retained in isolation and treated with additional drug therapy until their sputum becomes smear-negative. The immediate impact on patient care, the reduction of transmission of tuberculosis, and cost of providing care is very apparent. Because of the high specificity of these assays, they cannot identify the presence of other mycobacteria in mixed infections. It is, therefore, recommended that PCR should be augmented by culture to determine if other nontuberculosis mycobacteria are present in specimens. This is especially important in areas of the world where HIV infection is highly endemic and other nontuberculosis mycobacteria present problems for the differential diagnosis of tuberculosis. Recently, newer multiplex PCR assays have been developed which can be used for the detection of M. tuberculosis complex and nontuberculous mycobacteria. These assays are currently being characterized for the identification of mixed infections (Ahmed 1999; Yeboah-Manu et al. 2001). Most M. tuberculosis PCR assays are based on the detection of DNA or ribosomal RNA targets. Although beneficial for the initial diagnosis, such assays have proven unsuitable for rapidly monitoring therapeutic efficacy owing to the persistence of these nucleic acid targets long after the conversion of smears and cultures to negative (DesJardin et al. 1998; Hellyer et al. 1999a). It has recently been ascertained that the presence of mRNA is a good indicator for determining the viability of M. tuberculosis from sputum specimens. Using mRNA, an assay has been

Methodologies developed over 30 years ago for the detection of tuberculosis and drug susceptibility testing are cumbersome and require protracted periods of time to obtain results. The resurgence of tuberculosis and drug-resistant tuberculosis has promoted the development of a number of new options for the rapid laboratory diagnosis of M. tuberculosis. One of the most promising and exciting methodologies has been the introduction of assays employing PCR amplification technology to detect M. tuberculosis directly from clinical specimens. PCR-based assays for the diagnosis of tuberculosis and identification of drug-resistant strains are configured to yield results in a few hours to days because these assays can detect the presence of M. tuberculosis and/or mutations present in its genome that are associated with the development of drug resistance directly from crude biological specimens. This represents a major step forward in the ability to rapidly identify tuberculosis patients and patients harboring drug-resistant tuberculosis. Therefore, the implementation of these assays has the potential to improve patient care and provide substantial savings in the overall cost of patient care compared with conventional smear, culture, and speciation alone. In addition, since rapid detection allows for the rapid isolation of tuberculosis patients, the nosocomial or environmental spread of tuberculosis and drug-resistant-tuberculosis to susceptible individuals will most likely be reduced. However, the major drawbacks for the implementation of many of these assays in clinical laboratories in developing countries are the cost of the reagents used and the need for expensive equipment and trained individuals to perform the analysis. This review has attempted to describe many of the current molecular aspects of the detection of tuberculosis using PCR, the modes of action, the resistance mechanisms of the major drugs used to treat tuberculosis, and the current molecular assays for detecting drug resistance in M. tuberculosis. Although amplification assays hold significant promise to improve the laboratory diagnosis of tuberculosis,

208

the decision to perform these assays is complicated because most assays have decreased sensitivity with specimens that are AFB smear-negative. In addition, many other factors, such as cost, assay performance, and technical difficulty must be considered in order to facilitate the decision-making process about whether an amplification assay would be appropriate in a particular laboratory setting. As nucleic acid-based tests evolve, it is anticipated that they will become cheaper and simpler to perform. This is extremely important in developing countries, where resources are limited, and tuberculosis is highly endemic and often complicated by HIV infection. Therefore, research continues to be conducted to automate and simplify sample preparation, amplification, and amplicon detection procedures, thus making them easier to implement in clinical laboratories within both developed and developing countries. This will assist tuberculosis control programs with their overall goals of providing better patient care, reducing the transmission of tuberculosis, and providing the capability to monitor trends in drug resistance at the regional and local levels.

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losis by automated DNA sequencing. Arch Pathol Lab Med 119:131-138 Kent L et al (1996) Demonstration of homology between IS6110 of Mycobacterium tuberculosis and DNAs of other Mycobacterium spp.? J Clin Microbiol 33:2290-2293 Kent P, Kubica G (1985) Public health mycobacteriology: a guide for the Level III laboratory. US Department of Health and Human Services, Public Heath Service, CDC, Atlanta, pp 31-56 Kim BJ et al (2001) Detection of rifampin-resistant Mycobacterium tuberculosis in sputa by nested PCR-linked singlestrand conformation polymorphism and DNA sequencing. J Clin MicrobioI39:2610-2617 Kirschner P et al (1993) Genotypic identification of mycobacteria by nucleic acid sequence determination: report of a 2-year experience in a clinical laboratory. J Clin Microbiol 31:2882-2889 Konno K, Feldmann FM, McDermott W (l967) Pyrazinamide susceptibility and amidase activity of tubercle bacilli. Am Rev Respir Dis 95:461-469 Marttila HJ et al (1996) katG mutations in isoniazid-resistant Mycobacterium tuberculosis isolates recovered from Finnish patients. Antimicrob Agents Chemother 40:2187-2189 Mitarai S et al (2001) Potential use of Amplicor PCR kit in diagnosing pulmonary tuberculosis from gastric aspirate. J Microbiol Methods 47:339-344 Moore M et al (1997) Trends in drug-resistant tuberculosis in the United States. J Am Med Assoc 278:833-837 Mulcahy GM et al (1996) IS611O-based PCR methods for the detection of Mycobacterium tuberculosis. J Clin Microbiol 34:1348-1349 Mullis KB, Faloona FA (l987) Specific synthesis of DNA in vitro via a polymerase-catalyzed chain reaction. Methods Enzymol 155:335-350 Musser JM (l995) Antimicrobial agent resistance in mycobacteria: molecular genetic insights. Clin Microbiol Rev 8:496-514 Musser JM et al (1996) Characterization of the catalase-peroxidase gene (katG) and inhA locus in isoniazid-resistant and -susceptible strains of Mycobacterium tuberculosis by automated DNA sequencing: restricted array of mutations associated with drug resistance. J Infect Dis 173: 196-202 Nachamkin I, Kang C, Weinstein MP (l997) Detection of resistance to isoniazid, rifampin, and streptomycin in clinical isolates of Mycobacterium tuberculosis by molecular methods. Clin Infect Dis 24:894-900 Nolte FS et al (1993) Direct detection of Mycobacterium tuberculosis in sputum by polymerase chain reaction and DNA hybridization. J Clin MicrobioI31:1777-1782 Oh EJ et al (2001) Improved detection and differentiation of mycobacteria with combination of Mycobacterium Growth Indicator Tube and Roche COBAS AMPLICORiZ> System in conjunction with Duplex PCR. J Microbiol Methods 46: 29-36 Otal I et al (1997) Use of a PCR method based on IS611 0 polymorphism for typing Mycobacterium tuberculosis strains from BACTEC cultures. J Clin Microbiol 35:273-277 Piatek AS et al (1998) Molecular beacon sequence analysis for detecting drug resistance in Mycobacterium tuberculosis. Nat BiotechnoI16:359-363 Piatek AS et al (2000) Genotypic analysis of Mycobacterium tuberculosis in two distinct populations using molecular

210 beacons: implications for rapid susceptibility testing. Antimicrob Agents Chemother 44:103-110 Plikaytis BB et al (1993) Rapid, amplification-based fingerprinting of Mycobacterium tuberculosis. J Gen Microbiol 139:1537-1542 Poa CC et al (1990) Direct detection and identification of Mycobacterium tuberculosis by DNA amplification. J Clin MicrobioI28:1877-1880 Ramaswamy S, Musser JM (1998) Molecular genetic basis of antimicrobial agent resistance in Mycobacterium tuberculosis: 1998 update. Tuberc Lung Dis 79:3-29 Rossau R et al (1997) Evaluation of the INNO-LiPA Rif. TB assay, a reverse hybridization assay for the simultaneous detection of Mycobacterium tuberculosis complex and its resistance to rifampin. Antimicrob Agents Chemother 41:2093-2098 Rouse DA et al (1995) Characterization of the katG and inhA genes of isoniazid-resistant clinical isolates of Mycobacterium tuberculosis. Antimicrob Agents Chemother 39: 2472-2477 Selvakumar N et al (1997) Single strand conformation polymorphism profiles with biotinylated PCR products to detect mutation in rpoB gene of Mycobacterium tuberculosis. Curr Sci 73:774-777 Shalwar R et al (1993) Detection of Mycobacterium tuberculosis in clinical samples by amplification of DNA. J Clin MicrobioI29:712-717 Shah J et al (1995) Q-beta replicase-amplified assay for detection of Mycobacterium tuberculosis directly from clinical specimens. J Clin MicrobioI33:1435-1441 Shinnick TM, Jonas V (1994) Molecular approaches to the diagnosis of tuberculosis. In: Bloom B (ed) Tuberculosis: pathogenesis, protection and control. American Society for Microbiology Press, Washington DC, pp 517-530 Soini H et al (1992) Detection and identification of mycobacteria by amplification of a segment of the gene coding for the 32-kilodalton protein. J Clin MicrobioI30:2025-2028 Soini H et al (1996) Comparison of AMPLICOR® and 32-kilodalton PCR for detection of Mycobacterium tuberculosis from sputum specimens. J Clin MicrobioI34:1829-1830 Sougakoff W et al (1997) Nonradioactive single-strand conformation polymorphism analysis for detection of fluoroquinolone resistance in mycobacteria. Eur J Clin Microbiol Infect Dis 16:395-398 Southern EM (1975) Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Bioi 98:503-517 Sreevatsan S et al (1996) Characterization of rpsL and rrs mutations in streptomycin-resistant Mycobacterium tuberculosis isolates from diverse geographical localities. Antimicrob Agents Chemother 40:1024-1 026 Sreevatsan S et al (1997a) Mutations associated by pyrazinamide resistance in pncA of Mycobacterium tuberculosis complex organisms. Antimicrob Agents Chemother 41:636-640 Sreevatsan S et al (1997b) Ethambutol resistance in mycobacterium tuberculosis: critical role of embB mutations. Antimicrob Agents Chemother 41:1677-1681 Sreevatsan S et al. (1997c) Analysis of the oxyR-ahpC region in isoniazid-resistant and -susceptible Mycobacterium tuberculosis complex organisms recovered from diseased humans and animals in diverse localities. Antimicrob Agents Chemother 41:600-606 Stratton MA, Reed MT (1986) Short-course drug therapy for tuberculosis. Clin Pharm 5:977-987

D. 1. Williams Sullivan EA et al (1995) Emergence of fluoroquinolone-resistant tuberculosis in New York City. Lancet 345:1148-1150 Takayama K, Kilburn JO (1989) Inhibition of synthesis of arabinogalactan by ethambutol in Mycobacterium smegmatis. Antimicrob Agents Chemother 33:1493-1499 Takayama K et al (1979) Inhibition by ethambutol of mycolic acid transfer into the cell wall of Mycobacterium smegmatis. Antimicrob Agents Chemother 16:240-242 Takiff HE et al (1994) Cloning and nucleotide sequence of Mycobacterium tuberculosis gyrA and gyrB genes and detection of quinolone resistance mutations. Antimicrob Agents Chemother 38:773-780 Telenti A et al (1993a) Detection of rifampin-resistance mutations in Mycobacterium tuberculosis. Lancet 341:647-650 Telenti Aet al (1993b) Direct, automated detection of rifampinresistant Mycobacterium tuberculosis by polymerase chain reaction and single-strand conformation polymorphism analysis. Antimicrob Agents Chemother 37:2054-2058 Telenti A et al (1997a) Genotypic assessment of isoniazid and rifampin resistance in Mycobacterium tuberculosis: a blind study at reference laboratory level. J Clin Microbiol 35:719-723 Telenti A et al (1997b) The emb operon, a gene cluster of Mycobacterium tuberculosis involved in resistance to ethambutol. Nat Med 3:567-570 Temesgen Z et al (1997) Use of polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) analysis to detect a point mutation in the catalase-peroxidase gene (katG) of Mycobacterium tuberculosis. Mol Cell Probes 11 :59-63 Thierry D et al (1990) IS6110, an IS-like element of Mycobacterium tuberculosis complex. Nucleic Acids Res 18:188 Thomas GA, Williams DL, Soper SA (2001) Capillary electrophoresis-based heteroduplex analysis with a universal heteroduplex generator for detection of point mutations associated with rifampin resistance in tuberculosis. Clin Chern 47:1195-1203 van Embden JD et al (1993) Strain identification of Mycobacterium tuberculosis by DNA fingerprinting: recommendations for a standardized methodology. J Clin Microbiol 31: 406-409 van Soolingen D et al (1994) DNA fingerprinting of Mycobacterium tuberculosis. Methods EnzymoI235:196-205 Victor TC et al (1996) katG mutations in isoniazid-resistant strains of Mycobacterium tuberculosis are not infrequent. Antimicrob Agents Chemother 40:1572 Walker GT et al (1992) Strand displacement amplification-an isothermal, in vitro DNA amplification technique. Nucleic Acids Res 20:1691-1696 Whelen A et al (1995) Direct genotypic detection of Mycobacterium tuberculosis rifampin resistance in clinical specimens by using single-tube heminested PCR. J Clin Microbiol 33:556-561 Williams DL et al (1994) Characterization of rifampin resistance in pathogenic mycobacteria. Antimicrob Agents Chemother 38:2380-2386 Williams DL, Gillis TP, Dupree WG (1995) Ethanol fixation of sputum sediments for DNA-based detection of Mycobacterium tuberculosis. J Clin MicrobioI33:1558-1561 Williams DL et al (1996) PCR-heteroduplex detection of rifampin-resistant Mycobacterium tuberculosis. In: Persing D (ed) PCR protocols for emerging infectious diseases. ASM Press, Washington DC, pp 122-129

PCR and Diagnosis of Tuberculosis Williams DL et al (l998a) Contribution of rpoR mutations to development of rifamycin cross-resistance in Mycobacterium tuberculosis. Antimicrob Agents Chemother 42:1853-1857 Williams DL et al (l998b) Evaluation of a polymerase chain reaction-based universal heteroduplex generator assay for direct detection of rifampin-susceptibility of Mycobacterium tuberculosis directly from sputum specimens. Clin Infect Dis 26:446-450 Winder FG, Collins PB, Whelan D (1971) Effects of ethionamide and isoxyl on mycolic acid synthesis in Mycobacterium tuberculosis BCG. J Gen MicrobioI66:379-380 Winder FG (1982) Mode of action of the antimycobacterial

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agents and associated aspects of the molecular biology of the mycobacteria. In: Ratledge C, Stanford J (eds) The biology of the mycobacteria, vol 1. Academic Press, London, pp 353-438 Woods GL (2001) Molecular techniques in mycobacterial detection. Arch Pathol Lab Med 125:122-126 Yeboah-Manu D, Yates MD, Wilson SM (2001) Application of a simple multiplex PCR to aid in routine work of the mycobacterium reference laboratory. J Clin MicrobioI39:4166-4168 Zhang Y et al (1992) The catalase-peroxidase gene and isoniazid resistance of Mycobacterium tuberculosis. Nature 358:591-593

14 Hematologic Findings in Mycobacterial Infections Among Immunosuppressed and Immunocompetent Patients GORGUN AKPEK

CONTENTS 14.1

Introduction

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14.1.1 Mycobacterium Tuberculosis 214 14.2 14.2.1 14.2.2 14.2.3 14.2.4 14.2.5 14.2.6 14.2.7 14.3

14.3.1

14.3.2 14.3.3 14.3.4 14.3.5 14.3.6 14.3.7 14.3.8 14.3.9 14.4 14.4.1 14.4.2 14.4.3 14.5

Hematologic Findings in Tuberculosis 215 Anemia 216 White Blood Cell Abnormalities 216 Thrombocytopenia 216 Pancytopenia 216 Possible Mechanisms of Hematologic Findings in Tuberculosis 217 Prognostic Significance of Hematologic Abnormalities. 219 Tuberculosis-Induced Lymphopenia and Immunosuppression 219 Hematologic Abnormalities Associated with Mycobacterial Infections in Imrnunocompromised Hosts 220 Hematologic Complications of HIV Infection and AIDS 220 Mycobacterium avium Complex in HIV-Infected Patients 220 Anemia Associated with MAC in HIV-Infected Patients 220 Other Cytopenias Associated with MAC in HIV-Infected Patients 222 MAC Infections in Other Immunocompromised Hosts 222 Hemophagocytic Syndrome Associated with MAC 223 Miliary/Disseminated Tuberculosis in AIDS 223 Diagnostic Yield of Bone Marrow Aspiration/Biopsy for Mycobacterial Infections in Patients with HIV Infection 224 Other Mycobacterial Infections Associated with Hematologic Disorders 226 Coagulation Abnormalities Associated with Mycobacterial Infections and Clinical Presentations 226 Disseminated Intravascular Coagulation 226 Deep Vein Thrombosis Associated with Tuberculosis 226 Thrombotic Thrombocytopenic Purpura Associated with Mycobacterial Infections 227 Conclusion 227 References 227

G.AKPEK,MD Greenebaum Cancer Center at University of Maryland School of Medicine, 22 South Greene Street, Baltimore MD 21201, USA

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

14.1 Introduction The relationship between hematologic abnormalities and mycobacterial infections dates back to the beginning of the 20th century. Flinn and his colleagues suggested at that time that the change in hematologic parameters is the earliest finding of tuberculosis (TB) (Flinn and Finn 1929). The authors said,'In connection with the above studies we have formed the impression that an extension of the pathologic process in a tuberculosis lung usually manifests itself first in the blood picture, later by physical signs and x-ray, and often last of all by symptoms: Before embarking upon a general discussion of hematologic manifestations of mycobacterial infections, I would like to present two cases that were previously discussed at the Medical Staff Conference in the University of San Francisco, California, USA, in 1967. These cases have certain features of the history and clinical findings of TB, in particular, the striking difference in the hematological manifestations between the two cases. A brief summary about the demographics and clinical presentation of Mycobacterium TB infection is included thereafter.

Case 1. The first patient is a 50-year-old white man who came in for evaluation of a fever of about 7 months' duration. His symptoms began with multiple episodes of severe pain in the left upper quadrant of the abdomen and nausea. These symptoms were followed in a few days by fever and generalized malaise. According to the patient's description, the febrile episodes would last for approximately 1 week and recurred at approximately 4-week intervals with temperatures in the range of 38.3°C-40.6°C (lOI°F105°F). He was noted to have axillary and inguinal adenopathy 2 months later when seen by a physician because of persistent symptoms. Laboratory data included hemoglobin of 12.2 gm/dl, markedly elevated erythrocyte sedimentation rate, increased concentration of serum gammaglobulin, and a positive tuberculin test. Two months later, the patient underwent surgery for the repair of an incarcer-

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ated incisional hernia. An exploratory laparotomy performed at that time revealed no intraabdominal pathology. Two months later, the patient's fever recurred and was associated with night sweats and 13 pounds (6 kg) of weight loss since the onset of his symptoms. At that time no history could be obtained of cough, pleuritic chest pain, hemoptysis, or production of sputum. The family history was negative. The patient had been a heavy smoker for 20 years. On physical examination, the only abnormalities were slight adenopathy in the inguinal and axillary regions, hepatomegaly, and questionable splenomegaly. Body temperature was 38.3°C (101°F). Hemoglobin content was 8.7 g/dl, WBC of 3400/mm3, with 30% neutrophils, 65% lymphocytes, 3% monocytes, and 2% basophils. The platelet count was 301,000/mm 3, with reticulocytes forming 2.1 % of the total. Additional hematologic data included normal haptoglobulin, leukocyte alkaline phosphatase, coagulation parameters, and serum iron and iron-binding capacity. The bone marrow at that time showed generalized hyperplasia, predominantly of the erythroid series. Skin test was positive with PPD. A chest X-ray showed fibrocalcific densities. There was no active pulmonary disease, but there was evidence of old granulomatous disease. There were granulomas in the right upper lung field and some scattered granulomas in the right mid-lung field. All other work-up for fever of unknown origin was negative. A scalene lymph node biopsy showed multiple confluent and epithelioid caseous granulomas. The patient improved on an anti-TB regimen. Cultures of the scalene lymph node specimen grew acid-fast organisms.

Case 2. The second patient is a 62-year-old man with a chief complaint of tenderness in the left upper quadrant of the abdomen, with weight loss and weakness of 5 months' duration. A mass in the left upper quadrant was noted on routine physical examination. Four months later, the patient first noticed anorexia, weight loss, and weakness. Three months later, he developed anemia and was admitted to the hospital. The patient has had regular chest X-rays taken every 6 months for the past 2 years. These films have shown stable apical infiltrates. He was also known to have a positive PPD skin test. He had been a heavy smoker for the past 45 years; he has had chronic nonproductive cough and a history of acute upper gastrointestinal bleeding, which responded to medical management. On physical examination, the patient was pale and cachectic. Body temperature was 38°C (101 OF). He had several small lymphadenopathies. Lung expansion was decreased bilaterally, and the anteroposterior diam-

G.Akpek

eter of the chest was increased. There was dullness and increased fremitus on the right. Peristaltic movement was visible beneath a thin abdominal wall. The spleen, which was large and rock-hard, extended 8 cm below the left costal margin, and there was a tender nodule, 2x3 cm, at the anterior margin. The liver edge was felt 4 cm below the right costal margin. It was not tender and firm. Early clubbing of the fingers and severe muscular wasting of the extremities were noted. Leukocyte numbered 16,000/mm3 , with 60% neutrophils, many immature myeloid cells, 10% basophils, and 10% eosinophils. Hematocrit was 19%, reticulocyte count 2.5% of the total, and platelet count 80,000/mm 3• Normoblasts were present in the peripheral blood. Xray examination revealed dense bones. Patchy apical infiltrates, which had increased since the previous examination, were noted on chest X-ray. There was a large right pleural effusion. A skin test with PPD was positive. Thoracentesis and pleural biopsy were performed. The latter revealed caseating granulomas. No intrabronchiallesions were seen at bronchoscopy. A bone biopsy was performed since three previous marrow taps had been dry. The bone biopsy revealed sclerotic bone and myelofibrosis. Triple anti-TB therapy was begun. Subsequently, cultures of both sputum and pleural fluid grew acid-fast bacilli.

14.1.1

Mycobacterium Tuberculosis Currently, more than one-third of the world's population is infected with Mycobacterium TB: 8 million new cases and approximately 2 million deaths are reported each year (Dye et al. 1999). Although the lung is the primary site of disease in 80%-84% of cases of TB in the USA (Center for Disease Control and Prevention 2000), extrapulmonary TB has become more common with the advent of HIV infection, and the risk of TB increases as the immunosuppression progresses (Moore et al.1997; Jones et al.1993; Iseman 2000). The most common extrapulmonary sites of disease are the lymph nodes, pleura, and bones or joints (Center for Disease Control and Prevention 2000). Lymphatic TB is usually seen in children and young adults; more commonly in women (especially Asian and Indian women). It presents with unilateral, painless, cervical adenopathy, which is connected to the skin by sinus tracts late in the course of disease. Excisional biopsy with culture yields the diagnosis of TB lymphadenitis. PPD is usually positive. It may respond slowly to medication and rarely may require excision (Mandel et al. 2000).

Hematologic Findings in Mycobacterial Infections Among Immunosuppressed and Immunocompetent Patients

Clinical presentations ofTB have changed dramatically since the introduction of anti-TB agents. In the pre-antibiotic era, late generalized TB was often the primary disease, occurring mainly in young adults and frequently associated with pulmonary symptoms. In the antibiotic era, TB commonly occurs together with and is frequently obscured by other diseases. It often afflicts the elderly and is much less frequently accompanied by pulmonary symptoms (Slavin et al. 1980). Disseminated TB involving the lung, liver, spleen, bone marrow, and lymph nodes can occur occasionally in an immunocompetent host and is usually associated with hematologic abnormalities and poor outcome (Charfi et al.1998). Splenomegaly associated with fever is another clinical sign of disseminated TB (O'Reilly 1998). The histologic appearance in this rare form of disseminated hematogenous TB (nonreactive TB) shows nonspecific necrosis containing disintegrating polymorphonuclear leukocytes and enormous numbers of tubercle bacilli (O'Brien 1954). In a typical case, granulomas and epithelioid cells are lacking, although intermediate cases have areas more typical for T8. The gross pathologic findings are minute soft abscesses up to 1 cm, which always involve the liver and spleen, usually the marrow, commonly the lungs and kidneys, but almost never the meninges. The clinical picture may be overwhelming sepsis, with splenomegaly and often an inconspicuous diffuse mottling on the chest X-ray. Major hematologic abnormalities are common. Whether the lesions are typical or not, it is necessary to have bacteriologic confirmation of TB. Near these lesions, the bone marrow cellularity is often raised or lowered, reticular fibers are often increased, and sometimes reticulin fibrosis is marked (Tulliez 1976). In the following sections, common types of mycobacterial infections that are associated with various hematologic findings are discussed.

14.2 Hematologic Findings in Tuberculosis While most patients with TB do not manifest major hematologic abnormalities, some patients with late generalized or chronic hematogenous TB and most with nonreactive TB have serious hematologic abnormalities, including leukopenia, thrombocytopenia, anemia, leukemoid reactions, myelofibrosis, and polycythemia (Cameron 1974). Leukemoid reactions may suggest acute leukemia, although most patients in whom hematogenous TB coexists with the clinical picture ofleukemia have both diseases. Slavin and his

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colleagues reviewed the medical records of a community-based university teaching hospital over a lO-year period (1978 to 1987) to determine the clinical and laboratory characteristics, diagnostic methods, and prognostic variables in adults treated for miliary TB in the rifampicin era. They identified a total of 109 patients including 12 who did not have miliary nodules on the chest X-ray (all of whom were shown to have hematogenous dissemination). Hematologic abnormalities were common: leukopenia (less than 4xlO(9)/I) was present in 16 of 107 patients (15%), thrombocytopenia (less than 150x10(9)/L) in 24 of 104 (23%), and lymphopenia (less than 1.5X10(9)/L) in 82 of 94 (87%). Pancytopenia was found in 6 patients, 3 of whom recovered. Disseminated intravascular coagulation occurred in 4 patients, all of whom died (Slavin et al. 1980). In a recent study, investigators from India compared peripheral blood and bone marrow findings in patients with disseminated/miliary TB (DTB/MTB) as well as pulmonary TB (PTB) (Singh et al. 2001). They also assessed the effect of anti-TB therapy on the occurrence of hematologic abnormalities. Thirty-two patients with DTB/MTB and 23 patients with PTB were prospectively studied. All patients received standard anti-TB treatment. They were subjected to a hemogram including a peripheral blood examination, which was repeated on completion of the anti-TB therapy. Bone marrow aspiration and biopsy were also done in all patients before starting the treatment. Normocytic normochromic anemia was the most common abnormality observed in all groups and subgroups (DTB/MTB 84%, PTB 86%). Other hematological abnormalities of the white blood cells include leukopenia (DTB/MTB 25%, PTB 0%; p<0.02), neutropenia (DTB/MTB 22%, PTB 0%; p<0.04), lymphocytopenia, monocytopenia, leukocytosis, neutrophilia, lymphocytosis, and monocytosis. Pancytopenia was observed only in patients with DTB/MTB (p<0.05). Thrombocytopenia was more common in patients with DTB/MTB (p<0.007), whereas thrombocytosis was more common in patients with PTB (p
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G.Akpek

14.2.1 Anemia

even be the presenting feature of the latter form (Perez et al. 1998; Ghobrial and Albornoz 2001). When thrombocytopenia occurs in TB, it does so Severe anemia was quite rare in a large series of most commonly via nonimmunologic mechanisms, patients with pulmonary TB, occurring in less typically manifesting in the context of pancytopenia than 20%. It is, however, quite common and occurs that develops secondary to granulomatous infiltrain 60%-80% of patients with disseminated TB. tion of the bone marrow. However, thrombocytopeTherefore, severe anemia is the rule in advanced TB nia and possibly other hematologic complications (Mandell 2000). Normocytic, normochromic anemia associated with TB can be immune-mediated. In a (hemoglobin<10 gm/dl) and unexplained fever recent case report, a 49-year-old man who presented should raise the suspicion of disseminated TB. with immune thrombocytopenic purpura (ITP) and disseminated TB was described. In that particular case, the hematological and infectious abnormali14.2.2 ties, which did not respond to high-dose intravenous White Blood Cell Abnormalities corticosteroids and immunoglobulin, resolved after anti-TB treatment (Ghobrial and Albornoz 2001). An Leukopenia, leukocytosis, and lymphocytosis are immune basis for TB-induced ITP was also supported relatively uncommon in TB. The white blood cell by the presence of either platelet antigen-specific count is usually normal but may be between 10,000 antibodies or platelet surface membrane IgG in two and 15,000 cells/mm3 in miliary TB (Mandell 2000). studies (Jurak et al. 1983; Boots et al. 1992). In the Monocytosis is seen in less than 10% of patients. previous report, thrombocytopenia associated with The presence or absence of monocytosis used to be TB developing concurrently in a mother and son considered a prognostic marker for the clinical course was described. Antiplatelet antibodies were demonand outcome of patients with tuberculosis (Medical strated in the serum of both mother and son (Jurak Staff Conference 1967). A rising lymphocyte count et al. 1983). Thrombocytopenia and hyponatremia and falling monocyte count could be signs of a poor associated with miliary TB have also been described prognosis, and a rising monocyte count a sign of a (Cockcroft et al. 1976). good prognosis. However, this concept has never been There are other case reports in which patients with proved. Eosinophilia occurs in about 15% of patients disseminated TB presented with clinical and laboraand is more common in pulmonary TB than in extra- tory features of ITP (Talbot et al. 1998; Hernandezpulmonary TB. Maraver et al. 1996; al-Majed et al. 1995; Yasuda et al. Leukemoid reactions are extremely rare, occur- 1994; Pavithran and Vijayalakeshmi 1993; Singh et al. ring in less than 3% of patients with disseminated 1986; Chia and Machin 1979; Levy and Cooper 1964). TB. The peripheral blood findings and the clinical The majority of reported patients with TB and ITP features may be exactly the same as those of chronic were women of Middle Eastern and Asian descent. myelogenous leukemia or, rarely, acute myeloblastic Although TB-related ITP was distributed across all leukemia. Tuberculous leukemoid reactions and leu- age groups, it occurred most commonly between kemia may be differentiated by cytogenetic studies, the 3rd and 8th decades of life. Pulmonary TB repwhich in the case ofleukemia will reveal an abnormal resented the most common clinical presentation, karyotype pattern. In patients in whom TB is associ- having occurred in 33% of patients, followed by disated with the hematologic picture of acute leukemia, seminated TB and lymphadenitis at 19% each. Some it is likely that both diseases are present and that TB 81 % and 35% of patients presented with a platelet is complicating acute leukemia. The documented count less than 20x109II and 5X109/l, respectively. instances of TB producing the entire disease picture The highest platelet counts at presentation were seen of acute leukemia are extremely rare. in 3 of the 4 patients with TB lymphadenitis.

14.2.3 Thrombocytopenia

14.2.4 Pancytopenia

Thrombocytopenia is very rare in pulmonary TB. However, it is a relatively common feature of disseminated or miliary TB. Thrombocytopenia can

TB may be associated with pancytopenia and aplastic anemia. Disseminated TB should be considered when pancytopenia is associated with fever and weight loss

Hematologic Findings in Mycobacterial Infections Among Immunosuppressed and Immunocompetent Patients

or as a cause of other obscure hematologic disorders. Medd and Hayhoe described a disease called TB miliary necrosis with pancytopenia (Medd and Hayhoe 1955). This disorder had rather distinctive pathologic features with widespread miliary necrosis and very little tissue reaction. Clinical symptoms include a high, spiking fever which is called the 'typhoidal variant' of TB. Leukopenia and splenomegaly are present. This is a rare disease, but it is important to be aware of its existence and to differentiate it from aplastic anemia of other causes. The clue to the diagnosis is splenomegaly, which is not consistent with typical aplastic anemia. Pancytopenia can be due to hemophagocytic syndrome, an unusual hematologic manifestation of TB (Basu et al. 2000). TB-associated hemophagocytic syndrome was also reported in a hemodialysis patient who presented with fever of unknown origin, anorexia, weight loss, hepatomegaly, and pancytopenia (Yang et al. 1996). Bone marrow biopsy revealed marked hemophagocytosis and granuloma formation with positive staining for acid-fast bacilli. The patient expired shortly after making the diagnosis. Despite its high mortality, disseminated TB in association with pancytopenia may occasionally respond to anti-TB chemotherapy with bacteriologic cure of TB and concomitant resolution of the pancytopenia. Disseminated intravascular coagulopathy can be accompanied by pancytopenia in some of these patients (Rosenberg and Rumans 1978).

14.2.5 Possible Mechanisms of Hematologic Findings in Tuberculosis There are five possible explanations for hematologic abnormalities seen during the course of TB: 1. The first possibility is that the association of a blood disorder and TB may be purely coincidental. 2. The second possibility is that the blood disorder favors the development of TB, although this is relatively rare. TB is one of the infections commonly found in patients with hematologic disorders, particularly in those whose immunologic defense mechanisms have been further compromised by chemotherapy. 3. The third explanation is that treatment of blood disorders results in increased susceptibility to TB. Patients are treated with corticosteroids and alkylating agents, which may suppress the normal immune responses and impair the host defense. In patients with hematologic disorders, cellular

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immunity may be suppressed by the disease itself or by treatment with corticosteroids, immunosuppressants, or anticancer agents. Miliary TB developing in such compromised hosts is cryptic, and thus its diagnosis is difficult to make. Missing the diagnosis of miliary TB is a growing problem and demands special attention. In the years 1964 to 1974,37 patients with active TB were misdiagnosed in the Chaim Sheba Medical Center. The diagnosis was made only after death. Twentyone patients were over 60 years old. Eleven had hematological disorders (Rosenthal et al. 1975). Miliary TB is fatal if it cannot be detected in time. Therefore, the possibility of mycobacterial infection should always be kept in mind when treating patients with hematologic disorders. Consequently, early suspicion and diagnosis of systemic TB may be important. Unexplained pyrexia is the most common symptom of systemic TB (Uetake et al. 1990). Because of the poor prognosis of patients with mycobacterial infection and primary hematologic disorders, prophylactic antiTB medication may be considered when treating patients with hematologic disorders in areas endemic for TB (Morii and Narita 1998). 4. The fourth possibility is that TB is associated with the blood disease. The most common hematologic abnormality that is associated with TB is cytopenia. There are three possible ways in which TB could cause a reduction in circulating blood cells: a. As with any chronic infection, there may be a suppression of normal hematopoiesis. Chronic infections are the major causes of anemia of chronic disease. In association with the latter there is usually low serum iron and iron-binding capacity. The plasma iron turnover rate is rapid, but there is poor utilization of iron for erythropoiesis. It is likely that suppression of erythropoiesis in TB is partly due to increased cytokine release (TNF-a, tumor necrosis factoralpha) that is the major mechanism in anemia of chronic disease (Dallalio et al. 1999). b. TB can produce hypersplenism, and this might be a second cause of cytopenia. It essentially involves increased sequestration because of the large spleen. c. There is actual replacement of the marrow with tubercles and the associated fibrotic reaction. Occasionally, TB may produce changes in the blood that are difficult to distinguish from the underlying hematologic disease. In several large series of patients with TB, approximately 8%-10%

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were found to have associated primary blood disorders (Oswald 1963; Glasser et al.1970). Corr and his colleagues, in reviewing 364 patients with all types of TB, found that 17% had anemia, 3% had leukocytosis, and 1% had leukopenia. They found only one patient with immature granulocytes in the blood, a patient with metastatic carcinoma. They also described 6 patients who had primary hematologic disorders with superimposed TB (Corr et al. 1964). In the old days, patients who had leukemic blasts in the blood and bone marrow were given antiTB drugs, and all of them died during the initial acute illness without improvement of the hematologic picture. But since autopsy failed to reveal widespread leukemic infiltrates, leukemia was not believed to be present, and the blasts in the blood were considered to be a response to TB. However, subsequent epidemiologic studies failed to prove this concept. Some of these findings are undoubtedly secondary to the TB. In some cases, however, there is an underlying hematologic disease such as leukemia and aplastic anemia. Glasser et al. in their review suggest that anemia, leukopenia, monocytosis, and granulocytic leukocytosis certainly represent hematologic responses to TB, for they disappear following successful treatment with anti-TB drugs. But the 'leukemic' blood picture or pancytopenia does not resolve, and these patients almost invariably die after very brief illnesses (Glasser et al. 1970). Based on these observations, patients with TB who have blast cells in the peripheral blood and bone marrow also have leukemia and, therefore, merit consideration of anti-leukemic therapy in addition to treatment of TB. Similarly, there is no strong evidence that TB causes a reversible pancytopenia. Such patients, even with anti-TB therapy, invariably die in a relatively short time. However, several case reports suggest that treatment of TB rarely restores the blood picture to normal. This is important in the prognosis of these diseases. For example, the diagnosis of refractory anemia with excess blasts, a subtype of myelodysplastic syndrome, was made based upon morphological and cytogenetic criteria (del 20q) in a patient with TB lymphadenitis. Hematological parameters remained stable without any specific treatment for several months, cell counts even normalized under anti-TB therapy (Ugo et al. 1996). In another case report, large granular lymphocytosis associated with pulmonary TB was described. Anti-TB therapy was started, and

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soon after the clinical symptoms and pancytopenia improved, and 1 year later, the hematological abnormalities had disappeared (Otsuji et al. 1990). TB may occur in the setting of all myeloproliferative disorders. More than 100 patients with pulmonary TB and polycythemia vera have been reported. The association was sufficiently frequent that in the old days, the physicians considered that the lipids of the tubercle bacilli might have erythropoietic activity. Of all the myeloproliferative syndromes, it is myelofibrosis and myeloid metaplasia that have the most intriguing association with TB. There are a number of reasonably documented cases in which the myeloid metaplasia followed the onset of TB. The second case presented at the beginning of this chapter is an example of this. However, the mechanism of this association between the two diseases remained speculative. Karel Pelger described an abnormality of granulocyte nuclear segmentation in the context of advanced TB. It is now recognized that the Pelger-Huet nuclear anomaly (PHNA) can be either hereditary or acquired with systemic diseases, commonly hematologic dysplasias. A male patient presenting with cachexia, high fever, severe hypoproliferative anemia, and acquired PHNA was described. At autopsy, an overwhelming TB was discovered in the absence of any other underlying disease (Shenkenberg et al. 1982). Based on the above observations, the following guidelines in the approach to the association of TB and hematological disorders can be used. First, that the possibility of TB exists in any case of myelofibrosis and myeloid metaplasia, aplastic anemia, or atypical or poorly characterized blood disorder. In such a setting, one must make a rigorous search for acid-fast organisms by cultures of gastric aspirates, sputum, BAL, bone marrow, blood, and urine. In addition, the physicians may be forced to consider biopsy of an enlarged lymph node or, failing this, a 'blind' biopsy of the scalenus anticus node. This last procedure yielded the diagnosis in the first case presented at the beginning of this chapter. Molecular diagnostic methods such as polymerase chain reaction analysis should be utilized to diagnose TB in clinically suspicious cases when the standard methods fail to identify TB. 5. Finally, anti-TB drugs can cause hematologic abnormalities. These drugs may all individually or collectively produce pancytopenia or decrease individual blood elements. Anti-TB medications can cause hematologic side-effects, and the inci-

Hematologic Findings in Mycobacterial Infections Among Immunosuppressed and Immunocompetent Patients

dence of hematologic abnormality appears to be associated with the degree of immunosuppression (Kavesh et al. 1989). Leukopenia is the most common side-effect of anti-TB drugs. Anti-TB drugs may cause idiosyncratic reactions, malabsorption, interference with iron metabolism, and hemolysis in patients with red blood cell enzyme deficiencies. Idiosyncratic reactions manifested by depression of any or all of the three cellular blood elements may be caused by any of the anti-TB drugs. Para-aminosalicylic acid (PAS) and streptomycin are the drugs most often responsible (Whitfield 1970). In patients who have red blood cells deficient in enzymes such as glucose 6-phosphate dehydrogenase, oxidizing agents such as PAS may cause hemolytic anemia (Whitfield 1970). Evidence of small-bowel intestinal malabsorption was found in 36% of 14 patients studied who were taking PAS for TB (Akhtar et al. 1968). In another study of 68 patients taking PAS, approximately 90% had subnormal blood folic acid levels, in contrast to 35% of a control group of similar patients (Roberts et al. 1966). Both serum and stainable bone marrow iron levels are commonly elevated in patients taking isoniazid (INH) for 6 months. Sideroblastic anemia has also been reported in patients receiving INH therapy. This is likely to be related to interference with pyridoxine metabolism by INH (Whitfield 1970). Hematologic abnormalities developed in 4 of 814 patients (0.5%) with pulmonary TB who were treated for 9 months with INH and rifampicin, daily for 1 month and twice weekly for the other 8 months, between January 1976 and June 1981. Given the infrequency of hematologic side-effects, only clinical surveillance for toxicity was recommended (Dutt et al. 1983) for patients receiving anti-TB medication. Perhaps a complete blood count should be added to the liver function studies that are evaluated during the course of TB therapy.

14.2.6 Prognostic Significance of Hematologic Abnormalities Some of the hematologic manifestations of TB are predictive for the prognosis. In a recent study, the extent and severity of hematological abnormalities in 380 patients with pulmonary TB were evaluated. Full blood count, bone marrow aspiration smears, and bone marrow biopsy were performed. There was a

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close correlation between the hematologic abnormalities and the severity of clinical findings of pulmonary TB. This survey revealed that hematologic abnormalities are relatively common in severe pulmonary TB. Body weight loss, white blood cell count, hemoglobin level, and erythrocyte sedimentation rate appeared to be useful indices for the severity of TB. The return of these indices to a normal level may indicate disease control correlating with sputum conversion to acidfast bacilli negative status (Bozoky et al. 1997). In a retrospective cohort study, 26 patients (24%) died of miliary TB a median of 6 days after starting treatment. Survivors were followed up for a median of 51 weeks. Stepwise logistic regression identified age greater than 60 years, lymphopenia, thrombocytopenia, hypoalbuminemia, elevated transaminase levels, and treatment delay as independent predictors of mortality (Maartens et al. 1990).

14.2.7 Tuberculosis-Induced Lymphopenia and Immunosuppression TB is clearly responsible in some patients for CD4 cell lymphocytopenia that reverses with treatment (Onwubalili et al. 1987; Turett and Telzak 1994). Many HIV-negative patients with active TB have CD4 cell counts much lower than 500 cells/I, which return toward normal with treatment of TB. Recent clinical data on 85 HIV-negative patients with TB indicated that there is a close relationship between the CD4+ T-cell count and the severity of TB. The disease severity was associated with greater depression of the total lymphocyte and CD4 cell counts. CD4 cell counts returned to normal levels in most patients after 1 month of therapy (Jones et al. 1997). In TB, Mycobacterium tuberculosis (MTB)-stimulated T-cell responses are depressed transiently, whereas antibody levels are increased. Lymphoproliferative responses of peripheral blood mononuclear cells (PBMCs) from Pakistani TB patients to both mycobacterial and candidal antigens were suppressed by approximately 50% compared with healthy purified protein derivative (PPD)-positive household contacts. Production of interferon-gamma (IFN-y) in response to PPD also was depressed by 78%. Stimulation with PPD and the 30 kDa alpha antigen of MTB (30 kDa antigen) induced greater secretion of transforming growth factor-beta (TGF-~), but not of interleukin 10 (IL-lO) or TNF-a, by PBMCs from TB patients compared with healthy contacts. The degree of suppression correlated with the duration of treatment:

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patients treated for less than 1 month had significantly lower T-cell blastogenesis and IFN-y production and higher levels of TGF-~ than did patients treated for longer than 1 month. Neutralizing antibody to TGF-~ normalized the lymphocyte proliferation in response to PPD, partially restored blastogenesis to candidal antigen, and significantly increased PPD-stimulated production ofIFN-yin TB patients but not in contacts. Neutralizing antibody to IL-lO augmented, but did not normalize, T-cell responses to both PPD and Candida in TB patients and candidal antigen in contacts. TGF-~, produced in response to MTB antigens, may therefore playa prominent role in down-regulating potentially protective host effector mechanisms and can be an important mediator of immunosuppression in TB (Hirsch et al. 1996).

14.3 Hematologic Abnormalities Associated with Mycobacterial Infections in Immunocompromised Hosts 14.3.1 Hematologic Complications of HIV Infection and AIDS

The hematologic manifestations of HIV infection and AIDS are common and may cause symptoms that are life-threatening and impair the quality of life of these patients. These manifestations include morphologic abnormalities of peripheral blood and bone marrow changes (Aboulafia and Mitsuyasu 1991). Cytopenias are the most common hematologic findings in HIV patients. Anemia and neutropenia are generally caused by inadequate production because ofsuppression ofthe bone marrow by the HIV infection through abnormal cytokine expression and alteration of the bone marrow microenvironment. Thrombocytopenia is caused by immune-mediated destruction of the platelets in addition to inadequate platelet production. The incidence and severity of cytopenia are generally correlated to the stage of the HIV infection. Other causes of cytopenia in these patients include adverse effects of drug therapy, the secondary effects of opportunistic infections, especially mycobacterial infections, malignancies or other preexisting or coexisting medical problems that may be prevalent in the HIV-infected population. Diagnosis of

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effects of various infectious pathogens or malignancies. Infectious agents such as Mycobacterium avium complex (MAC) or TB may cause direct bone marrow suppression or reticuloendothelial system dysfunction, resulting in depressed blood cell counts (Castella et al. 1985; O'Hara 1989).

14.3.2

Mycobacter;um av;um Complex in HIV-Infected Patients Disseminated MAC infections are common in patients with HIVI AIDS, occurring in up to 50% of patients (Ellner et al.1991; Nightingale et al.1992). In contrast to the immunocompetent host, in which MAC disease is usually limited to the lungs, bacteremia is by far the most common syndrome in patients with AIDS. Frequently, there is widespread dissemination, often to the liver, bone marrow, lymph nodes (Fig. 14.1), and spleen. In one study, lymphadenopathy, hepatosplenomegaly, and severe anemia «8.5 g/dl) were seen in 37%, 24%, and 85% of patients evaluated, respectively (Benson and Ellner 1993). MAC infection is one of the most common complications seen during the course of HIV infection and is associated with significant suppression of blood counts (Castella et al. 1985). Bone marrow aspiration and biopsy may be useful in making a specific diagnosis of several complications of AIDS that result in cytopenia. In histologic sections of bone marrow, the diagnosis of MAC infection is suggested by the finding of granulomas and aggregates of foamy histiocytes (Figs. 14.1b and 14.2a,b) in which the organisms can be seen by acid-fast staining (Fig. 14.2c). Granuloma formation is frequently lacking or scarce (Fig. 14.2b), so the pathologist should be alerted that disseminated MAC is suspected to ensure that acidfast staining is performed (French et al. 1997).

14.3.3 Anemia Associated with MAC in HIV-Infected Patients Severe anemia (hematocrit <26%) has been reported to be present in 76% of patients with disseminated MAC disease (Horsburgh et al. 1994). The presence of anemia has been correlated with the presence of

the mechanism and cause of the cytopenia may allow

disseminated MAC disease in HIV-infected patients

for specific management (Coyle 1997). In evaluating HIV-infected patients with abnormal blood counts, one must consider the hematologic

who have absolute CD4+ lymphocyte counts below 100lml (Havlick et al. 1992). The survival of patients with MAC disease was negatively correlated to the

Hematologic Findings in Mycobacterial Infections Among Immunosuppressed and Immunocompetent Patients

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a

a

b

b

c Fig.14.la-c. Lymph node histology in an HIV-infected patient with co-existing MAC infection. a Poorly formed granulomas (-100). b Poorly formed granulomas composed of numerous foamy histiocytes (-400). c AFB stain shows numerous intracellular acid-fast mycobacteria (M. avium intracellulare) (-1000). Courtesy of Metin Ozdemirli, MD, PhD, Assistant Professor in Hematopathology, Georgetown University, Washington, DC, USA

Fig.14.2a-c. Bone marrow histology in an HIV-infected patient with co-existing MAC infection. a Numerous, well formed granulomas (-100). b A few paratrabecular poorly formed granulomas (-100). c AFB stains show scattered acid-fast mycobacteria (M. avium intracellulare) (-1000). Courtesy of Metin Ozdemirli, MD, PhD, Assistant Professor in Hematopathology, Georgetown University, Washington, DC, USA

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presence of anemia (Horsburgh et al. 1994). The presence of anemia, fever, and weight loss in patients with advanced immunodeficiency should prompt an evaluation for MAC disease (Coyle 1997). The anemia in MAC disease is thought to be due to high levels of inflammatory cytokines as well as a direct disturbance of the bone marrow microenvironment by mycobacteria (Coyle 1997). Serum TNF levels were demonstrated to be markedly elevated in children with anemia and MAC diseases. In a recent study, the hematologic manifestations of MAC in 37 HIV-infected infants and children were reviewed. Anemia was the predominant feature in all patients, with severe anemia (hemoglobin <6 g/dl) occurring in 7 of 34 (21 %) patients. This was followed by leukopenia (79%), monocytosis (82%), thrombocytopenia (59%), leukoerythroblastic changes (68%), and neutropenia (41 %). Serum TNF-a was markedly elevated in all patients with MAC, and there appeared to be an association between elevated TNF-a and anemia in these patients (Ellaurie and Rubinstein 1995). MAC infection may disrupt erythropoiesis in HIV patients by direct invasion of the bone marrow. Patients with disseminated MAC appear to have greater impairment of erythropoiesis than those without MAC. This impairment appears to be mediated by selective suppression of hematopoietic progenitors (Gascon et al. 1993) and production of inhibitory TNF-a (Ellaurie and Rubinstein 1995). To elucidate the mechanisms of anemia and other cytopenias in HIV patients, various cytokine and cytokine receptor concentrations were measured by ELISA in bone marrow aspirate supernatants from 19 HIV patients undergoing diagnostic evaluation and 14 healthy paid volunteer controls. IL-l ~ and IFN-y were rarely detectable. All cytokines/ receptors detectable in marrow supernatant, except RANTES, showed mean concentrations 1.6- to 6.2-fold higher in patients with HIV compared with healthy controls. Elevated TNF-a and MIP-l ~ was associated with marrow involvement by lymphoma, Hodgkin disease, or mycobacterial infection. Concentrations of all cytokines/receptors measured correlated with the severity of the anemia. CD8+ lymphocytes were inversely correlated with concentrations of all cytokines measured other than MIP-la (Dallalio et al.1999).

14.3.4 Other Cytopenias Associated with MAC in HIV-Infected Patients

Bone marrow infiltration with MAC may cause thrombocytopenia or increase the severity of exist-

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ing HIV-associated thrombocytopenia. However, thrombocytopenia due to bone marrow infiltration is not nearly as common as anemia of MAC infection (Coyle 1997). The absence or presence of megakaryocytes on bone marrow examination is often useful in distinguishing thrombocytopenia caused by decreased production due to marrow infiltration of mycobacteria from thrombocytopenia caused by increased destruction during the course of HIV infection or due to drug side-effect (Coyle 1997). Bone marrow infiltration with disseminated MAC infection may cause neutropenia by suppression of bone marrow progenitors (Coyle 1997).

14.3.5 MAC Infections in Other Immunocompromised Hosts

Infection with atypical mycobacteria occurs mainly in patients with a compromised cellular immune system, in particular in those with a defective Tcell or monocyte function. The specific immune response of an adolescent HIV-negative patient with disseminated M. avium infection and fatal varicella zoster virus infection was studied in a patient who presented with dysplastic hematopoesis of all cell lineages and anemia plus leukopenia. No hematologic malignancy was found. Peripheral lymphopenia and monocytopenia as well as a lack of natural killer (NK)-cells and B-cells were noted. Lymphocytes consisted of T-cells (95%), which contained up to 40% of TCR y8+CD4-CD8- T-cells, few monocytes and B-cells. Approximately 50% of CD3+ T-cells showed a CD57+ NK-like phenotype. Functional analysis of mononuclear cells revealed a good antigen-specific T-cell function if the antigen-presenting cells were supplemented from a HLA-matched donor. Moreover, a strong M. avium specific cytotoxicity mediated by TCR a~+ T-cells could be found in vitro and even ex vivo. In contrast, NK-killing was absent. No evidence for a defect in IL-12 or IFN-g production and signaling was found (Wendland et al. 2000). In a patient with pulmonary MAC disease associated with idiopathic CD4+T lymphocytopenia, hematologic studies showed a low CD4+ cell count in the absence of any identifiable immunodeficiency, including HIV infection. With the combination of chemotherapy and surgery, he had a good clinical outcome (Ishida et al. 1998). Disseminated atypical MAC infection in a patient receiving interferon treatment for hairy-cell leukemia was also described (Maurice et al. 1988).

Hematologic Findings in Mycobacterial Infections Among Immunosuppressed and Immunocompetent Patients

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14.3.6 Hemophagocytic Syndrome Associated with MAC This rare manifestation of MAC was recently described. A 37-year-old man with insulin-dependent diabetes mellitus complicated by end-stage renal disease who had received a second cadaveric kidney transplant 4 years earlier presented with symptomatic splenomegaly, progressive anemia, prolonged fever, dysphagia, and weight loss. The first kidney transplant, as well as a pancreatic transplant, had been lost because of acute rejection 7 and 3 years previously, respectively. Owing to chronic rejection of his kidney transplant, he required intensive immunosuppressive therapy consisting of tacrolimus, mycophenolate mofetil, and prednisone. Abdominal CT performed on admission revealed splenomegaly with a subcapsular hematoma. Analysis of a bone marrow aspirate revealed numerous large histiocytes with striated cytoplasm (onion-skin appearance), resembling Gaucherie's cells. Acid-fast staining of a bone marrow biopsy specimen showed that the histiocytic inclusions were actually innumerable acidfast bacilli. PCR analysis of the bone marrow identified the microorganism as MAC. Despite appropriate antibiotic therapy with azithromycin and ethambutol, respiratory, renal, and liver failure developed, and the patient ultimately died of profound lactic acidosis and septic shock due to disseminated MAC infection (Argiris et al. 1999).

a

14.3.7 Miliary/Disseminated Tuberculosis in AIDS HIV-infected patients are predisposed not only to reactivation of remote TB but also to rapid progression of recently acquired infection (Daley et al.1992; Di Perri et al.1989). It is also probable that AIDS increases the susceptibility to acquisition of new infection, and the diagnosis of TB among hospitalized adults aged 15-44 years is also very commonly associated with concurrent HIV infection (40% of patients) (Rosenblum et al. 1994). With advanced HIV infection, TB often has an atypical presentation, with extrapulmonary disease a prominent feature. The most common forms of extrapulmonary TB are lymphadenitis and disseminated disease (Fig. 14.3). In patients with advanced HIV, TB may present as progressive primary infection or disseminated disease. In AIDS patients, 10% with TB and 38% with extrapulmonary TB have miliary disease (Shafer et al. 1991).

Fig. 14.3a-c. Lymph node histology in an HIV-infected patient with co-existing tuberculosis. a Granulomas with central necrosis (-25). b Granulomas with central necrosis and occasional Langerhans giant cells (-100). c AFB stain shows acidfast mycobacteria (M. tuberculosis) (-1000). Courtesy of Metin Ozdemirli, MD, PhD, Assistant Professor in Hematopathology, Georgetown University, Washington, DC, USA.

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Major constitutional symptoms and hectic fevers are characteristic. The chest X-ray is abnormal in 80% and may include typical miliary mottling. Only 10% are tuberculin-positive (Salzman et al. 1992). The sputum smear is positive in only 25% (Shafer et al. 1991), but cultures of many materials are positive, including blood in 50%-60%. Biopsies show a typical tuberculous histologic appearance but with more stainable organisms than in non-HIV miliary TB (Fig. 14.3). In contrast, the histologic picture is often nonreactive TB in fatal cases (Salzman et aI. 1992). Miliary TB in HIV-infected persons may also cause acute respiratory distress syndrome or tuberculous papular skin lesions. Smears of respiratory secretions are positive in 80%. Fulminant miliary TB may be associated with severe refractory hypoxemia (adult respiratory distress syndrome) and disseminated intravascular coagulation (DIC). In such cases, adjunctive corticosteroids (60-80 mg of prednisone daily) are indicated.

14.3.8 Diagnostic Yield of Bone Marrow Aspiration! Biopsy for Mycobacterial Infections in Patients with HIV Infection Hematology consultants are frequently involved in the care of patients with HIV1AIDS through requests for diagnostic bone marrow (BM) aspiration and biopsy, particularly when opportunistic mycobacteria or histoplasma infections are suspected. MAC and TB infections in particular continue to be important causes of HIV-related deaths (Selik et aI. 1995; Sehonanda et aI.1996; Chin et aI.1994). Consequently, a determination of optimal strategies for the diagnosis of these infections continues to be an important clinical issue. While multiple retrospective studies have been reported (Barreto et aI. 1993; Northfelt et aI. 1991; Ciaudo et aI. 1994; Riley et aI.1995; Benito et aI. 1997; Kilby et aI. 1998), no consensus has emerged with respect to the specific value of BM examinations in the diagnosis of MAC or TB infections in immunocompromised HIV-infected patients. BM examination can be a useful method of diagnosing opportunistic mycobacterial and fungal infections in patients with fever, anemia, or neutropenia, and underlying HIV infection. Detection of granuloma with or without positive AFB staining is a common and valuable histologic clue to opportunistic infection. The diagnostic yield of BM granuloma formation was evaluated in 6988 BM biopsies taken from 1973 to 1986. Granulomas were identified in

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72 specimens. The granulomas were associated with infectious disease (30%), hematologic disorders (25%), sarcoidosis (11 %), nonhematologic malignancies (10%), drug reaction (5%), other diseases (6%), and no final diagnosis (6%). Patients with fever of unknown origin were 15 times more likely to have marrow granulomas than patients biopsied for other reasons (Bhargava and Farhi 1988). In another series of 342 BM examinations from 314 patients with HIV infection, 70 examinations (20%) detected opportunistic mycobacterial or fungal infections. Of the 314 patients, III had such infections, and, hence,63% (70/111) were detected by BM examination. Special stains for microorganisms detected 16 (32%) of 50 MAC, 10 (22%) of 45 TB infections, 8 (73%) of 11 Histoplasma capsulatum (HC) infections, and 5 (83%) of 6 Cryptococcus neoformans infections. BM cultures detected 36 (72%) of the 50 MAC infections, 13 (29%) of the 45 TB infections, and 63% of the fungal infections. Marrow examination revealed infection in only 1 of the 70 specimens (1 %) collected to evaluate thrombocytopenia alone or hematologic malignancy, but in 69 (25%) of 274 with fever, neutropenia, anemia, or miscellaneous other indications for marrow examination. Granulomas were detected in 102 (30%) of the biopsy specimens, including 71 (64%) of those in patients with mycobacterial or fungal infection. The granulomas showed caseous necrosis in 9, all in patients with TB, and the 27 patients with TBassociated granulomas tended to show large, tightly cohesive granulomas. The presence of granulomas correlated with opportunistic infection in 82 (80%) of 102 cases. Without granulomas, special stains were positive in only 8 (3%) of 240 specimens, suggesting that special stains alone may not be a cost-efficient way to diagnose such infections (Nichols et al. 1991). Although these pathogens are not associated with specific BM findings, disseminated MAC or TB may cause increased reticulum, occasional granulomas, and positive smears for AFB (more abundant in MAC cases and relatively sparse in TB cases), and rarely pseudo-Gaucher cells in the BM (Solis et al. 1986; Argiris et al. 1999). The most common manifestation of fungal and mycobacterial infection is a diffuse marrow infiltrate of loose aggregates and clusters of macrophages (Fig. 14.2b) (Castella et al. 1985; O'Hara 1989). The configuration of acid-fast bacilli in or around the granuloma also differs between these two Mycobacterium species. In TB,AFBs resemble a bunch of cigarettes with a single cigarette dropped next to the bunch. In MAC, the AFBs tend to be seen as clumps of bacilli in loose aggregates (Carl J. O'Hara, personal communication). Histiocytic erythrophagocytosis has

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Table 14.1. Sensitivity, specificity, and positive and negative predictive values of studies for identification of mycobacterial infection and histoplasma (Akpek et al. 2001) Predictive value Study

Sensitivity"

Specificitt

PositiveC

Negatived

BM culture Blood culture (+) AFB in BM (+) Granuloma

63% 63% 19% 34%

100% (24/24) 100% (24124) 100% (24/24) 96% (23124)

100% (20/20) 100% (20/20) 100% (616) 91% (11112)

67% 86% 48% 52%

(20/32) (20132) (6132) (11132)

(24/36) (31/36) (24/50) (23/44)

Sensitivity: The percent (or proportion) of patients ultimately diagnosed with MAC/TB or HC who had positive studies. b Specificity: The percent (or proportion) of patients who had negative studies who ultimately did not have MAC/TB or He. C Positive predictive value: The percent (or proportion) of patients who had positive studies who were ultimately diagnosed with MAC/TB or He. d Negative predictive value: The percent (or proportion) of patients who had negative studies who were ultimately not diagnosed with MAC/TB or HC a

also been observed and is a nonspecific finding often seen in association with infections, including mycobacterial infections and lymphomas. Successful detection of organisms in the BM of AIDS patients requires the use of special stains and sensitive culture techniques (O'Hara 1989). The highest yield from special stains is obtained when there is a plentiful infiltrate of macrophages, especially in aggregates or in poorly formed granulomas (Castella et al. 1985). Even in the absence of noticeable granulomas or macrophage infiltration, acid-fast organisms and fungi can be diagnosed when present in high numbers (Cohen et al.1983). In order to determine the value of BM culture and BM histology in the diagnosis of opportunistic MAC/ TB and HC infections in immunosuppressed patients with HIV, we retrospectively reviewed the records of 56 adult patients with HIV who underwent a single BM aspiration, biopsy, and culture because of unexplained fever and/or other clinical features suggestive of MAC/TB or HC infection (Akpek et al. 2001). Thirty-two patients (57%) were ultimately diagnosed with MAC/TB (n=30) or HC (n=2) infection by positive cultures of BM, blood, sputum, or bronchoalveolar lavage (BAL) fluid or by the histologic detection of organisms in biopsies of BM or other tissues. The diagnostic sensitivity of blood cultures was equivalent to that of BM culture (63%) in the diagnosis of MAC/TB and HC infections, as reported by others (Northfelt et al.1991; Kilby et al.1998) and was greater than that of BM histopathology alone (34%) (Table 14.1). Blood cultures were found to be negative in 5 of 20 patients for which BM samples were culture-positive. Granuloma and/or histologically apparent organisms were seen in BM biopsy specimens in 11 of 32

individuals (34%) ultimately diagnosed with MAC/TB or HC infections. Among these 11 patients, both granuloma and acid-fast staining organisms were found in the BM biopsy specimens of 2 individuals for whom both BM and blood cultures were negative. The diagnosis would have been missed in 6 patients (19%) ifthe BM had not been examined. The 34% diagnostic sensitivity of BM histopathology observed in our study is similar to the 20%-30% sensitivities reported in other studies (Riley et al. 1995; Kilby et al. 1998; Nichols et al. 1991). One-fourth of BM biopsy specimens showing granuloma were not associated with positive blood or BM cultures, and this finding suggested a 9% falsepositive rate for this histopathologic feature by itself. The low diagnostic sensitivity of BM histopathology alone is not surprising. An autopsy study of 44 AIDS patients with MAC bacteremia found no histologic evidence of MAC in 30% (Torriani et al. 1994). Other studies have also indicated that some individuals suffer mycobacterial bacteremia without detectable organ or tissue invasion (Torriani et al. 1996). A detailed evaluation of clinical and laboratory parameters observed in our study population indicates that the specific clinical features of high peak temperature, longer duration of febrile days, and elevated direct bilirubin at least greater than 1 mg! dl of the upper limit are predictive of MAC/TB or HC infections and are therefore useful in selecting patients most likely to derive diagnostic benefit from BM examination (Akpek et al. 2001). With recent evidence supporting the value of MAC prophylaxis in immunosuppressed HIV-infected patients (Pierce et al. 1996), it is likely that in the future an increasing proportion of patients may receive antimycobacterial prophylaxis at the time of diagnostic evaluation for infection. This change in practice

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could affect the diagnostic yield of both cultures and BM histopathology. Furthermore, with the development of new molecular methods for the detection of mycobacterial DNA or ribosomal RNA in clinical specimens within 24 h, with sensitivities ranging from 40% to 77% and specificities greater than 95% (Havlir and Barnes 1999; Barnes 1997; Condos et al. 1996), it is likely that a reluctance to carry out diagnostic BM examinations will continue, particularly given the additional considerations of cost, patient discomfort, risk of needle-stick exposures for individuals involved in BM sampling, and evidence for responses to empiric anti-MAC therapy in some patients. While the diagnostic sensitivity of BM cultures may not be greater than that of blood cultures in detecting MAC/TB or HC infections in immunosuppressed HIV + patients, histopathologic examination of BM specimens often results in the relatively rapid identification of nearly one-third of infected patients who underwent BM examination and can also identify infections in some patients who are culture-negative. Based on the above findings, we should continue to use BM aspiration, biopsy, and culture for the diagnosis of opportunistic MAC/TB or HC infections in immunosuppressed HIV + patients, particularly when selected clinical features are present.

14.3.9 Other Mycobacterial Infections Associated with Hematologic Disorders Mycobacterial disease, especially atypical mycobacteria, is relatively often seen in hairy-cell leukemia (HCL). The clinical picture is usually dominated by persistent fever. Sweet's syndrome manifested by fever, skin rash, and HCL has been described (Kramers et al. 1992). Blood cultures grew M. kansasii. The patient recovered after treatment with recombinant IFN-a and tuberculostatic drugs. The skin lesions completely regressed within 1 week after the start of r-IFN-a. Leukopenia secondary to M.leprae was also described (Brooks et al. 1990).

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14.4 Coagulation Abnormalities Associated with Mycobacterial Infections and Clinical Presentations 14.4.1 Disseminated Intravascular Coagulation DIC is a very rare complication of pulmonary TB. However, there have been numerous case reports published about the association between DIC and TB (Krishnaswamy 1969; Goldfine et al. 1969; Mavligit et al. 1972; Jenss and Ostendorf 1980). Clotting factors might be locally consumed, thus producing the syndrome of 'multifocal vasculopathic coagulation' (Krauss and Walker 1979).A patient with cavitary TB complicated with DIC has been described (Fujita et aI.1997). Rifampin was considered to treat the clinical course of DIe. Another patient developed subclinical DIC due to anti-TB drugs, probably rifampicin. The patient also developed marked leucocytosis, a flu-like illness, intravascular hemolysis, and acute renal failure as part of the drug reaction (Ip et al. 1991). A review of all 13 patients reported to date shows that the patients are generally black, middle-aged, male, alcoholic, and febrile. The form of TB is generally miliary and is associated with a high mortality. Eight of these patients had associated ARDS. Only one patient had an acute tuberculous peritonitis. In 6 patients the coagulopathy began after the start of therapy; steroids did not appear to affect survival. The exact pathophysiologic mechanisms involved in the development of DIC are unknown (Stein and Libertin 1990). TB-associated hemophagocytic syndrome (HPS) has recently been recognized as a benign reactive histiocytic proliferation with marrow hemophagocytosis. A patient with TB complicated by severe BM failure and DIC was reported. The immunological disturbances usually occurring in miliary TB may playa role in the pathogenesis of HPS (Eliopoulos et al. 1992).

14.4.2 Deep Vein Thrombosis Associated with Tuberculosis Deep venous thrombosis (DVT) associated with TB infection has rarely been reported (Gogna et al. 1999). In a pediatric patient who developed DVT of the left leg in association with pulmonary TB, transient protein S deficiency and anticardiolipin

Hematologic Findings in Mycobacterial Infections Among Immunosuppressed and Immunocompetent Patients

IgG and IgM antibodies were identified (CasanovaRoman et al. 2002). In a retrospective analysis of clinically diagnosed and lower limb DVT proven by contrast venography, DVT complicated admissions in 46 (3.4%) of 1366 adult patients treated in a TB hospital during 1986. Analysis of 7542 admissions during 1978-1986 showed a relative risk of about 5 in patients treated with regimens including rifampicin compared with other regimens. DVT was significantly more common in the winter months and usually occurred within 2 weeks of treatment being started (White 1989). This probable association between rifampicin and DVT does not contraindicate use of this drug, but measures to prevent DVT should be taken for patients receiving rifampicin.

14.4.3 Thrombotic Thrombocytopenic Purpura Associated with Mycobacterial Infections

Thrombotic thrombocytopenic purpura (TTP) during infectious diseases is a known but rare event (Pene et al. 2001). Various therapeutic approaches were used with the patient who developed TTP during the course of primary TB infection: fresh frozen plasma infusions and plasma exchange, specific anti-TB therapy, antiplatelet drugs, and steroids. A complete remission occurred 3 months after the onset of the acute disease (Toscano et al. 1995). One of the hypotheses about the pathogenesis of TTP might be an increased procoagulant activity of IL-l on endothelial cells. Rifampicin therapy was reported to be associated with the development of TTP in a patient with TB (Fahal et al. 1992). A patient with disseminated MAC infection also developed TTP (Skopinski et al. 2001). Excessive bleeding with unclear etiology can occur rarely in patients with TE. A fatal case of pulmonary TB masquerading as diffuse alveolar hemorrhage after autologous stem-cell transplant was recently reported (Keung et al. 1999).

14.5 Conclusion The types and mechanisms of hematologic findings seen during the course of mycobacterial infections were covered in this chapter. Hematologic findings in patients with active mycobacterial

227

infections are usually considered by clinicians a part of the chronic inflammatory condition, and thus they are usually overlooked. However, it is extremely important to recognize the diagnostic and prognostic value of these hematologic findings because of the possible impact on the outcome of these patients. Severe hematologic abnormalities indicate an advanced mycobacterial infection that requires immediate attention regarding diagnosis and treatment, which may alter the course in these deadly diseases.

References Aboulafia DM, Mitsuyasu RT (1991) Hematologic abnormalities in AIDS. Hematol Oncol Clin North Am 5:195-214 Akhtar AJ, Crompton GK, Schonell ME (1968) Para-aminosalicylic acid as a cause of intestinal malabsorption. Tubercle 49:328-331 Akpek G et al (2001) Bone marrow aspiration, biopsy, and culture in the evaluation of HIV-infected patients for invasive mycobacteria and histoplasma infections. Am J HematoI67:100-106 Al-Majed SA et al (1995) Tuberculosis presenting as immune thrombocytopenic purpura. Acta HaematoI94:135-138 Argiris A, Maun N, Berliner N (1999) Mycobacterium avium complex inclusions mimicking Gaucher's cells. N Engl J Med 340:1372 Barnes PF (1997) Rapid diagnostic tests for tuberculosis: progress but no gold standard. Am J Respir Crit Care Med 155:1497-1498 Barreto JA et al (1993) Isolation of Mycobacterium avium complex from bone marrow aspirates of AIDS patients in Brazil. J Infect Dis 168:777-779 Basu S, Mohan H, Malhotra H (2000) Pancytopenia due to hemophagocytic syndrome as the presenting manifestation of tuberculosis. J Assoc Physicians India 48:845-846 Benito N et al (1997) Bone Marrow Biopsy in the diagnosis of fever of unknown origin in patients with acquired immunodeficiency syndrome. Arch Intern Med 57:1577-1580 Benson CA, Ellner JJ (1993) Mycobacterium avium complex infection and AIDS: advances in theory and practice. Clin Infect Dis 17:7 Bhargava V, Farhi DC (1988) Bone marrow granulomas: clinicopathologic findings in 72 cases and review of the literature. Hematol PathoI2:43-50 Boots RJ, Roberts AW, McEvoy D (1992) Immune thrombocytopenia complicating pulmonary tuberculosis. Case report and investigation of mechanism. Thorax 47:396-397 Bozoky G et al (1997) Hematologic abnormalities in pulmonary tuberculosis. Orv HetilI38:1053-1056 Brooks BJ Jr,Alvarez S, Yoder L (1990) Leukopenia secondary to Mycobacterium leprae. J La State Med Soc 142:35-36 Cameron SJ (1974) Tuberculosis and the blood: a special relationship. Tubercle 5:65-72 Casanova-Roman M et al (2002) Deep venous thrombosis associated with pulmonary tuberculosis and transient protein S deficiency. Scand J Infect Dis 34:393-394

228 Castella A et al (1985) The bone marrow in AIDS: a histologic, hematologic and microbiologic study. Am J Clin Pathol 84: 425 Centers for Disease Control and Prevention (2000) Reported tuberculosis in the United States, 1999. Centers for Disease Control and Prevention, Atlanta Charfi MR et al (1998) Disseminated tuberculosis in nonimmunocompromised host: three case reports. Rev Med Interne 19:917-920 Chia YC, Machin SJ (1979) Tuberculosis and severe thrombocytopenia. Br J Clin Pract 33:55-56 Chin DP et al (1994) The impact of Mycobacterium avium complex bacteremia and its treatment on survival of AIDS patients - a prospective study. J Infect Dis 170:578-584 Ciaudo M et al (1994) Revisited indications for bone marrow examinations in HIV-infected patients. Eur J Haematol 53: 168-174 Cockcroft DW et al (1976) Miliary tuberculosis presenting with hyponatremia and thrombocytopenia. Can Med Assoc J 115:871-873 Cohen RJ et al (1983) Occult infections with M. intracellulare in bone marrow biopsy specimens from patients with AIDS. N Engl J Med 308:1475 Condos R et al (1996) Peripheral-blood-based PCR assay to identify patients with active pulmonary tuberculosis. Lancet 347:1082-1085 Corr WP, Kyle RA, Bowie EJW (1964) Hematologic changes in tuberculosis. Am J Med Sci 248:709-714 Coyle TE (1997) Hematologic complications of human immunodeficiency virus infection and AIDS. In: Gold JWM, Telzak EE, White DA (eds) Management of the HIV-infected patient, part II. Infections and malignancies associated with HIV infection. Saunders, Philadelphia, pp 449-470 (Medical clinics of North America, vol 81) Daley CL, Small PM, Schecter GF (1992) An outbreak of tuberculosis with accelerated progression among persons infected with the human immunodeficiency virus. N Engl J Med 36:231-235 Dallalio G et al (1999) Cytokine and cytokine receptor concentrations in bone marrow supernatant from patients with HIV: correlation with hematologic parameters. J Invest Med 47:477-483 Di Perri G, Danzi MC, DeChecchi G (1989) Nosocomial epidemic of active tuberculosis among HIV-infected patients. Lancet 2:1502-1504 Dutt AK, Moers D, Stead WW (1983) Undesirable side effects of isoniazid and rifampin in largely twice-weekly shortcourse chemotherapy for tuberculosis. Am Rev Respir Dis 128:419-424 Dye C et al (1999) Consensus statement: global burden of tuberculosis: estimated incidence, prevalence, and mortality by country: WHO Global Surveillance and Monitoring Project. JAMA 282:677-686 Eliopoulos G et al (1992) Tuberculosis associated hemophagocytic syndrome complicated with severe bone marrow failure and disseminated intravascular coagulation. Nouv Rev Fr HematoI34:273-276 Ellaurie M, Rubinstein A (1995) Elevated tumor necrosis factor alpha in association with severe anemia in human immunodeficiency virus infection and mycobacterium avium intracellulare infection. Pediatr Hematol Oncol 12: 221-230 Ellner n, Goldberger MJ, Parenti DM (1991) Mycobacterium

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avium infection and AIDS: a therapeutic dilemma in rapid evolution. J Infect Dis 163:1326-1335 Fahal IH et al (1992) Thrombotic thrombocytopenic purpura due to rifampicin. Br Med J 304:882 Flinn JW, Finn RS (1929) Annu Rev Tuberculosis 20:347 French AL, Benator DA, Gordin FM (1997) Nontuberculous mycobacterial infections. In: God JWM, Telzak EE, White DA (eds) The management of the HIV-infected patient, part II. Infections and malignancies associated with HIV infection. Saunders, Philadelphia, pp 361-379 (Medical clinics of North America, vol 81) Fujita M et al (1997) Disseminated intravascular coagulation associated with pulmonary tuberculosis. Intern Med 36: 218-220 Gascon P, Sathe SS, Rameshwar P (1993) Impaired erythropoiesis in the acquired immunodeficiency syndrome with disseminated Mycobacterium avium complex. Am J Med 94:41-48 Ghobrial MW, Albornoz MA (2001) Immune thrombocytopenia: a rare presenting manifestation of tuberculosis. Am J HematoI67:139-143 Glasser RM, Walker RI, Herion JC (1970) The significance of hematologic abnormalities in patients with tuberculosis. Arch Intern Med 125:691-695 Gogna A et al (1999) Tuberculosis presenting as deep vein thrombosis. Postgrad Med J 75:104-105 Goldfine ID et al (1969) Consumption coagulopathy in miliary tuberculosis. Ann Intern Med 71:775-777 Havlick JA et al (1992) Disseminated mycobacterium avium complex infection: clinical identifiers and epidemiologic trends. J Infect Dis 165:577-580 Havlir DV, Barnes PF (1999) Tuberculosis in patients with human immunodeficiency virus infection. N Engl J Med 340:367-373 Hernandez-Maraver D et al (1996) Immune thrombocytopenic purpura due to disseminated tuberculosis. Acta Haematol 96:266 Hirsch CS et al (1996) Cross-modulation by transforming growth factor beta in human tuberculosis: suppression of antigen-driven blastogenesis and interferon gamma production. Proc Natl Acad Sci USA 93:3193-3198 Horsburgh CR et al (1994) Predictors of survival in patients with AIDS and disseminated mycobacterium avium complex disease. J Infect Dis 170:573-577 Ip M, Cheng KP, Cheung WC (1991) Disseminated intravascular coagulopathy associated with rifampicin. Tubercle 72:291-293 Iseman MD (2000) Tuberculosis in relation to human immunodeficiency virus and acquired immunodeficiency syndrome. A clinician's guide to tuberculosis. Lippincott Williams and Wilkins, Philadelphia, pp 199-252 Ishida T et al (1998) Pulmonary Mycobacterium avium disease in a young patient with idiopathic CD4+ T lymphocytopenia. Intern Med 37:622-624 Jenss H, Ostendorf P (1980) Leukopenia and consumption coagulopathy in miliary tuberculosis. Schweiz Med Wochenschr 110:1208-1213 Jones BE et al (1993) Relationship of the manifestations of tuberculosis to CD4 cell counts in patients with human immunodeficiency virus infection. Am Rev Respir Dis 148: 1292-1297 Jones BE et al (1997) CD4 cell counts in human immunodeficiency virus-negative patients with tuberculosis. Clin Infect Dis 24:988-991

Hematologic Findings in Mycobacterial Infections Among Immunosuppressed and Immunocompetent Patients Jurak SS, Aster R, Sawaf H (1983) Immune thrombocytopenia associated with tuberculosis. Clin Pediatr (Phila) 22: 318-319 Kavesh NG, Holzman RS, Seidlin M (1989) The combined toxicity of azidothymidine and antimycobacterial agents. A retrospective study. Am Rev Respir Dis 139:1094-1097 Keung YK et al (1999) Mycobacterium tuberculosis infection masquerading as diffuse alveolar hemorrhage after autologous stem cell transplant. Bone Marrow Transplant 23:737-738 Kilby JM et al (1998) The yield of bone marrow biopsy and culture compared with blood culture in the evaluation of HIV-infected patients for mycobacterial and fungal infections. Am J Med 104:123-128 Kramers C et al (1992) Sweet's syndrome as the presenting symptom of hairy cell leukemia with concomitant infection by Mycobacterium kansasii. Ann Hematol 65:55-58 Krauss JS, Walker DH (1979) Miliary tuberculosis and consumption of clotting factors by multifocal vasculopathic coagulation. South Med J 72:1479-1481 Krishnaswamy V (1969) Disseminated tuberculosis presenting as a bleeding disorder. J Indian Med Assoc 53:85-87 Levy M, Cooper BA (1964) Thrombocytopenic purpura associated with tuberculous lymphadenitis. Can Med Assoc J 90:373-374 Maartens G, Willcox PA, Benatar SR (1990) Miliary tuberculosis: rapid diagnosis, hematologic abnormalities, and outcome in 109 treated adults. Am J Med 89:291-296 Mandell GL et al (2000) Principles and practice of infectious diseases. Mycobacterial infections Maurice PD et al (1988) Mycobacterium avium-intracellulare infection associated with hairy-cell leukemia. Arch Dermatol 124:1545-1549 Mavligit GM, Binder RA, Crosby WH (1972) Disseminated intravascular coagulation in miliary tuberculosis. Arch Intern Med 130:388-389 Medd WE, Hayhoe FGJ (1955) Tuberculous miliary necrosis with pancytopenia. Quart J Med 24:351 Medical Staff Conference (1967) Hematologic manifestations of tuberculosis. Calif Med 106:215-221 Moore M, McCray E, Onorato 1M (1999) TB-AIDS versus nonAIDS TB cases, United States, 1993-1997.1nt J Tuberc Lung Dis S20-S20 abstract Morii T, Narita N (1998) Mycobacterial infection in patients with hematologic disorders. Nippon Rinsho 56:3209-3211 Nichols L et al (1991) Bone marrow examination for the diagnosis of mycobacterial and fungal infections in the acquired immunodeficiency syndrome. Arch Pathol Lab Med 115:1125-1132 Nightingale SD et al (1992) Incidence of Mycobacterium avium-intracellulare complex bacteremia in human immunodeficiency virus-positive patients. J Infect Dis 165:1082-1085 Northfelt DW et al (1991) The usefulness of diagnostic bone marrow examination in patients with human immunodeficiency virus (HIV) infection. J Acquir Immune Delic Syndr 4:659-666 O'Brien JR (1954) Nonreactive tuberculosis. J Clin Pathol 7: 216-225 O'Hara CJ (1989) The lymphoid and hematopoietic systems. In: Harawi SJ, O'Hara CJ (eds) Pathology and pathophysiology of AIDS and HIV-related diseases. Mosby, St Louis, pp 150-164

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Onwubalili JK, Edwards EJ, Palmer L (1987) T4lymphophenia in human tuberculosis. Tubercle 68:195 O'Reilly RA (1998) Splenomegaly in 2,505 patients in a large university medical center from 1913 to 1995. West J Med 169:78-87 Oswald NC (1963) Acute tuberculosis and granulocytic disorders. Br Med J 2:1489-1496 Otsuji A et al (1990) Transient large granular lymphocytosis associated with pulmonary tuberculosis: a case report. Rinsho Ketsueki 31:1955-1959 Pavithran K, Vijayalekshmi N (1993) Thrombocytopenic purpura with tuberculous adenitis. Indian J Med Sci 47: 239-240 Pene F et al (2001) Septic shock and thrombotic microangiopathy due to Mycobacterium tuberculosis in a nonimmunocompromised patient. Arch Intern Med 161: 1347-1348 Perez de Llano LA, Soilan del Cerro JL, Garcia Pais MJ (1998) Imune thrombocytopenic purpura as presenting form of miliary tuberculosis. Arch Broncho PneumoI34:411-412 Pierce M et al (1996) A randomized trial of clarithromycin as prophylaxis as prophylaxis against Mycobacterium avium complex infection in patients with advanced acquired immunodeficiency syndrome. N Engl J Med 335:384-391 Riley UB et al (1995) Detection of mycobacteria in bone marrow biopsy specimens taken to investigate pyrexia of unknown origin. J Clin PathoI48:706-709 Roberts PD, Hoffbrand AV, Mollin DL (1966) Iron and folate metabolism in tuberculosis. Br Med J 5507:198-202 Rosenberg MJ, Rumans LW (1978) Survival of a patient with pancytopenia and disseminated coagulation associated with miliary tuberculosis. Chest 73:536-539 Rosenblum LS et al (1994) Effect of HIV infection and tuberculosis on hospitalizations and cost of care for young adults in the United States, 1985 to 1990. Ann Intern Med 121:786-792 Rosenthal T, Pitlik S, Michaeli D (1975) Fatal undiagnosed tuberculosis in hospitalized patients. J Infect Dis 131 [Suppl):S51-S56 Salzman SH et al (1992) The role of bronchoscopy in the diagnosis of pulmonary tuberculosis in patients at risk for HIV infection. Chest 102:143-146 Sehonanda A, Choi YJ, Blum S (1996) Changing patterns of autopsy findings among persons with acquired immunodeficiency syndrome in an inner-city population. Arch Pathol Lab Med 120:459-464 Selik RM, Chu SY, Ward JW (1995) Trends in infectious disease and cancers among persons dying of HIV infection in the United States from 1987 to 1992. Ann Intern Med 123:933-936 Shafer RW et al (1991) Extrapulmonary tuberculosis in patients with human immunodeficiency virus infection. Medicine 70:384-397 Shenkenberg TD, Rice L, Waddell CC (1982) Acquired PelgerHuet nuclear anomaly with tuberculosis. Arch Intern Med 142:153-154 Singh KJ et al (2001) Significance ofhaematological manifestations in patients with tuberculosis. J Assoc Physicians India 49:790-794 Singh SP et al (1986) Tubercular lymphadenitis with purpura. J Indian Med Assoc 84:247-249 Skopinski S et al (2001) Mycobacterium avium complex sep-

230 ticemia: a new cause of thrombocytopenic thrombotic purpura. Rev Med Interne 22:400-401 Slavin RE, Walsh TJ, Pollack AD (1980) Late generalized tuberculosis: a clinical pathologic analysis and comparison of 100 cases in the preantibiotic and antibiotic eras. Medicine (Baltimore) 59:352-366 Solis DC, Belmonte AH, Ramaswamy G (1986) Pseudo-Gaucher cells in Mycobacterium avium-intracellulare infection in the acquired immunodeficiency syndrome (AIDS). Am J Clin Pathol 85:233 Stein DS, Libertin CR (1990) Disseminated intravascular coagulation in association with cavitary tuberculosis. South Med J 83:60-63 Talbot S et al (1998) Mediastinal nodal tuberculosis presenting as immune thrombocytopenia. Aust NZ J Med 28:465-466 Torriani PJ et al (1994) Autopsy findings in AIDS patients with mycobacterium avium complex bacteremia. J Infect Dis 170:1601-1605 Torriani PJ et al (1996) Disseminated Mycobacterium avium complex: correlation between blood and tissue burden. J Infect Dis 173:942-949 Toscano Vet al (1995) Thrombotic thrombocytopenic purpura associated with primary tuberculosis. Infection 23:58-59 Tulliez M (1976) Bone marrow's histopathology in tuberculosis

G.Akpek of the hematopoietic organs. Pathol Bioi (Paris) 24:699-711 Turett GS, Telzak EE (1994) Normalization of CD4+ T-Iymphocyte depletion in persons without HIV infection treated for tuberculosis. Chest 105:1335 Uetake T et al (1990) Clinicopathological study of miliary tuberculosis in patients with hematologic disease. Kekkaku 65:273-283 Ugo V et al (1996) Myelodysplasia and tuberculosis. Bull Cancer 83:548-552 Wendland T et al (2000) Strong alpha beta and gamma delta TCR response in a patient with disseminated Mycobacterium avium infection and lack of NK cells and monocytopenia. Immunol Lett 72:75-82 White NW (1989) Venous thrombosis and rifampicin. Lancet 2:434-435 Whitfield CL (1970) Hematologic abnormalities in tuberculous patients. Arch Intern Med 126:698 Yang CW et al (1996) Tuberculosis-associated hemophagocytic syndrome in a hemodialysis patient: case report and review of the literature. Nephron 72:690-692 Yasuda Y et al (1994) A case of intractable pulmonary tuberculosis complicated by idiopathic thrombocytopenic purpura. Nippon Kyobu Geka Gakkai Zasshi 42: 2301-2305

15 Immunodiagnostics for Latent Tuberculosis Infection ROHIT

K.

KATIAL

CONTENTS 15.1 15.2 15.3 15.4 15.5 15.6 15.7 15.8 15.9 15.10

Introduction 231 History of TB Skin Testing 231 TB Immune Response 232 PPD Strength 232 PPD Testing Methodology 233 Mantoux Testing Method of Measuring Induration 233 TB Skin Test Interpretation 234 Booster 235 Adverse Reactions to PPD Testing 235 New Trends in Diagnosing Latent TB Infection 235 References 237

The opinions or assertions contained herein are the private views of the author and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.

15.1 Introduction Historical accounts date mycobacterial infections back thousands of years, but it was not until the late 19th century that the causative, agent responsible for tuberculosis (TB) was discovered. The veterinary industry in its attempt to eradicate bovine TB led the effort to diagnose both latent and active TB infections. The skin testing method successfully used in animals was soon optimized for human diagnostics. Screening methods have changed little in the last 100 years, and the skin test is fraught with limitations including poor specificity due to crossR. K. KATIAL, MD Associate Professor of Medicine, National Jewish Medical and Research Center Denver, 1400 Jackson Street, Denver, CO 80206, USA

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

reactivity with nontuberculous strains, difficulty in interpretation, and test interference by underlying co-morbid conditions. Because of the resurgence of TB infection associated with the AIDS epidemic and with increasing urban crowding, more specific and sensitive tests that will detect exposure to Mycobacterium tuberculosis (MTB) are needed. New in vitro diagnostics are being evaluated as potential replacements for the old TB skin test.

15.2 History of T8 Skin Testing TB was an epidemic that first appeared in animals in the Paleolithic period long before the disease occurred in man some 8000 years ago (Bates and Stead 1993). Four thousand years later, one finds written reference to TB in the Vedas (Kiple 1993). In the Indian subcontinent, the Hindus referred to TB as consumption (Davis 2000), a term used until quite recently. As urban development increased and city centers were formed in the early 1600s, the incidence of TB increased sharply. Over the subsequent 200 years, the epidemic spread throughout Western Europe. At the end of the 18th century, TB was rampant, but the causes were speculative and treatment ineffective. In 1882, Robert Koch isolated the tubercle bacillus and thus began the rapid advancement in understanding both the disease pathophysiology and diagnostics (Koch 1890, 1891). Robert Koch developed a MTB filtrate known as old tuberculin (OT) from heat-sterilized cultures, which he mistakenly promoted as a therapeutic agent for TB. Soon thereafter, OT began to be evaluated for use in early diagnosis, initially in cattle by comparing skin testing reactivity with autopsy data. The association of subclinical infection with a reactive skin test was made when asymptomatic cattle with positive skin tests demonstrated tuberculi on autopsies (Pearson 1892). Any skin test reactivity at this point was considered positive for TB because nonspecific

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reactivity from nontuberculous strains had not been recognized. After widespread testing in animals, the occasional discrepancy between skin test reactivity and the absence of organisms on autopsy became apparent. By the 1930s, it was widely accepted in the veterinary community that skin test conversion could occur after exposure to nontuberculous strains of mycobacteria (Hagan 1931). Similar nonspecific reactivity was seen in humans when large-scale testing was done through the 1930s and 1940s. In addition, it was noted that OT showed batch-to-batch variability and led to inconsistent skin test results (Snider 1982). With this observation, work began on developing a more consistent and standardized product. In 1934, Florence Seibert prepared the purified protein derivative (PPD), and in 1941, Seibert and Glenn prepared lot no,49608, the international skin test standard reagent PPD-S (Seibert and Glenn 1941). All PPD preparations from that point forward had to be bioequivalent to PPD-S.

15.3 18 Immune Response The injurious effects from MTB are a result of the defensive responses exhibited by the host. The infectious process begins with inhalation of particles in the respirable range of 1-5 flm. These particles settle in the alveolus where they are engulfed by alveolar macrophages. The immune response to TB is a complex interaction between antigen-presenting cells (APC) and a variety of T-Iymphocytes, with a humoral response being much less significant. The MTB bacillus is taken up by a phagosome within the APC that attempts to fuse with a lysosome and ultimately create a mature phagolysosome. However, one of the mechanisms of immune evasion by TB is the prevention of the formation of the mature phagolysosome (Kaufmann 2001). The intracellular presence of the bacillus results in complexing of TB antigens with MHC class II molecules. This leads to activation of CD4+ T-cells, which produce IFN-y among other cytokines and ultimately recruit more macrophages to the site of infection, thus perpetuating the cycle (Iseman 1999). Antigen presentation also occurs through nonpolymorphic CD1 and polymorphic MHC class I molecules, thus leading to activation of CD8+ and double-negative a~T-cells. Evidence is also mounting that yoT-cells may contribute to the tuberculin response (Kaufmann 2001). All these T-Iymphocytes have the ability to produce IFN-y, with CD4+ cells being the primary producer

R. K. Katial

as well as the cell central to the recall delayed-type hypersensitivity (DTH) response seen after injection of PPD in individuals previously exposed to MTB. The contribution of other cytokines such as IL-12, IL-18, and TNF-~ to the pathogenesis and protective response of TB infection has been nicely elaborated in other reviews (Collins and Kaufmann 2001; Iseman 1999; Daniel 1980; Daniel et al.2000; Tsuyuguchi 1996). IFN-yis the primary cytokine involved with governing immune protection to TB and has recently been used in the development of immunodiagnostics. TB-infected individuals present tuberculin antigens by various ways and generate effector T-cells, which then continue to circulate in the blood. The nonsterilizing quality of the initial exposure may serve to continually stimulate the immune system, thus maintaining a reservoir of MTB-specific T-cells. The response to PPD is a classic DTH reaction, involving vasodilation, edema, and infiltration initially of antigen-specific T-cells which then secrete cytokines leading to recruitment of other nonspecific inft.ammatory cells (Ahmed and Blose 1983). The result of these inft.ammatory events is induration beneath the skin and some degree of erythema. The maximum induration is generally seen 48 h after injection of PPD, and this is not correlated with the erythema. DTH responses can persist for years after exposure to the bacillus. The immune mechanism of the DTH response differs from the IFN-yresponse mounted for protection from the disease. Orem and Copper (1999) postulated that immune protection is governed by cytokine production such as IFN-y, while the DTH response may be a primary result of chemokine production. The clinical importance of this is that in actively infected individuals, the DTH reaction may be depressed initially but returns within a month of therapy, whereas IFN-y may remain suppressed for at least 12 months (Ellner 1997; Hirsch et al. 1996, 1999). This clearly suggests that in vitro measurement of IFN-y production is not a direct correlate of the less expensive PPD and recall antigen (e.g., measles, mumps, tetanus) skin tests but rather that the two reactions are governed by different immune mechanisms.

15.4 PPD Strength In the USA, two types of tuberculin are available: OT and PPD. OT is only used with multipuncture devices, whereas PPD is used for both multipuncture and the intracutaneous test. PPD is manufactured by protein

Immunodiagnostics for Latent Tuberculosis Infection

233

precipitation of culture titrate using either tricWoro- Induration at the site of injection is usually read at 48acetic acid or ammonium sulfate. Although both prep- 72 h. Howard and Solomon (1988) evaluated readings arations are standardized by bioequivalency using a at 24, 48, and 72 h and reported 71 % sensitivity and skin testing methodology (Villarino et al. 1999), the 9% false-positive rate at 24 h. Thus, the authors recomantigen content of the two may differ due to the dif- mended reading the test at the standard 48-72 h, while ferences in the precipitation methods. PPD contains being aware that some reactions may occur earlier and primarily small proteins (less than 10,000 Da) but also others may persist longer than 72 h. has polysaccharides and lipids. The small proteins and lack of adjuvant prevent PPD from being sensitizing (American Thoracic Society 2000). The PPD used for intracutaneous testing comes in 15.6 three concentrations: 1 tuberculin unit (TU), 5 TU, Mantoux Testing Method of Measuring and 250 TV. PPD 5 TU is the only strength that is Induration bioassayed (standardized in vivo to the PPD-S). PPD 1 TU was shown to have only 50% sensitivity in The CDC standard for reading PPD induration is children, while PPD 250 TU identified all specific and palpating along the transverse axis of the forearm nonspecific reactors (Murtagh 1980; Gryzbowski et (Core Curriculum on Tuberculosis, Centers for al. 1969). Palmer (1945) studied student nurses who Disease Control 1994). However, several investigawere tested with PPD 5 TU and 250 TV. PPD 5 TU tors have compared this palpation method with a proved to be highly sensitive in identifying students ballpoint method first introduced by Sokal (1975), with pulmonary calcifications and/or lung infiltrates. who claimed a reduction in the observer variability On the other hand, reactivity with PPD 250 TU did with the pen method. Correlation between these two not correlate with pulmonary findings or contact methodologies is high, and differences between readhistory. Therefore, the 1 and 250 TU concentrations ings are small and often not clinically relevant. When should not be used for testing because of lack of Pouchot et al. (1997) compared PPD readings by palstandardization. pation versus the ballpoint method, they found a high correlation between the two techniques but reported a 38% broader area of imprecision with palpation. The skin test readers in the study were not blinded 15.5 to the patients, and only two very experienced readPPD Testing Methodology ers performed all the tests. A study by Howard and Solomon (1988) evaluating 806 volunteers found The two primary skin-testing methods used are the discordance between the two methodologies in the multipuncture device and the Mantoux test. Multiple 5-14 mm range. The readers in their study were also puncture devices such as the tine test are inexpen- not blinded. The authors suggested that the readings sive, simple to apply, and much more rapid. They obtained with the pen method should be interpreted introduce antigen through tuberculin-coated prongs with caution in the 5-14 mm range. Jordan et al. on the applicator device, or by puncturing through (1987) and Bouros et al. (1991) conducted doublea liquid film placed on the forearm; however, such blind studies comparing the two methods, and both devices have numerous drawbacks including unre- showed that the pen method is comparable to palpaliable dose delivery (Lunn 1980), inconsistent tech- tion in the hands of experienced readers. Bouros and niques of administration, and significant false-posi- colleagues (1992) later studied the two methods with tive reactions. A study by the Research Committee of readings from both experienced and inexperienced the British Thoracic Association (1982) showed up to readers. No significant differences were found in any 23% variability in subjects with duplicate tine tests. range of measurement by the two groups using both Because of these shortcomings, the current recom- methods. The authors concluded that inexperienced mendation is that positive tine tests need validation readers can use either methodology accurately. Longby the commonly adopted Mantoux method, which field and colleagues (1984) studied interobserver has become the standard recommended by the variability in 101 patients and found no significant United States Centers for Disease Control (CDC). difference between the two methods. They found The Mantoux test is performed by injecting 0.1 ml comparable variability between the two techniques; of PPD 5 TU intradermally with a 26-27 gauge needle using a 10 mm cut-off, less than 7% of readings would with bevel upward, creating a pale bleb above the skin. have changed the clinical interpretation.

234

R. K. Katial

At our institution we use the ballpoint method, measuring along two axes of the forearm. We retrospectively evaluated 5680 skin test records and analyzed only the positive records (380), comparing the transverse to the longitudinal axis as well as the average of the two. We found no statistically significant difference (p=0.135) between the transverse and longitudinal readings; in fact, the total number of subjects classified positive and negative were the same in each group, using both a 10 mm and 15 mm cut-off, although the specific individuals varied (Table 15.1) (Hershey et al. 2001). This suggests that the two readings are equivalent. However, when the larger of the two readings was used to determine the classification, a slightly higher number of people (24/380 with a 15 mm cut-off) were classified as positive than by the single transverse reading. When the average of the two readings was used, the results were similar to the standard transverse method but may reflect enhanced precision because two readings have been made. The intraobserver variability has been reported to be 3.0 mm greater or less than the first measurement (Pouchot et al. 1997). In our data, the variability between the two readings was

3 mm or less in 81 % of the subjects. However, choosing the larger of the two measurements provided slightly greater sensitivity. It appears that adherence to one technique and proper application and training are more important than which technique or axis is used.

15.7 T8 Skin Test Interpretation In determining the cut-off for a clinically positive result indicating exposure to MTB, one must understand the reactivity patterns in various populations as well as the factors contributing to false-positive and false-negative results. In the 1950s, the World Health Organization (WHO) collated data of skin test induration for patients in TB hospitals throughout the USA, Europe, and Southeast Asia. The highest number of reactors had indurations of approximately 16-17 mm with a normal distribution. In every country, the frequency curves overlapped. In some regions, a bimodal distribution was described

Table 15.1. Comparison of skin test readings by reading direction (transverse vs longitudinal) No. of subjects

Percentage

(n=380)

Transverse classification at ~1O mm cut-off: Negative Positive Longitudinal classification at ~10 mm cut-off: Negative Positive Transverse classification at ~15 mm cut-off: Negative Positive Longitudinal classification at ~15 mm cut-off: Negative Positive Identical readings in mm Transverse reading larger than longitudinal No. of readings with difference >3 mm Longitudinal reading larger than transverse No. of readings with difference >3 mm No. of readings reclassified" at 15 mm cut-off No. reclassified" at 15 mm cut-off where reading difference >3 mm No. of readings reclassified" at 10 mm cut-off No. reclassified" at 10 mm cut-off where reading difference >3 mm

59 321

15.5% 84.5%

59 321

15.5% 84.5%

167 213

43.9% 56.1%

167 213 108 106 34 166 39 24

43.9% 56.1% 28.4% 27.9% 8.9% 43.7% 10% 6.3%

9 7

2.4% 1.8%

3

0.7%

" Standard classification is based on transverse reading. Reclassification reflects change to positive classification when larger longitudinal direction is used

235

Immunodiagnostics for Latent Tuberculosis Infection

with one peak at 5-9 mm and another at 16-17 mm (Snider 1982). Based on previous animal data, it was felt that the smaller peak reflected reactivity to nontuberculous (NTM) strains, such as M. aviumintracellulare (MAl). Between 1958 and 1970, a study evaluating 275,558 Navy recruits tested all subjects with both PPD-S and PPD-B (MAl strains). The individuals with large reactions to nontuberculous PPD tended to have smaller reactions (6-11 mm) with PPD-S (Edwards et al. 1969). The incidence of active TB in 0-5 mm PPD reactors was 36/100,000, in 6-11 mm PPD reactors it was 110/100,000, and with indurations with PPD >12 mm the incidence of disease was 380/100,000. In another study, Palmer et al. (1959) evaluated skin-test reactivity in Pakistani children and again demonstrated a bimodal distribution with peaks at 2-5 mm and 17 mm. They concluded that the first peak was due to NTM, and the larger size peak represented true TB reactors. The reactions from NTM tend to be smaller than from MTB. Thus, increasing the cut-off for a positive reaction increases the specificity but reduces the sensitivity. In the USA, this has been the rationale for a 15 mm cut-off, since the prevalence of NTM is high (particularly in the southern USA) and of MTB low. A value of 15 mm is also close to the peak of reactivity described by the WHO in true reactors. In groups at high risk for TB, the cut-off is lowered in order to improve the sensitivity; immunocompromised groups, in particular, may have smaller size reactions or become anergic due to immune dysregulation, and thus the cut-off has been reduced to 5 mm.

15.8 Booster Although the PPD skin-test reactivity can persist throughout life, occasionally there is a diminution or absence in the DTH response to PPD over time. In such individuals, a return in response may be seen if tested sequentially over several weeks. This phenomenon of accentuation of response after repeat testing is commonly known as the booster effect and must not be interpreted as a new skin test conversion. Boostering most often occurs in persons older than age 55 years in whom cellular immunity may wane. Health care institutions where repeat TB testing is performed use an initial screening two-step test (two PPD skin tests about 3 weeks apart) to establish a baseline reactivity, in order to avoid falsely classifying a repeat test at a later time as a new conversion.

15.9 Adverse Reactions to PPD Testing Generally, adverse reactions to TB skin testing are rare; however, immediate hypersensitivity reactions have been reported and are in no way correlated to underlying TB infection (Tarlo et al. 1977; Wright et al. 1989). Individuals may also develop vesicular or ulcerating lesions at the site of PPD injection. These severe reactions occur in a small percentage ofpositive reactors; however, a previous positive does not predict an increased likelihood of developing a severe cutaneous reaction (Reichman and O'Day 1977). Health care providers use topical corticosteroid creams to treat these local reactions, but one controlled study using hydrocortisone did not demonstrate efficacy, although the use of a more potent steroid may have shown benefit (Hanson and Comstock 1968).

15.10 New Trends in Diagnosing Latent TB Infection The immune response to mycobacterial infection is predominantly cellular (Kaufmann 2001). The PPD skin test has been a convenient, cost-effective method for assessing cell-mediated immune responses to mycobacterial-derived proteins. Although the test is reasonably priced, there continue to be multiple factors challenging the accuracy of the PPD skin test (ST) in different settings. These factors include (but are not limited to) variability in operator placement and reading, cross-reactivity among mycobacterial species (including M. avium and BeG), the need for the patient to return in 48-72 h for a reading, and the modulation of the skin response due to underlying illness or immunosuppression. Clearly, there is a need for another more sensitive and specific test that would overcome the limitations of the skin test. In addition, the tools used to diagnose active disease are currently different from the skin test, which is used to detect exposure. The major immunodiagnostic advances to date have centered on more sensitive and rapid testing to determine the presence of active disease, but progress in the area of detecting exposure in healthy individuals has been slower. Recent work has shifted to identifying recombinant and purified antigens that may be used for skin testing and in immunoassays with greater sensitivity. One of the first tuberculosis complex-specific antigens discovered was MPT64, a

R. K. Katial

236

24 kDa protein. More recently, other antigens have been purified, including 38 kDa (antigen b), 10 kDa, 18 kDa, MPT59 (Ag85B), and ESAT-6 (Gennaro 2000). MPT64 has produced disappointing results when used as a skin-test reagent. Only 6% of PPD-reactive TB-positive patients responded to MPT64 in comparison with a 50% reactivity with MPT59 (Wilcke et al. 1966). Antigen b has been shown to be very antigenic and, when studied in guinea pigs, elicited a positive skin test in MTB-vaccinated animals but not in those exposed to other strains. The antigen appears to be more specific than PPD (Haslov et al. 1990). Vordermeier et al. (1992), using an epitope located near the 38 kDa antigen of MTB, elicited a DTH reaction in PPD-positive individuals but not in negative ones. These antigens may find a role in immunoassays and possibly in skin testing by providing the ability to detect newly exposed individuals with greater specificity as well as to differentiate those vaccinated from those infected. The immune response to MTB is highly dependent upon IFN-y production by macrophages and antigen-specific T-cells; over the past decade, there has been an increasing interest in the development and application of in vitro culture assays measuring IFN-y production in response to tuberculin antigen stimulation as a substitute diagnostic screening test for the classic PPD skin test (Lein and von Reyn 1997). Initially using peripheral blood mononuclear cells, the methodology evolved to a whole blood culture technique that was first validated in Australian cattle. These studies demonstrated that the IFN-y test had greater diagnostic sensitivity, lower cost, and rapid results for cattle TB screening (Rothel et al. 1992; Wood et al. 1991; Wood and RotheI1994). This method was developed for human TB testing using human PPD, avian PPD, and the mitogen phytohemagglutinin (PHA). A standardized diagnostic kit with a specifically defined data analysis procedure has been marketed by CSL in Australia (now Cellestis, Australia): QuantiFERON-TB or Q-IFN. In various studies comparing the Q-IFN assay with PPD-ST, the agreement ranges from 40% to 100% when looking at subjects without active disease or a history of active disease (Table 15.2). Agreement has been lower in those with active disease. Streeton et al. (1998) reported a sensitivity and specificity of 90.5% and 98%, respectively, for diagnosing MTB exposure in human subjects. In their study, the gold standard for diagnosis was the PPD-ST, and the study subjects were stratified according to their skin test induration and risk of exposure to tuberculosis. Kimura et al. (1998) and

Table 15.2. Agreement between Q-1FN and SKT for latent TB infection in various studies Reference

Skin test classification

Agreement between Q-1FN test and SKT

(Q-1FN/SKT)a N (HIV-) 68% P (HIV-) 70% 700/0 Overall, H1VN (H1V+) 85% 40% P (H1V+) 61% Overall, H1V+ 40% N (H1V -) Converse et aI. (1997) P (H1V - ) 100% Overall, H1V72% N (H1V+) 73% P(H1V+) 92% Overall, H1V+ 79% 100% Desem and Jones N 90% (1998) P 95% Overall 80% KatiaI et aI. N (2001) 80% P Overall 80% 500/0 N (H1V-) Kimura et aI. (1998) P (H1V -) 89% 59% Overall, HIV 85% N (H1V+) 56% P (H1V +) 82% OveraIl, H1V + 900/0 Mazurek et aI. N 65% (2001) P 85% Overall Pottumarthy et aI. N (high-risk country) 89% (1999) P (high-risk country) 64% N(HCW) 81% P (HCW) 67% 79% OveraIl 88% N Streeton et aI. (1998) 900/0 P 88% Overall Bellete et aI. (2002)

(43/63) (921131) (135/194) (22126) (ll/28) (33/54) (6115) (17117) (23/32) (16122) (ll/12) (27/34) (10/10) (9/10) (19/20) (16/20) (16/20) (32/40) (115/229) (63171) (178/300) (128/151) (9/16) (137/167) (738/818) (1471227) (885/1045) (135/151) (55/86) (64179) (32/48) (286/364) (480/545) (163/182) (643/727)

With ~15% = positive Q-1FN, excluding those with active disease or past history of active disease N =negative skin test defined at various cut-offs depending on risk; P =positive skin test defined at various cut-offs depending on risk; Hew = health care worker

a

Converse et al.(1997) used Q-IFN in studies comparing the IFN release assay with PPD-ST in populations at risk for MTB exposure (intravenous drug users with or without HIV infection). They found that the Q-IFN assay detected more reactors than PPD-ST. Agreement between the two tests was weak. We studied 40 patients and found good agreement between PPD-ST and the Q-IFN kit (kappa=0.73). We evaluated the agreement between in vivo and in vitro tests and did not refer to sensitivity and specificity because they assume comparison to an adequate gold standard, which we feel does not exist

237

Immunodiagnostics for Latent Tuberculosis Infection

(Katial et al. 2001). Recently, Mazurek and colleagues (2001) evaluated 1226 volunteers and found overall 83% agreement between the IFN-y assay and skin test in individuals at both low and high risk for latent TB infection. However, only 68% agreement was noted in the positive PPD-ST group. A similar study by Bellete et al. (2002) reported an overall agreement in a USA cohort of 79% (in Baltimore), but lower agreement (68%) was seen in Ethiopia, an endemic TB area. In addition, the authors found poor reproducibility in the in vitro results from one test to another. One significant drawback of both the skin test and the Q-IFN test is the nonspecific response to PPD because of cross-reactivity between tuberculin and other mycobacterial species. Although the Q-IFN test does distinguish M. avium from MTB reactivity, it does not differentiate between responses from MTB and other mycobacterial species such as M. kansasii, M. marum, and M. africanum. The false-positivity in the PPD skin testing due to BCG vaccination is well documented. However, the in vitro IFN-yproduction by BCG-vaccinated individuals in response to PPD may also be influenced by cross-reacting mycobacterial antigens. Streeton et al. (1998) included BCG vaccinees in their study but were unable to discern the effects of BCG on the assay results. Therefore, additional studies are needed to delineate the diagnostic value of the Q-IFN kit in this population. The in vitro diagnostic system affords a distinct advantage over PPD-ST in that one can test for tuberculin-specific proteins without unnecessarily exposing the patient. The low-molecular-weight antigen ESAT-6 (6 kDa) has been shown to differentiate between MTB and BCG strains and thus may serve as an additional stimulant to determine the effect of BCG. Recently, ESAT-6 was evaluated in the Q-IFN assay and found to differentiate those infected with TB from controls, with high sensitivity and specificity (Johnson et al. 1999). We studied low-molecular-weight culture filtrate proteins, culture filtrate proteins minus lipoarabinomannan, soluble cell wall proteins, and cytosolic proteins in whole blood culture, and none of the subfractions performed any better than the whole PPD (Katial et al. 2001). However, the crude preparations used in this study did stimulate IFN-y production in sensitized individuals and should be further purified and studied in the whole blood system. The immune response to TB is complex and directed to a heterogeneous mixture of antigens rather than anyone protein. Therefore, studying a cocktail of native or recombinant antigens may prove to be more specific and sensitive in diagnosing TB than anyone immunodominant protein. The advantages of the

blood test include the absence of any reading or placement variability and the need for only one office visit. The current disadvantages are the need for stringent laboratory requirements dealing with blood handling, cell culture, and ELISA testing. The areas needing clarification include defining the performance characteristics and lower cut-off limit for the enzyme immunoassay. Data are needed on temporal measurements to determine if the time of day or different days have any impact on the whole blood stimulation response. Finally, the cut-offs differentiating a positive from a negative response suggested in the Q-IFN kit need to be verified based on the prevalence of disease in different populations as has been done with PPD-ST. These issues should be addressed and followed up by large-scale trials to assess the true sensitivity, specificity, and positive predictive value of the Q-IFN kit, prior to Widespread use for clinical MTB testing. The assessment of IFN-y production by TB-specific lymphocytes is also being studied by more sensitive techniques such as flow cytometry and Elispot assays. Tilley and Menon (2000) demonstrated the correlation between intracellular staining of IFN-y in TB-specific lymphocytes with the extracellular secretion of IFN-y as measured by the Elispot assay. The authors were also able to conclude that the IFNy response as measured by the intracellular staining correlated directly with the Mantoux skin test. As the data in TB patients using these techniques increase, the understanding of the underlying TB immune response will become clear, and some combination of tests may become the new standard of care for the diagnosis of latent TB infection.

References Ahmed AR, Blose DA (1983) Delayed type hypersensitivity skin testing: a review. Arch DermatoI119:934-945 American Thoracic Society and Centers for Disease Control and Prevention (2000) Diagnostic standards and classification of tuberculosis in adults and children. Am J Crit Care Med 161:1376-1395 Bates JH, Stead WW (1993) The history of tuberculosis as a global epidemic. Med Clin North Am 77:1205-1217 Betiete B et al (2002) Evaluation of a whole-blood interferon-y release assay for the detection of Mycobacterium tuberculosis infection in 2 study populations. Clin Infect Dis 34: 1449-1456 Bouros D et al (1991) Palpation vs pen method for the measurement of skin tuberculin reaction (Mantoux test). Chest 99:416 Bouros D et al (1992) The role of inexperience in measuring tuberculin skin reaction (Mantoux test) by the pen or palpation technique. Respir Med 86:219-223

238 Centers for Disease Control (1994) Core curriculum on tuberculosis, 3rd edn. Centers for Disease Control, Atlanta, p 9 Collins H, Kaufmann S (2001) The many faces of host responses to tuberculosis. Immunology 103:1-9 Converse PJ et al (1997) Comparison of a tuberculin skin test in high-risk adults of human immunodeficiency virus infection. J Infect Dis 176:144-150 Daniel T (1980) The immunology tuberculosis. Clin Chest Med 1:189-201 Daniel TM, Boom WH, Ellner JJ (2000) Immunology of tuberculosis. In: Reichman L, Hershfield ES (eds) Tuberculosis: a comprehensive international approach, 2nd edn. Dekker, New York, pp 187-214 Davis AL (2000) A historical perspective on tuberculosis and its control. In: Reichman L, Hershfield ES (eds) Tuberculosis: a comprehensive international approach, 2nd edn. Dekker, New York, pp 3-54 Desem N, Jones SL (1998) Development of a human gamma interferon enzyme immunoassay and comparison with tuberculin skin testing for detection of Mycobacterium tuberculosis infection. Clin Diagn Lab Immunol 5: 531-536 Edwards LB et al (1969) An atlas of sensitivity to tuberculin, PPD-B and histoplasmin in the United States. Am Rev Respir Dis 99:1-132 Ellner JJ (1997) The immune response in human tuberculosis-implications for tuberculosis control. JID 176: 1351-1359 Gennaro ML (2000) Immunologic diagnosis of tuberculosis. Clin Infect Dis 30:s243-s246 Gryzbowski S, Brown MT, Stothard D (1969) Infections with atypical mycobacteria in British Columbia. CMAJ 100: 896-900 Hagan WA (1931) The no lesion case problem in the tuberculosis eradication campaign. Cornell Vet 21:163-171 Hanson ML, Comstock GW (1968) Efficacy of hydrocortisone ointment in the treatment of local reactions to tuberculin. Am Rev Respir Dis 97:472-473 Haslov K et al (1990) Comparison of the immunological activity of five defined antigens from mycobacterium tuberculosis in seven inbred guinea pig strains. The 38 kDa antigen is immunodominant. Scand J ImmunoI31:503-514 Hershey J, Engler RJ, Katial RK (2001) Tuberculin skin tests: to measure or not to measure in two directions? JACI 107: s254 Hirsch CS et al (1996) Cross-modulation by transforming growth factor b in human tuberculosis: suppression of antigen-driven blastogenesis and interferon g production. Proc Natl Acad Sci USA 93:3193-3198 Hirsch CS et al (1999) Depressed T-cell interferon-y responses in pulmonary tuberculosis: analysis of underlying mechanisms and modulation with therapy. JID 180:2069-2073 Howard T, Solomon DA (1988) Reading the tuberculin skin test: Who, when and how. Arch Intern Med 148:2457-2459 Iseman M (1999) Immunity and pathogenesis. In: A clinician's guide to tuberculosis. Lippincott Williams and Wilkins, Philadelphia, pp 63-96 Johnson PDR et al (1999) Tuberculin-purified protein derivative, MPT-64, and ESAT-6 stimulated gamma interferon responses in medical students before and after mycobacterium bovis BCG vaccination and in patients with tuberculosis. Clin Diagn Lab Immunol 6:934-937 Jordon T et al (1987) Tuberculin reaction size measurement by

R. K. Katial the pen method compared to traditional palpation. Chest 92:234-236 Katial RK et al (2001) Cell mediated immune response to tuberculosis purified protein derivative: comparison of TB skin testing to in-vitro g-interferon production in whole blood culture. Clin Diagn Lab Immunol 8:339-345 Kaufmann SH (2001) How can immunology contribute to the control of tuberculosis? Nature Rev Immunol1:20-30 Kimura M et al(1998) Comparison between a whole blood interferon-gamma release assay and tuberculin skin testing for the detection of tuberculosis infection among patients at risk for tuberculosis exposure. J Infect Dis 179: 1297-1300 Kiple KF (ed) (1993) The Cambridge world history of human disease. Cambridge University Press, Cambridge Koch R (1890) Ober bacterilogische Forschung. Dtsch Med Wochenschr 16:756 Koch R (1891) Fortsetzung der Mitteilungen tiber ein Heilmittel gegen Tuberculose. Dtsch Med Wochenschr 891:17-101 Lein D, von Reyn F (1997) In vitro cellular and cytokine responses to mycobacterial antigens: application to diagnosis of tuberculosis infection and assessment of response to mycobacterial vaccines. Am J Med Sci 313:364-371 Longfield J et al (1984) Interobserver and method variability in tuberculin testing. Pediatr Infect Dis 3:323-326 Lunn JA (1980) Reasons for variable response to tine test. Br Med J 280:223 Mazurek GH et al (2001) Comparison of a whole-blood interferon gamma assay with tuberculin skin testing for detecting latent Mycobacterium tuberculosis infection. JAMA 286:1740-1747 Murtagh K (1980) Unreliability of the Mantoux test using 1 TU PPD in excluding childhood tuberculosis in Papua New Guinea. Arch Dis Child 55:795-799 Grme I, Cooper A (1999) Cytokine/chemokine cascades in immunity to tuberculosis. Immunol Today 20:307-312 Palmer CE (1945) Nontuberculous pulmonary calcification and sensitivity to histoplasmin. Public Health Rep 60,513-520 Palmer CE et al (1959) Experimental and epidemiologic basis for the interpretation of tuberculin sensitivity. J Pediatr 55:413-428 Pearson L (1892) Tuberculin as a diagnostic agent. Med News 60:358-359 Pouchot J et al (1997) Reliability of tuberculin skin test measurement. Ann Intern Med 126:210-214 Pottumarthy S et al (1999) Evaluation of the tuberculin gamma interferon assay: potential to replace the Mantoux skin test. J Clin Microbiol 37:3229-3232 Reichman LB, G'Day R (1977) The influence of a history of a previous test on the prevalence ands size of reactions to tuberculin. Am Rev Respir Dis 115:737-741 Research Committee of the British Thoracic Association (1982) Reproducibility of the tine tuberculin test. Br J Dis Chest 76:75-78 Rothel JS et al (1992) The gamma-interferon assay for diagnosis of bovine tuberculosis in cattle: conditions affecting the production of gamma-interferon in whole blood culture. Aust Vet J 69: 1-4 Seibert FB, Glenn JT (1941) Tuberculin purified protein derivative: preparation and analysis of a large quantity for standard. Am Rev Tuberc 44:9-25 Snider D (1982) The tuberculin skin test. Am Rev Respir Dis 125:s108-s118

Immunodiagnostics for Latent Tuberculosis Infection Sokal JE (1975) Measurement of delayed skin test responses. N Engl J Med 293:501-502 Streeton JA,Desem N, Jones SL (1998) Sensitivity and specificity of a gamma interferon blood test for tuberculosis infection. Int J Tuberc Lung Dis 2:443-445 Tarlo SM et al (1977) Immediate hypersensitivity to tuberculin in in-vivo and in-vitro studies. Chest 71:33-37 Tilley PAG, Menon IN (2000) Detection of Mycobacteriumspecific interferon-gamma-producing human T lymphocytes by flow cytometry. APMIS 108:57-66 Tsuyuguchi I (1996) Regulation of the human immune response in tuberculosis. Infect Agents Dis 5:82-97 Villarino ML et al (1999) Comparable specificity of 2 commercial tuberculin reagents in persons at low risk for tuberculous infection. JAMA 281:169-171

239 Vordermeier HM et al (1992) M. tuberculosis-complex specific T-cell stimulation and DTH reactions induced with a peptide from the 38-kDa protein. Scand J Immunol 35: 11-718 Wilcke JT et al (1966) Clinical evaluation of MPT-64 and MPT59, two proteins secreted from mycobacterium tuberculosis, for skin test reagents. Tuber Lung Dis 77:250-256 Wood PR, Rothel JS (1994) In vitro immunodiagnostic assay for bovine tuberculosis. Vet MicrobioI40:125-135 Wood PR et al (1991) Field comparison of the interferongamma assay and the intradermal tuberculin test for the diagnosis of bovine tuberculosis. Aust Vet J 68:286-290 Wright DN, Ledford DK, Lockey RF (1989) Systemic and local allergic reactions to the tine test purified protein derivative. JAMA 262:2999-3000

Organ-related Chapters

16 Childhood Tuberculosis PETER R.

DONALD

CONTENTS Introduction 243 Epidemiology of Childhood Tuberculosis 243 Pathogenesis and Clinical Manifestations of Childhood Tuberculosis 245 Central Nervous System Tuberculosis 248 16.4 Intracranial Tuberculomata 250 16.5 16.6 Childhood Tuberculosis and HIV/AIDS 251 16.7 Diagnosis of Tuberculosis in Childhood 251 Tuberculosis in Infancy 254 16.8 Tuberculosis During Adolescence 255 16.9 16.10 Treatment of Tuberculosis in Childhood 256 16.11 Drug-resistant Tuberculosis in Childhood 257 16.12 Prevention and Control of Tuberculosis in Childhood 258 References 261

16.1 16.2 16.3

tion. It is of considerable interest that the frequency with which these various features are seen varies with age and therefore probably reflects changes in the immune response to tuberculosis infection. Perhaps because of this wide spectrum of pathology, childhood tuberculosis will be looked upon by some as a relatively benign manifestation of tuberculosis infection and regarded by others as a major child health problem, particularly in developing countries. This chapter will describe the epidemiology of tuberculosis in childhood, the most important clinical features of childhood tuberculosis, the interaction of childhood tuberculosis and HIV/AIDS, and the diagnosis and management of childhood tuberculosis.

16.1 Introduction

16.2 Epidemiology of Childhood Tuberculosis

Childhood tuberculosis refers to a wide spectrum of manifestations of tuberculosis seen in children from birth to adolescence. At one extreme, particularly in the very young, are life-threatening disseminated forms of tuberculosis, such as tuberculous meningitis and miliary tuberculosis. At the other extreme, enlargement of the mediastinal lymph nodes may pass entirely unnoticed, and the development of a positive tuberculin test will be the only sign that tuberculosis infection has occurred. As the children enter adolescence, "adult-type" pulmonary tuberculosis will be seen with increasing frequency, characterized by the development of cavitation involving mainly the apices of the lungs. Also at this age, large pleural effusions with straw-coloured fluid become more common as a manifestation of primary infec-

The incidence of childhood tuberculosis will be determined by the frequency of exposure to a source of infection, which will nearly always be an adult with sputum microscopy smear-positive, cavitating pulmonary tuberculosis. In developed communities, tuberculosis has become mainly a disease of the elderly, with a male predominance, occurring amongst the economically deprived, living on the fringes of society. Small foci of disease may also be found amongst disadvantaged groups such as immigrants. Children will thus not often be exposed to the risk of infection and disease. In developing communities, tuberculosis will be a disease of young adults, often with a female predominance. Children aged 15 years or less may constitute 40% or more of the population, and it is therefore not surprising that the incidence of childhood tuberculosis is far higher in a developing community than a developed community and that children make up a far greater portion of the tuberculosis case load. Thus, not only are there more young children in these communities, but they will be exposed to tuberculosis infection at a much

P. R. DONALD, MD, FRCP (Edin), FCP (SA), DCH (Glasgow), DTM&H (London) Department of Paediatrics and Child Health, Faculty of Health Sciences, University of Stellenbosch, P.O. Box 19063, 7505, Tygerberg, South Africa M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

244

younger age than would be the case in a developed community. Because more serious forms of tuberculosis such as miliary tuberculosis and tuberculous meningitis tend to occur in younger children, these potentially deadly forms of tuberculosis will occur more frequently in developing communities. During the last decade tuberculosis has been acknowledged as a worldwide threat to health, and in 1993 the World Health Organization declared the tuberculosis situation in the world a global emergency. Although considerable effort has since been expended in promoting the diagnosis of adult pulmonary tuberculosis by sputum smear microscopy and curing patients with directly observed short course treatment (DOTS), the burden of childhood tuberculosis frequently goes unrecognized. In developed countries, this is understandable as children may constitute less than 5% of the tuberculosis case load; in developing countries, however, this percentage may rise to 20% or even 40% in certain high-incidence countries and communities. Because of the difficulty of diagnosing tuberculosis in childhood, estimates of the global burden of childhood tuberculosis are at best an educated guess. In an often quoted estimate, the number of cases of childhood tuberculosis occurring in 1990 was put at 1.3 million, leading to 450,000 deaths (Kochi 1991). In other estimates, an arbitrary figure of 10% appears to have been used to calculate the portion of the tuberculosis burden attributable to children. Thus, it was predicted that during 2000 just over 1,000,000 cases of childhood tuberculosis would occur in the world. In the African region, however, under the influence of HIV/AIDS, 447,000 children would make up 20% of the tuberculosis burden, in contrast to the 1990 estimate of 90,000 cases of childhood tuberculosis for the region (Dolin et al. 1994). That such a dramatic increase has in fact occurred is suggested by data from several sources. In Malawi, for example, the number of children 0-14 years of age with tuberculosis managed at the Queen Elizabeth Central Hospital increased from 64 in 1986 to 507 in 1995. In 1995 and 1996,64% of children being treated for tuberculosis were mY-seropositive (Harries et al. 1997). In contrast to the above estimates, which must be open to considerable doubt, the risk of infection to which children are exposed can be objectively quantified by determining the annual risk of tuberculosis infection (ART!). ART! is determined by tuberculin testing a representative group of children at regular intervals to detect the incidence of infection and is considered one of the most objective ways to evaluate the tuberculosis situation in any community (Bleiker

P. R. Donald

1991). While ART! in most developed countries will be in the region of 0.01 %, it may rise as high as 2% or 3% in developing countries, implying that between a third and a half of the population will be infected by 15 years of age. From this figure it then becomes possible to predict more accurately the number of cases of childhood tuberculosis that are likely to arise in a particular community. It is disturbing that several recent studies from the developing world have shown no fall in ART! over long periods. In the Chingleput district of south India, for example, ART! has remained at 2% since observations started in 1968 (Tuberculosis Research Centre 2001). In Tanzania, ART! was 1.0% during 1988-1992 and 0.9% during 1993-1998. In this instance, the relatively constant ART! is reason for a certain amount of optimism, in that adult tuberculosis notifications have doubled under the influence of mY/AIDS during this same period (Tanzania Tuberculin Survey Collaboration 2001). This "success" is ascribed to the early adoption and implementation of the DOTS strategy by Tanzania. Figure 16.1 illustrates the age- and sex-related incidence of tuberculosis up to the age of 20 years in a developing community. There are several noteworthy features. Firstly, there is a very high incidence of tuberculosis in a developing community in early childhood, with a slight but consistent male predominance in the first year of life. This susceptibility of the young infant to tuberculosis is even more striking when considered as a proportion of the infected population, and very high rates of disease following infection of 5,000 to 6,000/100,000 population have been calculated for infected infants (Rich 1951; Bentley et al. 1954). Not only are the very young more susceptible to tuberculosis disease, but the disease is c:

o

~::>

250

Co

8. 8o 200 o o....

g 150

Tuberculous meningitis Miliary tuberculosis Lymphobronchial tuberculosis 'Adult type' tuberculosis

C1l

"t:l

'0

.5

'" 100

.~

~ 2 ~

501....&........- -......- _ - -.....-__.--_

Fig. 16.1. Age- and sex-related incidence of tuberculosis up to the age of 20 years in a typical developing community

245

Childhood Tuberculosis

likely to be more serious, disseminated and to take the form of tuberculous meningitis or miliary tuberculosis. With increasing age both the frequency and severity of disease decline until a nadir is reached between 5 and 10 years of age, the so-called "safe school age" of the old German authors. As adolescence is entered, the incidence of disease rises again, "adult-type" pulmonary tuberculosis with apical cavitation becomes the norm, and large pleural effusions with a straw-coloured exudate are frequently encountered.

16.3 Pathogenesis and Clinical Manifestations of Childhood Tuberculosis Following infection, the clinical manifestations of tuberculosis will develop in a certain pattern, which was described as the "time-table of tuberculosis" by the great Swedish paediatrician, Arvid Wallgren (1948). As a generalization it is usually stated that disease will occur in approximately 10% of individuals following infection and that the greatest risk for most manifestations of disease is in the 3-12 months following upon infection, although a lifetime risk of disease does remain. In some communities disease may follow infection in as many as 15% or 20% of individuals. The "timetable of tuberculosis" is summarized in Fig. 16.2. Within 3-8 weeks of infection, the majority of infected individuals will become tuberculin-positive

Time after primary infection

and experience an unobtrusive ,fever of onset' (Wallgren 1928). By 1 month later, the features of primary tuberculosis will start to be seen, and by the end of one year after infection, most cases of tuberculous meningitis, miliary tuberculosis and pleural effusion will have occurred. In contrast, although many cases of osteoarticular tuberculosis will develop within a year ofinfection, they will continue to occur for several years after infection. Interestingly' although haematuria will often be detected shortly after infection and M. tuberculosis can be cultured from the urine, renal tuberculosis will seldom be seen sooner than 5 years after infection (Munro 1944). Following upon infection, two events playa major role in determining the clinical manifestations of childhood tuberculosis. Firstly, before the establishment of cellular immunity to M. tuberculosis, lymphohaematogenous dissemination of organisms occurs and will distribute small numbers of organisms throughout the body, but particularly to sites with a good blood supply. In addition to reaching the bone ends, meninges and kidneys, bacilli also again reach the lungs and in the form of Simon foci may later give rise to adult tuberculosis. Should exceptionally large numbers of organisms be liberated into the blood by erosion into a blood vessel within a lymph node or following the establishment of tubercles within a blood vessel, a tuberculous septicaemia ensues, and small tubercles will develop throughout the body. In the lungs, these give rise to small, uniformly sized nodules the size of millet seeds on chest radiography, and hence the name miliary tuberculosis (Fig. 16.3). The second important factor in the pathogenesis of childhood tuberculosis is the role of the medias-

Clinical Manifestation Fever ofOnset

2 - 3 months Tuberculin Test Positive

Primary puhnonary TB TB Meningitis Miliary TB TB Pleural effusion

3 - 12 months

I

I

ttl

oS

is ~

isc.. 0

§'"

f I ()

0

.3.

~

~:

r;;'

6 - 24 months

II

Osteo-articular TB

> 5 years

II

RenalTB

Fig. 16.2. The timetable of tuberculosis

Fig.16.3. Massive haematogenous dissemination of bacilli leading to multiple small nodules less than 2 mm in diameter evenly distributed throughout the lungs

246

tinal nodes which form part of the primary or Ghon complex in the lungs. Following inhalation of a small droplet 5-10 flm in diameter containing a very small number of M. tuberculosis organisms, a tuberculous focus becomes established in the lungs. From the primary or Ghon focus organisms spread via the lymph ducts to the regional lymph nodes. Most often, only the nodes, either hilar (Fig.16.4) or paratracheal (Fig. 16.5} or both, are seen on a chest radiograph. Occasionally, the primary focus is visible or more commonly it may become visible some 6-9 months later as calcification develops. In a majority of cases, there is only a single primary focus, but in approxi-

P. R. Donald

mately 20% of individuals two or more primary foci may be seen, as illustrated in Fig. 16.6. Enlargement of the hilar nodes with or without ulceration gives rise to a spectrum of pathological changes including segmental or lobar collapse or hyperinflation, collapse consolidation, and segmental or lobar expansile consolidation with or without cavitation. With complete obstruction, collapse of a lobe or segment will develop (Fig. 16.7}. With partial obstruction and a ball-valve effect, hyperinflation of a lobe or segment or a whole lung may develop (Fig. 16.8). Ulceration of a node and discharge of its contents into the relevant bronchus may lead to collapse consolidation or in the absence of obstruction to a lobar or segmental opacification or the appearance of an expansile pneumonia. The histology of these lesions may vary according to the immune response and the numbers of organisms present in the lesion (Seal and Thomas 1956). At one extreme, a benign ,tuberculin' response may be seen with a good prognosis and clearing within 2-3 months. At the other extreme, caseation with cavity formation may develop and lead to bronchiectasis and permanent lung damage (Fig. 16.9}. Should partial obstruction also be present, a grossly enlarged tension cyst may be formed. This course of events is summarized in Fig. 16.10. In the past, these usually well defined lesions were referred to as epituberculosis, segmental tuberculosis, or endobronchial tuberculosis. They are perhaps best grouped together

Fig. 16.4. Enlargement of the hilar nodes in a child 2 years of age with a Mantoux test giving an induration of 20 mm and the gastric aspirate positive on culture for M. tuberculosis

Fig. 16.5. Enlargement of the right paratracheal nodes in a 5year-old child. Sputum positive on culture for M. tuberculosis

Fig. 16.6. Right-sided paratracheal enlargement with calcification appearing in the nodes and in three right-sided primary foci in a 3-year-old child. Gastric aspirate positive on culture for M. tuberculosis

Childhood Tuberculosis

247

Fig. 16.7. Collapse of the right middle lobe in a 2-year-old child who presented with persistent cough and wheeze. Gastric aspirate positive on culture for M. tuberculosis. A Mantoux test gave an induration of 18 mm

b

Fig. 16.8. Enlargement of the paratracheal nodes with hyperinflation of the right lung in a 2-year-old child with gastric aspirate positive on culture for M. tuberculosis

Fig. 16.9. Consolidation of the left upper lobe with several cavities enlarged by pressure inflation. A fine nodularity is also present in the right lung, which may indicate bronchogenic dissemination and a small left-sided pleural reaction. Gastric aspirate positive on culture for M. tuberculosis

as lymphobronchial tuberculosis, thus emphasizing the role of both lymph node enlargement and bronchial disease in determining the varied features of these lesions which, none the less, have a common origin. Any primary tuberculosis infection will be accompanied by a greater or lesser degree of lympho-hae-

matogenous dissemination of organisms throughout the body. These have a predilection for certain organ systems where they may establish themselves and give rise to disease if not controlled by the individual's immune response. The most important site where extrapulmonary disease may arise in childhood is the central nervous system.

P. R. Donald

248

Benign "Tuberculin Response"

Fig.16.10. Lymphobronchial tuberculosis: the spectrum of possible consequences of tuberculous involvement of the mediastinal nodes during primary tuberculosis

16.4

Central Nervous System Tuberculosis Tuberculous meningitis (TBM) is the most serious complication of childhood tuberculosis and has its highest incidence between the ages of 2 and 3 years. At this age it is often associated with miliary tuberculosis, and if untreated a majority of children with miliary tuberculosis will die of TBM. In both developed and developing countries the diagnosis of TBM is frequently delayed, with disastrous consequences for the patient as the prognosis is closely linked to the stage of the disease at the time of diagnosis. A classification of the stage of TBM developed by the British Medical Research Council in 1948 is still useful. Patients with early signs of meningeal irritation but no other focal signs are at stage I TBM. Patients diagnosed at this point should recover fully. When focal neurological signs appear or the patient is mentally confused, the disease is considered to be at stage II. Although the majority of patients presenting at stage II will survive, they are likely to do so with a physicalor intellectual deficit. By stage III, the patient is comatose, unable to localise pain, and may have a complete hemiplegia or rarely a quadriplegia. A third of these patients may die, and the great majority of survivors will have severe physical and mental handicaps (Medical Research Council 1948). Although TBM may occur at any time following primary infection, it occurs most often approximately 3 months after primary infection as result of the rupture of a parenchymal focus, or less often a

meningeal focus into the cerebrospinal fluid (CSF). This release of antigens into the CSF elicits a severe inflammatory response, which gives rise to a thick gelatinous exudate. This exudate envelops the base of the brain and the adjacent structures. This in turn leads to cranial nerve palsies, vasculitis, and raised intracranial pressure due to obstruction to the flow of CSF. The vasculitis affects the larger blood vessels such as the middle cerebral artery and the smaller blood vessels of the basal ganglia and will often lead to infarctions and irreversible brain damage. TBM usually has an insidious onset lasting a week or more marked by increasing lassitude, loss of appetite and irritability. Occasionally, a more acute onset may be seen resembling that of other forms of bacterial meningitis. Many children will experience a preceding loss of weight. Common presenting complaints include vomiting, cough, fever, apathy and headache; this last complaint being seen mainly in children older than 3 years. Because of the non-specific nature of these features, a high index of suspicion is necessary when these complaints persist. A tuberculin test, a chest radiograph or enquiry as to household contact with an adult with ,smear-positive' pulmonary tuberculosis may lead to the early diagnosis of TBM or to the prevention of TBM in some instances by the early prescription of antituberculosis treatment. In any case where doubt is present, a lumbar puncture should be done. The CSF in TBM will typically be clear with a mean cell count of approximately 100Xl06/L, predominantly lymphocytes, a mean protein of 1.5 giL, and a mean glucose of 1.8 mmollL. It is very important to note that this is a typical picture. In 5%-10% of cases, a cell count of >500x106 /L with a predominance of polymorphonuclear leucocytes may be found; CSF protein levels may be normal or between 0.45 giL and 0.8 giL in close to 20% of cases; the CSF glucose may be >2.2 mmollL in as many as 30%-40% of cases (Donald et al. 1991). There is thus ample room for mistakes to be made. In any case of doubt, it is better to initiate antituberculosis treatment and review the diagnostic evidence later. The diagnosis of TBM is confirmed by a culture of M. tuberculosis from the CSF. This is, however, positive in only a minority of cases. This is probably due to the relatively small amounts of CSF that are submitted for culture from children. Support for the diagnosis is provided by culture of M. tuberculosis from another source such as gastric aspirate or lymph node biopsy, a chest radiograph suggestive of tuberculosis, a positive Mantoux test, or a history of close contact with an adult with sputum "smear-positive" tuberculosis.

Childhood Tuberculosis

249

A chest radiograph may show evidence of respira- raised CSF white cell count or protein concentration tory tuberculosis in up to 70% of children with in such cases would provide sound support for a deciTBM, while a Mantoux test should be positive in a sion to continue antituberculosis treatment. The management of TBM involves three aspects: majority of children. It must be emphasized, however, that a negative Mantoux test does not exclude TBM. the elimination of viable M. tuberculosis from the Approximately 50% of children with TBM will have lesions, the control of raised intracranial pressure a history of contact with an adult with pulmonary and the prevention of further brain damage related tuberculosis, and in many cases this will be a family to the presence of the basal exudate, and the associated hypersensitivity and vasculitis. member, often the mother or a grandparent. There are almost no controlled trials evaluating Cranial computed tomography or magnetic resonance imaging, if available, may also assist and show different regimens for treating TBM. Consequently, hydrocephalus associated with the basal enhance- a variety of recommendations can be found in the literature and various official documents. Standard ment and possibly cerebral infarctions (Fig. 16.11). Other diagnostic aids include CSF polymerase short course regimens given for 6 months and all chain reaction, the detection of tuberculostearic acid containing rifampicin for the full 6 months have been in the CSF, CSF adenosine deaminase concentrations, reported to be successful by several groups (Biddulph CSF lactate or lactate dehydrogenase concentrations, 1990; Jacobs et al. 1992). Our own preference is for a and the bromide partition test. None of these tests at 6-month regimen of isoniazid, rifampicin, pyrazinpresent has a totally satisfactory sensitivity or speci- amide and ethionamide, with isoniazid and rifampificity, and while they may be valuable in individual cin given in a dose of 20 mg/kg body weight. In our patients, the final decision as to whether to treat a region there is an overall incidence of isoniazid resispatient remains a clinical one assisted mainly by the tance of 10%. Approximately half of these isolates are resistant at isoniazid concentrations of <5 fig/ml, a clinical features and the CSF results. In cases of doubt it can sometimes be valuable concentration easily exceeded even in fast acetylto repeat the lumber puncture a week or two after ators by giving a higher dose of isoniazid (Donald treatment has been started. It would be most unusual et al. 1992). Rifampicin is a critical sterilizing agent for the CSF findings to normalize in such a relatively in tuberculosis regimens. It is, however, 80% protein short space of time in the case of TBM. A persistently bound, and relatively low concentrations enter the CSF when given in a dosage of 10 mg/kg (Humphries 1992). Ethionamide is notorious for causing gastric irritation and nausea but obtains a satisfactory entry into the CSF (Donald and Seifart 1992) and is much better tolerated by children than adults. We have used this regimen in over 200 patients to date and have experienced relatively few problems with drug toxicity; we documented relapse in only one patient in whom the dosages of the drugs were reduced after 2 months of treatment. If the intracranial pressure is monitored, it will be found to be raised in nearly all children presenting with stage II or III TBM. In those children who have a communicating hydrocephalus and the absence of other intracranial pathology has been confirmed by computed tomography or magnetic resonance imaging, raised intracranial pressure can be successfully managed by using furosemide (1 mg/kg/day) and acetazolamide (100 mglkg/day). The presence of communication between the ventricles and the spinal Fig. 16.11. Cranial computed tomography with contrast in a canal can be demonstrated by injecting air at the time 2-year-old child with tuberculous meningitis showing acute of lumbar puncture and taking an X-ray of the skull, hydrocephalus and periventricular oedema. Diffuse enhancewhich should show air in the ventricles (Fig. 16.12). If ment in the territory of the right middle cerebral artery is present indicating ischaemia. A mass effect also indicating air is seen at the base of the brain and not in the ventricles, a non-communicating hydrocephalus is probably ischaemic changes is seen in the right caudate nucleus

250

Fig. 16.12. Skull radiograph of a child with tuberculous meningitis. Air was injected at the time of lumbar puncture and is seen at the base of the brain and in the ventricular system, indicating that a communicating hydrocephalus is present

present, and a ventriculo-peritoneal shunt is urgently required to relieve the raised intracranial pressure. As tuberculin hypersensitivity is thought to play an important role in the formation of the basal exudate in TBM and its associated vasculitis, there is a long tradition of using corticosteroids to manage this problem. At first, it was reported that corticosteroids decreased mortality but did not affect the outcome amongst survivors (Freiman and Geefhuysen 1970; Shao et al. 1980). In a later study corticosteroids improved not only morbidity but also outcome (Girgis et al.1991). In a more recent, randomised trial, prednisone was also shown to improve morbidity and outcome. Interestingly, it did not appear to have any effect upon raised intracranial pressure (Schoeman et al. 1996). Tuberculomata, when present, resolved more quickly, and fewer new tuberculomata developed in those patients receiving corticosteroids.

P. R. Donald

In a review of 202 cases of TBM seen at our hospital, associated granulomas were present in 34 (17%) children (Ravenscroft et al. 2001). Two necrotic processes occur in these lesions. In gummatous necrosis the inflammatory granulation tissue itself becomes necrotic, and the fibrovascular stroma can be identified on silver reticulin staining. The process can repeat itself intermittently, giving rise to a lamellated appearance. In the second process there is no fibrovascular component, and the consistency of the contents can vary from caseous to purulent liquid. Gummatous necrosis is isodense or hyperdense on cranial CT, while caseous necrosis is hypodense or isodense, reflecting the more fluid character of the contents (Rutherfoord and Hewlett 1994). Intracranial tuberculomata may be asymptomatic and discovered by chance or present with convulsions or signs or symptoms of raised intracranial pressure. Unless the lesion is situated at some critical point in the central nervous system, medical treatment as for TBM and augmented by corticosteroids will usually be sufficient. As is the case with tuberculous cervical lymphadenopathy, it is not unknown for these lesions to enlarge paradoxically despite successful antituberculosis treatment. Should the lesion give rise to symptoms, either due to its location or due to raised intracranial pressure, a course of corticosteroids may expedite the shrinkage of the lesion.

16.5 Intracranial Tuberculomata Tuberculomata are common intracranial tumours in those communities where tuberculosis is common. They may be single or multiple in 15%-20% of cases (Jamieson 1995). They may occur in isolation or in association with tuberculous meningitis (Fig. 16.13).

Fig. 16.13. Computed cranial tomography with contrast in a child with stage II tuberculous meningitis. There is meningeal enhancement in the left Sylvian fissure and multiple, homogeneously enhancing granulomata

251

Childhood Tuberculosis

16.6 Childhood Tuberculosis and HIVI AIDS The last decade has witnessed the continued spread of HIV/AIDS throughout the world and its pernicious effect upon the incidence of tuberculosis. Nowhere has the deleterious interaction of these two formidable diseases been more dramatic than in the countries of sub-Saharan Africa where the tide of HIV/AIDS and tuberculosis is threatening to overwhelm the already struggling health services. Not surprisingly, this dual epidemic is also affecting childhood tuberculosis, and very high rates of HIV seropositivity have been recorded amongst children with tuberculosis (Chintu et al. 1993; Harries et al. 1997). Because of the difficulty ofconfirming the diagnosis of tuberculosis in children, it is uncertain how many of these children really do have tuberculosis. In addition to tuberculosis, these HIV-infected children are also susceptible to a variety of other bacterial pathogens including S. pneumonia, H. influenza and S. aureus as well as pathogens such as Pneumocystis carinii, respiratory syncytial virus and cytomegalovirus (Graham et al. 2001). Lymphocytic interstitial pneumonitis frequently presents with a reticulonodular appearance and hilar adenopathy on chest radiographs and can easily be confused with miliary tuberculosis. In a study from Johannesburg, M. tuberculosis was isolated from 8.5% of 423 HIVinfected children and 7.6% of 434 uninfected children (Mahdi et al. 2000). In Cape Town M. tuberculosis was similarly isolated from 10% of HIV-infected children and from 14% ofa group of non-HIV-infected children (Zar et al. 2000). Amongst children with lung disease persisting more than a month, M. tuberculosis was isolated from 29% of both HIV-infected and non-HIVinfected children (Jeena et al. 1998). A post-mortem study of 32 HIV-infected children from Botswana confirmed the presence of tuberculosis in 4 (l2.5%) (Ansari et al. 1999). These findings all suggest that tuberculosis is definitely a problem in HIV-infected children and that a high index of suspicion is always required. In an endemic area, however, it is but one of a number of other infections to which these children are subject. HIV-infected children may present with all of the features of childhood tuberculosis seen in immunocompetent children. Several studies from the developed world have found an increased incidence of extrapulmonary tuberculosis, as is the case in HIVinfected adults (Chan et al. 1996; Khouri et al. 1987; Thomas et al. 2000). This has, however, not been the case in studies from Africa (Chintu and Zumla 1995). Despite this, it is necessary to consider tuberculosis in

the differential diagnosis of any lesion not responding to conventional treatment in these children.

16.7 Diagnosis of Tuberculosis in Childhood The diagnosis of tuberculosis in childhood requires a high degree of suspicion but at the same time a balanced clinical perspective. Suspicion is required, as the features of childhood tuberculosis may be subtle and non-specific. Failure to gain weight properly may be the only clinical sign that a child is in the active phase of primary tuberculosis infection. Balance is required, as the urgency of making a diagnosis of tuberculosis must be weighed against factors such as the child's age and the severity of the child's illness. In a child 8 years of age with a subtle picture of hilar enlargement on chest radiography and a vague history of indisposition, one may safely choose to await further developments and the results of investigations before making a final diagnosis. In a young infant with an enlarged liver and spleen and an illdefined nodular opacification on chest radiography, it is a matter of urgency to commence antituberculosis treatment as soon as possible and to dispute later as to the accuracy of the diagnosis. In an adult it is unwise to accept a diagnosis of tuberculosis without microbiological confirmation either by way of culture of M. tuberculosis or by visualization of acid-fast bacilli on microscopy of a clinical specimen. Childhood tuberculosis is paucibacillary, and cavitation of the lung tissue is relatively unusual. Consequently, as few organisms are excreted, it would be equally unwise to await . microbiological confirmation of the diagnosis of childhood tuberculosis before commencing treatment. Even with intensive investigation of children with probable tuberculosis in specialist institutions, microbiological confirmation of the diagnosis will seldom be obtained in more than 50% of cases (Schaaf et al. 1995; Smith et al. 1996; Lobato et al. 1998). In the community, where most cases of childhood tuberculosis must be diagnosed and managed, fewer than 10% of cases are likely to be confirmed by culture or microscopy (Jacobs et al. 1987). In view of the lack of sensitivity of gastric aspirate culture and microscopy to detect M. tuberculosis in children, attempts have been made to use PCR in the detection of mycobacterial DNA. While satisfactory sensitivity and specificity have been claimed by some (Pierre et al. 1993; Delacourt et al. 1995), other

252

P. R. Donald

investigators consider the technique to be unreliable at present (Noordhoek et al. 1994; Smith et al. 1996). Unfortunately, whatever one's views of this technology, it is unlikely to be available in precisely those communities where most cases of childhood tuberculosis occur. The diagnosis of childhood tuberculosis consequently remains a clinical process drawing on the patient's history, clinical examination, chest radiography, tuberculin testing and lastly culture of gastric aspirate or sputum in older children. Making use of this process, the World Health Organization has recommended a hierarchical approach leading to children being classified as suffering from suspect, probable or confirmed tuberculosis. This approach is summarized in Table 16.1 (World Health Organization 1989). A history of close household contact with an adult with microscopy smear-positive pulmonary tuberculosis should immediately raise the suspicion that infection may have occurred. From one-third to twothirds of children so exposed may be infected (Brailey 1940; Shaw and Wynn-Williams 1963; van Geuns et al. 1975). It is also recommended that a cough and wheeze not responding to appropriate treatment, failure to recover from a preceding illness, or loss of weight or overt malnutrition should also raise the suspicion of tuberculosis in a child. The sensitivity and specificity of these criteria have, however, seldom been determined. Amongst a group of 627 children <5 years of age attending an outpatient department in an area with a particularly high incidence of tuberculosis, 206 (33%) were found to have one or more of the above criteria for suspect tuberculosis (Houwert et al. 1998). The children were evaluated by gastric aspi-

rate, Mantoux testing and chest radiography. After reviewing the diagnostic criteria 2 months later, 23 children (11 %) were considered to have probable tuberculosis, and a further 10 (5%) had confirmed tuberculosis. The most rewarding criterion was close household tuberculosis contact, and 23 (35%) of such children had either confirmed or probable tuberculosis compared with 13 (22%) of 46 children with persistent cough and 24 (15%) of 157 children with loss of weight. Of 11 children who had all 3 criteria, 7 (63%) had probable (4) or confirmed (3) tuberculosis. Since this study the spread of HIV/AIDS has complicated the interpretation of these diagnostic criteria considerably. Many children with HIV/AIDS will have lost weight, many will be exposed to household tuberculosis contact and will be suffering from recurrent or persistent respiratory infections. As the resources of many developing countries to carry out further diagnostic investigations in children are limited, it seems inevitable that many HIV-infected children who do not have tuberculosis will be placed on antituberculosis treatment. In another study children who presented with probable tuberculosis were investigated. There was no difference between the proportion of children later thought to have probable or confirmed tuberculosis and those found not to have tuberculosis in the presence of clinical features such as weight loss, cough or wheezing lasting more than 2 weeks, hepatosplenomegaly or peripheral lymphadenopathy. Furthermore, in this high tuberculosis incidence population, although 43% and 56%, respectively, of the children with confirmed and probable tuberculosis had an adult household contact with tuberculosis, so did 21 % of those later thought not to have tuberculosis. To add further diagnostic confusion, 10% of

Table 16.1. World Health Organization (1989) provisional guidelines for the diagnosis of pulmonary tuberculosis in children A. Suspect tuberculosis

B. Probable tuberculosis

C. Confirmed tuberculosis

1. An ill child with a history of contact with a confirmed case of pulmonary tuberculosis

A suspect case and any of the following:

2. Any child:

1. Positive (~10 mm) induration on tuberculin testing

1. Detection by microscopy or culture of tubercle bacilli from secretions or tissues or 2. The identification of the tubercle bacilli as Mycobacterium tuberculosis by culture characteristics

2.1 Not regaining normal health after measles or whooping cough 2.2 With loss of weight, cough and wheeze not responding to antibiotic therapy for respiratory disease 2.3 With painless swelling in a group of superficial nodes

2. Suggestive appearances on chest radiograph 3. Suggestive histologic appearance of biopsy material 4. Favourable response to specific antituberculous therapy

Childhood Tuberculosis

253

Tuberculin testing is one of the most important the children with tuberculosis confirmed by culture had a chest radiograph which was considered normal investigations supporting the diagnosis of tubercuon blind reading by an independent panel (Schaaf et losis in a child. It must, however, be emphasized that al. 1995). This last finding is not unexpected, as it a positive tuberculin test, however defined, means is known that when such children are evaluated by only that a child has been infected by M. tuberculosis. chest computed tomography, hilar nodal enlarge- The younger the child, the more significant a positive ment will frequently be visible (Delacourt et al.1993). tuberculin test is as infection is likely to have occurred This finding does emphasize the uncertain division recently, and infection in a young child is more likely between what clinicians regard as infection only and to proceed to disease than in an older child. disease in childhood tuberculosis. The tuberculin test must be interpreted in the light In any area where childhood tuberculosis is of the child's clinical condition, the epidemiological common, children will also suffer from a multitude of background and whether or not BCG vaccination has other infectious, allergic and congenital conditions, been administered. There is also a small number of and will often be malnourished to a greater or lesser individuals who appear unable to respond to tubercudegree. It is not surprising that many of these chil- lin, perhaps on a genetic basis (van Eden et al. 1983). dren will be inappropriately treated for tuberculosis. Recent childhood viral disease, live virus vaccines Table 16.2 lists some of these conditions which in our such as measles and rubella vaccines, severe malnuexperience have caused diagnostic problems. When trition, overwhelming tuberculosis disease, corticotuberculosis treatment of a child is commenced on steroid therapy and HIV/AIDS may all be responsible uncertain grounds, it is essential for the clinician to for a false-negative tuberculin test. Nearly two-thirds keep the case under review and to consider other of HIV-infected children with tuberculosis may have a negative tuberculin test (Chan et al. 1996; Mukadi diagnostic options. Culture and microscopy of gastric aspirate are et al. 1997). Nonetheless, even in communities with a the means by which tuberculosis will most often be particularly high incidence of tuberculosis and HIV confirmed in childhood. Although a relatively simple infection, the tuberculin test remains a valuable diagprocedure, attention to detail will improve the results nostic aid. The majority of children with tuberculo(Pomputius et al. 1997). Although hospitalization is sis in these communities will not be HIV-infected, usually considered necessary for gastric aspirate, this and even amongst those who are HIV-infected, the is not necessarily so (Lobato et al. 1998). Alternative suppression of tuberculin hypersensitivity will be means of collecting specimens for culture from chil- related to the stage of AIDS in each child (Schaaf et dren are nasopharyngeal aspirate, which could also al. 1998). be used in community work (Franchi et al.1998), and In individuals who have received BCG vaccine, a sputum induction (Zar et al. 2000), both of which will transverse induration of ~15 mm should be taken give a comparable yield of positive cultures. When- to indicate M. tuberculosis infection, where BCG has ever sufficient resources are available, every attempt not been given ~10 mm, and in those who are HIVshould be made to confirm the diagnosis of tuber- infected ~5 mm (Harries and Maher 1996). culosis in a child. A successful culture may reveal Chest radiography may provide valuable supportunexpected drug resistance (Steiner et al. 1985), ing evidence of the presence of unsuspected tubercuwhile RFLP strain typing may explain unexpected losis in a child and is often the means by which the transmission patterns (Barnes et al. 1997). extent of disease will be evaluated. It is therefore nec-

Table 16.2. Differential diagnosis of childhood tuberculosis Segmental or bronchopneumonic opacification with or without cavitation on chest radiograph Hilar or paratracheal adenopathy Asthma with a mucous plug Foreign body Bronchial compression due to tumours, congenital abnormalities Lobar emphysema Bronchiectasis Recurrent aspiration

Cystic fibrosis Hypersensitivity syndromes Loeffler syndrome

Lymphoma Teratoma Neurofibroma

Tropical eosinophilia Necrotizing bacterial pneumonias Lung abscess Diaphragmatic hernia Echinococcus cysts

Other tumours and malignancies Fungal infections Sarcoidosis Bronchogenic or dermoid cyst

254

P. R. Donald

b

a Fig. 16.14a,b. Chest radiographs of a 3-year-old child presenting with recurrent cough and wheeze. a Chest radiograph taken in poor inspiration showing possible hilar enlargement. b A chest radiograph of the same child taken 30 min later showing the shadow to be the descending branch of the right pulmonary artery

essary that the clinician be aware of the importance of a good quality chest radiograph. Common technical faults in children's chest radiographs include inadequate inspiration, excessive lordosis, rotation of the chest, and faulty exposure or processing, leading to a film that is overexposed or underexposed. One of the most common problems is poor inspiration, leading to excessive prominence of the descending branch of the right pulmonary artery (Grzybowski 1954). To the inexperienced this can easily assume the appearance ofhilar adenopathy (Fig. 16.14). In babies up to the age of 18 months, the thymus will frequently be visible and give rise to confusion, particularly if the shadow is atypical or the radiograph rotated or taken in poor inspiration (Fig. 16.15).

of the neonate (Pillay et al. 2001; Ahmed et al. 1999; Adhikari et al. 1997). Infection of the very young infant or neonate may be the result of transplacental infection in utero or infection may take place during or shortly after birth. If infection is antenatal and transplacental, the primary focus of infection will be in the liver, and there will be enlargement of the regional nodes in the porta hepatis. These infants are often symptomatic, with loss of weight, tachypnoea and wheezing or bronchial breathing audible on auscultation (Schaaf et al.I993).

16.8 Tuberculosis in Infancy If untreated, tuberculosis has its highest mortality and morbidity during infancy, and the consequences of a delay in diagnosis and treatment are potentially more serious at this age than in older children. In the experience of Wallgren (1938), 36% of infants less than 1 year of age at the time of diagnosis died, while Edith Lincoln (1950) reported that 55% of infants diagnosed when less than 6 months of age died. With the spread of HIVI AIDS, tuberculosis has become a common cause of obstetric mortality and morbidity, and this has inevitably increased the risk of antenatal or postnatal tuberculosis infection

Fig. 16.15. A typical thymus shadow projecting into the upper right lung field in a 15-month-old child

Childhood Tuberculosis

Hepato-splenomegaly may be present, and tuberculosis may be a cause of prolonged neonatal jaundice (Schaaf and NelI992). Chest radiography will often show a miliary pattern. Airway narrowing is frequently present and will sometimes be more clearly seen on a high kilo-volt radiograph. Cavitation may be present as early as 5 weeks of age (Cunningham 1982). Gastric aspirate or tracheal aspirate will give a positive culture in a higher percentage of cases than in older children, and as many as 70%-80% of infants may have a positive culture for M. tuberculosis (Schaaf et al.1993; Vallejo et al.1994). Unfortunately, the tuberculin test will frequently be negative during the acute phase of the illness but should not be ignored. Extrathoracic lymph node enlargement may be palpated as early as 4 weeks of age, and hilar node enlargement may be seen on chest radiograph even earlier. Chest radiography and sputum culture of the mother may be rewarding procedures (Schaaf et al. 1991), and the possibility of maternal urogenital tuberculosis should be considered. Other family members and even hospital personnel should not be forgotten as the possible source of infection. Infants born to a mother with tuberculosis are at considerable risk of infection and disease. Even if the mother is sputum microscopy ,smear-negative' but culture positive, a significant risk of infection still exists because of the closeness of the contact between the mother and her newborn infant. A number of studies have shown convincingly that isoniazid will protect such exposed infants against the risk of infection and disease (Dormer et al. 1959; Kendig 1960; Light et al. 1974). If the diagnosis of maternal tuberculosis is made shortly before or shortly after birth, an alternative approach would be to give the infant isoniazid and rifampicin for as long as the mother is herself being treated.

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Tuberculin testing of large groups of adolescents has found similar rates of tuberculosis infection in both genders or a slight male predominance in some cases (Hall 1957). Nonetheless, the risk of developing tuberculosis during adolescence has been found to be 2 to 6 times higher in girls (Smith 1967). The development of tuberculosis is also often associated with menarche (Comstock et al. 1974). It is therefore attractive to ascribe this susceptibility to ,adult-type' tuberculosis to the hormonal and metabolic perturbations of puberty, and Arvid Wallgren (1938) commented, "It is quite likely that the liability to pulmonary tuberculosis (in adolescence) is intimately linked up with endocrine activity". It is now known that the balance between the Thl and Th2 families of cytokines may be regulated by the adrenal steroids. Glucocorticoids may promote a Th2-type response, which would be disadvantageous to the course of tuberculosis, whereas dehydroepiandosterone will tend to promote a Thl-type response (Rook et al. 1993). This is also the age at which large strawcoloured pleural effusions are more often seen following primary infection (Fig. 16.16). It is of interest that despite the higher incidence of adult-type tuberculosis in girls at this age, these large effusions are much more frequent in boys (Bentley et al. 1954; Enarson et al.1982; Weber et al. 2000). If infection occurs after 7 years of age, the chance of developing disease during puberty has been put at 8% in American studies (Lincoln et al. 1960). When tuberculin conversion occurs during adolescence, it

16.9 Tuberculosis During Adolescence Following the onset of puberty there is a rapid rise in the incidence of tuberculosis, although presumably the risk of tuberculosis infection remains similar. The nature of tuberculous disease also undergoes a marked change and now takes the form of,adult-type' disease. This is characterized by the development of apical lesions and the propensity to develop cavitation, which not only contributes to lung destruction but also leads to the expectoration of microscopy smear-positive sputum, so completing the cycle of infection.

Fig. 16.16. A large, right-sided, pleural effusion in a 12-yearold adolescent who presented with fever and right-sided chest pain. The Mantoux test gave an induration of 19 mm, and the sputum was positive on culture for M. tuberculosis, but negative for acid-fast bacilli on microscopy

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is far more likely to be followed by disease. As many as 15% of such recently infected adolescents may develop the disease, and disease is most likely to occur within 1-3 years of infection (Smith 1967). In view of the various hormonal and social adaptations occurring during adolescence, it is not surprising that non-compliance has been identified as a problem in these children (Nemir 1986; Weber et al. 2000). Careful attention to potential problems and community networking is necessary to assist these patients to successfully complete therapy (Wilcox and Laufer 1994). The combination of HIV infection and tuberculosis in adolescence makes compliance even more difficult to achieve (Hoffman et al. 1996).

16.10

Treatment of Tuberculosis in Childhood The principles of the treatment of childhood tuberculosis are the same as those that apply to adults. A 2-month intensive bactericidal phase of isoniazid, rifampicin, pyrazinamide and ethambutol or streptomycin is followed by a 4-month sterilizing continuation phase with isoniazid and rifampicin.. The aim of the intensive phase is to reduce the number of rapidly metabolizing active organisms as quickly as possible. This leads to the symptomatic improvement, a reduction in the risk of infection to others, while the use of a multidrug regimen will prevent the development of drug resistance. The most effective bactericidal drugs are isoniazid, which kills 90% of active organisms within 48 h (Donald et al. 1997), ofloxacin and rifampicin (Sirgel et al. 1993). Most cases of tuberculosis in childhood are paucibacillary and "smear-negative", as children do not often develop cavitation. Consequently, the risk of developing drug resistance is probably not as great as in adults, and the intensive phase can safely be undertaken with isoniazid, rifampicin and pyrazinamide, unless there is a history of contact with a case of drug-resistant tuberculosis. In that case, the regimen should be appropriately adjusted to take into account the resistance pattern of the contact's isolates. Where cavitation is present, it is probably advisable to assume the presence of a reasonably large bacterial population even if the smear is negative, and to use four drugs in the intensive phase as in adults. The 4month continuation phase is also undertaken with isoniazid and rifampicin. The aim of the 4-month continuation phase is the elimination of all remaining residual forms of M.

P. R. Donald

tuberculosis to prevent relapse occurring. The most valuable sterilizing agents are rifampicin and pyrazinamide and to a lesser extent isoniazid (Mitchison 2000). The loss of rifampicin with the development of multidrug resistance necessitates the use of much longer, complicated and potentially toxic regimens. In the case of serious forms of extrapulmonary tuberculosis or disseminated tuberculosis, official documents often recommend the same treatment regimens as for new ,smear-positive' adult pulmonary tuberculosis. More conservative clinicians might prefer to extend the continuation phase to 7 months of isoniazid and rifampicin (Harries and Maher 1996). Our own practice for children with miliary tuberculosis, tuberculous meningitis or other cases where sequestered lesions might be present is to use a combination of isoniazid, rifampicin, pyrazinamide and ethionamide, all given for 6 months (Donald et al. 1998). Isoniazid has excellent pharmacokinetics and a very large therapeutic margin between the highest serum concentration that can be achieved without undue toxicity and the lowest concentration at which a bactericidal effect can still be measured (Donald et al. 1997). Pyrazinamide also has good pharmacokinetics and enters the cerebrospinal fluid with ease (Donald and Seifart 1988), as does ethionamide (Donald and Seifart 1989). Rifampicin, however, is highly protein bound and at the usual dose of 12 mg/kg body weight is probably operating at the lower border of its efficacy. Any further reduction in dose will increase relapse rates (Long et al. 1979) and decrease bactericidal activity (Sirgel et al. 1993). Rifampicin has also been shown to have poor penetration into chronic tuberculous empyema (Elliot et al. 1995) and cerebrospinal fluid, as is the case with ethambutol (Ellard et al. 1993). As ethionamide is better tolerated by children than adults, we advocate its use in preference to ethambutol in those situations where isoniazid resistance is a potential threat or where other drugs, such as rifampicin, may be at a pharmacokinetic disadvantage. The dosages of the more commonly used drugs for the management of tuberculosis in children are given in Table 16.3. In Table 16.4 the dosages of the alternative drugs are given. The use of these agents may be necessitated by the detection or suspicion of drug resistance or by the development of drug toxicity. These agents are as a generalization less efficient in the treatment of tuberculosis and tend to be associated with greater toxicity. Before embarking on their use, it is wise to consult those experienced in their usage. There is good evidence that adult smear-negative pulmonary tuberculosis can be treated for 4 months

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Childhood Tuberculosis Table 16.3. Treatment of tuberculosis in children. Dosage and action of antituberculosis drugs Drug Isoniazid Rifampicin Pyrazinamide Ethambutol Ofioxacin a Streptomycin

Action Bactericidal Sterilizing

Twice weekly intermittent Daily dosage (maximum mg) mglkg (maximum mg) mglkg

+++ ++

10-20 10-20 25-35 15-20 15 20

-

++ ++ +

+ +++ +++ ?a

(300) (600) (2000) (1250) (800) (1000)

20-40 10-20 50-70 50 25-30

(900) (600) (4000) (1250) ? (1500)

aThere is as yet relatively little experience with the use of ofioxacin. It has been shown to have a high early bactericidal activity and is a valuable drug to have in reserve when hepatotoxicity or drug resistance precludes the use of other established drugs. There is, as yet, no information as to its possible sterilizing activity

Table 16.4. Treatment of tuberculosis in children. Dosage of ,second-line' drugs Drug

Daily dosage mg/kg

Maximum dosage

Ethionamide Kanamycin Amikacin Capreomycin Cycloserine Para-aminosalicylic acid Thiacetazonea

15-20 15-20 15-20 15-20 15 300 4

1g 750 mg 750 mg 750 mg 1g 10 g 150 mg

aCommence thiacetazone with 0.5 mglkg for the 1st week, 1 mglkg the 2nd week and 4 mglkg from the 3rd week

with very low relapse rates (Hong Kong Chest Service et al. 1989; Dutt et al. 1989). As most childhood tuberculosis is of limited extent and smear-negative, it seems probable that the same 4-month regimens might also apply to children. However, as there are, as yet, no clinical trials to support this approach, most official documents still recommend 6 months of treatment for all forms of childhood tuberculosis. In contrast to the prospect of, perhaps, shortening the length of treatment for children with tuberculosis, there is increasing evidence that in the presence of HIV infection, treatment should be prolonged to 9 months. Of 14 HIV-infected children with cultureproven tuberculosis, 4 were still culture-positive 4-14 months after commencing treatment (Schaaf et al. 1998). Recently, it was reported that HIV-infected adults with pulmonary tuberculosis treated for less than 9 months had an increased incidence of relapse within 30 days of stopping treatment as compared with those treated for longer than 9 months (Driver et al. 2001). The reasons for this finding are uncertain, but the poor absorption of antituberculosis agents in adults with HIVI AIDS has been documented (Peloquin et al. 1996). Others have not found any associa-

tion between tuberculosis recurrence and antituberculosis drug concentrations in HIV-infected patients (Narita et al. 2001). No similar pharmacokinetic data exist for children. The management of childhood tuberculosis is not a priority in most developing communities, where hard-pressed health service staff have difficulty in ensuring the compliance of smear-positive adult pulmonary tuberculosis patients. Under these circumstances treatment is often given by family members, and there must be some doubt about the extent of compliance that is achieved. Intermittent treatment of children, given two or three times weekly, is an acceptable alternative to daily treatment and can lead to equivalent rates of adherence (te Water Naude et al. 2000). This would also make supervision of treatment easier for the health services. A further problem encountered in the management of childhood tuberculosis is the lack of formulations specifically designed for children. Several commercial fixed dose combination preparations are now available, but in their absence ad hoc preparations must often be constituted by clinic personnel. It is very important that such ad hoc preparations should not be made up before administration and that they should not be mixed with vitamin solutions as this can lead to a rapid decline in the drug concentrations (Seifart et al. 1991).

16.11

Drug-resistant Tuberculosis in Childhood Drug-resistant tuberculosis in children is important from two points of view. Firstly, it is important for the individual patient that it should be diagnosed expeditiously and managed appropriately. This is particularly important in HIV-infected individuals,

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who may deteriorate rapidly and die if appropriate treatment is not started as soon as possible (Small et al. 1993). Secondly, it is important as drug resistance in children will nearly always be primary resistance, and the incidence and patterns of resistance in children will probably reflect those circulating amongst adults in a community (Rieder 1993). Despite early evidence that INH-resistant organisms were less pathogenic for laboratory animals, there can be no doubt now that INH-resistant organisms can be transmitted and can cause disease (Snider et al. 1985). In an evaluation of 128 children who were in close household contact with an adult with multidrug-resistant tuberculosis, 66 (52%) were found to be infected and a further 15 (12%) to have tuberculosis disease. RFLP strain typing of M. tuberculosis cultured from these children found identical drug susceptibility patterns and strains amongst the children and their contacts in a majority of cases (Schaaf et al. 2000). In nearly 80% of cases, the index case was a family member. As only a minority of diseased children are likely to produce a culture of M. tuberculosis for drug susceptibility testing, it is important that an accurate history always be obtained of possible drugresistant contacts. This will enable the construction of the most appropriate treatment regimen as soon as possible. This is particularly important in those children with HIV-infection and life-threatening forms of disease such as tuberculous meningitis or miliary tuberculosis. In the Western Cape Province of South Africa, the rates of initial isoniazid resistance and multidrug resistance among adults were 3.9% and 1.1 %, respectively, between 1992 and 1993 (Weyer et al. 1995). From 1995 to 1998, 306 cultures of M. tuberculosis obtained from children aged 0-13 years of age were evaluated for drug susceptibility. Among children 0-5 years of age, the incidence of isoniazid resistance and multidrug resistance was 5.6% and 1%, respectively, which did not differ significantly from that found earlier in adults. This indicates that the incidence of resistance in children probably reflects the transmission of drug-resistant strains that is occurring amongst adults. Where cultures can be obtained from children and tested for drug susceptibility, this will offer a relatively simple means of monitoring drug resistance in a community. In children with a culture of M. tuberculosis resistant to isoniazid only, the use of a standard WHO retreatment regimen is considered adequate. This consists of 2 months of isoniazid, rifampicin, pyrazinamide, ethambutol and streptomycin followed by 1 month of isoniazid, rifampicin, pyrazinamide and

P.R. Donald

ethambutol and a 6-month continuation phase of isoniazid, rifampicin and ethambutol (Crofton et al. 1997). The use of isoniazid in the face of resistance is controversial. In primary isoniazid resistance, low-level isoniazid resistance (MIC<5Ilg/ml) may be found in more than half of the patients (Canetti 1965; Tripathy et al. 1969; Schaaf et al. 2000). These concentrations are easily attainable with a dose of 10-20 mg/kg isoniazid, which will usually be well tolerated by young children. In the case of resistance to at least isoniazid and rifampicin (multidrug resistance), a 5-drug intensive phase is considered mandatory (Crofton et al. 1997) and should be given for 3 months or until smear conversion. The continuation phase should last for 18 months after smear conversion and should contain at least three drugs to which the organism is sensitive. In most childhood disease a culture of M. tuberculosis may not be obtained. In these cases it is advisable to treat the child according to the susceptibility pattern of the adult contact and to use at least three drugs to which the child has not been exposed before.

16.12 Prevention and Control of Tuberculosis in Childhood Tuberculosis infection in childhood is the consequence of the inhalation of small aerosol droplets 5-10 flm in diameter containing 1-3 M. tuberculosis bacilli. These are expectorated by adults, who will usually be suffering from cavitating pulmonary tuberculosis and whose sputum will be positive on microscopy for acid-fast bacilli. There is therefore little doubt that the control of tuberculosis in adults would rapidly eliminate childhood tuberculosis as a serious health problem. It is equally clear that there is little prospect that tuberculosis will be controlled in developing countries in the foreseeable future and that the main focus of tuberculosis control programmes will continue to be the supervision of directly observed short course treatment for sputum ,smear-positive' adults. Nevertheless, it should be emphasized that even within the constraints imposed by financial restrictions and the lack of resources, opportunities exist to reduce the impact of tuberculosis on children. In order to make use of these opportunities, we need to continually remind ourselves that tuberculosis is an infectious disease and that in a high incidence community those most

Childhood Tuberculosis

often affected will be young adults in their reproductive years. In many developing communities it is also women who are bearing the brunt of the HIV/AIDS epidemic and, as indicated above, HIV/AIDS-associated tuberculosis has become an important cause of obstetric mortality and morbidity. These women will be in constant close contact with their own children and those of their extended families. In addition to the more obvious measures of chemoprophylaxis and BCG vaccination, there are several other ways by which the force of the infectious process as it affects children, but also adults, can be reduced. It is often forgotten that paediatric outpatient facilities and in particular the overnight holding wards which are commonly encountered in the developing world can serve as a focal point for infectious disease transmission. Young children attending these facilities will often be accompanied by parents or caregivers, who may themselves be sick. In an evaluation of young children less than 18 months of age with suspected tuberculosis attending one such facility, a policy of taking a chest radiograph of the accompanying parent or caregiver revealed pulmonary tuberculosis in 18% of cases. Amongst the adults accompanying 17 children less than 6 months of age, this was an even more rewarding procedure, and tuberculosis was found in 6 adults (35%). The identification of these adults not only contributed to strengthening the diagnosis of tuberculosis in their children, but also helped prevent the further spread of tuberculosis in their families and in the outpatient department. Two other measures, which can be considered in busy health care facilities where children and their caregivers congregate, are attention to ventilation and the use of ultraviolet light. Good ventilation can significantly reduce the density of bacilli in the air. Merely renewing the air 6 times in an hour has been calculated to reduce the density of bacilli to 100th of what it was beforehand (Riley and O'Grady 1961). Ultraviolet light can also contribute to the killing of bacilli (Riley et al. 1976). If the provision of artificial ultraviolet light is thought too expensive, the provision of large windows directed appropriately to make maximum use of available sunlight can contribute further to reducing the risk of tuberculosis infection.

259

In the very young, disease is particularly likely to take the form of disseminated forms of tuberculosis such as tuberculous meningitis or miliary tuberculosis. Mortality rates for those infected at an age of under 1 year and untreated have been calculated to be between 5000 and 6000 per 100,000 population (Rich 1951; Bentley et al. 1954). The identification of young children in close contact with an adult with sputum microscopy "smear-positive" pulmonary tuberculosis therefore offers an opportunity for the prevention of disease in these children and the early diagnosis and treatment of disease in those already infected. Depending upon the resources available, such children should have a Mantoux test to identify those infected and a chest radiograph to detect subclinical disease. As it may take up to 10 -12 weeks for tuberculin hypersensitivity to develop, it is prudent to commence chemoprophylaxis with isoniazid in these children exposed to infection. After 3 months the Mantoux test can be repeated. If this is positive, chemoprophylaxis should be continued to 6 months, and if negative, BCG vaccination can be considered. A number of controlled clinical trials have demonstrated the efficacy of isoniazid chemoprophylaxis when given to children and adults with asymptomatic primary infection (Ferebee 1970). Not only is the incidence of disease reduced, but more serious forms of disseminated tuberculosis are prevented. Isoniazid chemoprophylaxis for 3 months, 6 months and 12 months reduced the risk of tuberculosis by 21%, 65% and 75%, respectively. (International Union against Tuberculosis Committee on Prophylaxis 1982). In an analysis of the cost effectiveness of different durations of prophylaxis, it was then claimed that 6 months of chemoprophylaxis offered the best compromise (Snider et al.1986), and this is currently the duration of isoniazid chemoprophylaxis recommended in many official documents. A more recent analysis of data from several studies has however shown that 9 months of chemoprophylaxis probably offers the optimal protection against the development of tuberculosis disease (Comstock 1999). A major impediment to the successful implementation of chemoprophylaxis is non-compliance, and relatively low percentages of adults and children in both developing and developed countries who complete the prescribed course of treatment (Woebeser et al. 1989; Kopanoff et al. 1978). In developing comChemoprophylaxis. Between 50% and 60% of young munities health care staff are already hard pressed children in close household contact with an adult to ensure that their adult ,smear-positive' patients with sputum microscopy ,smear-positive' pulmo- complete their therapy, and it is hardly surprising nary tuberculosis will become infected. Approxi- that chemoprophylaxis is not accorded a very high mately 10% of those infected may become diseased. priority. In our own experience of 193 children pre-

260

senting with tuberculous meningitis in the Western Cape Province of South Africa, 77 (40%) had a close household contact who had been treated for pulmonary tuberculosis within the previous 2 years. Only 17 (22%) of these children had, however, been prescribed isoniazid chemoprophylaxis, and a mere 7 completed 3 months of prophylaxis (Donald et al. 1995).

In the face of these dismal figures, it is important to prioritise and to give our attention to those at greatest risk. These are undoubtedly the children under 2 years of age in household contact with an adult with sputum ,smear-positive' pulmonary tuberculosis. These adults will frequently be a parent or grandparent or another caretaker. As these individuals must themselves receive supervised treatment, it should add relatively little to the burden of the health care personnel to ensure that their children receive prophylactic treatment at the same time. Although isoniazid for 6 months remains the most frequently recommended prophylaxis regimen, there has been considerable interest in shorter regimens containing rifampicin and pyrazinamide. This interest has been sharpened by our inability to halt the ongoing spread of HIV-associated tuberculosis and evidence from Peru that even a model national tuberculosis control programme may not be able to reduce the incidence of tuberculosis successfully even in the absence of HIV/AIDS (Chaisson 2000). In experiments with M. tuberculosis-infected mice, rifampicin for 3 months or rifampicin and pyrazinamide for 2 months were more effective than 6 months of isoniazid in reducing the proportion of mice with positive spleen cultures (Lecoeur et al. 1989). Several controlled trials have now found rifampicin and pyrazinamide for 2 months to give results equivalent to those of 6 months of isoniazid (Halsey et al. 1998; Mwinga et al. 1998; Gordin et al. 2000). There are at present few data relating to children regarding this approach, but there seems no reason to expect different results.

Bacille

Calmette-Guerin Vaccination. Bacille Calmette-Guerin (BCG) vaccination has been practised for more than 80 years, but there is still no consensus as to its value in preventing tuberculosis in childhood. Analysis of a number of clinical trials in which BCG was evaluated has shown effects ranging from significant protection to an increased incidence of disease. Case-control studies have consistently shown a protective effect against disseminated forms of tuberculosis such as TBM and miliary tuberculosis. It should be pointed out that some case-control stud-

P. R. Donald

ies made use of controls that were not in contact with a patient with tuberculosis and so would automatically tend to show some degree of protection. Nevertheless, the current consensus is that BCG does offer a degree of protection of between 60%-80% against disseminated forms of tuberculosis, and BCG forms part of the World Health Organization Expanded Programme of Immunization. BCG will, however, have only a limited effect upon the epidemiological situation in a community. It does not break the chain of infection and protects the individual only against disease dissemination, but not infection (Styblo and Meijer 1976). BCG has also been evaluated in a variety of populations in different parts of the world. In the light of the above variations in strains, methods of administration and populations in which BCG has been evaluated, it is perhaps not surprising that conflicting results have been obtained. BCG is derived from a virulent bovine tubercle bacillus which was attenuated over a 13-year period of subculturing and 230 transfers from one subculture to another. Following this, a number of culture samples were distributed all over the world, and these were in turn subjected to further subculturing on a variety of different media. In this manner a number of daughter strains have been created, possibly by encouraging the emergence of minority strains within each population (Osborn 1983). BCG has been administered to a diversity of populations in a number of different countries orally, by scarification, by percutaneous multiple puncture and by intradermal injection. It is therefore perhaps not surprising that widely differing results have been obtained and that there is no consensus as to the value of BCG. Amidst the uncertainty of its action with regard to tuberculosis, it is of interest to note a number of other instances in which BCG appears to have had an undoubted effect upon the immune system. Thus, BCG has been documented to be instrumental in helping to control leprosy in Malawi (Karonga Prevention Trial Group 1996) and has a well substantiated role in the management of bladder cancer (Alexandroff et al. 1999). It is also significant to note that following the discontinuation of BCG immunization in Sweden, the incidence of atypical mycobacterial lymphadenitis increased dramatically (Katila et al. 1987). It has also been speculated that BCG immunization might be the reason why HIV/AIDS patients in Sweden have a much lower incidence of Mycobacterium avium complex infections than patients in the USA and that it may therefore be of importance in reducing the impact of HIV infection (Kallenius et al. 1989). There is also some evidence that BeG vaccina-

261

Childhood Tuberculosis

tion may have a role in preventing certain forms of malignancy (Grange and Stanford 1990). Intradermal BCG vaccination will usually lead to the formation of a small superficial ulcer approximately 4 weeks after vaccination. This heals over 8-10 weeks and leaves a flat scar some 50 mm in diameter. Complications may be seen in 3%-4% of individuals, particularly if care is not taken with regard to the technique. The importance of staff training has been emphasized (Jeena et al. 2001). For this reason complications tend to be more common following intradermal vaccination than after percutaneous vaccination. Complications encountered include axillary lymphadenopathy with suppuration in some cases, abscess formation at the injection site, especially if the vaccine is delivered subcutaneously, and disseminated forms of disease such as osteoarticular involvement or, more rarely, tuberculous meningitis. Disseminated BCG disease will usually be seen exclusively in those with severe immunosuppression. Although disseminated BCG was in the past mainly a disease of infants, it is now increasingly seen in adults and older children and often in association with HIV/AIDS (Talbot et al. 1997). At present, HIV infection is not considered a contraindication to BCG vaccination, and BCG should continue to be given to all infants even if HIV-infected provided they have no symptoms of AIDS. Other factors which playa role in the occurrence of complications include the type of vaccine used and the dose of vaccine given. In Sweden between 1972 and 1974, 29 patients with osteo-articular disease were reported per 100,000 children vaccinated. When the BCG strain was changed, no more cases occurred (Romanus 1987). In several countries the Pasteur strain has been noted to be more reactogenic than other strains, and several outbreaks of lymphadenitis followed a change to the Pasteur strain. In another instance an outbreak of lymphadenitis followed a change of vaccine from the Pasteur strain to Tokyo 172 and was found to be due to the injection of an inappropriately high dose of vaccine (Kabra et al. 1993). The management of BCG lymphadenitis is controversial. Most lesions will ultimately heal spontaneously. In the case of suppurative lesions, needle aspiration from a distance of 2-3 cm has been shown to bring about a more rapid regression of adenopathy and to prevent sinus formation (Banani and Alborzi 1994). It has also been claimed that streptomycin administration into the nodes during the non-suppurative phase prevents suppuration and causes earlier healing than the previously advised use of erythromycin (Kuyucu et al. 1998). Surgery has been advo-

cated for large lesions, but it is uncertain whether the long-term results are indeed cosmetically better than a more conservative approach. In the case of disseminated forms of BCG disease, chemotherapy must be given, and it should be remembered that BCG is resistant to pyrazinamide. With regard to HIV infection it is currently recommended that BCG vaccine should not be given to those who are HIV-infected and have signs and symptoms of AIDS. In the case of those who are HIVinfected only, the benefits of BCG vaccination appear to outweigh the potential risks (O'Brien et al. 1995). In this context it should be noted that a recent study amongst adult volunteers demonstrated viable BCG mycobacteria draining from the vaccination ulcer 2 months after vaccination. These organisms could theoretically pose a risk to other immunosuppressed individuals who might be in close contact with the vaccinated infant (Hoft et al. 1999).

References Adhikari M, Pillay T, Pillay DV (1997) Tuberculosis in the newborn: an emerging disease. Pediatr Infect Dis J 16: 1108-1112 Ahmed Y, Mwaba P, Chintu C, Grange J, Ustianowski A, Zurnla A (1999) A study of maternal mortality at the University Teaching Hospital, Lusaka, Zambia: the emergence of tuberculosis as a major non-obstetric cause of maternal death. Int J Tuberc Lung Dis 3:675-680 Alexandroff AB, Jackson AM, O'Donnel et al (1999) BCG immunotherapy of bladder cancer: 20 years on. Lancet 353:1689-1694 Ansari NA, Kombe AH, Kenyon TA et al (1999) Mortality and pulmonary pathology of children with HIV infection in Francis town, Botswana. Int J Tuberc Lung Dis 3 [Suppl]:S201 Bentley FJ, Grzybowski S, Benjamin R (1954) Pleural effusion. Tuberculosis in childhood and adolescence. National Association for the Prevention of Tuberculosis, London, pp 50-54 Bleiker MA (1991) The annual risk of infection rate, the tuberculin survey and the tuberculin test. Bull Int Union Against Tuberc 66:53-56 Brailey M (1940) A study of tuberculous infection and mortality in children of tuberculous households. Am J Hyg 31:1-43 Canetti G (1965) Present aspects of bacterial resistance in tuberculosis. Am Rev Respir Dis 92:687-703 Cauthen GM, Pio A, ten Darn HG (1988) Annual risk of infection. World Health Organization WHO/TB/88 154:1-34 Chaisson RE (2000) New developments in the treatment of latent tuberculosis. Int J Tuberc Lung Dis 4:S176-S181 Chan SP, Birnbaum J, Rao M, Steiner P (1996) Clinical manifestations and outcome of tuberculosis in children with acquired immunodeficiency syndrome. Pediatr Infect Dis J 15:443-447 Chintu C, Zumla A (1995) Childhood tuberculosis and infection with the human immunodeficiency virus. J R Coli Phys Lond 29:92-95

262 Chintu C, Bhat G, Luo C et al (1993) Sero-prevalence of human immunodeficiency virus type 1 in Zambian children with tuberculosis. Pediatr Infect Dis J 12:499-504 Comstock GW (1999) How much isoniazid is needed for the prevention of tuberculosis among immunocompetent adults? Int J Tuberc Lung Dis 3:847-850 Comstock GW, Livesay VT, Woolpert SF (1974) The prognosis of a positive tuberculin reaction in childhood and adolescence. Am J EpidemioI99:131-138 Crofton J, Chaulet P, Maher D (1997) Guidelines for the management of drug-resistant tuberculosis. World Health Organization, Geneva, WHO/TB/96.210 (Rev 1) Delacourt C, Mani TM, Bonnerot V et al (1993) Computed tomography with normal chest radiograph in tuberculous infection. Arch Dis Child 69:430-432 Delacourt C, Poveda J-D, Chureau C, Beydon N et al (1995) Use of polymerase chain reaction for improved diagnosis of tuberculosis in children. J Pediatr 126:703-709 Dolin PJ, Raviglione MC, Kochi A (1994) Global tuberculosis incidence and mortality during 1990-2000. Bull WHO 72: 213-220 Donald PR, Seifart HI (1988) Cerebrospinal fluid pyrazinamide concentrations in children with tuberculous meningitis. Pediatr Infect Dis J 7:469-471 Donald PR, Seifart HI (1989) Cerebrospinal,fluid concentrations of ethionamide in children with tuberculous meningitis. J Pediatr 115:483-486 Donald PR, van Zyl LE, de Villiers J (1995) BCG vaccination status of children with tuberculous meningitis and the use of unsupervised isoniazid prophylaxis. S Afr Med J 85:167-170 Donald PR, Schoeman JF, van Zyl LE, de Villiers IN, Pretorius M, Springer P (1998) Intensive short course chemotherapy in the management of tuberculous meningitis. Int J Tuberc Lung Dis 2:704-711 Dormer BA, Swart JA, Harrison I (1959) Prophylactic isoniazid protection of infants in a tuberculosis hospital. Lancet 2: 902-904 Driver CR, Munsiff SS, Li J et al (2001) Relapse in persons treated for drug-susceptible tuberculosis in a population with a high coinfection with human immunodeficiency virus in New York City. Clin Infect Dis 33:1762-1769 Dutt AK, Moers D, Stead WW (1989) Smear- and culture-negative pulmonary tuberculosis: four-month short course chemotherapy. Am Rev Respir Dis 139:867-870 Ellard GA, Humphries MJ, Allen BW (1993) Cerebrospinal fluid drug concentrations and the treatment of tuberculous meningitis. Am Rev Respir Dis 148:650-655 Elliot AM, Berning SE. Iseman MD, Peloquin CA (1995) Failure of drug penetration and acquisition of drug resistance in chronic tuberculous empyema. Tubercle Lung Dis 76: 463-467 Franchi LM, Cama RI, Gilman RH, Montenegro-James S, Sheen P (1998) Detection of Mycobacterium tuberculosis in nasopharyngeal aspirate samples in children. Lancet 352:1681-1682 Gordin FM, Chaisson RE, Matts JP et al (2000) An international randomized trial of rifampin and pyrazinamide versus isoniazid for prevention of tuberculosis in HIV-infected persons. J Am Med Assoc 283:1445-1450 Graham SM, Coulter JBS, Gilks CF (2001) Pulmonary disease in HIV-infected African children. Int J Tuberc Lung Dis 5:12-23 Grange JM, Stanford JL (1990) BCG vaccination and cancer. Tubercle 71:61-64

P. R. Donald Grzybowski S (1954) Radiology in childhood tuberculosis. Tubercle 35:113-117 Halsey NA, Coberly JS, Desormeaux J et al (1998) Rifampicin and pyrazinamide vs. isoniazid for prevention of tuberculosis in HIV-I infected persons. Lancet 351:786-792 Harries AD, Maher D (1996) TB/HIV a clinical manual. World Health Organization, Geneva, WHO/TB/96.200 Harries AD, Parry C, Mbewe LN et al (1997) The pattern of tuberculosis in Queen Elizabeth Central Hospital, Blantyre, Malawi: 1986-1995. Int J Tuberc Lung Dis 1:346-351 Hoffman ND, Kelly C, Futterman D (1996) Tuberculosis infection in human immunodeficiency virus-positive adolescents and young adults: a New York City cohort. Pediatrics 97:198-203 Hoft DF, Leonardi C, Milligan T et al (1999) Clinical reactogeincity of intradermal Bacille Calmette-Gutfrin vaccination. Clin Infect Dis 28:785-790 Hong Kong Chest Service/ Tuberculosis Research Centre, Madras/British Medical Research Council (1989) A controlled trial of 3-month, 4-month and 6-month regimens of chemotherapy for sputum-smear-negative pulmonary tuberculosis. Am Rev Respir Dis 139:871-876 Houwert KAF, Borggreven PA, Schaaf HS, Nel E, Donald PR, Stolk J (1998) Prospective evaluation of World Health Organization criteria to assist diagnosis of tuberculosis in children. Eur Respir J 11:1116-1120 Humphries MJ (1992) The management of tuberculous meningitis. Thorax 47:577-581 International Union Against Tuberculosis (1982) Efficacy of various durations of isoniazid preventive therapy for tuberculosis: five years of follow up in the IUAT trial. Bull WHO 60:555-564 Jacobs M, Yach D, Fisher S, Kibel M, Hattingh, Coetzee G (1987) Mangement of children with tuberculosis in a local authority of Cape Town. Southern Afr J Epidemiol Infect 2:15-18 Jamieson DH (1995) Imaging intracranial tuberculosis in childhood. Pediatr Radiol 25: 165-170 Jeena PM, Mitha T, Bamber S, Wesley A, Coutsoudis A, Coovadia HM (1996) Effects of human immunodeficiency virus on tuberculosis in children. Tuberc Lung Dis 77:437-443 Jeena PM, Coovadia HM, Thula SA et al (1998) Persistent and chronic lung disease in HIV-l-infected African children. AIDS 12:1185-1193 Jeena PM, Chhagan MK, Topley J et al (2001) Safety of the intradermal Copenhagen BeG vaccine in neonates in Durban, South Africa. Bull WHO 79:337-343 Kabra SK, Jain Y, Seth MV (1993) BCG associated adenitis. Lancet 341:970 KaIlenius G, Hoffner SE, Svenson SB (1989) Does vaccination with Bacille Calmette-Guerin protect against AIDS? Rev Infect Dis 11:349-351 Karonga Prevention Group (1996) Randomised controlled trial of single BCG, repeated BCG, or combined BCG and killed Mycobacterium leprae vaccine for prevenyion of leprosy and tuberculosis in Malawi. Lancet 348:17-24 Katila ML, Brander E, Backman A (1987) Neonatal BCG vaccination and mycobacterial cervical adenitis in childhood. Tubercle 68:291-296 Kendig EL (1969) Prognosis of infants born to tuberculous mothers. Pediatrics 26:97-100 Khouri YF, Mastrucci MT, Hutto C, Mitchell CD, Scott GB (1987) Mycobacterium tuberculosis in children with immu-

Childhood Tuberculosis nodeficiency virus and routine childhood immunisations. Lancet 2:669-672 Kochi A (1991) The global tuberculosis situation and the new control strategy of the World Health Organization. Tubercle 72: 1-6 Kuyucu N, Kuyucu S, Ocal B et al (1998) Comparison of oral erythromycin, local administration of streptomycin and placebo therapy for non-suppurating Bacillus CalmetteGuerin lymphadenitis. Pediatr Infect Dis J 6:524-525 Lecoeur HF, Truffot-Pernot, Grosset JH (1989) Experimental short-course preventive therapy of tuberculosis with rifampin and pyrazinamide. Am Rev Respir Dis 140: 1189-1193 Light IT, Saidleman M, Sutherland JM (1974) Management of newborns after nursery exposure to tuberculosis. Am Rev Respir Dis 109:415-418 Lincoln EM, Gilbert LA, Morales SM (1960) Chronic pulmonary tuberculosis in individuals with known previous primary tuberculosis. Dis Chest 5:473-482 Lobato MN, Loeffler AM, Furst K, Cole B, Hopewell PC (1998) Detection of Mycobacterium tuberculosis in gastric aspirates collected from children: hospitalization is not necessary. Pediatrics 102, URL: http://www.pediatrics.orglcgi/ content/full/l02/4/e40 Long MW, Snider DE, Farer LS (1979) US Public Health Service co-operative trial of three rifampicin -isoniazid regimens in treatment of pulmonary tuberculosis. Am Rev Respir Dis 119:879-894 Madhi SA, Petersen K, Madhi A, Khoosal M, Klugman KP (2000) Increased disease burden and antibiotic resistance of bacteria causing severe community-acquired lower espiratory tract infections in human immunodeficiency virus type-1 infected children. Clin Infect Dis 31:170-176 Medical Research Council (1948) Streptomycin treatment of tuberculous meningitis. Lancet 1:582-596 Mitchison DA (2000) Role of individual drugs in the chemotherapy of tuberculosis. 1nt J Tuberc Lung Dis 4:796-806 Munro WT (1944) Tubercle bacilluria in the child. Edinb Med J 51:101-106 Mukadi YD, Wiktor SZ, Coulibaly I-M et al (1997) Impact of HIV infection on the development, clinical presentation and outcome of tuberculosis among children in Abidjan., Cote d'Ivoire. AIDS 11:1151-1158 Mwinga A, Hosp M, Godfrey-Faussett P et al (1998) Twice weekly tuberculosis preventive therapy in HIV infection in Zambia. AIDS 12:2447-2457 Narita M, Hisada M, Thimmappa B et al (2001) Tuberculosis recurrence:multivariate analysis of serum levels of tuberculosis drugs, human immunodeficiency virus status, and other risk factors. Clin Infect Dis 32:515-517 Nemir RL (1986) Perspectives in adolescent tuberculosis: three decades of experience. Pediatrics 78:399-405 Noordhoek GT, Kolk AH, Bjune G et al (1994) Sensitivity and specificity of PCR for detection of Mycobacterium tuberculosis: a blind comparison study among seven laboratories. J Clin MicrobioI32:277-284 O'Brien KL, Ruff AJ, Louis MA et al (1995) Bacillus CalmetteGuerin complications in children born to HIV-1-infected women with a review of the literature. Pediatrics 95: 414-418 Peloquin CA, Nitta AT, Burman WJ et al (1996) Low antituberculosis drug concentrations in patients with AIDS. Ann Pharmacother 30:919-925

263 Pillay Y Kahn M, Moodley Jet al (200!) The increasing burden of tuberculosis in pregnant women, newborns and infants under 6 months age in Durban, Kwazulu-Natal. S Afr Med J 91:983-987 Ravenscroft A, Schoeman JF, Donald PR (2001) Tuberculous granulomas in childhood tuberculous meningitis: radiological features and course. J Trop Pediatr 47:5-12 Rieder HL (1993) Drug-resistant tuberculosis: issues in epidemiology and challenges for public health. Tuberc Lung Dis 75:321-323 Riley RL, O'Grady F (1961) Airborne infection: transmission and control. Macmillan, New York Riley RL, Knight M, Middlebrook G (1976)Ultraviolet susceptibility of BCG and virulent tubercle bacilli. Am Rev Respir Dis 113:413-418 Rook GAW, Onyebujoh P, Stanford JL (1993) Th1->Th2 switch and loss of CD4 cells in chronic infections: an immunoendocrinological hypothesis not exclusive to HIV, Immunol Today 14:568-569 Romanus V (1987) Bacillus Calmette-Guerin-immunized and unimmunized children in Sweden: a ten-year evaluation following the cessation of general Bacillus Calmette Guerin immunization of the newborn in 1975. Pediatr Infect Dis J 6:272-280 Rutherfoord GS, Hewlett RH (1994) Atlas of correlative surgical and neuropathology and imaging (Gresham GA, ed). Kluwer Academic, Dordrecht, pp 47-74 Schaaf HS, Nel ED (1992) Tuberculosis presenting as cholestatic jaundice in early infancy. J Pediatr Gastroenterol Nutr 15:437-439 Schaaf HS, Smith J, Donald PR, Stockland B (1989) Tuberculosis presenting in the neonatal period. Clin Pediatr 28: 474-475 SchaafHS, Donald PR, Scott F (1991) Maternal chest radiography as supporting evidence for the diagnosis of tuberculosis in childhood. J Trop Pediatr 37:223-225 Schaaf HS, Gie RP, Beyers N, Smuts, Donald PR (1993) Tuberculosis in infants less than 3 months of age. Arch Dis Child 69:371-374 Schaaf HS, Geldenhuys A, Gie RP, Cotton MF (1998) Culturepositive tuberculosis in human immunodeficiency virus type I-infected children. Pediatr Infect Dis J 17:599-604 Schaaf HS, Vermeulen HAS, Gie RP, Beyers N, Donald PR (1999) Evaluation of young children in household contact with adult multidrug-resistant pulmonary tuberculosis cases. Pediatr Infect Dis J 18:494-500 Schaaf HS, Gie RP, Beyers N, Sirgel FA, de Klerk, Donald PR. (2000a) Primary drug-resistant tuberculosis in children. Int J Tuberc Lung Dis 4:1149-1155 SchaafHS,Van Rie A, Gie RP et al (2000b) Transmission of multidrug-resistant tuberculosis. Pediatr Infect Dis J 19:695-699 Seifart HI, Parkin DP, Donald PR (1991) The stability of isoniazid, rifampicin and pyrazinamide suspensions used for the treatment of tuberculosis in children. Pediatr Infect Dis J 10:827-831 Shaw JB, Wynn-Williams N (1954) Infectivity of pulmonary tuberculosis in relation to sputum status. Am Rev Tuberc 69:724-732 Sirgel FA, Botha FJH, Parkin DP et al (1993) The early bactericidal activity of rifabutin in patients with pulmonary tuberculosis measured by sputum viable counts - a new method of drug assessment. J Antimicrob Chemother 32: 867-875

264 Small PM, Schafer RW, Hopewell PC et al (1993) Exogenous reinfection with multidrug-resistant Mycobacterium tuberculosis in patients with advanced HIV infection. N Engl J Med 328:1137-1144 Smith KC, Starke JR, Eisenach K, Ong LT, Denby M (1996) Detection of Mycobacterium tuberculosis in clinical specimens from children using a polymerase chain reaction. Pediatrics 97:155-160 Smith MHD (1967) Tuberculosis in adolescence. Characteristics, recognition, management. Clin Pediatr 6:9-15 Snider DE, Kelly GD, Cauthen GM, Thompson NJ, Kilburn JO (1985) Infection and disease among contacts of tuberculosis cases with drug-resistant and drug susceptible bacilli. Am Rev Respir Dis 132:125-132 Snider DE, Caras GJ, Koplan JP (1986) Preventive therapy with isoniazid. Cost effectiveness of different durations of therapy. J Am Med Assoc 255:1579-1583 Steiner P, Rao M, Mitchell M, Steiner M (1985) Primary drug resistant tuberculosis in children. Am J Dis Child 139:780-782 Tanzania Tuberculin Survey Collaboration (2001) Tuberculosis control in the era of the HIV epidemic: risk of tuberculosis infection in Tanzania, 1983- I998. Int J Tuberc Lung Dis 5:103-112 Talbot EA, Perkins MD, Fagundes S et al (1997) Disseminated Bacille Calmette-Guerin disease after vaccination: case report and review. Clin Infect Dis 24:1139-1146 Te Water Naude JM, Donald PR, Hussey GD et al (2000) Twice weekly vs.daily chemotherapy for childhood tuberculosis. Pediatr Infect Dis J 19:405-410 Thomas P, Bornschlegel K, Singh TP et al (2000) Tuberculosis in human immunodeficiency virus-infected and human immunodeficiency virus-exposed children in New York City. Pediatr Infect Dis J 19:700-706 Tripathy SP,Menon NK, Mitchison DA et al (1969) Response to

P. R. Donald treatment with isoniazid plus PAS of tuberculosis patients with primary isoniazid resistance. Tubercle 50:257-268 Udani PM (1983) Tuberculosis on children in India. A major health hazard! Pediatr Clin India 18: 11-42 Vallejo JG, Ong LT, Starke JR (1994) Clinical features, diagnosis, and treatment of tuberculosis in infants. Pediatrics 94: 1-7 Van Eden W, De Vries RR, Stanford JL et al (1983) HLA-DR3 associated genetic control of response to multiple skin tests with new tuberculins. J Immunogenet 10:107-114 Van Geuns HA, Meijer J, Styblo K (1975) Results of contact investigation in Rotterdam, 1967-1969. Bull Int Union Against Tuberc 50:107-121 Wallgren A (1928) Initial fever in tuberculosis. Am J Dis Child 36:1341-1345 Wallgren A (1938) Pulmonary tuberculosis. Relation of childhood infection to disease in adults. Lancet 1:417-420 Wallgren A (1948) The ,time-table' of tuberculosis. Tubercle 29:245-251 Weber HC, Beyers N, Gie RP, Schaaf HS, Fish T, Donald PR (2000) The clinical and radiological features of tuberculosis in adolescents. Ann Trop Paediatr 20:5-10 Weyer K, Groenewald P, Zwarenstein M, Lombard CJ (1995) Tuberculosis drug resistance in the Western Cape. South Afr Med J 85:499-504 Wilcox WD, Laufer S (1994) Tuberculosis in adolescents. Clin Pediatr 33:258-262 World Health Organization (1989) Provisional guidelines for the diagnosis and classification of the EPI target diseases for primary health care, surveillance and special studies. EPIIGEN/83/4 Zar HJ, Tannenbaum E, Appoles P, Roux P, Hanslo D, Hussey G (2000) Sputum induction for the diagnosis of pulmonary tuberculosis in infants and young children in an urban setting in South Africa. Arch Dis Child 82:305-308

17 Primary Tuberculosis in Adults M. MONIR MADKOUR

CONTENTS 17.1 17.2 17.3 17.4 17.5 17.6 17.7 17.8 17.9 17.10 17.11 17.12

Epidemiology of Primary Tuberculosis in Adults 265 Pathogenesis of Primary Pulmonary Tuberculosis 266 Culture Yield of Bacilli from Primary Lesion and Primary Complex 267 Groups at Risk of Primary Tuberculosis 267 Clinical Features and Diagnosis of Primary Tuberculosis in Adults 268 Lung Infiltrates and Consolidation 268 Lymphadenopathy 269 Pleural Effusion 269 Miliary Tuberculosis 269 Microbiological Confirmation 269 Treatment and Possible Paradoxical Transient Worsening 270 Conclusion 270 References 270

Traditionally, primary tuberculosis is a disease of childhood (Beyers 1979). This remains true in poor, developing countries where tuberculosis is endemic, and infections commonly start during childhood (see Chap. 16). This tradition, however, has been modified in rich, developed and industrialized countries that adopted successful tuberculosis control programs starting in the nineteenth century. Developed industrialized countries at present harbor only 5% of the world burden of tuberculosis, and the population group most infected is over 65 years of age (Alexander et al. 1979) (see Chap. 3). In these developed countries, exposure to the infection occurs mostly in the elderly population, leading to primary pulmonary tuberculosis. During the current epidemic of HIV, co-infection of adults with primary tuberculosis has been increasingly reported, leading to its dissemination (Pitchenik and Rubinson 1985; Wasser et al. 1988). This shift towards the presentation of primary tuberculosis in the elderly and among HIV-infected patients appears M. M. MADKOUR, MD, DM, FRCP Consultant, Department of Medicine, Riyadh Armed Forces Hospital, P.O. Box 7897, C-119, Riyadh 11159, Saudi Arabia

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

to be related to decreasing childhood exposure in the developed, industrialized countries (Khan et al. 1977; Miller and MacGregor 1978; Woodring et al. 1986; Choyke et al. 1983; Hulnick et al.I983). As a consequence of this shift of primary tuberculosis to the adult population, some authors from developed countries suggested that the term 'childhood tuberculosis' and 'adult tuberculosis' be abandoned (Berger and Granada 1974; Choyke et al.I983). We reviewed the medical records of 10 adult patients with primary tuberculosis who attended our hospital from 1990 through 2000. Their clinical features will be discussed in this chapter. The imaging features of these patients, including the follow-up radiograph findings during treatment and after its completion, are clearly described in our separate chapter specially devoted to the radiology of pulmonary tuberculosis. Imaging figures on primary pulmonary tuberculosis are numbers: 23.3,23.4,23.8,23.9,23.10,23.12,23.16, 23.17 and 23.18.

17.1 Epidemiology of Primary Tuberculosis in Adults Since the shift of patient care from long-term sanatorium management into general hospitals, the clinicians' awareness of primary tuberculosis has decreased. This is because tuberculous patients are no longer managed by clinicians with a special interest in the disease, along with the decline in the incidence of the disease in the populations of developed countries (Ellersten 1959; Khan et al. 1977; Varkey and Politis 1981; Choyke et al. 1983). The incidence of primary tuberculosis has been reported to range between 10% and 34% (Stead et al. 1968; Khan et al. 1977; Miller and MacGregor 1978; Woodring et al. 1986; Buckner et al. 1990; Miller et al. 1993; Miller 1994; McAdams et al. 1995). Most of the epidemiological data on primary tuberculosis in adults are reported from the USA and Europe.

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The criteria adopted to determine the incidence of adult primary tuberculosis in various reported series vary slightly among different authors. The criteria for diagnosis basically rested upon the conversion of PPD skin testing as well as imaging features (Chiba and Kurihara 1979; Choyke et al. 1983). Choyke and colleagues from Duke and Yale Universities reviewed 103 patients with adult-onset primary pulmonary tuberculosis seen over a period of 6 years. Their criteria included recent PPD skin test conversion with adenopathy or pleural effusion in a patient with no history of tuberculosis and previously normal chest radiographs. Black male predominance was noted in approximately 60%, and 73.8% was aged 40 years or more. These authors reported that the incidence of active primary tuberculosis in adult is approximately 10%-20%. Miller and Miller (1993) considered a recent conversion of the PPD skin test with isolated pleural effusion, lymphadenopathy, isolated middle and lower lobe infiltration, and most cases of miliary tuberculosis as diagnostic of primary tuberculosis. These authors estimated the incidence of primary tuberculosis in adults as ranging from 23% to 34%. In Norway, Heldal and colleagues (2000) reviewed the cases of Norwegian-born patients with pulmonary tuberculosis. They found that most cases in their series were due to endogenous reactivation of the disease. The incidence of adult primary pulmonary tuberculosis in these patients was reported to be 10% in 1975,19% in 1985, and 16% in 1995.

17.2 Pathogenesis of Primary Pulmonary Tuberculosis Primary pulmonary tuberculosis is transmitted by inhalation of air-borne Mycobacterium tuberculosis present in the cough particles from the sputum of a smear-positive patient. The inhaled bacilli usually deposit in the middle or lower lung field. The exact mechanisms of the protective immunity response against the development of the disease in humans have not been totally clarified (Ellner 1997). M. tuberculosis lipoproteins and glycolipids induce activation of macrophage, T-cell, and cytokine expression (Wallis and Johnson 2001). Alveolar macrophages phagocytose the bacilli, and activation of the cell-mediated immune response (CMI) plays an essential role in combating infection (Reddy and Hayworth 2002; Garcia et al. 2002). The bacilli may

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survive, especially within nonactivated monocytel macrophages that enter the alveoli from the bloodstream (Dannenberg 2001). Early in the primary infection (within a few hours), the bacilli are transported by macrophages to the hilar and/or paratracheal lymph nodes (Milburn 2001). Tissue-damaging delayed hypersensitivity (DTH) develops, and the bacilli-laden macrophages are killed. Key factors in this process include monocyte-derived interleukin (IL)-12 and tumor necrosis factor (TNF)-oc as well as T-cell-derived IL-2 and interferon (IFN)-y. These cytokines playa crucial role in the induction of macrophage-mediated elimination of mycobacteria (Vanham et al. 1997; Garcia et al. 2002). During active pulmonary tuberculosis, signs of both immune depression and immune activation are concomitantly present (Vanham et al.1997). The balance of cytokines produced by lymphocytes in response to infection is believed to have a profound effect on the clinical outcome. Depression of peripheral blood T-cell and cytokine production has been demonstrated during active tuberculosis disease (Garcia et al. 2002). As the infection progresses, local areas of inflammation with granuloma formation and cellular infiltrates occur in the middle or lower zones of the lung. This is the pulmonary component of the primary Ghon focus and, in combination with hilar and/or paratracheallymphadenitis, forms the primary complex. Tuberculin conversion may occur 3-6 weeks after the initial infection (Milburn 2001). The outcome of the infection depends on the interaction between the host immune system response and the bacilli. In patients with strong and competent cellular immunity, the Ghon focus and regional lymphadenitis heal with fibrosis and calcifications within weeks or months. However, the primary complex lesion may progress into lung parenchymal or lymph node infection or both in what is known as progressive primary tuberculosis. Many tuberculosis specialists adopted the use of the term 'progressive primary tuberculosis' if it occurs within 3-8 months after tuberculin conversion. About 10% of all cases of primary tuberculosis progress to a chronic form indistinguishable from reactivation disease (Goppert and Left 1979). Within the first year of primary pulmonary infection, the incidence of clinically significant disease is approximately 1.5%, and the cumulative risk during the first 5 years is 5%-10% (Chiba and Kurihara 1979). Balasubramanian and colleagues (1994) from Wisconsin, USA, extensively reviewed the published work of other investigators which dealt with the pathogenesis of tuberculosis. Particular emphasis was laid on the infective dose, the yield of bacilli from the pri-

267

Primary Tuberculosis in Adults

mary lesion, predominant locations, and the argument regarding the endogenous versus exogenous pathway leading to post-primary tuberculosis. The following paragraphs include some personal abstracts as well as the investigators' views and schools of thought on the issues of the pathogenesis of primary pulmonary tuberculosis. The size of the infective dose has been debated among investigators in a review article. On the one hand, some investigators indicated that a large infectious dose occurred more frequently in household contacts of sputum-positive cases. The infective dose includes the number of bacilli per infectious particles inhaled during anyone period of exposure. Other investigators indicated that the infectious dose in tuberculosis was very small. The size of a droplet nucleus disseminated during a cough by a sputum-positive tuberculosis patient is 5.0 ~m in diameter. It is estimated that the number of bacilli in a droplet nucleus is 1-10. Accordingly, these observations suggest that the infectious dose in tuberculosis is very low. The location of the primary complex was noted by Medlar (1948) in his series of 105 individuals found during autopsies performed on 1225 bodies. The single primary complex was located within 1 cm of the pleural surface in 85%, and in the lower half of the lung field in 66%, while only 12% were supraclavicular; he ascribed this pattern of lung lesion distribution to the direction of the airflow. The primary focus is the initial lesion produced by tubercle bacilli in any tissue. The primary or Ghon complex includes both the primary focus and homologous lesions in the draining lymph nodes. The primary complex most commonly occurs in the lung, but may also develop in the skin, intestines, genital tract, and tonsils. A mucous membrane primary focus may not incite a typical tuberculous healing reaction, so that only fibrocalcific lymph nodes may remain as indicators of a primary infection in these tissues. Therefore, fibrocalcific lesions in the lung or lymph nodes of a patient with organ and miliary tuberculosis may be taken to represent evidence of a prior primary infection (Slavin et al. 1980).

17.3 Culture Yield of Bacilli from Primary Lesion and Primary Complex Canetti (1972) suggested 'that tubercle bacilli do not survive indefinitely in tuberculous foci'. Work on guinea-pigs with inoculations of the component

of the primary complex (before the era of chemotherapy) indicated that no live bacilli could be cultured in 85% of calcified lesions and in 50% in the encapsulated stage. This review explored as well the work and school of thought of other investigators on how a calcified primary focus can be a source of reactivation of the disease when live bacilli no longer exist. Theories of alternative locations created during the primary disease by the progeny of bacilli from the primary lesion which had been disseminated hematogenously have been postulated. Other aspects of pathogenesis including the postprimary tuberculosis and the specified pathways (endogenous versus exogenous) by which the disease may occur later in life have already been elaborated.

17.4 Groups at Risk of Primary Tuberculosis Adults and the elderly in developed countries with diseases that affect the integrity of their immune system will increase the chances for the development of primary tuberculosis infection (Alexander et al. 1979; Ikejoe et al. 1992). Young adults with preexisting HIV infection are particularly susceptible to co-infection with primary pulmonary tuberculosis. Patients on chemotherapy or steroids for cancer and other diseases are particularly vulnerable to the development of primary tuberculosis. Drug abusers, the homeless, and the elderly residing in nursing homes are susceptible to the development of adult primary pulmonary tuberculosis. Traveling to endemic areas or a long airplane flight has been reported as risk factors for the transmission of tuberculosis. Kenyon and colleagues (1996) from the USA reported the transmission of tuberculosis during a long flight (8.75 hours) from a 32-year-old Korean woman tourist to four passengers on the same flight in April 1994. The patient was traveling from Chicago to Honolulu, and she had been on antituberculous treatment for the past 2 years. She was coughing during the flight and had fever. Eventually, she became very sick and was admitted to hospital and died 1 week later with massive hemoptysis. The sputum smear was highly positive, and culture was positive for M. tuberculosis. The CDC was involved in the investigation that included notifications to the passengers of that flight. Careful and thorough epidemiological screening was conducted including all risk factors and previous PPD skin test history. Four patients who were known

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tuberculin skin test-negative had initial testing after exposure which was negative and had a final test repeated 12 weeks later that showed conversion to positive results. In the Netherlands, Cobelens et al. (2000) investigated Dutch long-term travelers to countries of high tuberculosis endemicity. PPD skin testing was done before traveling and 2-4 months after their return. The results of 656 individuals were reported: there were 12 with M. tuberculosis infection, and 2 had active disease (1.8%). The overall incidence rate was estimated as 3.5 per 1000 person-months of travel and 2.8 per 1000 person-months of travel after the exclusion of health-care workers. The inclusion criteria for this study were over 15 years of age, not yet received BCG vaccination, and intended to travel for 3-12 months to these highly endemic countries. Exclusion criteria were history of tuberculosis or positive skin test, diabetes mellitus, HIV, or history of immunosuppressive therapy.

17.5 Clinical Features and Diagnosis of Primary Tuberculosis in Adults Primary pulmonary tuberculosis in adults may present with constitutional symptoms as well as cough, fever, hemoptysis, or weight loss that are often misdiagnosed initially as bacterial pneumonia. It is only because of the atypical clinical features in association with the so-called 'unusual' radiographic findings (Segarra et al. 1963; Parmar 1967; Dodd et al. 1978; Palmer 1979; Hadlock et al. 1980; Stead 1981; Lee et al. 1993) or the adoption of 'routine' microbiological examination of the sputum by smear staining and culture for acid-fast bacilli that an accurate diagnosis can be achieved (Choyke et al. 1983). A high index of suspicion by the attending clinician is essential for an early diagnosis. Failure in considering tuberculosis as a possible cause in these patients will delay the initiation of appropriate chemotherapy. The disease may progress, and serious dissemination to other body organs or systems may occur. Guidelines and criteria were used by several authors to identify and classify patients as having adult primary pulmonary tuberculosis (Stead et al. 1968; Khan et al. 1977; Choyke et al. 1983). Khan and colleagues (1977) classified adult patients with tuberculosis in the lower lung field as having primary pulmonary tuberculosis if one or more of the following criteria were also present: (1) known recent tuberculin conversion, (2) tuberculous pleural effusions

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without roentgenographic evidence of post-primary disease, (3) hilar adenopathy with or without parenchymal infiltration. These authors found 12 patients with adult primary pulmonary tuberculosis in their large series of 88 adult patients with newly proven diagnosis of active pulmonary tuberculosis who fulfilled these criteria. They were seen over a 12-month period and attended two hospitals in Boston, USA. Ten patients were young adults (19-38 years old), and 2 were in their 60s. Choyke and colleagues (1983) from the USA adopted the same criteria and reported their own series of 103 adult patients with primary pulmonary tuberculosis with positive M. tuberculosis cultures from at least one source. In our own series of 10 adult patients with primary pulmonary tuberculosis, the criteria for the classification depended mainly on radiographic findings. Recent PPD skin test conversion or the status of a previous tuberculin test is unknown in many of our patients. Choyke and colleagues (1983) from the USA stated: 'The diagnosis of primary tuberculosis rests upon tuberculin skin test (PPD) conversion.' However, they reported that there was inadequate documentation of the PPD skin test in their own series. Symptoms lasting a few days or weeks at the time of presentation are commonly reported in 84% by Khan et al. (1977) and Choyke et al. (1983). These included constitutional symptoms, fever, cough, and hemoptysis. The initial diagnosis of tuberculosis on admission was only made in 10%, and 70% were initially diagnosed to have 'bacterial pneumonia', and diagnosis was delayed for up to 6 weeks as reported in Choyke's series of 103 patients.

17.6 Lung Infiltrates and Consolidation Plain radiographs of the chest may look normal, and lung infiltrates may only be depicted on CT. Segmental or lobar consolidation of the right middle or lower lobe is the most common pattern of distribution in primary tuberculosis in adults as we noted in 6 of our patients (60%) (Figs. 23.3,23.9,23.16, and 23.18). Consolidation in the upper lobe may also occur, but it is rare. Associated hilar or right paratracheal lymphadenopathy with consolidation was noted in these 6 patients as well. Cavitation (Dahl 1952) in primary tuberculous consolidation was noted in 1 of our patients (Fig. 23.4). In the series of 12 patients reported by Khan et al. (1977), consolidations in the lower and middle lobes

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were noted in 6 patients (50%) and in the upper lobe, in 1 patient. In Choyke and colleagues' (1983) series of 103 patients, they reported consolidations in the lower and middle lobes in 77 patients (75%) and in the upper lobe in 36 patients (35%), bilateral in 13 (13%), cavitations in 8 (8%), and normal radiographs in 10 patients (10%). In Belgium, van den Brande and colleagues (1998) reported the incidence of adult pulmonary tuberculosis in a low prevalence area. They reviewed the chest radiographs of patients who had bacteriologically proven pulmonary tuberculosis over two periods (1981-1985 and 1986-1990). They found 114 and 105 patients, respectively. Approximately 50% of these patients were aged 65 years and over. Radiological features were classified as 'usual' or 'unusual' presentation.'Unusual' radiological features were defined as solitary pleural effusion, isolated hilar or mediastinal lymphadenopathies, normal chest xray, lower lung field tuberculosis, nodular lesions, diffuse infiltration, and atelectasis. The usual imaging features of pulmonary tuberculosis were present in 76% and 68%, respectively. Unusual imaging features of pulmonary tuberculosis were present in 24% and 35%, respectively. The authors noted the shift in the incidence of tuberculosis to elderly subjects who had never been infected before. They also noted that their 'unusual' imaging features resemble those observed in childhood primary pulmonary tuberculosis. They concluded that there is a recent trend towards a more 'unusual' presentation of primary pulmonary tuberculosis in the elderly.

17.7 Lymphadenopathy Unilateral or bilateral hilar lymphadenopathy and/or right paratracheal lymph node enlargement are the hallmarks of primary tuberculosis. They were noted in 9 patients with adult primary pulmonary tuberculosis (90%) in our own series, and their imaging features are illustrated in our chapter on radiography of pulmonary tuberculosis (Figs. 23.3, 23.4, 23.6, 23.7, 23.8,23.9,23.12,23.16, and 23.18). Hilar and/or paratracheal tuberculous lymphadenopathy in primary tuberculosis is more commonly reported in children than adults (McAdams et al. 1995; Woodring et al. 1986; Leung et al. 1992). Caseation and necrosis of tuberculous hilar or paratracheal lymph nodes may occur (Fig.23.8). Enlarged lymph nodes may obstruct the airway and may lead to atelectasis. It may invade the surrounding structures, particularly

the esophagus, phrenic nerve, recurrent laryngeal nerve, superior vena cava, or pericardium (Figs. 23.10 and 23.11). Other authors reported the incidence of tuberculous hilar lymphadenopathy as 15%-50% in their series (Khan et al. 1977; Choyke et al. 1983).

17.8 Pleural Effusion Pleural effusion in primary tuberculosis in an adult may occur in 29%-70% of patients (Roper and Waring 1955; Stead et al. 1968; Miller and MacGregor 1978; Khan et al. 1977; Choyke et al. 1983; Epstein et al. 1987). It is often unilateral, but bilateral effusion may rarely occur (Fig. 23.12). Associated parenchymal lesions and hilar lymphadenopathy may be present but not depicted on plain radiographs. Computed tomography is more sensitive in depicting such an association. Pleural effusion due to primary tuberculosis in adults was noted in one patient from our series (Fig. 23.12).

17.9 Miliary Tuberculosis Miliary tuberculosis may occur in both primary and reactivation tuberculosis (Munt 1972; Gelb et al.1973; Sahn and Neff 1974; Grieco and Chmel 1974). It is increasingly reported in immunosuppressed adults, particularly with HIV co-infection, in up to 13% (Choyke et al. 1983; Lee and 1m 1995). The plain radiograph may initially look normal, and CT is more sensitive in depicting the miliary lung shadowing.

17.10 Microbiological Confirmation Microbiological confirmation of the diagnosis in adult primary pulmonary tuberculosis may be difficult. The sputum smear and culture with positive yield were reported in as many as 60%-70% (Khan et al. 1977; Choyke et al. 1983). Bronchoscopy to obtain samples was performed in 34 patients, and in 27, the cultures were positive as reported by Choyke et al. (1983). Pleural fluid and biopsies were positive with yield of the bacilli in 10 out of 26 cases reported by the

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same authors. Other sources reported about pathological specimens obtained by open lung biopsies and thoracotomy in difficult-to-diagnose cases.

17.11

Treatment and Possible Paradoxical Transient Worsening The treatment of primary tuberculosis in adults does not differ from the treatment of reactivation disease. Directly observed therapy (DOT) is the most appropriate therapeutic regimen for primary pulmonary tuberculosis in adults. It is usually given on an outpatient basis for 6 months. In the initia12-month phase, four drugs are used (rifampicin, isoniazid, pyrazinamide, and either ethambutol or streptomycin) followed by a 4-month continuation phase of rifampicin and isoniazid. Treatment is usually given daily but can be given thrice weekly (see Chap. 44). During the initial 3 months of chemotherapy, paradoxical transient worsening of the original radiographic findings or development of new lesions may occur, as reported by many authors (Weber et al. 1968; Matthay et al. 1974; Campbell and Dyson 1977; Amodio et al. 1986; Lamont et al. 1986; Akira et al. 2000). The mechanisms and pathogenesis of this paradoxical response remain unclear. Enhanced immune responses to a sudden destruction and release of tubercular antigens or even a drug reaction has been postulated by several authors (Onwubalili et al. 1986; Marshall and Chambers 1988; Akira et al. 2000). Paradoxical transient worsening should be differentiated from true worsening of tuberculous lesions due to co-infection with HIY, other bacteria, or fungi. In our series, worsening of the original parenchymal shadowing as well as the development of new ipsilateral or contralateral consolidations were noted in two patients (Fig. 23.16 and 23.17). Radiological evaluation should be done at 2-3 months after initiation of chemotherapy (Bass et al. 1986).

17.12

Conclusion Primary pulmonary tuberculosis in adults is rarely reported in endemic developing countries, where it is mostly reported in children. The recent PPD skin test conversions, considered as important criteria for the diagnosis in developed countries, are difficult to

M. M. Madkour

document in most patients in endemic, resourcepoor countries. In developed, industrialized countries where the tuberculosis control program has been applied for many years, with a low incidence of the disease in the population, primary pulmonary tuberculosis has shifted to adults and the elderly population. The criteria for classification of primary pulmonary tuberculosis in adults, particularly, the recent PPD skin test conversions, can be applicable. The clinical and imaging features of adult primary pulmonary tuberculosis are no longer considered as 'usual' because of the shift of the disease to adults in developed countries. The clinical, imaging, and other investigations to confirm the diagnosis are discussed. Our own experiences with 10 patients with adult primary pulmonary tuberculosis have been discussed, and the imaging features of these patients can be seen in our separate chapter, Imaging of Pulmonary Tuberculosis, Figs. 23.3, 23.4, 23.8, 23.9, 23.10, 23.12, 23.16,23.17, and 23.18. Paradoxical transient worsening of radiology features during the early phase of chemotherapy is also documented.

References Akira M, Sakatani M, Ishikawa H (2000) Transient radiographic progression during initial treatment of pulmonary tuberculosis: CT findings. J Comput Assist Tomogr 24:426-43 I Alexander WJ, Avent CK et al (1979) Simple primary tuberculosis in an elderly woman. J Am Geriatr Soc 27:123-125 Amodio J, Abramson S, Berdon W (1986) Primary pulmonary tuberculosis in infancy: a resurgent disease in urban United States. Paediatr RadioI16:185-189 Balasubramanian V et al (1994) Pathogenesis of tuberculosis: pathway to apical localization. Tuberc Lung Dis 75: 168-178 Bass JB, Farer LS, Hopewell PC et al (1986) Treatment of tuberculosis and tuberculosis infection in adults and children. Am Rev Respir Dis 134:355-363 Berger HW, Granada MG (1974) Lower lung field tuberculosis. Chest 65:522-526 Beyers JA (1979) The radiological features of primary pulmonary tuberculosis. S Afr Med J 55:994-997 Buckner CB, Walker CW et al (1990) Radiologic manifestations of adult tuberculosis. J Thorac Imaging 5:28-37 Campbell lA, Dyson AJ (1977) Lymphnode tuberculosis: a comparison of various methods of treatment. Tuberculosis 58:171-179 Canetti G (1972) Endogenous reactivation and exogenous reinfection. Their relative importance with regard to the development of non-primary tuberculosis. Bull Int Union Tuberc 47:116-122 Chiba Y, Kurihara T (1979) Development of pulmonary tuberculosis with special reference to the time interval after tuberculin conversion. Bull Int Union Tuberc 54:263-264

Primary Tuberculosis in Adults Choyke PL,Sostman HD et al (1983) Adult onset of pulmonary tuberculosis. Radiology 148:357-362 Cobelens FGJ, Deutekom HV et al (2000) Risk of infection with Mycobacterium tuberculosis in travelers to areas of high tuberculosis endemicity. Lancet 356:461-465 Dahl RV (1952) The first appearance of a pulmonary cavity after primary infection with relation to time and age. Acta Tuberc Scand 27:140 Dannenberg Am Jr (2001) Pathogenesis of pulmonary Mycobacterium bovis infection: basic principles established by the rabbit model. Tuberculosis 81:87-96 Dodd GD, Capitanio MA et al (1978) Case 11 (primary tuberculosis). In: Film interpretation session. Radiological Society of North America, 64th scientific assembly and annual meeting, Nov 1978. Summary of discussion and diagnoses. Radiology 129:831 Ellertsen E (1959) Epidemics of primary tuberculosis and their significance. Acta Tuberc Scand 37:203 Ellner JJ (1997) Regulation of the human immune response during tuberculosis. J Lab Clin Med 130:469-475 Epstein DM, Kline LR et al (1987) Tuberculous pleural effusions. Chest 91: 106 Garcia M, Vargas A, Castej6n R et al (2002) Flow-cytometric assessment of lymphocyte cytokine production in tuberculosis. Tuberculosis 82:37-41 Gelb AF, Lefler C et al (1973) Miliary tuberculosis. Am Rev Respir Dis 108:1327 Goppert EF, Left A (1979) The pathogenesis of pulmonary and military tuberculosis. Arch Intern Med 139: 1381-1383 Grieco MH, Chmel H (1974) Acute disseminated tuberculosis as a diagnostic problem. Am Rev Respir Dis 109:554 Hadlock FP, Park SK et al (1980) Unusual radiographic findings in adult pulmonary tuberculosis. AJR 134:1015-1018 Heldal E et al (2000) Pulmonary tuberculosis in Norwegian patients. The role of reactivation, re-infection and primary infection is assessed by previous mass screening data and restriction fragment length polymprphism analysis. Int J Tuberc Lung Dis 4:300-307 Hulnick DH, Naidich DP, McCauley Dr (1983) Pleural tuberculosis evaluated by computed tomography. Radiology 149: 759-765 Ikejoe J, Kakeuchi N et al (1992) CT appearance of pulmonary tuberculosis in diabetic and immunocompromised patients: comparison with patients who had no underlying disease. AJR 159:1175-1179 Kenyon TA, Valway SE et al (1996) Transmission of multidrug-resistant Mycobacterium tuberculosis during a long airplane flight. N Engl J Med 334:933-938 Khan MA, Kovnat DM et al (1977) Clinical and roentgenographic spectrum of pulmonary tuberculosis in the adult. Am J Med 62:31-38 Lamont AC, Cremin BJ, Pelleret RM (1986) Radiological patterns of pulmonary tuberculosis in paediatric age group. Pediatr RadioI16:2-7 Lee KS, 1m JG (1995) CT in adults with tuberculosis of the chest: characteristic findings and role in management AJR 164:1361-1367 Lee KS, Song KS et al (1993) Adult-onset pulmonary tuberculosis: findings on chest radiographs and CT scans. AJR 160:753-758 Leung AN, Muller NL, Pineda PR et al (1992) Primary tuberculosis in childhood. Radiographic manifestations. Radiology 182:87-91

271 Marshall BG, Chambers MA (1988) Central nervous system tuberculosis: the paradox of host immune response. J Infect 36:3-4 Matthay RA, Neff TA, Iseman MD (1974) Tuberculous pleural effusion developing during chemotherapy for pulmonary tuberculosis. Am Rev Respir Dis 109:469-472 McAdams HP, Erasmus J, Winter JA (1995) Radiologic manifestations of pulmonary tuberculosis. Radiol Clin North Am 33:655-678 Medlar EM (1948) The pathogenesis of minimal pulmonary tuberculosis: a study of 1225 necropsies in cases of sudden and unexpected death. Am Rev Tuberc 58:583-611 Milburn HJ (2001) Primary tuberculosis. Curr Opin Pul Med 7:133-141 Miller WT (1994) Tuberculosis in the 1990s. Radiol Clin North Am 32:649-661 Miller WT, MacGregor RR (1978) Tuberculosis: the frequency of unusual radiographic findings. AJR Am J Roentgenol 130:867-875 Miller WT, Miller WT Jr (1993) Tuberculosis in the normal host: Radiological findings. Semin RoentgenoI28:109-118 Munt RW (1972) Miliary tuberculosis in the chemotherapy era: with a clinical review in 69 American adults. Medicine (Baltimore) 51:139 Onwubalili JK, Scott GM, Smith H (1986) Acute respiratory distress related to chemotherapy of advanced pulmonary tuberculosis. A study of two cases and review of the literature. OJ Med 59:599-610 Palmer PES (1979) Pulmonary tuberculosis - usual and unusual radiographic presentations. Semin RoentgenoI14:204-243 Parmar MS (1967) Lower lung field tuberculosis. Am Rev Respir Dis 96:310 Pitchenik AE, Rubinson HA (1985) The radiographic appearance of tuberculosis in patients with the acquired immunodeficiency syndrome (AIDS) and pre-AIDS. Am Rev Respir Dis 131:393-396 Reddy VM, Hayworth DA (2002) Interaction of Mycobacterium tuberculosis with human respiratory epithelial cells (Hep-2). Tuberculosis 82:31-36 Roper WH, Waring JJ (1955) Primary serofibrinous pleural effusion in military personnel. Am Rev Tuberc 71:616 Sahn S, Neff TA (1974) Miliary tuberculosis. Am J Med 56:495 Segarra F, Sherman DS et al (1963) Lower lung field tuberculosis. Am Rev Respir Dis 87:37-40 Slavin RE, Walsh TJ et al (1980) Late generalized tuberculosis: a clinical pathologic analysis and comparison of 100 cases in the preantibiotic and antibiotic eras. Medicine 59: 352-366 Stead WW, Kerby GR et al (1968) The clinical spectrum of primary tuberculosis in adults. Confusion with reinfection in the pathogenesis of chronic tuberculosis. Ann Intern Med 68:731-745 Stead WW (1981) Tuberculosis among elderly persons: an outbreak in a nursing horne. Ann Intern Med 94:606 Van den Brande PV, Dockx S et al (1998) Pulmonary tuberculosis in the adult in a low prevalence area: is the radiological presentation changing? Int J Tuberc Lung Dis 2:904-908 Vanham G, Toossi Z, Hirsch CS et al (1997) Examining a paradox in the pathogenesis of human pulmonary tuberculosis: immune activation and suppression/anergy. Tuberc Lung Dis 78:145-158 Varkey B, Politis J (1981) Pulmonary tuberculosis. A multifaceted disease. Postgrad Med 69:117-121, 124-126, 129

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M. M. Madkour Weber AL, Bird KT, Janower ML (1968). Primary tuberculosis in children with particular emphasis on changes affecting the tracheobronchial tree: AJR 103:123-132 Woodring JH, Vandiviere H et al (1986) The radiographic features of pulmonary tuberculosis. AJR 146:497-506

18 Miliary/Disseminated Tuberculosis M. MONIR MADKOUR

mary tuberculosis, immediately after the post-primary period, or at a time far remote from the post-primary 18.1 Introduction 273 period as late generalized tuberculosis (LGT) (Slavin 18.2 Epidemiology of MiliarylDisseminated et al. 1980). A wide spectrum of pathological features Tuberculosis 274 occurs as a result of hematogenous dissemination of 18.3 Pathology and Pathogenesis the bacilli. This spectrum of pathology is determined of Miliary/Disseminated Tuberculosis 275 18.4 Clinical Features of Miliary/Disseminated by the size of the bacillary inoculum load, the viruTuberculosis 277 lence of the bacilli, and the status of the host immune 18.5 Meningitis and Tuberculomas response. It ranges from a rare but acute fulminating in Miliary/Disseminated Tuberculosis 277 form due to the release of massive myriads of caseous 18.5.1 Case Illustration 1 279 18.5.2 Case Illustration 2 283 and necrotic tubercles into the blood with a nonreac18.5.3 Case Illustration 3 288 tive and an anergic response, very low count of CD4+ 18.5.4 Case Illustration 4 290 T-cells with scanty or absent granuloma formation; 18.5.5 Case Illustration 5 292 that form of the disease is only diagnosed at autopsy. 18.6 Adult Respiratory Distress Syndrome If, on the other hand, tuberculous bacteremia is slight and Disseminated Intravascular Coagulation in Miliary Tuberculosis 292 with the formation of few tubercles, this discrete type of 18.7 Pneumothorax in Miliary/Disseminated generalized dissemination is usually without immediTuberculosis 293 ate clinical significance, although these tubercles serve 18.8 Diagnosis of MiliarylDisseminated as 'seed beds' for the later development of organ tuberTuberculosis 293 culosis or LGT (Slavin et al. 1980). Between these two 18.9 High Resolution CT 296 18.10 Laboratory Diagnosis of Miliary pathological and clinical extremes lies a spectrum of Tuberculosis 296 pathology that varies in severity. The more common 18.10.1 Polymerase Chain Reaction 297 classic miliary tuberculosis resembles the fulminating 18.11 Treatment of MiliarylDisseminated form (Prout et al. 1980). Miliary tuberculosis is defined Tuberculosis 297 as a hematogenous dissemination of the bacilli resultReferences 298 ing in widespread, active, visceral, caseous tubercle formations measuring 1-3 mm in diameter (the size of millet seeds) with radiologic or pathologic evidence of pulmonary micronodules (Sahn and Neff 1974; Slavin et al. 1980; Penner et al. 1995). Disseminated tubercu18.1 losis is defined as a hematogenous transmission of the Introduction bacilli with active caseous tubercle formation in two Miliary/disseminated tuberculosis signifies the wide- or more extrapulmonary sites and with no pulmonary spread occurrence of caseating visceral tuberculosis miliary nodular shadowing on chest radiography that occurs by hematogenous dissemination of the (Penner et al. 1995; Sahn and Neff 1974). Proudfoot bacilli from an active caseous focus or foci located in the et al. (1969) described the fulminating dissemination lung or extrapulmonary sites. Hematogenous dissemi- form of tuberculosis in patients with other co-existing nation of the bacilli may occur during the course of pri- underlying disease that may lead to a clinical presentation with atypical features due to an impaired cellmediated immune response and the absence of miliary lung shadowing as 'cryptic disseminated tuberculosis', M. M. MADKOUR, MD, DM, FRCP Consultant, Department of Medicine, Riyadh Armed Forces which is usually diagnosed at autopsy. Disseminated tuberculosis is a diagnostic challenge even in endemic Hospital, P.O. Box 7897, C-119, Riyadh 11159, Saudi Arabia

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M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

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areas when the attending clinician has a high index of suspicion. Chest radiography is usually the initial diagnostic investigation for miliary tuberculosis. The sensitivity of chest radiography was found to range from 59% to 69% in a study based on population and group control subject (Kwong et al. 1996). ARDS may occur as a complication of miliary tuberculosis, and chest radiography may be difficult to interpret since the miliary nodules are superimposed on a more diffuse ground (Armstrong et al. 1995). Fatal consequences if undiagnosed and untreated at an early stage may affect 21 %-64% of patients with disseminated tuberculosis (Monie et al. 1983; Al-Jahdali et al. 2000; Prout et al. 1980; Bobrowitz 1982). Miliary/disseminated tuberculosis has increased in incidence in the USA, particularly among HIV co-infected patients (Rieder et al. 1991; Hill 1991; FitzGerald et al. 1991; Korzeniewska-Kosela et al. 1992). Iatrogenic miliary/disseminated tuberculosis due to Mycobacterium bovis, induced by intravesical BCG immunotherapy for the treatment of urinary bladder cancer, has been increasingly reported (Foster 1997; McParland et al. 1992; Palayew et al. 1993).

18.2 Epidemiology of Miliary/Disseminated Tuberculosis The incidence of miliary/disseminated tuberculosis is difficult to determine in either developing or developed countries (Vijayan 2000). Many patients were undiagnosed in life, and it is only at autopsy that the disease may be found (JuuI1977; Bobrowitz 1982; Slavin et al. 1980; Prout et al. 1980). In the USA, Slavin et al. (1980) from Johns Hopkins reviewed the records of 120 autopsies performed between May 1937 and December 1959. They excluded 20 cases due to missed records. The remaining 100 autopsies had microbiologically proven TB, histopathological features, and evidence of hematogenous spread involving the spleen, liver, lung, bone marrow, kidney, adrenal glands, and other organs. The total number of autopsies performed during these 22 years was 14,224, and LGT was found in 120 (0.8%). Sixty of the 100 patients lived in the pre-antibiotic era (mid-1948) and 40 in the antibiotic period. Male predominance was noted in 61 (61 %), of whom 44% were black. There were 39 women, 28% of whom were black. The total number of black patients was 72 and white patients, 28. The authors estimated that 1 case of LGT was found in every 142 autopsies.

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In Canada, Long et al. (1997) reviewed the records of 2013 patients with active tuberculosis between January 1, 1979, and December 31,1993, to determine the clinical-pathologic-radiologic correlation in disseminated tuberculosis with and without a miliary pattern on radiography. All patients came from Manitoba, with a low seroprevalence of HIV in that area. They adopted a rigorously defined; radiographic or histopathologic evidence of hematogenous dissemination and found 56 patients (3%) (42 miliary and 14 nonmiliary). Women were 2.4 times more likely to be affected than men in this series. The mean age for both sexes was 50±26 years. Fourteen patients died, of whom 5 (12%) had miliary and 9 (64%) had nonmiliary disseminated tuberculosis. In Glasgow, Scotland, Monie et al. (1983) reviewed the records of 1000 patients with tuberculosis reported during a 3-year period (1976-1978) and found 28 (2.8%) patients with miliary tuberculosis. Seventeen (61%) had miliary shadowing, 7 (25%) had other radiological changes consistent with active or previous pulmonary tuberculosis, and 4 (14%) had no radiological changes suggesting pulmonary tuberculosis. About 50% of patients were over 60 years of age, and 23% were non-European in origin. These authors reported fatalities in 9 (32%) of the 28 patients with miliary tuberculosis. Ormerod and Horsfield (1995) from Blackburn, UK, reviewed notified cases of tuberculosis in the Blackburn, Hyndburn and Ribble Valley District Health Authority (DHA), an area of high prevalence for tuberculosis. They found 39 cases of miliary tuberculosis over 16 years (1978-1993 inclusive). Fourteen patients had miliary TB, and 25 had cryptic miliary TB. The authors noted ethnic differences with regard to the number of cases and the age at onset. The mean age among Caucasian patients was 51.3 years, while among Indian subcontinent (ISC) patients, it was 37 years. The incidence of miliary tuberculosis in Blackburn was approximately 0.25/100,000 in the Caucasian ethnic group and 7.99/100,000 in the ISC ethnic group. These authors reported the death rate due to miliary tuberculosis as 10%. In Denmark, Juul (1977) reported on clinically undiagnosed, active tuberculosis in 895 autopsies. They found active tuberculosis undiagnosed in life in 86 (0.1 %) patients. Miliary tuberculosis found in 38 (44.2%). The mean age of these patients was 70.7 years, with a female predominance. In NewYork,Bobrowitz (1982) reported 21 patients in whom tuberculosis was not diagnosed in life. At autopsy, 10 had suffered miliary tuberculosis and 11, pulmonary tuberculosis. Fifteen were male and

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6 female, and 13 were white, 6 black, and 2 Hispanic. Over 70% of the patients were more than 60 years of age. The main diagnosis of the 10 patients with miliary tuberculosis on admission was pneumonia, malignancy, or sepsis. The authors explained the failure to discover tuberculosis in these patients as due to combinations of other diseases and conditions. The incidence of miliary tuberculosis in developing countries is more difficult to determine (Prout et al. 1980). Lack of notification of miliary tuberculosis is due to failure to make the diagnosis while alive in countries like South Africa, which has a high incidence of tuberculosis (Prout et al. 1980). These authors reviewed the computerized records of medical diagnoses over a 6year period and found 64 cases of miliary or disseminated tuberculosis. Thirty-seven cases fulfilled the inclusion criteria: miliary lung shadowing, detection of the bacilli by stain or culture, caseating granulomas from liver or bone marrow biopsies, and involvement of two or more organs. These authors also reviewed the autopsies of 2,200 patients who died between 1973 and 1978 and found a further 34 cases (of them 9 fell into both groups and were excluded). A total number of 62 cases (live and autopsies) was reviewed. Eight (12.9%) were white, 20 (32.3%) colored, and 34 (54.8%) black. Thirty-six (58.1%) were male and 26 (41.9%) female. Over 72% of men and 42% of women were over 40 years of age. Alcoholism, malnutrition, diabetes, cytotoxicity or radiotherapy for malignancies were concomitantly present in 25 patients (40.3%). Forty patients (64%) died, and 31 deaths were directly attributed to disseminated tuberculosis. In Saudi Arabia, AI-Jahdali et al. (2000) reported 780 cases of tuberculosis seen over a period of 7 years. Miliary tuberculosis was found in 47 (6%) patients, and 68% were over 60 years of age. A male predominance was noted (n=30), and the mean age was 61 years for both sexes. Risk factors such as diabetes, prior tuberculosis, chronic liver disease, renal failure, immunosuppressive drugs, and malignancies were present in over 50% of these patients. Ten patients died (21 %), all were due to miliary tuberculosis. In our own hospital in Riyadh, computerized records of medical diagnoses for patients admitted during the period from 1983-2000 inclusive (using ICD-9 code description) revealed a total number of 2,484 tuberculosis patients, with miliary tuberculosis reported in 79 patients (3.18%). Since the HIV epidemic in 1980s, the incidence of miliary/disseminated tuberculosis in HIV co-infected patients in the USA has increased. The incidence of miliary/disseminated tuberculosis has therefore increased from 1.3% of all reported cases of tuber-

culosis to 8%-10% among HIV co-infected patients (Rieder et al. 1991; Hill 1991; Schaefer et alI991).

18.3 Pathology and Pathogenesis of Miliary/Disseminated Tuberculosis Acute miliary/cryptic disseminated tuberculosis is part of a broad spectrum of hematogenous spread of Mycobacterium tuberculosis with various and variable degrees of clinical manifestation and severity. It is most commonly encountered in children and young adults in developing countries. It may occur during primary disease or within 6-8 months of primary disease (progressive primary). In endemic areas, hematogenous spread may occur in neonates, infants, and children or in immunocompromised patients, leading to primary miliary or disseminated tuberculosis. In developed countries, adults particularly those co-infected with HIV may develop primary miliary/disseminated tuberculosis via hematogenous transmission of the infection. Miliary/disseminated tuberculosis may occur in post-primary disease, either due to endogenous reactivation or exogenous re-infection (Auerbach 1944,1959). Hematogenous spread of the bacilli from a focus or foci located in the lung or extrapulmonary sites is the source of infection. Transmission of the organisms via the lymphatics to the blood circulation or direct invasion of the blood vessels by liquefied caseous material may occur due to a rupture or erosion of a contiguous focus or foci (Geppert and Leff 1979; Yu et al. 1986; Murray et al. 1978; Prout et al. 1980). Slavin et al. (1980) used the term late generalized tuberculosis (LGT) to describe generalized hematogenous spread occurring at a time far remote from the post-primary period. If tuberculous bacteremia is slight, a discrete type of generalization is usually without immediate clinical significance, although these 'seed beds' may serve later in the development of organ tuberculosis and LGT. However, if the generalization of the tuberculous bacteremia is massive, necrotizing tubercles are formed in various organs, and this is known as acute miliary tuberculosis. In postprimary disease, it is often believed that a single focus at the pulmonary or extrapulmonary site is considered the source of hematogenous spread of the bacilli. Clinical and pathological studies reported by several authors indicated that more than one focus located at different unrelated anatomical sites in various body organs may be reactivated simultaneously, discharg-

276

ing an enormous quantity of mycobacterial inoculum into the bloodstream. Slavin et al. (1980) stated that 'Late Generalized Tuberculosis (LGT) derived from a single extrapulmonary focus was very infrequent (7%); whereas in more than half of the cases, the origin of dissemination appears to have been derived from large foci present in a variety of organs'. This may occur intermittently, episodically, or continuously in 54% of cases (Pagel et al. 1964; Saye 1936; Slavin et al. 1980; Jacques and Sloan 1970). Evidence of intermittent or episodic hematogenous spread of infection was noted at autopsy. Soft exudative tuberculous lesions were mixed with other lesions showing partial or complete healing with fibrosis, calcifications, and ossifications (Slavin et al. 1980; Saye 1936; Jacques and Sloan 1970). It has been debated by some authors whether the lung is the main source of focal active caseous spread via the hematogenous route to other body organs; they believe that an extrapulmonary focus or foci are the most common source of hematogenous spread of infection. Slavin et al. (1980) reported that 'in the antibiotic era, chronic pulmonary tuberculosis and late generalized tuberculosis (LGT) coexisted far less commonly than they did prior to the advent of chemotherapy'. They reviewed the clinical and autopsy findings of 100 patients with LGT in two eras (pre-antibiotic and antibiotic periods) and concluded,'thus, both clinical and autopsy findings in the antibiotic period support Biehl's statement - that only a minority of cases of miliary tuberculosis arise from patients with pulmonary tuberculosis'. Hematogenous release of large quantities of necrotic caseous material of uniform size spread via the blood will cause embolization of the capillaries of most organs, particularly those with the richest vascular supply such as the liver, spleen, bone marrow, brain, and lungs. It is generally fatal if undetected and not treated early. At the other end of the spectrum of the hematogenous bacteremia, few bacilli may be discretely seeded into these body organs without immediate clinical manifestation. At a later stage, these hematogenous 'seed beds' may be reactivated in an organ or in all organs, with the development of miliary tuberculosis. They may also remain nonprogressive and well localized and cause few or no clinical symptoms. The course of the disease may take the form of 'chronic miliary tuberculosis', which is slowly progressive and not fatal (Pagel et al. 1964; Saye 1936). Fatal cases due to late generalized miliary tuberculosis do occur, but some clinicians consider these as representative of the terminal event of long-standing pulmonary or extrapulmonary disease (Yu et al.1986; Slavin et al. 1980). Factors determining the pattern of

M. M. Madkour

the disease presentation will depend on the size of the bacilli inoculum, its virulence, and the host immune response. In its severe acute fulminating form, septicemia may occur with extensive tissue damage and necrosis with very little evidence of a cell-mediated immune response. The diagnosis of this form is mostly missed in life because of the absence of the typical miliary lung shadowing seen on chest radiography, and the diagnosis is only made at autopsy (Chapman and Whorton 1946; Biehl 1958; Treip and Meyers 1959; Proudfoot et al.1969; Munt 1972; Prout et al.1980). Proudfoot et al. (1969) described this form of the disease as 'cryptic disseminated tuberculosis', Patients with cryptic disseminated tuberculosis may have a co-existing underlying disease that may present with atypical features and also cause impairment of the cell-mediated immunity such as alcoholism, cirrhosis, malnutrition, diabetes mellitus, connective tissue diseases, HIV, or may be taking immunosuppressive chemotherapy, and the diagnosis is then missed in life, with an absence of miliary lung shadowing, and is usually made at autopsy (Millar and Horn 1979; Bobrowitz 1982; Yu et al. 1986; Crump 1998). Patients in the late stage of AIDS with disseminated tuberculosis have a very low count of CD4+ T-cells and an anergic response with scanty or absent granuloma formation as reported by Zumla and Grange (see Chap. 29). In immunocompetent patients, the cell-mediated immune response (CM!) and tissue-damaging delayed hypersensitivity (DTH) responses will be activated. The bacilli cell wall antigens will activate the macrophages, CD4+ T cell, increased production of cytokines, TNF-a, IFN -y, IL-12 to combat the infection. The bacilli may survive, and during these responses concomitant immune depression and immune activation occur at the same time (Dannenbergh 2001; Vanham et al. 1997; Ellner 1997). The infection may overcome the immune system responses, and the disease progresses. At sites of the capillary bed seeded with bacilli, granuloma formation with central caseation and necrosis may occur simultaneously in all affected body organs. Adult respiratory distress syndrome (ARDS) is known as a complication of miliary/disseminated tuberculosis; it requires mechanical ventilation and has a high mortality rate ranging from 40% to 60% (Mohan et al. 1996; Dyer and Potgieter 1984; Murray et al. 1978; Dyer et al. 1985; Dee et al. 1980). The exact pathogenetic mechanisms by which miliary tuberculosis causes ARDS is not clearly understood. Penner et aI. (1995) suggested that the immunological aspects and pathogenesis of ARDS caused by miliary tuberculosis are similar to those caused by Gram-negative sepsis. In

MiliarylDisseminated Tuberculosis

277

miliary tuberculosis, a massive release of mycobacteria including fever, sweating, loss of appetite, weight lipoarabino-mannan cell wall antigens causes wide- loss, and weakness. Respiratory symptoms may spread perifocal inflammatory responses, injury to the include dry or productive cough, hemoptysis, shortalveolocapillary membrane, interstitial granulomatous ness of breath, and pleuritic chest pain. Neurological infiltration, obliterative endarteritis, increased capillary symptoms such as headaches, confusion, disorientaendothelial cell susceptibility to the toxic effect of the tion, cranial nerve palsies, or even coma may be the released TNF-a and ICAM-l (Penner et al.1995; Sutton presenting features. A history of tuberculosis may be et al. 1974; Petty and Ashburgh 1971; Massaro and Katz present in 10%-20% of patients (Slavin et al. 1980). 1964; Ashburgh et al.1967; McClement et al.1951). Fever is the most common symptom and may be The alveoli will be filled with inflammatory exu- the only presenting feature (pyrexia of unknown dative edema due to increased local vascularity, with origin). Other symptoms of tuberculosis related to vasculitis leading to pulmonary edema which is the other body systems or organs such as musculoskhallmark of ARDS (So and Yu 1981; Penner et al. eletal, genitourinary tract, or the abdomen are less 1995; Dee et al. 1980). The alveolar exudate mate- frequently encountered at the time of presentation. rial includes mostly polymorphonuclear leukocytes, Concomitant chronic illnesses such as diabetes melerythrocytes, fibrin, as well as caseating granulomas. litus, alcoholism, connective tissue diseases, chronic This will lead to mismatching of ventilation and per- renal failure, silicosis, HIV, or immunosuppressive fusion and an impaired diffusion capacity (Mohan et chemotherapy may be found in patients with miliary/ al.1996; William and Yoo 1973). disseminated tuberculosis. The physical signs may be Acute miliary/disseminated tuberculosis may few, including tachypnea, wasting, lymphadenopathy, also be caused by Mycobacterium bovis. Miliary M. hepatic and splenic enlargement, cutaneous lesions, bovis induced by intravesical BCG immunotherapy or features of meningitis (Ray et al. 2002; Sharma used for the treatment of bladder cancer has been et al. 1981; Pasculle et al. 1980; Bateman et al. 1980; reported (Deresiewicz et al. 1990; Rawls et al. 1990; K6ylii et al.1997; Shibolet et al.1979; Prout et al.1980; Kesten et al. 1990; Gupta et al. 1988; McParland et al. Evans et al. 1998; Long et al. 1997). The frequency of 1992; Iantorno et al. 1998; Palayew et al. 1993; Foster symptoms and signs of miliary/disseminated tuber1997; Jasmer et al. 1996; Rabe et al. 1999; Soloway culosis as reported by some authors are shown in 1988). The mechanism by which BCG induces mili- Tables 18.1 and 18.2. ary tuberculosis has been debated among authors (Lotte et al. 1984; de Hertogh et al. 1989; Orihvela et al. 1987). Some authors suggested that it is a hypersensitivity reaction in response to BCG, particularly 18.5 when they failed to grow the organisms. Other Meningitis and Tuberculomas authors explained the widespread lung shadowing in Miliary/Disseminated Tuberculosis as due to hematogenous dissemination of the bacilli which were isolated from various pathological fluid Miliary/disseminated tuberculosis may involve the and tissue biopsy specimens. Other nontuberculous central nervous system with evidence of meningitis Mycobacterium species may cause miliary and dis- or tuberculomas in up to 30% of patients (Slavin et seminated diseases similar to those caused by M. al.1980; Biehl 1958; Maartens et al.1990). Headaches, tuberculosis. These nontuberculous mycobacteria are hemiplegia, seizures, and coma may indicate involveparticularly found in patients with HIV. Mycobacte- ment by meningitis and/or tuberculoma, as noted in rium avium-intracellulare, M. kansasii, and M. fortui- our case no. 3 (Fig. 18.3f,g). However, the patients may tum are the ones most frequently reported (Bone and have no symptoms that are related to the central nerStableforth 1981; Longdale et al. 1992). vous system, and cerebral tuberculoma may only be depicted by MRI. The cerebrospinal fluid (CSF) may be either clear or turbid with lymphocytic pheocytosis, raised protein concentration, with a low level of 18.4 glucose (Gelb et al. 1973). Cerebrospinal fluid smear Clinical Features of Miliary/Disseminated is rarely positive for acid-fast bacilli, and culture may Tuberculosis yield the bacilli in up to 20% of patients (Hill 1991). The prognosis may be poor if undiagnosed and not The clinical symptoms at the time of presentation of treated early, with the development of hydrocephalus, miliary/disseminated TB may only be constitutional coma, and death.

54

109

21 26

59

67

62

63

Long et al. (1997)

Maartens et al. (1990)

Bobrowitz (1982) Stenius-Aarniala (1979)

Prout et al. (1980)

Munt (1972)

Biehl (1958)

Chapman and Whorton (1946)

79

62

84

44

95 88

92

82

72

Fever (%)

82

63

65

63

43 15

72

59

60

Cough (%)

-

-

-

37

-

19

72

26

30

Expectorant (%)

64

23

1

37

33 31

72

30

34

Dyspnea (%)

-

-

-

15

-

72

11

-

84

69

63

Munt (1972)

Biehl (1958)

62

72 82 96 44

60

-

33

-

62

67

-

-

62

6

6

8.5

15

-

13

Pleural effusion 8 46 36 57

30

-

12

15 12

52 62

72 53

35

13 36

-

4 20 21 28

9

14

-

-

85

61

95

59

33 38

92

62

30

Hemoptysis Weight loss (%) (%)

-

-

38 16

Epididymo-orchitis, subcutaneous abscess arthritis 13

Others

Fatigue - 49 Sweating - 45 Sweating - 37 Weakness - 70 Abdominal pain - 21 Musculoskeletal - 13 Disorientation and confusion - 52 Abdominal pain - 35 Fatigue - 35 Nausea & vomiting - 23 Anorexia - 51 Weakness - 42 Abdominal pain - 30 Confusion - 17 Abdominal pain - 7 Weakness - 93 Anorexia - 91 Weakness - 65 Anorexia - 42 Abdominal pain - 10 Anorexia - 90

Others

Neck stiffness 26 Pericardial effusion 8 Choroidal TB 7 -

20 -

7

18

10

17

12

25

-

-

Headaches (%)

Hepato- Spleno- Ascites CNS megaly megaly

Chest pain (%)

No. of Fever Tachypnea Wasting Lympha- Chest signs denopathy cases

Al-Jahdali et al. (2000) 47 Long et al. (1997) 54 Maartens et al. (1990) 109 Prout et al. (1980) 62

Reference

Table 18.2. Most common signs of miliary/disseminated tuberculosis

47

No. of cases

Al-Jahdali et al. (2000)

Reference

Table 18.1. Most common symptoms of miliary/disseminated tuberculosis

s:: l:

~ ...

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~ ~

I~

MiliarylDisseminated Tuberculosis

18.5.1 Case Illustration 1

A 39-year-old male clerk working in our hospital presented to me on 8 September 1999 with a I-month history of right knee pain which was mild and associated with swelling. Symptoms were progressive. He was in good health before presentation and denied a history of trauma. He was always overweight and did not notice any recent weight loss, and had no fever or sweating. Musculoskeletal system investigation was otherwise normal. He was using analgesics as self-medication, which were controlling his knee pain. There was no low-back pain or other systemic symptoms that could be related to connective tissue diseases. He was treated in the ophthalmology clinic for dryness of the eyes but that lasted only for a few months before resolving. He denied a history of drinking raw milk or consumption of raw liver or meat or contact with animals. Other systemic enquiries were normal. On physical examination he looked well, apyrexial, not in pain and not pale. The right knee was swollen with effusion but not tender or warm and had a full range of movement. There was no thigh or leg muscle wasting. Other joint examinations were normal. Other systematic physical examination showed no lymphadenopathy, and other systems were normal. Synovial fluid aspiration was obtained, and other investigations included hemogram, ESR, biochemical profiles including serum urate, blood culture, and Brucella agglutinins, plain radiography of the knees and chest. He was referred to our orthopedic surgeon for arthroscopy, but he refused this investigation. The hemoglobin was 13.2 gldl with normal white cell count, but the ESR was raised 50 mm/h. Biochemical parameters were normal apart from slightly raised serum urate at 467 f.lmolll (normal range 210-430 f.lmolll). Chest and knee radiography results were normal (Fig. 18.1a,b). Synovial fluid white cell count was normal, and culture was negative. Plain radiography and MRI of the right knee showed two small defects in the joint's surface on the medial condyle of the femur, one measured 7 mm and the second 3-4 mm in diameter. This was interpreted as osteonecrosis but could also be due to an inflammatory process (Fig. 18.1c-f, j). Arthroscopy was refused again by the patient. He was taking Diclofenac retard 100 mg once daily orally and was controlling his mild knee pain, and the swelling resolved. Four months later he presented to the emergency room with a 1O-day history of fever, rigor, night sweating, and 4-day history of cough with whitish sputum, left pleuritic chest pain, and shortness of breath. He also had a history of diarrhea for 3 days before presentation. He was anorexic

279

with occasional vomiting, and although he was on a weight-reducing diet, he did not notice faster weight reduction. On physical examination in the emergency room, he looked unwell, tachypnea, feverish 40°C, pale, and had lost 5 kg of weight since last weighed 4 months earlier. There was no lymphadenopathy, no positive abnormal sounds heard over the lung, and no pleural rub. Abdominal examination revealed an enlarged, tender liver extending 4 cm below the costal margin and enlarged spleen extending 3 cm below the costal margin, but there was no ascites or other palpable masses. The right knee was swollen with mild knee effusion. Chest radiograph looked normal, but the hemoglobin decreased to ILl gldl with normal blood film, and there was evidence of malaria, while the white cell count was normal. Blood culture was done, and the blood biochemical parameters were normal. When I reviewed the patient the following day, a softer chest radiograph was done which showed faint reticular lung shadowing at both lung bases (Fig. 18.lg). Miliary tuberculosis was the presumptive admission diagnosis, and he was started on four-drug chemotherapy. Other investigations were carried out during admission. The sedimentation rate (ESR) was 90 mm/h, negative blood and sputum cultures. Brucella serology was repeated, autoimmune screenings were all negative. Liver enzymes were abnormal; ALT 79 U/l (normal range 2-40 U/I); alkaline phosphatase 1151 U/I (normal range 98-279 U/I), albumin 33 gil (normal range 38-51 gil), urate 467 f.lmolll (normal range 210-430 Ilmolll), and total bilirubin was normal 12 f.lmolll (normal range 2-22 f.lillolll). The tuberculin test was negative; it had been done twice, once at the initial visit 4 months earlier and during the current admission. MRI of the chest showed diffuse confluent miliary lung shadowing widely spread over both lung fields with small areas of nonhomogeneous consolidation in the lateral segment of the right middle lobe (Fig. 18.1h,i). Ultrasound of the right knee showed significant synovial thickening but no effusion. Ultrasound of the abdomen showed an enlarged spleen with a span of 16 cm but without focal lesions in it; the liver was enlarged, but no focal lesions were depicted; and there was no definite para-aortic lymphadenopathy. The other abdominal organs were normal. The nonsteroidal anti-inflammatory medication was discontinued, and the patient remained on antituberculous medication. Bronchoscopy was done which showed an inflamed bronchial mucosa but no endobronchial lesions, and bronchoalveolar lavage (BAL) was performed. BAL was sent for cytology, AFB smear, and culture - post-bronchoscopy sputum specimens were sent for microbiological examination.

280

M. M. Madkour

a

b

[>

c Fig. 18.1 a Frontal radiograph of the right knee at the initial presentation with monoarthritis. This was interpreted as showing no bony abnormalities. b Chest radiograph at the initial presentation with right knee monoarthritis, showing no abnormal imaging features. c, d MRI of the right knee: sagittal Tl-weighted images demonstrate presence of effusion (arrow) and two osteochondral lesions (arrowheads) at the medial femoral condyle appearing as central areas of increased signal intensity surrounded by signal void rim. Appearances are typical of osteochondritis dissecans, but an infective pathology is also possible. e, f MRI of the right knee: sagittal T2-weighted images at the same level demonstrates joint effusion better (arrow) and the osteochondral defect as high signal intensity indicating activity (arrowheads). g Chest radiograph during acute presentation demonstrates numerous fine discrete nodules bilaterally (arrowheads) consistent with miliary tuberculosis. h Axial CT scan with lung windowing demonstrates generalized increase in parenchymal density with ill-defined fine nodular pattern in a random distribution (arrowheads). i Axial CT scan at a caudal level demonstrates air-space consolidation in the left lower lobe (arrowheads). j Frontal radiograph of the right knee during the acute miliary tuberculosis presentation demonstrates evidence of periarticular osteoporosis (arrowheads) and subchondral erosions (arrows). Note preservation of joint space (*). k Isotope bone scan (99mTc) demonstrates marked tracer uptake in the right knee (arrowheads). I Isotope bone scan demonstrates tracer uptake in 010 vertebral body (arrowheads). m Axial CT of the lung with mediastinal windowing demonstrates destruction of the lower dorsal vertebral body with associated paravertebral abscess (arrows). n Sagittal gadolinium-enhanced Tl-weighted MR image of the spine demonstrates destruction of the vertebral body (arrows), paraspinal abscess (large arrowheads) with subligamentous spread (small arrowheads) causing compression of the spinal cord (*).0 Axial gadolinium-enhanced Tl-weighted MR image with fat saturation demonstrates paraspinal abscess with wall enhancement (arrows)

281

Miliary/Disseminated Tuberculosis

e

f

[>

282

M. M. Madkour

k

n

m

o

Fig. 18.1 (Continued) k-o

MiliarylDisseminated Tuberculosis

283

The patient agreed to arthroscopy, which showed a cough, expectoration, loss of appetite, and weight hemorrhagic hypertrophic synoviurn with grade II loss. The swelling in the forehead was painless, and degenerative changes at the medial femoral condyle. she denied any history of head trauma. She had low Debridement, synovial tissue biopsies, and wash-out back pain and amenorrhea for the same duration. She were sent for histopathological and microbiological was in perfect health before the present illness. Other examination. Bone marrow biopsy was performed. systemic reviews were noncontributory, but she gave The patient responded to the antituberculous treat- a history of contact with a housemaid who had pulment, and the fever and dyspnea began to improve monary tuberculosis 6 years before the onset of the within 1 week of hospitalization. However, he com- current illness. She had no family history of tubercuplained of back pain, and there was tenderness over losis. She was a high school student and single. She T9-1O. He later admitted that he had had occasional was initially diagnosed to have tuberculosis a few back pain before, but it was so mild that it was relieved days before her presentation to our hospital. She initially presented to our satellite military hoswith the nonsteroidal anti-inflammatory treatment he used for his knee. Isotope bone scan and MRI of the pital in Al-Kharj (80 km south of Riyadh) and was spine and other joints were performed. MRI showed diagnosed as having tuberculosis and was referred to destruction of T9 with collapse of the vertebral body, our hospital a few days after initiating her on antitugibbus deformity, and para-spinal abscess with exten- berculous antibiotics. On physical examination, the sion into the epidural space (Fig. 18.1m-o). Isotope patient was unwell, pale, underweight (38 kg) with bone scan showed increased uptake at T9-1O and in forehead cystic swelling measuring 3.0x2.0 cm in the right knee (Fig. 18.1k,1). Histopathological results diameter. It was not tender or hot or red, and there of the bone marrow showed multiple areas of granulo- was no discharge from it. She had fever with a temmatous lesions with central caseation, but bacilli were perature of 39SC and tachycardia of llO/min. She not seen, and the culture was later reported as negative. had no peripheral lymphadenopathy. Cardiovascular, The histopathological findings of the synovial tissue respiratory, abdominal, and central nervous system and debridement specimen showed multiple granulo- examinations showed no abnormalities. Joint examimatous synovitis with central caseation. BAL culture nations were normal; she had localized tenderness and post-bronchoscopy sputum grew M. tuberculosis on percussion over multiple areas of the spine, but that was sensitive to isoniazid, rifampicin, pyrazin- there were no deformities or kyphosis. The hemoamide, and ethambutol. The temperature settled after gram showed WBC 5.3X109, hemoglobin 8.1 g/dl, and 9 days of antituberculous medication. The difficulties ESR 90 mm/h. Clinical chemistry parameters were in the diagnosis of this patient were due to several normal. Chest radiograph showed normal cardiac factors: the mild nature of the right knee symptoms size and clear lung fields. There were two ill-defined, with absence of constitutional symptoms, the refusal soft-tissue mediastinal masses on the right lateral of exploratory arthroscopy as an important diagnos- border and upper left border of the cardiac shadow tic means of investigation, the use of nonsteroidal with no calcification. Frontal and lateral dorsolumbar anti-inflammatory medication that masked back pain spine radiographs showed loss of height of L2 and despite the enquiry into spinal symptoms, the initially reduced bone density ofL! and L3 (Fig. 18.2a). Sagitnormal-appearing chest radiograph was done in the tal CT showed destruction of L2 (Fig. 18.2b). MRI of emergency room when he presented with acute chest the lumbar spine showed destruction of the body of and constitutional symptoms, the multiplicity of skel- L2 with compression of the dural space by a paraetal foci that were the most likely source of hematog- spinal abscess (Fig. 18.2c-e). Postcontrast CT of the enous dissemination rather than a single focus. The abdomen showed anterior subligamentous abscess patient responded well and continued antituberculous with a large right psoas muscle abscess (Fig. 18.2f,g). medication for 12 months. He has been followed up MRI of the abdomen at the same level showed a for over 2 years with no evidence of recurrence or any large right psoas abscess displacing the right kidney neurological or other complications. (Fig. 18.2h). Drainage of the right psoas abscess was performed in the prone position (Fig. 18.2i). The dorsal spine MRI showed another lesion 18.5.2 affecting the mid-dorsal region (Fig. 18.2j,k). Chest Case Illustration 2 CT with contrast of lung and mediastinal windows depicted a small lung parenchymal granuloma A 16-year-old Kuwaiti girl presented on 29 July 2000 and caseating lymph nodes in the retrosternal with a 6-month history of forehead swelling, fever, carina, subcarinal region, and prevascular groups

284

M. M. Madkour

a

b

c

d[> Fig. IS.2a-s. A 16-year-old girl presented with painless, soft-tissue swelling of the forehead, fever, cough, and low-back pain. a Frontal and lateral radiographs of the dorsolumbar spine demonstrate loss of height of L2 vertebral body (arrow) due to destructive lesion demonstrated better on the lateral view (arrowheads). There is also reduced bone density of the vertebral body of L1 and L3 and narrowing of disc spaces (D). b Sagittal reformatted CT image demonstrates destruction of the body of L2 with sclerosis of the remaining part (arrowhead). c MRI of the lumbar spine: sagittal post-enhanced Tl-weighted image demonstrates destruction of the body of L2 with large tuberculous cavity (arrow). Note posterior comparison on the dural space (open arrow). d Right para-sagittal image demonstrates anterior subligamentous tuberculous abscess (arrows) which had a tract to form right paraspinal abscess (A) in a. e Sagittal T2-weighted image with fat suppression demonstrates the paraspinal abscess as high signal intensity mass (A), the subligamentous abscess (long arrows), diffused increased signal intensity of the body of L2 and to lesser extent the body of L1 (open arrowheads). Note abscess cavity in L2 (arrow). f Post-enhanced CT of the abdomen at the level of L2 demonstrates destruction of the vertebral body (black arrow), anterior subligamentous abscess (arrowhead), and a large right psoas muscle abscess. g Post-enhanced axial CT at a caudal level demonstrates further destruction of L2 vertebral body (black arrow), tracking of the anterior subligamentous abscess (open black arrow), into a large right psoas muscle abscess (A). h MRI of the abdomen at same level as f: post-enhanced Tl-weighted image demonstrates destruction of

MiliarylDisseminated Tuberculosis

285

e

f

g

h the body of L2 (black arrow) and a large psoas muscle abscess (A), note the enhancing thick wall of the abscess (small arrows). The abscess is displacing the right kidney (thick black arrow). i Axial CT of the abdomen demonstrates percutaneous insertion of drainage catheter at the site of psoas abscess (arrow) (the examination is performed in the prone position). j Sagittal MRI of the dorsal spine: T2-weighted image with fat suppression demonstrates large anterolateral abscess appearing as diffuse high signal intensity anterior and to the right of mid-dorsal region (arrows). No associated bone or disc lesion is seen. k, I MRI of the same patient. Post-enhanced II-weighted sagittal (k) and axial (I) images demonstrate the abscess (A) as low signal intensity surrounded by thick enhancing wall (arrows). m, n CT of the chest: post-enhanced CT at the level of aortic arch. m Lung window demonstrates narrow lung parenchyma separate from small granuloma (arrow). n Mediastinal window demonstrates caseating lymph node with characteristic ring enhancement in the retrosternal and prevascular group (arrows). 0, p Post-enhanced axial CT at the level above the carina (0) and subcarinal (p) demonstrates appearance characteristic of subcarinal region. Note ring enhancement of the wall (arrow). q, r Frontal and lateral skull radiographs demonstrate focal area of bone destruction in the frontal bone. Note loss of the outer table of the skull bone on the lateral radiograph (white arrows) and focal ill-defined radiolucency due to bone destruction (black arrows). s Axial CT of the brain demonstrates bone destruction of the frontal bone (curved arrow) and associated soft-tissue mass due to abscess formation (white arrow)

l>

286

Fig. 18.2 (Continued) i-m

M. M. Madkour

m[>

MiliarylDisseminated Tuberculosis

287

n

o

q

p

s r

Fig. 18.2 (Continued) n-s

288

(Fig. 18.2m-p). Plain radiograph of the skull depicted a focal area of bone destruction in the frontal bone (Fig. 18.2q,r). Axial CT of the brain showed a softtissue abscess associated with frontal bone destruction (Fig. 18.2s). Ultrasound of the abdomen showed no evidence of hepatic or splenic involvement, and CT showed no intra-abdominal free fluid or other abdominal organ involvement. Culture of psoas abscess drainage yielded M. tuberculosis after 14 days incubation and was sensitive to all antituberculous agents. The forehead abscess was drained by our neurosurgeon, and tissue biopsies were obtained. Histopathological examination of the forehead abscess showed caseating granulomas, and culture yielded M. tuberculosis. The patient was treated with isoniazid 300 mg, rifampicin 450 mg, pyrazinamide IG, ethambutol 800 mg, and pyridoxine 25 mg as single oral daily dosing for 2 months and continued on isoniazid and rifampicin for a further 10 months. She responded well to treatment while in hospital, and her temperature settled with weight gain. She remained in hospital for 2 months and was discharged in September 2000. She stayed in Riyadh with members of her family and was followed up in the outpatient clinic regularly. She made a full recovery with no sequelae. This patient had disseminated tuberculosis with spinal disease at multiple levels, mediastinallymph node abscesses, psoas abscess, and forehead abscess. Although there was no lung parenchymal active disease depicted on plain chest radiography, CT showed small parenchymal lung granuloma. This patient did not have HIV or other diseases and was not on any medication that could have contributed to such severe disseminated tuberculosis.

M. M. Madkour

18.5.3 Case Illustration 3

A 27-year-old man transferred to our infectious disease unit isolation room with advanced AIDS, multidrug-resistant pulmonary tuberculosis, left hemiplegia due to tuberculous abscess of the brain, and recurrent seizures. This patient was diagnosed in another hospital in Riyadh with pulmonary tuberculosis and HIV co-infection in 1997. His pulmonary tuberculosis relapsed in 1999 due to poor compliance with medication. He was moved from one hospital to another and finally came to our hospital on 29 April 2001 until his death on 3 November 2001 due to disseminated multidrug-resistant tuberculosis. On arrival at our hospital, he was cachectic, pale, dyspneic, had oral thrush, and looked very ill. The hemogram showed low WBC 2.8109, and CD4 count ranged between 14 and 30/111, hemoglobin was 8.2 g/dl, and ESR was 84 mm/h. The HIV viral load was 75,000 COP/ml in 1999. Sputum culture yielded M. tuberculosis resistant to rifampicin and isoniazid. He was already on AZT, lamuvidine, rifampicin, clarithromycin, co-trimoxazole, fluconazole, phenytoin, and pyridoxine. Chest radiograph showed paratracheal and hilar lymphadenopathy and fibronodular infiltrative left upper lobe lesions with thin-walled cavities (Fig. 18.3a). Axial CT of the chest showed evidence of endobronchial tuberculosis with caseating hilar lymphadenopathy (Fig. 18.3b-d). In June 2001, the patient developed abdominal pain, vomiting, abdominal distension, and constipation for 2 days. The abdomen was tender all over with absent bowel sounds. Abdominal radiograph and axial CT showed

Fig. 18.3a. Plain chest radiograph demonstrates paratracheal and hilar adenopathy (arrows) and fibronodular infiltrative changes in the left upper lobe (curved arrow) with thin-walled cavities (arrowheads). b Axial CT of the chest with lung windowing demonstrates nodular and branching opacities of endobronchial tuberculosis (arrowheads) in both upper lobes, dilated bronchi (arrows). c Axial CT at caudal level, lung windowing demonstrates multiple thin cavities (arrows). d Axial post-enhanced CT of the chest at the level of carina demonstrates enlarged lymph nodes with typical ring enhancement and caseating center (arrows). e Axial post-enhanced CT of the abdomen demonstrates significantly dilated small-bowel loops (B) and caseating mesenteric lymph node (curved arrow). There was no ascites (dry type). At surgery, 20 cc of pus were aspirated from the mesenteric abscess. f MRI of the brain: post-enhanced TI-weighted image demonstrates tuberculoma and tuberculous abscess in the left parietal lobe. Note the enhancement of the tuberculoma (arrowhead) and the irregular enhancing wall of the tuberculous abscess (arrow). g MRI post-enhanced fast spin-echo inversion recovery image (FSEIR) at the same level demonstrates surrounding edema (arrowheads)

a

l>

Miliary/Disseminated Tuberculosis

dilated small-bowel loops and caseating mesenteric lymphadenopathy. Exploratory laparotomy after taking all precautionary measures in the theatre was performed. A massively distended small bowel was noted with mild changes in color. There was a large inflammatory mass in the root of the mesentery of

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the small bowel. Thick pus was freely present in the abdominal cavity, and 20 cc was aspirated and sent to the Microbiology Department. Bowel adhesions were noted and released. It was decided to close with interrupted sutures, and the patient tolerated the procedure. In October 2001, he went into a coma,

b

c

d

e

f

g

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and brain MRI showed enlargement of the tuberculoma of the brain with development of left parietal lobe brain abscess (Fig. 18.3f,g). The patient died 1 month later.

18.5.4 Case Illustration 4 A 21-year-old married female patient presented to the surgical department with a right iliopsoas mass. She had a history of abdominal pain lasting 6 months associated with fever, profuse night sweating, loss of appetite, and weight loss. She was well before that time and had no previous illnesses. She noted a swelling in the right inguinal region which was associated with a gradual but progressive pain that increased with flexion of the right hip and was relieved by extension of the leg. The pain became worse 2 months before presentation, and the swelling became larger, and she noted a loss of 13 kg in weight. She had an associated history of dysuria and dribbling of urine during the 2 months before presentation. She had no hematuria but had loin pain on both sides. Other systematic reviews were noncontributory. She was using pain-killers to relieve her pain during that time which had been provided by a private clinic. She was also given several courses of antibiotics for a period

M. M. Madkour

of 2-3 months before presentation to our hospital. There was no past history of any illnesses. She had married at the age of 18 years and had one healthy boy. She had a history of vaginal discharge which was yellowish after IUCD insertion 1 year before presentation, and it was subsequently removed. On physical examination, she was underweight, and blood pressure was 92/66 mmHg. There was a cystic swelling at the right inguinal area. Chest examination showed dextrocardia and situs inversus. There were positive clinical findings in the lungs including crepitations and bronchial breathing in the left upper zone. The heart was otherwise normal. Abdominal examination revealed soft lax abdomen with no masses or organomegaly. The right iliac fossa was tender with vague fullness but no definite masses felt. She was pale and feverish, with a temperature of 38.5°C. The patient felt pain during examinations of her hip joint and resisted manipulation. Other systemic examinations were normal. The hemogram showed normal white cell count, hemoglobin 8.8 gldl, and ESR 90 mml h. Biochemical parameters were normal. Chest radiograph showed dextrocardia and pneumonic consolidation in the left mid-zone (Fig. 18.4a). Axial CT of the chest showed airspace consolidation with air bronchogram (Fig. 18.4b). Axial CT of the chest postcontrast showed an abscess in the left erector spinae muscle (Fig. 18.4c,d).

a Fig. 18.4a-h. A 21-year-old woman with situs inversus and dextrocardia presented with rigor, fever, night sweating, loss of weight, and right hip pain. She was found to have a right iliopsoas mass. a Chest radiograph demonstrates pneumonic consolidation in the left mid-zone (arrow) (figure should read situs inversus). b Axial CT of the chest with lung windowing demonstrates air space consolidation with air bronchogram (arrowheads). There is minimal para-pneumonic effusion (open arrow). c, d Axial post-enhanced CT of the patient at the thoraco-abdominal region demonstrates abscess cavity in the left erector spinae muscle (arrows). Note the situs inversus with the liver on the left (arrowhead) and dextrocardia. e, fAxial CT of the pelvis: nonenhanced (e) and post-contrast-enhanced (0 axial images at the same level demonstrate multiple pelvic abscesses (A). Note enhancement of the walls of the abscesses (arrows; B). g, h Axial CT at the level of the hip joints: nonenhanced (g) and post-contrast-enhanced (h) axial images demonstrate right inguinal abscess

Miliary/Disseminated Tuberculosis

Axial CT of the pelvis pre- and post-enhancement showed large multiple pelvic abscesses with wall enhancement (Fig. 18.4e,f). Axial CT at the level of the hip joints showed right inguinal abscess with ring enhancement after contrast (Fig. 18.4g,h). Percutaneous drainage of the right inguinal abscess and other pelvic abscesses was performed under CT guidance.

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Other sputum cultures and cultures of the abscess contents yielded M. tuberculosis that was sensitive to all antituberculous drugs. Histopathology of the inguinal abscess wall showed granulomas. The patient had negative testing for HIV and no evidence of any underlying diseases. She responded well to antituberculous treatment without any sequelae.

c

e

f

g

h

292 18.5.5 Case Illustration 5

A 26-year-old man was referred from Al-Kharj (80 kIn south of Riyadh) with a 6-month history of fever, sweating, dry cough, left-sided chest pain, dyspnea on mild exertion, weakness, loss of appetite, weight loss, and back pain. He had a strong family history of tuberculosis. He was initially treated with antibiotics and analgesics, but his symptoms gradually progressed. He was healthy previously and was not on any medication prior to the presenting illness. Other systemic reviews were normal. On physical examination, he looked unwell, pale, underweight, and his temperature was 38.5°C. There was no palpable peripherallymphadenopathy. Chest examination revealed features of leftsided pleural effusion. Cardiovascular system examination was normal. The abdomen was soft, but there was a splenomegaly with tenderness on palpation. There was no other organ enlargement and no ascites. The spine showed no deformities, but tenderness was elicited at different areas on percussion, mostly at the mid-thoracic and lumbar spine. There was no evidence of neurological deficit, and the fundi were normal. The hemogram showed a normal white cell count, hemoglobin 8.3 g/dl, and ESR 94 mm/h. All biochemical parameters were normal. Chest radiograph showed left-sided, encysted pleural effusion, and a paraspinal shadow was noted, consistent with a paraspinal abscess (Fig. 18.5a). Plain radiograph of the thoracolumbar spine depicted a paraspinal abscess with narrowing of the disc space at TlO-ll {Fig. 18.5d). Ultrasound of the abdomen showed a poorly defined, hypoechoic lesion in the spleen consistent with a splenic abscess (Fig. 18.5j). Axial CT of the chest showed a large, encysted, left pleural effusion with pleural thickening {Fig. 18.5b). MRI of the dorsolumbar spine showed several lesions affecting the vertebral bodies at multiple levels in the thoracic and lumbar vertebrae with paraspinal abscess formation {Fig. 18.5c,f,h,i). Pleural aspiration and biopsy were performed for histopathological and microbiological investigations. Pleural biopsy showed multiple areas of granulomas consistent with tuberculosis. The patient was seen by the spinal surgeon, and surgery was planned after initiating antituberculous treatment. Paraspinal abscess drainage and bone fusion for stabilization of the spine were performed {Fig. 18.5e). Culture of the granulation tissue and abscess content were positive for M. tuberculosis which was sensitive to all antituberculous drugs. Histopathology of spinal granulation tissue showed caseating granulomas. Serological testing

M. M. Madkour

for HIV was negative. The patient responded well to treatment. His antituberculous treatment was extended to 16 months because of the multiplicity of spinal lesions. He made a full recovery and had no spinal deformities or late neurological deficits.

18.6 Adult Respiratory Distress Syndrome and Disseminated Intravascular Coagulation in Miliary Tuberculosis ARDS is an uncommon but serious complication of miliary tuberculosis with a high hospital mortality rate of up to 69%, similar to that of other etiologies such as Gram-negative sepsis (Penner et al. 1995). It has no pathognomonic clinical or imaging features that could differentiate a tuberculous from a nontuberculous etiology. Goldfine et al. (1969) were the first to describe respiratory failure in patients with miliary tuberculosis, and Agarwal et al. (1977) were the first to use mechanical ventilation for such patients. The criteria for diagnosing ARDS is based on the American-European Consensus Conference (Bernard et al. 1994) which includes: 1. The ratio of partial pressure of arterial oxygen (Pa02) to the fraction of inspired oxygen (Fi0 2) is ::;200. 2. Chest radiographic features of bilateral lung infiltrates. 3. A pulmonary artery occlusion pressure ::;18 mmHg. 4. Or absence of clinical or imaging evidence of raised left atrial pressure. The onset of ARDS due to miliary tuberculosis is often preceded by fever and chest symptoms for a few weeks, but may occur acutely over a few days with intense dyspnea (Mohan et al.1996; Murray et al. 1978; So and Yu 1981; Dyer et al. 1985). A high index of suspicion by the treating clinician and willingness to consider tuberculosis as a possible cause of ARDS of unknown origin are essential and may reduce the mortality. Tachypnea and bilateral inspiratory crackles over both lungs may be found. Other physical examination results may detect splenomegaly, hepatomegaly, and signs of meningitis. Some authors have suggested that ARDS due to miliary tuberculosis may have a longer duration of symptoms than 1 week, while Gram-negative septicemia and viral pneumonia produce symptoms much faster. Hypotension is uncommon (7%) in ARDS due to miliary tuberculosis, while it is more frequent in ARDS due

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to sepsis (Dyer et al. 1985). Disseminated intravascu- TB is not clear, but disseminated emphysematous lar coagulation (DIC), acute renal failure, hepatitis, tuberculosis, rupture of a pleural bleb, or rupture of and intercurrent infections are common features a subpleural caseous miliary nodule may be the cause (up to 87.5%) in ARDS due to miliary tuberculosis (Mert et al. 2001). There are only a few single case and Gram-negative septicemia (Murray et al. 1978; reports on such complications in the literature. Mert Piqueras et al. 1987; Dyer et al. 1985; Mohan et al. el al. (2001) found eight cases in the English literature 1996). Death may occur with 1-7 days of the onset between 1974 and 1999 and reported one case of their of ARDS (Murray et al. 1978), and early diagnosis own. These authors reported their own series of 38 and initiation of antituberculous chemotherapy may patients with miliary tuberculosis, only 1 of whom reduce the mortality (Mohan et al.1996). had pneumothorax while on antituberculous treatThe etiological diagnosis of ARDS due to miliary ment. The size of the pneumothorax as noted by other tuberculosis may be achieved in up to 35% of patients authors ranged from small up to 80%. Pneumothorax by sputum smear and in 20% by urine sediment smear in these rare cases was mostly unilateral. Graf-Deuel showing the bacilli. The chest radiograph may be and Knoblauch (1994) described 12 patients with bilatstrongly suggestive of miliary tuberculosis in 15% eral pneumothorax due to various causes and reviewed of patients (Dyer et al. 1985). Other investigations the literature and found 56 published cases including in smear-negative patients should include bron- 3 patients due to miliary tuberculosis. Chandra et al. choscopy with brushing, transbronchial lung biopsy, (1988) described an 18-year-old woman with miliary bone marrow trephine, and liver biopsies as well as tuberculosis. She was given antituberculous chemolumbar puncture if features of meningitis are present. therapy, but on the 20th day of admission, she develThe hemogram often shows normal white cell count, oped bilateral simultaneous pneumothorax that was anemia, or pancytopenia. Patients with ARDS due to aspirated by needle and tube drainage and improved. miliary tuberculosis may develop disseminated intra- Two weeks later, recurrent right-sided pneumothorax vascular coagulation (Die). The pathogenesis and was followed by left-sided pneumothorax and a bronfactors contributing to DIC occurrence are not clear. chopleural fistula that required surgery and responded Tuberculous vasculitis may possibly be a contributing well to treatment. Severe chest pain and breathlessness factor to the initiation oflocal consumption of clotting may occur at the onset of pneumothorax, even while factors leading to Die. Subclinical coagulopathy may the patient is on chemotherapy. It may respond to possibly occur as indicated by the presence of micro- needle aspiration, tube drainage, or may require thothrombi in the biopsy specimen from these patients. racotomy if a bronchopleural fistula develops. The development of DIC may be noted with clinically overt bleeding or the results of laboratory tests consistent with its occurrence (Murray et al. 1980; Dyers et al. 1985; Maartens et al. 1990). The development 18.8 of DIC in such cases is often fatal (Rosenberg and Diagnosis of Miliary/Disseminated . Rumans 1978). In endemic areas or when clinical and Tuberculosis imaging features are suggestive of miliary tuberculosis as a possible cause of ARDS, empirical antituberculous The chest radiograph is the most important initial treatment should be commenced while the diagnosis diagnostic tool for patients with miliary tuberculosis is actively pursued. (Berger and Samortin 1970). However, most authors reported a wide range in the incidence of depicting miliary lung nodularity: from 30% to 93% of patients. The diagnostic accuracy of the chest radiograph was 18.7 determined with a high specificity and good interobPneumothorax in Miliary/Disseminated server agreement by Kwong and colleagues (1996) from Vancouver, Canada. These authors reviewed all Tuberculosis cases with miliary TB diagnosed over a lO-year period Pneumothorax as a complication of miliary tuberculo- (1982-1992), with inclusion of a group of control subsis is extremely rare (Mert et al. 2001; Graf-Deuel and jects and interpretation by three independent blinded Knoblauch 1994; Chandra et al. 1988). Pneumothorax observers. They identified miliary nodular lung shadin cavitary pulmonary tuberculosis may occur due to owing with a sensitivity ranging from 59% to 69%, rupture of the subpleural cavity into the pleural space. higher in those with HIV (71 %-85%), and lower when The possible mechanism of pneumothorax in miliary the diagnosis was made only at autopsy (30%-60%).

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b a

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h

g

Fig.18.5a-j. A 26-year-old male patient presented with chest pain, fever, rigor, abdominal and back pain. a Chest X-ray demonstrates large, left-sided, encysted, pleural effusion (arrowhead). Note paraspinal shadow consistent with abscess formation (open arrows). b Axial post-contrast-enhanced CT demonstrates collapsed left upper lobe (black arrowhead) and a large pleural effusion (open arrow). Note thickening of the parietal pleura (small arrows). c MRI of the spine: post-enhanced II-weighted image demonstrating lesion in the vertebral body of Dll (large white arrow); note dural enhancement (small arrowheads). Note also enhancement of the thickened visceral and parietal pleura (small white arrows) around the pleural effusion (large arrowhead). d Frontal X-ray of the dorsolumbar spine demonstrates paraspinal abscess (curved arrow). Narrowing of the disc at DlO-ll level (open arrows). e Postsurgical frontal radiograph of dorsolumbar spine demonstrates resolution of the paraspinal abscess (drained surgically). Bone fusion for stabilization has been performed (long arrows). f Sagittal post-enhanced II-weighted image demonstrates multiple spinal involvement by tuberculous foci (arrows). Note large intraspinal abscess involving two adjacent vertebral bodies and crossing the intervening disc space (open arrow). Abscess is also tracking anteriorly along the anterior spinal ligament (long arrows). Note enhancement of the dura (arrowheads). g MRI of the spine after surgery: sagittal proton-density and T2-weighted image demonstrate marked improvement with resolution of the osteomyelitis and paraspinal abscess. Bone graft (arrow) has been performed for stabilization. h Sagittal post-enhanced II-weighted image demonstrates enhancement of the last two lumbar vertebral bodies (arrows) and a small intravertebral abscess (arrowhead). i Sagittal proton and T2-weighted images at the same level demonstrates the abscess cavity at L5 (arrows). j Same patient, ultrasound examination of the spleen demonstrates poorly defined, hypoechoic lesion in the spleen consistent with splenic abscess (arrows)

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The interobserver agreement of the three independent radiologists was 90%. The chest radiography features of miliary tuberculosis characteristically consist of widespread, bilateral, nodular lung opacities in the upper and lower zones often measuring 1-3 mm in diameter in 90% of patients and greater than 3 mm in 10% (Kwong et al. 1996). Areas of consolidation may be noted in up to 30% of patients (Fig. 18.1i) and are depicted better by CT of the chest. Parenchymal lung cavities may be seen in 3%-11.9% of patients with miliary tuberculosis (Kwong et al. 1996; Long et al. 1997; Hong et al. 1998). An associated mediastinal and/or hilar lymphadenopathy may be noted in about 15% of patients (Kwong et al. 1996). Other additional radiographic findings may include pleural effusion and calcified granulomas (Fig. 23.14a, b).

18.9

High Resolution (T HRCT of the chest findings in patients with miliary tuberculosis has been reported in only a few articles with a relatively small number of patients (Oh et al. 1994; Optican et al. 1992; McGuinness et al.1992). These reports suggested that HRCT is more specific and observed the following imaging findings in patients with miliary tuberculosis, miliary nodules, groundglass opacities (GGOs), reticulation, and interlobular septal thickening. Oh et al. (1994) described the GGOs as multiple microscopic granulomas with acid-fast bacilli after obtaining transbronchiallung biopsies of these areas. The GGOs appear as random patchy opacities and are the second most common (miliary nodules being the first) HRCT feature of miliary tuberculosis. A large retrospective study on HRCT findings of miliary tuberculosis was reported by Hong et al. (1998) from Seoul, Korea. They reviewed 25 patients with microbiologically andlor histopathologically proven miliary tuberculosis who had undergone HRCT. Miliary nodules that are uniformly distributed throughout both lung fields, mostly ranging from 1-3 mm in diameter and sharply defined, were the most common findings in 24 of the 25 patients (96%). Larger nodules up to 5 mm in diameter due to coalescence or enlargement of granulomas were noted in 5%-10% of all nodules. GGOs occurred in 23 (92%) of these patients and are considered the second most common CT finding. These authors observed that in two of their patients with severe dyspnea and impending ARDS due to miliary TB, extensive GGOs were depicted by HRCT. Interlobar reticulation and interlobar septal thicken-

M. M. Madkour

ing were found in 44% each. The authors also reported other HRCT findings including pre-existing TB lesions in 44%, lymphadenopathy in 32%, pleural effusion in 16%, and bronchogenic spread in 16%. Diverse diseases may cause a similar miliary lung shadowing including hematogenous dissemination of infectious diseases, sarcoidosis, metastatic malignancy, histoplasmosis, pneumoconiosis, and interstitial fibrosis (Curull et al.1985; Willcox et al.1986). Centrilobular (core) and paraseptal (peripheral) nodules may be identified with HRCT. Similar additional findings in chest radiography such as pleural effusion, lung cavities, and lymphadenopathy may also be noted (Hong et al. 1998). The imaging features of miliary tuberculosis are not pathognomonic of the disease (McGuinness et al.1992; Chugh and Agarwal 1997; Miyake et al. 1997).

18.10

Laboratory Diagnosis of Miliary Tuberculosis A rapid and specific laboratory diagnosis is the most pressing need in confirming the diagnosis of miliary tuberculosis. The many weeks that are required for culture yield in patients with miliary tuberculosis cannot be used as a means of confirming the diagnosis before starting chemotherapy. A rapid confirmatory laboratory investigation may not always be easy to achieve. A chest radiograph showing miliary nodular lung shadowing in the presence of clinical Table 18.3. Rapid diagnosis by Ziehl-Neelsen stain: number of patients and percentage of positive AFB Body fluid

Prout et aI. (1980)

39 (31%) Sputum 17 (18%) Urine 31 (3%) CSF Bronchial lavage 3 (100%)

Maartens et aI. (1990) 64 22 24 51

(33%) (14%) (8%) (27%)

Table 18.4. Rapid diagnosis by tissue biopsies: number of patients and percentage of positive granulomata Biopsy site

Al-Jahdali et al. (2000)

Maartens et aI. (1990)

Prout et al. (1980)

Liver Bone marrow TransbronchiaI Lymph nodes

16 (88%) 11 (73%) 10 (70%) 2 (100%)

11 (100%) 22 (82%) 48 (63%) 9 (100%)

12 (92%) 15 (71%) 2 (100%)

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features that suggest miliary tuberculosis may be the only available clues for the attending clinician. Maartens et al. (1990) reported on 109 patients with miliary tuberculosis, and in 7 patients, the diagnosis was based on clinical grounds and classical miliary nodules on chest radiography; they were treated with chemotherapy with a good response. Rapid confirmation of the diagnosis of miliary tuberculosis may be achieved in up to 83% of patients by means of ZieW-Neelsen stain and by the finding of granulomata in tissue biopsies or by fine-needle aspiration (AI BWa12001; Maartens et al. 1990; Prout et al. 1980; Al-Jahdali et al. 2000). The most common body fluids used for Ziehl-Neelsen stain include sputum, gastric fluid aspirate, urine, CSF, bronchial lavage and brushings, and pleural fluid (Sharma et al. 1988) (Table 18.3). Common sites of tissue biopsies to detect granulomata in patients with miliary TB include transbronchial lung tissue, bone marrow trephine, liver, pleura and lymph nodes (Stallworth et al. 1980; Steiner et al.1976) (Table 18.4). Sputum culture in patients with miliary tuberculosis may be positive in 30%-60% (Prout et al. 1980; Monie et al. 1983; Maartens et al. 1990; Al-Jahdali et al. 2000).

18.10.1 Polymerase Chain Reaction PCR assays are a rapid, specific, and noninvasive method of confirming the diagnosis of tuberculosis. PCR using the IS6110 method can be used in identifying the DNA fingerprinting of M. tuberculosis in the sputum, urine, bronchial lavage, gastric aspirate, blood, and tissue biopsies. It has a specificity of 100% and sensitivity of 95% with a turnaround time of 2436 h (Clarridge et al. 1993; Shalwar et al. 1993; Nolte et al. 1993). This rapid and specific diagnostic tool is very useful in confirming the diagnosis of miliary tuberculosis when it is available. Penner et al. (1995) used PCR to determine the strain of Mycobacterium. Tuberculosis was found in 6 of their 13 patients (46%) with miliary tuberculosis, pulmonary and disseminated disease with respiratory failure that required mechanical ventilation. In disseminated tuberculosis, extrapulmonary systems and organs affected can be diagnosed with other investigations appropriate to the site of involvement. These may include various imaging modalities with guided tissue biopsies, sur- . gical drainage of abscesses as demonstrated in the five case illustrations from our own patients. Other investigations should include serological testing for

HIV and PPD skin test. The hemogram may show pancytopenia or 10wWBC (Cassim et al.1993). Tuberculin skin test may be positive in 25%-75% of patients with miliary/disseminated tuberculosis, as reported in various series, but is low among those co-infected with HIV (Hill 1991; Maartens et al. 1990; Gelb et al. 1973; Grieco and Chmel1974; Munt 1972).

18.11 Treatment of Miliary/Disseminated Tuberculosis The treatment of miliary/disseminated tuberculosis is similar to that used for pulmonary and extrapulmonary disease. In miliary tuberculosis, the four-drug regimen includes isoniazid, rifampicin, pyrazinamide, and ethambutol which is used for 2 months and is followed by isoniazid and rifampicin for a further 4-6 months. Drug susceptibility and resistance should be determined. In patients co-infected with HIY, the duration of treatment should be extended to at least 9 months. In disseminated tuberculosis, the duration of treatment may be extended to at least 12 months, particularly when the bone is involved. Surgical intervention may be required to stabilize the spine, release abdominal adhesions if intestinal obstruction arises, drain abdominal, paraspinal, inguinal abscesses, or treat other pulmonary or extrapulmonary complication (see case illustrations). The use of corticosteroids as a modulator of the inflammatory process in miliary tuberculosis with ARDS, meningitis, or pericarditis has been reported by many authors and debated by others (Dyer and Potgieter 1984; So and Yu 1981). Penner et al. (1995) used steroids in 8 of their 13 patients (61.5%) with miliary and pulmonary tuberculosis with ARDS and respiratory failure; they required mechanical ventilation. The median time interval between hospitalization and commencement of treatment was 2 days (range 1-36 days) (Maartens et al.1990). Fever resolved in approximately 7 days (range 1-55 days). Death occurred in 25% of patients within 1-2 weeks of receiving treatment. The most important single factor in the mortality of patients with miliary tuberculosis is a delay in the diagnosis (Maartens et al. 1990). Other factors that contribute to mortality include old age, lymphopenia, hypoalbuminemia, elevated liver transaminases, and delay in early commencement of treatment. Other underlying chronic illnesses may contribute to mortality. The development of complications such as ARDS, DIC, Addison's

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disease, acute renal or multiorgan failure also contributes to the raised rate of mortality. The mortality rate among patients with miliary tuberculosis is approximately 70%, and 77% among those requiring mechanical ventilation due to ARDS, DIe leading to respiratory failure. Mortality rates reported in large series ranged between 20% and 80% of patients (Maartens et al. 1990; Prout et al. 1980; AI-Jahdali et a1.2000; Monie et al.1983; Stenius-Aarniala and Tukiainen 1979; Dahmash et al. 1995; Evans et al. 1998; Mohan et al.1996; Ormerod and Horsfield 1995).

References Agarwal MK, Muthuswamy PP et al (1977) Respiratory failure in pulmonary tuberculosis. Chest 72:605-609 Al Bhlal LA (2001) Fine-needle aspiration cytology of postvaccinial disseminated bacillus Calmette-Guerin infection. Diagn CytopathoI24:333-335 Al-Jahdali H,Al-Zahrani K et al (2000) Clinical aspects of miliary tuberculosis in Saudi adults. Int J Tuberc 4:252-255 Armstrong P, Wilson AG, Dee P et al (1995) Imaging of disease of the chest, 2nd edn. Mosby Year Book, Chicago, p 183 Ashburg DG, Bigelow DB et al (1967) Acute respiratory distress in adults. Lancet 2:319 Auerbach 0 (1944) Acute generalized miliary tuberculosis. Am J Pathol 20: 121-136 Auerbach 0 (1959) The natural history of the tuberculous pulmonary lesion. Med Clin North Am 43:239-251 Bateman DE, Makepeace W et al (1980) Miliary tuberculosis in association with chronic cutaneous tuberculosis. Br J Dermatol103:557-560 Berger HW, Samortin TG (1970) Miliary tuberculosis: diagnostic methods with emphasis on the chest roentgenogram. Chest 58:586-589 Bernard GR, Artigas A et al (1994) The American-European Consensus conference on ARDS: definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 149:818-824 BieW JP (1958) Miliary tuberculosis: a review of 68 adult patients admitted to a municipal general hospital. Am Rev Tuberc Pul Dis 77:605-622 Bobrowitz ID (1982) Active tuberculosis undiagnosed until autopsy. Am J Med 72:650-658 Bone M, Stableforth D (1981) Miliary infection to Mycobacterium aYium-intracellulare. Tubercle 62:211-213 Cassim KM, Gathiram Vet al (1993) Pancytopenia associated with disseminated tuberculosis, reactive histiocytic haemophagocytic syndrome and tuberculous hypersplenism. Tubercle Lung Dis 74:208-210 Chandra KS, Prasad AS et al (1988) Recurrent pneumothoraces in miliary tuberculosis. Trop Geogr Med 40:347-349 Chapman CB, Whorton CM (1946) Acute generalized miliary tuberculosis in adults. A clinicopathological study based on 63 cases diagnosed at autopsy. N Engl J Med 235:239-248 Chugh 1M, Agarwal AK (1997) Bilateral miliary pattern in sarcoidosis. Indian J Chest Dis Allied Sci 39:245-249

M. M. Madkour Clarridge J et al (1993) Large-scale use of polymerase chain reaction for detection of Mycobacterium tuberculosis in a routine mycobacteriology laboratory. J Clin Microbiol 31: 2049-2056 Crump JA (1998) Miliary tuberculosis with paradoxical expansion of intracranial tuberculomas complicating human immunodeficiency virus infection in a patient receiving highly active antiretroviral therapy. Clin Infect Dis 26: 1008-1009 Curull V, Morell F et al (1985) Dyspnea, fever and miliary pattern. Chest 88:285-286 Dahmash NS, Fayed DF et al (1995) Diagnostic challenge of tuberculosis of the elderly in hospital: experience at a university hospital in Saudi Arabia. J Infect 31:93-97 Dannenberg AM Jr (2001) Pathogenesis of pulmonary Mycobacterium boYis infection: basic principles established by the rabbit model. Tuberculosis 81:87-96 Dee P, Teja K et al (1980) Miliary tuberculosis resulting in adult respiratory distress syndrome: a surviving case. Am J Roentgenol134:569-572 De Hertogh Fierer E et al (1989) Hypersensitivity reaction to bacillus Calmette Guerin treated with plasmapheresis. Am J Med 86:343-344 Deresiewicz RL, Stone RM, Aster JC et al (1990) Fatal disseminated mycobacterial infection following intravesical bacillus Calmette Guerin. J UroI144:1331-1334 Dyer RA, Potgieter PD (1984) The adult respiratory distress syndrome and bronchogenic pulmonary tuberculosis. Thorax 39:383-387 Dyer RA, Chappell WA et al (1985) Adult respiratory distress syndrome associated with miliary tuberculosis. Crit Care Med 13:12-15 Ellner JJ (1997) Regulation of the human immune response during tuberculosis. J Lab Clin Med 130:469-475 Evans RH, Evans M et al (1998) Massive hepatosplenomegaly, jaundice and pancytopenia in miliary tuberculosis. J Infect 36:236-239 FitzGerald JM, Grzyrowski S et al (1991) The impact of immunodeficiency virus infection on tuberculosis and its control. Chest 100: 191-200 Foster DR (1997) Miliary tuberculosis following intravesical BCG treatment. Br J Radiol 70:429-431 Gelb AF, Leffler C et al (1973) Miliary tuberculosis. Am Rev Respir Dis 108:1327-1333 Geppert EF, Leff A (1979) The pathogenesis of pulmonary and miliary tuberculosis. Arch Intern Med 139:1381-1383 Goldfine ID,Schachter H et al (1969) Consumption coagulopathy in miliary tuberculosis. Ann Intern Med 71:775-777 Graf-Deuel E, Knoblauch A (1994) Simultaneous bilateral spontaneous pneumothorax. Chest 105:1142-1146 Grieco MH, Chmel H (1974) Acute disseminated tuberculosis as a diagnostic problem. A clinical study based on 28 cases. Am Rev Respir Dis 109:554-560 Gupta RC, Lavengood R et al (1988) Miliary tuberculosis due to intravesical bacillus Calmette-Guerin therapy. Chest 94: 1296-1298 Hill AR (1991) Disseminated tuberculosis in the acquired immunodeficiency syndrome era. Am Rev Respir Dis 144: 1164-1170 Hong SH, 1m JG et al (1998) High resolution CT findings of miliary tuberculosis. J Comput Assist Tomogr 22: 220-224 Iantorno R, Nicolai M et al (1998) Miliary tuberculosis of the

Miliary/Disseminated Tuberculosis lung in a patient treated with bacillus Calmette-Guerin for superficial bladder cancer. J Urol 159: 1639-1640 Jacques J, Sloan JM (1970) The changing pattern of miliary tuberculosis. Thorax 25:237-240 Jasmer RM, McCowin MJ et al (1996) Miliary lung disease after intravesical bacillus Calmette-Guerin immunotherapy. Radiology 201:43-44 Juul A (1977) Clinically undiagnosed active tuberculosis. Acta Med Scand 202:225-229 Kesten S, Title L et al (1990) Pulmonary disease following intravesical BCG treatment. Thorax 45:709-710 Korzeniewska-Kosela M, FitzGerald JM et al (1992) Spectrum of tuberculosis in HIV infected patients in British Columbia: a report of 40 cases. Can Med Assoc J 146: 1927-1934 Koylii R, Tozkoparan E et al (1997) Unusual miliary tuberculosis presenting with generalized lymphadenopathy and abdominal involvement. Int J Tuberc Lung Dis 1:474-476 Kwong JS, Carignan S et al (1996) Diagnostic accuracy of chest radiography. Chest 110:339-342 Langdale LA, Meissner M et al (1992) Tuberculosis and the surgeon. Am J Surg 163:505-509 Long R, O'Connor R et al (1997) Disseminated tuberculosis with and without a miliary pattern on chest radiograph: a clinical-pathologic-radiologic correlation. Int J Tuberc Lung Dis 1:52-58 Lotte A, Wasz-Hockert 0 et al (1984) BCG complications. Estimates of the risks among vaccinated subjects and statistical analysis of their main characteristics. Adv Tuberc Res 21: 107-193 Maartens G, Willcox PA et al (1990) Miliary tuberculosis: rapid diagnosis, haematologic abnormalities, and outcome in 109 treated adults. Am J Med 89:291-296 Massaro D, Katz S (1964) Rapid clearing in hematogenous pulmonary tuberculosis. Arch Intern Med 113:573 McClement JH, Renzetti AD, Carroll D et al (1951) Cardiopulmonary function in hematogenous pulmonary tuberculosis in patients receiving streptomycin therapy. Am Rev Tuberc 64:583 McGuinness G, Naidich DP et al (1992) High resolution CT findings in miliary lung disease. J Comput Assist Tomogr 16:384-390 McParland C, Cotton DJ et al (1992) Miliary Mycobacterium bovis induced by intravesical bacilli Calmette-Guerin immunotherapy. Am Rev Respir Dis 146:1330-1333 Mert A, Bilir M et al (2001) Spontaneous pneumothorax: a rare complication of miliary tuberculosis. Ann Thorac Cardiovasc Surg 7:45-48 Millar JW, Horne NW (1979) Tuberculosis in immunosuppressed patients. Lancet 1:1176-1178 Miyake S, Yoshizawa Yet al (1997) Non-Hodgkin's lymphoma with pulmonary infiltrates mimicking miliary tuberculosis. Intern Med 36:420-423 Mohan A, Sharma SK et al (1996) Acute respiratory distress syndrome (ARDS) in miliary tuberculosis: a twelve year experience. Indian J Chest Dis Allied Sci 38:157-162 Monie RDH, Hunter AM et al (1983) Retrospective survey of the management of miliary tuberculosis in South and West Wales, 1976-8. Thorax 38:369-372 Munt PW (1972) Miliary tuberculosis in the chemotherapy era: with a clinical review in 69 American patients. Medicine 51:139-155 Murray HW, Tuazon CU et al (1978) The adult respiratory

299 distress syndrome associated with miliary tuberculosis. Chest 73:37-43 Myers JA (1970) Miliary tuberculosis in the elderly. Br Med J 1:565 Nolte FS et al (1993) Direct detection of Mycobacterium tuberculosis in sputum by polymerase chain reaction and DNA hybridization. J Clin MicrobioI31:1777-1782 Oh YU, Kim YH et al (1994) High-resolution CT appearance of miliary tuberculosis. J Comput Assist Tomogr 18:862-866 Optican RJ, Ost A et al (1992) High-resolution computed tomography in the diagnosis of miliary tuberculosis. Chest 102:941-943 Orihuela E, Herr HW, Pinsky CM et al (1987) Toxicity of intravesical BCG and its management in patients with superficial bladder tumors. Cancer 60:326-333 Ormerod LP, Horsfield N (1995) Miliary tuberculosis in a high prevalence area of the UK: Blackburn 1978-1993. Resp Med 89:555-557 Pagel W, Simmonds FAH et al (1964) Pulmonary tuberculosis, 4th edn. Oxford University Press, London . Palayew M, Briedis D et al (1993) Disseminated infection after intravesical BCG immunotherapy. Chest 104:307-309 Pasculle AW, Kapadia SB et al (1980) Tuberculous bacillemia, hyperpyrexia, and rapid death. Arch Intern Med 140:426-427 Penner C, Roberts D et al (1995) Tuberculosis as a primary cause of respiratory failure requiring mechanical ventilation. Am J Respir Crit Care Med 151:867-872 Petty TL, Ashburg DG (1971) The adult respiratory distress syndrome: clinical features, factors influencing prognosis and principles of management. Chest 60:233-239 Piqueras AR, Marruecos L et al (1987) Miliary tuberculosis and adult respiratory distress syndrome. Intensive Care Med 13:175-182 Pitchenik AE, Fertel D, Bloch AB (1988) Mycobacterial disease: epidemiology, diagnosis, treatment,and prevention. Clin Chest Med 9:425-441 Proudfoot AT, Asktan A, Douglas AC et al (1969) Miliary tuberculosis in adults. Br Med J 2:273-276 Prout S, Benatar SR et al (1980) Disseminated tuberculosis. S Afr Med J 58:835-842 Rabe J, Neff KW et al (1999) Miliary tuberculosis after intravesical bacilli Calmette-Guerin immunotherapy for carcinoma of the bladder. Am J Roentgenoll72:748-750 Rawls WH, Lamm DL et al (1990) Fatal sepsis following intravesical bacillus Calmette Guerin administration for bladder cancer. J UroI144:1328-1330 Ray M, Kataria S et al (2002) Unusual presentation of disseminated tuberculosis. Indian Pediatr 39:88-91 Rieder HL, Kelly GD, Bloch AB et al (1991) Tuberculosis diagnosed at death in the United States. Chest 100:678-681 Rosenberg MJ, Rumans LW (1978) Survival of a patient with pancytopenia and disseminated coagulation associated with miliary tuberculosis. Chest 73:536-539 Sahn SA, Neff TA (1974) Miliary tuberculosis. Am J Med 56: 495-505 Saye L (1936) Tuberculosis miliar cronica. Rev Med Barcelona 25:387-423 Shafer RW, Kim DS et al (1991) Extrapulmonary tuberculosis in patients with human immunodeficiency virus infection. Medicine 70:384-397 Shalwar R et al (1993) Detection of Mycobacterium tuberculosis in clinical samples by amplification of DNA. J Clin MicrobioI29:712-717

300 Sharma SK, Shamim SQ et al (1981) Disseminated tuberculosis presenting as massive hepatosplenomegaly and hepatic failure. Am J Gastroenterol 76:153-156 Sharma SK,Pande IN et al (1988) Bronchoalveolar lavage (Bal) in miliary tuberculosis. Tubercle 69:175-178 Sharma SK, Pande IN et al (1992) Pulmonary function and immunologic abnormalities in miliary tuberculosis. Am Rev Respir Dis 145:1167-1171 Shibolet A, Dan M et al (1979) Recurrent miliary tuberculosis secondary to infected ventriculoatrial shunt. Chest 76:328-330 Slavin RE, Walsh TJ et al (1980) Late generalized tuberculosis: a clinical pathologic analysis and comparison of 100 cases in the preantibiotic and antibiotic eras. Medicine 59:352-366 So SY, Yu D (1981) The adult respiratory distress syndrome associated with miliary tuberculosis. Tubercle 62:49-53 Soloway MS (1988) Intravesical therapy for bladder cancer. Urol Clin North Am 15:661-669 Stallworth JR, Brasfield DM et al (1980) Congenital miliary tuberculosis proved by open lung biopsy specimen and successfully treated. Am J Dis Child 134:320-321 Steiner P,Rao M et al (1976) Miliary tuberculosis in two infants

M. M. Madkour after nursery exposure: epidemiologic, clinical, and laboratory findings. Am Rev Respir Dis 113:267-271 Stenius-Aarniala BS, Tukiainen P (1979) Miliary tuberculosis. Acta Med Scand 206:417-422 Sutton FD, Hudson LD et al (1974) Recognition and management of the adult respiratory distress syndrome. Chest 66:34S-36S Treip C, Meyers D (1959) Fatal tuberculosis in a general hospital. A diagnostic problem. Lancet 1:164-1'67 Vanham G, Toossi Z, Hirsch CS et al (1997) Examining a paradox in the pathogenesis of human pulmonary tuberculosis: immune activation and suppression/anergy. Tubercle Lung Dis 78:145-158 Vijayan VK (2000) Disseminated tuberculosis. J Indian Med Assoc 98:107-109 Willcox PA, Potgieter PD et al (1986) Rapid diagnosis of sputum negative miliary tuberculosis using the flexible fibreoptic bronchoscope. Thorax 41:681-684 Williams MH, Yoo OH (1973) Pulmonary function in miliary tuberculosis. Am Rev Respir Dis 107:858 Yu YL, Chow WH et al (1986) Cryptic miliary tuberculosis. Q J Med 59:421-428

19 Tuberculosis and Pregnancy M. MONIR MADKOUR

risk factor for the development of tuberculosis has never been proven, as suggested in the past (Snider 19.1 Introduction 301 1984; Espinal et al. 1996). Pregnancy has no effect 19.2 Epidemiology 301 on the incidence or prognosis of tuberculosis. The 19.3 Pathogenesis 302 effect of tuberculosis on the outcome of pregnancy, 19.4 Pregnancy-Tuberculosis: Interrelations 303 the fetus, and the neonate has lost most of its 19.5 Clinical Features 303 19.6 Personal Series 303 importance due to the existence of effective anti19.6.1 Case Illustration 1 304 tuberculous agents. However, a delay in diagnosing 19.6.2 Case Illustration 2 304 active tuberculosis poses a real risk to the pregnant 19.6.3 Case Illustration 3 306 woman, fetus, and infant. Tuberculosis in pregnant 19.7 Diagnosis 306 19.8 PPD Skin Test 306 women may be asymptomatic, particularly when 19.9 Chest Radiography 307 it invades extrapulmonary sites in the body, and 19.10 Microbiology and Other therefore presents a great risk of neonatal morbidAdvanced Laboratory Tests 307 ity and mortality. Symptoms related to tuberculosis 19.11 Breast-Feeding and Its Contraindications 307 may be mild and mimic those caused by normal 19.12 Treatment of Active TB During Pregnancy 308 19.13 Treatment of Multidrug-Resistant TB pregnancy such as dyspnea and fatigue (Gogus et al. During Pregnancy 309 1993; Machin et al. 1992). The disease may first pres19.14 Preventive Treatment During Pregnancy 309 ent in the neonate, and acute tuberculosis may later References 311 be discovered in the mother. Hageman et al. (1980) reported that tuberculosis was initially presented and diagnosed in neonates in 15 of 26 cases, and subsequent investigations of their mothers detected 19.1 active disease. Congenital and neonatal tuberculosis Introduction associated with undiagnosed and untreated mothers carries an infant mortality rate of 50% (Nemir The prevalence of tuberculosis in women of child- and O'Hare 1985). Antenatal screening of pregnant bearing age and during pregnancy is increasing women in endemic areas should include plain chest both in developing countries and among ethnic radiography if pulmonary tuberculosis is suspected, immigrants in urban areas of developed countries with proper shielding of the abdomen. (Centers for Disease Control and Prevention 1994, The outcome of pregnancy for the tuberculous 1995; Ahmed et al. 1999; Hageman 1998). The mor- woman, fetus, and neonate who are treated promptly bidity and mortality among pregnant women with with antituberculous drugs is similar to that for pregtuberculosis, the fetus, and the neonate have also nant women without tuberculosis. increased, particularly among those co-infected with HIV (Adhikari et al.1997).A high index of suspicion by attending clinicians and effective measures during the prenatal period are essential for reducing these 19.2 risks (Starke 1997). Pregnancy as a predisposing or Epidemiology

CONTENTS

M. M. MADKOUR, MD, DM, FRCP Consultant, Department of Medicine, Riyadh Armed Forces Hospital, P.O. Box 7897, C-119, Riyadh 11159, Saudi Arabia

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

Specific epidemiological data on the incidence of tuberculosis during pregnancy at present is unknown even in developed countries such as the USA. Available data from the 1970s, based on hospitalized

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pregnant women with tuberculosis in a New York hospital, was estimated by Schaefer et al. (l975) as ranging from 0.6% to 1% and was higher (3.2%) among those with pulmonary disease. These data were equivalent to those from nonpregnant women with tuberculosis of comparable age. In the late 1980s and 1990s, the incidence of tuberculosis in the USA has increased in young adults and children, which implies that tuberculosis during pregnancy may be more prevalent. Such a rise was attributed to the HIV epidemic as the most important risk factor, immigrants of different ethic origin coming from countries where tuberculosis is endemic, decline in public health services, and increased transmission in congregate settings. Tuberculosis among foreign-born persons has increased from 22% in 1986 to 35% in 1995 in the USA (McKenna et al.1995). The epidemiology of tuberculosis in England and Wales has changed its pattern since 1988 (Ormerod 2001). During the 1980s, white ethnic women over the age of 50 contributed 50% of the cases, and only a minority of patients were of child-bearing age (Medical Research Council 1992). In 1998, over 56% of cases were foreign-born immigrants from the Indian subcontinent and of African ethnic origin. The median age of these immigrants was under 30 years, while among the white ethnic women, tuberculosis declined to 37% with a minority of child-bearing age (Rose et al. 2001). In developing countries, poverty compounded by HIV infection form closely associated risk factors and contributed to an estimated 70% mortality due to tuberculosis in the age group 15-40 years including women of child-bearing age (Connolly and Nunn 1996). In Africa, there are no data on the number of women of child-bearing age co-infected with HIV and tuberculosis. The World Health Organization (WHO) estimated that about 50% of women of childbearing age living in sub-Saharan Africa has been infected with M. tuberculosis (Connolly and Nunn 1996). In South Africa, the incidence of tuberculosis is 311 per 100,000 population, and the prevalence rate of HIV infection at an antenatal clinic was reported as 7.6% (Epidemiology Comments, Department of Health, Pretoria 1996). In developing countries, the maternal mortality attributed to tuberculosis is high. Ahmed and colleagues (l999) from Zambia reported hospital-based, nonobstetric maternal mortality among pregnant women with tuberculosis. These authors analyzed 251 maternal deaths over a 2-year period (1996-1997) in Lusaka University Hospital.

A total of 106 (42%) maternal deaths was due to direct obstetric causes, and 145 (58%) were due to nonobstetric causes. Tuberculosis, a nonobstetric cause of maternal death, was associated with 25% of pregnant women. Other reports from Zambia indicated that 25% of antenatal women were infected with HIV, and a rate of 1 woman in 8 was presumed to be co-infected with HIV and TB. The risk of developing overt tuberculosis is expected at 8% annually (Fylkesnes et al. 1997; Dolin et al. 1994). Neonatal tuberculosis is rare, and there are no reports of a recent increase in incidence from countries with a high incidence of HIV infection. Adhikari et al. (l997) from South Africa reported a hospitalbased incidence of neonatal tuberculosis. Eleven neonates with culture-confirmed tuberculosis were reported from King Edward VIII Hospital in Natal, seen in a I-year period (l996-1997). The mothers of six of these neonates were co-infected with TB and HIV. One neonate and two mothers died within the first 3 months. These data suggest that the increase in the co-infections of pregnant women in endemic areas for both diseases was associated with an increased incidence of neonatal TB.

19.3 Pathogenesis The pathogenesis of tuberculosis during pregnancy is similar to that in nonpregnant women. Mycobacterium tuberculosis enters the body commonly by inhalation. The bacilli are ingested by the alveolar macrophages. A few weeks later two responses take place: tissuedamage response (delayed-type hypersensitivity-specific humoral response) and macrophages-activating response (cell-mediated immunity). Cytokines produced by alveolar macrophages and T-Iymphocytes (CD4+) take an active role in the host defense. Subsequently, granuloma formation occurs in the lungs. Granulomas may heal with fibrosis and scarring, but some bacilli may remain viable and reactivate if the patient's immunity is suppressed. Hematogenous spread of the bacilli to the placenta from pulmonary or extrapulmonary disease is the most common route of transmission. Rarely, transmission by direct spread and extension of the disease from pre-existing genital tuberculosis may occur (Hallum and Thomas 1995; Kaplan et al. 1980; BazazMalik et al. 1983). The organisms are transmitted to the placenta and may infect the chorionic villi, amniotic fluid, and decidua. The bacilli may be transmit-

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ted to the fetus via the umbilical vein, infecting the liver first, and may pass through the main circulation, leading to lung disease. Fetal ingestion or aspiration of infected amniotic fluid may also be another mode of transmission of tuberculosis to the fetus in utero or the time of birth (Vallejo and Starke 1992). Transmission of infection in the neonatal period may also occur via inhalation if the mother is not diagnosed or treated.

19.4 Pregnancy-Tuberculosis: Interrelations "For the virgin, no marriage; For the married, no pregnancy; For the pregnant, no confinement; For the mother, no suckling." In an excellent comprehensive review on the interrelationships between tuberculosis and pregnancy, Miller and Miller (1996) abstracted these statements from archaic reports reflecting the opinions and advice of scientists and clinicians in various medical eras. The influence of pregnancy as a risk factor for the development of tuberculosis, altering the course of the disease and prognosis, has intrigued clinicians for centuries since the days of Hippocrates through the early 1920s. The pendulum of opinion swung widely from the beneficial value of pregnancy on tuberculosis to the detrimental effect on the patient as it worsened the course of the disease, and abortion was even advised. Even before the discovery of antituberculous treatment, pregnancy was reported not to worsen the course of the disease (Hill 1928, cited by Miller and Miller 1996). Shortly after the introduction of antituberculous drugs, many reports in the early 1950s, 1960s, and 1970s confirmed that there was no significant difference between the patients who improved and those whose tuberculosis progressed during pregnancy or after delivery (Cohen et al.1952; Hedvalll953; Schaefer et al.1975; Espinal et al.1996). There is no evidence that pregnancy increases the risk of tuberculosis in the postpartum period in HIVinfected or uninfected women (Espinal et al. 1996). The effect of tuberculosis on the course of pregnancy, fetus, and neonate is similar to that in nontuberculous pregnant women. Untreated active tuberculosis poses a real great risk to the pregnant woman, fetus, and neonate. Women with active tuberculosis have a significantly

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higher incidence of spontaneous abortion, congenital malformations of the fetus, and neonatal disease (Bjerkedal et al. 1975).

19.5 Clinical Features Tuberculosis may present initially with symptoms mimicking those physiologically related to normal pregnancy such as dyspnea, fatigue, and lack of energy. The attending clinician has to have a high index of suspicion and make diligent efforts to diagnose the disease in order to prevent fetal and neonatal infection, particularly in endemic areas and among groups at risk (HIV, alcoholics, drug addicts, the homeless). Pregnancy does not alter the mode of onset or the presentation of initial symptoms. However, one-half to one-third of pregnant women with tuberculosis are asymptomatic and unaware of the disease, and the diagnosis may be missed (Wilson et al. 1973; Schaefer et al. 1975; Carter and Mates 1994). However, the clinical features of tuberculosis during pregnancy are similar to those in nonpregnant women.

19.6 Personal Series In our series, review of the medical records of pregnant women with active tuberculosis who attended the Military Hospital in Riyadh were analyzed. Between 1985 and 2000, there were 39 patients with active tuberculosis during their pregnancy. Their age ranged between 16 and 42 years (average 19.7 years). We found a past history of tuberculosis (treated or partially treated) in 13 patients (33.3%). History of contact and a family history of tuberculosis were found in 9 patients (23%). Pulmonary tuberculosis was the most common site of infection and found in 23 of these pregnant women (59%). Extrapulmonary localizations of active tuberculosis were found in 16 (41 %). Cough, fever, easy fatigability, shortness of breath, and weight loss were the most common presenting features and found in 23 patients (59%). Accidental discovery of cervical lymph adenopathy during antenatal screening was noted in 9 patients (23%). Four women were aware of the cervical lymphadenopathy, while the other 5 women were unaware of

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its presence. None of the pregnant women with tuberculous lymphadenitis were symptomatic at the time of the antenatal screening. The 4 women who were aware of lymph node enlargement did not notice any recent changes in size. Two of these women with TB lymphadenitis presented with pancytopenia or thrombocytopenic purpura (see case illustrations). The mean gestational age at the time of clinical presentation or suspicion during antenatal screening was 24.6 weeks, with a range of 1-35 weeks. Tuberculous pleural effusion was found in 3 patients (7.7%). One patient had a vulval swelling that was biopsied and found to be tuberculous by culture and histopathology findings (2.6%). One patient had military tuberculosis (2.6%). One patient had tuberculosis of the knee (2.6%). One patient had cold abscess in the right thigh (see case illustration) (2.6%). All 39 patients had positive tuberculin skin tests. Pulmonary tuberculosis was diagnosed in 23 pregnant women by plain chest radiography findings and confirmed by cultures from sputum, early morning gastric aspiration, and urine, identifying M. tuberculosis. None of the 39 patients in our series had HIV co-infection, drug-resistant tuberculosis, or nontuberculous mycobacterial disease. In New York, the incidence of tuberculosis during pregnancy has increased in association with the HIV epidemic. Margono et al. (1994) reviewed the computerized records of 16 pregnant women with active tuberculosis attending two hospitals. In a 6year period (1985-1991) they found 5 cases, while they found 11 cases in the following 2-year period (1991-1992). A HIV test was positive in 7 among 11 tested pregnant women with tuberculosis. Pulmonary tuberculosis was the most common site (10 cases, 62.5%), and extrapulmonary sites were found in 6 cases (37.5). Tuberculous lymphadenitis was the least common site of extrapulmonary localization reported by these authors in contrast to our own series where the lymph node was the most common location. Early reports on tuberculosis during pregnancy in the USA mostly involved pulmonary localizations (Good et al. 1981). In Great Britain, pregnant women with tuberculosis mostly had an extrapulmonary site of the disease. In a prospective study carried out in Northwick Park District General Hospital, Llewelyn et al. (2000) reported 13 pregnant women with active tuberculosis seen prospectively over a 30-month period (1995-1998). Extrapulmonary sites of localization of tuberculosis were present in 9 patients (69.2%). All patients in this recent study were immigrants to Britain.

M. M. Madkour

19.6.1 Case Illustration 1 A 36-year-old Saudi woman in the 24th week of pregnancy presented with a swelling in the middle third of the right thigh. The swelling started as a small area but increased in size over the following 3 months before presentation, when it became painful. There was no history of trauma or discharge. The patient had fever, sweating, and loss of appetite over the same period. She had never been ill before, and other systematic enquiries were negative. The patient was not acutely ill or in distress. A large soft-tissue swelling extending through the anterolateral aspect of the proximal third of the right thigh was seen. The skin over it was normal, and it was slightly tender. The uterus size corresponded with 24 weeks' gestation. The hemogram, coagulation profile, and biochemical values were normal. ESR was 40 mm/h. Ultrasound of the right thigh depicted a large, soft-tissue, cystic swelling with thick mobile fluid, which could be an abscess or hematoma. It measured 16 cm in length and contained about 800 ml of fluid (Fig. 19.1a). MRI of the right thigh was done, axial T1 and T2 slices obtained through both upper femora and the lower pelvis. The post-gadolinium images were not diagnostic due to the patient's movement. MRI depicted a huge, well-defined, elliptical mass in the right rectus femoris muscle extending from its attachment down to the distal thigh (Fig.1b,c). Similar masses were also noted in the right iliopsoas muscle and right pectineus muscle. These masses showed low T1 and high T2 signal intensity, most probably indicating pus caused by tuberculous abscesses. No bone involvement was seen, and MRI of the thoracolumbar spine showed no evidence of spinal involvement (Fig. 19.1b,c). Aspiration of 200 ml of yellowish purulent pus was obtained and sent for microbiological examination and culture for tuberculosis. The culture yielded M. tuberculosis that was sensitive to all antituberculous drugs. Rifampicin, INH, and ethambutol were given to this patient, and she responded well to treatment. A normal, spontaneous, full-term delivery of a healthy infant was the result in this patient.

19.6.2 Case Illustration 2 A 33-year-old woman presented to my clinic with a 2-month history of fever, sweating, and drug cough.

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a

c Fig.19.1a-d. A 36-year-old pregnant woman presented with a swelling of her right thigh. a Ultrasound shows a well-defined cystic mass with relatively thick wall (curved arrow) consistent with localized abscess. TI-weighted (b) and T2-weighted (c) MRI of the same patient show the abscess in the right vastus lateralis muscle as low signal intensity lesion on TI and as homogeneous high signal intensity on T2 (arrowheads). d MRI of lower pelvis demonstrated a gravid uterus with gestational sac (arrowheads). This was done in an attempt to trace the source of this tuberculous abscess and avoid missing abdominal or pelvic pathology (the safety of MRI in pregnancy is not yet clear). Patient completed the treatment and delivered a normal healthy boy

She had lost 21 kg in weight over that period. She cough, and weight loss. She looked pale, feverish, but was 95 kg in weight before the illness and 74 kg at there was no change in the size of the left supraclathe time of presentation. She had a past history of vicular lymph nodes. There were no other clinical two swellings on the left side of the neck for the past findings. There were purpura and petechiae over the 17 years with no recent changes in their size. She had lower limbs. Repeat chest radiograph, with shield five healthy children. The patient looked pale, her tem- over the abdomen, remained normal. The hemoperature was 38.3°C. There were two enlarged lymph gram showed pancytopenia with Hb 10.9 G/dl, WBC nodes in the left supraclavicular region but no other 2.400/mm3, platelets 31,OOO/mm 3, and the blood film clinical findings. The hemogram showed Hb 1O.9G/dl, showed microcytic hypochromic features. Her serum WBC 9000/mm 3 , platelets 211,OOO/mm 3, and the blood iron and other biochemical parameters were otherfilm showed hypochromic microcytic anemia. wise normal. Coombs test was negative. Bone marrow Biochemical parameters were normal, but the aspiration and biopsy showed hypercellularity in the Mantoux test was positive. The patient refused lymph myeloid and erythroid series with normal maturanode biopsy and discharged herself against medical tion and increased number of megakaryocytes. advice. Two months later she presented to me with a The marrow iron store was normal. Ultrasound of 3-day history of hematuria and skin petechiae over the abdomen was normal. Lymph node biopsy was her legs. She was pregnant with gestational age of performed and showed granulomas with caseation. 9 weeks. She continued to have fever, sweating, dry The biopsy culture yielded M. tuberculosis 4 weeks

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later. She responded well to antituberculous treatment, and the hemogram returned to normal after 3 months. She subsequently had a normal, spontaneous delivery of a healthy baby.

19.6.3 Case Illustration 3 A 30-year-old woman from AI-Qurayyat, northern Saudi Arabia, was referred to our hematologist because of thrombocytopenia, anemia, and convulsions 5 days after a normal delivery. The patient was well during her antenatal follow-up until the last month of her pregnancy when she presented with epistaxis and melena. At that time, her hemoglobin was only 5.8 Gldl, low platelet of 12,OOO/mm3 with normal white cell count. The bleeding time was prolonged, and bone marrow aspiration could not be done at the referring hospital. She was suspected to have idiopathic thrombocytopenic purpura and was started on prednisolone 60 mg oral daily. She was given 5 units of blood and 4 units of platelets and vitamin K. Five days prior to her transfer to our hospital, she delivered a healthy girl. After delivery, she developed headache and recurrent attacks of convulsions. Brain CT scan with contrast was normal. Her fits were controlled with phenytoin. She was admitted on arrival to our general intensive care unit (GICU). She gave a history of easy bruising for the past few years and had not been investigated for this complaint. She had delivered a baby boy 4 years ago with fetal abnormalities, the exact nature of which was not known, who died 3 months after birth. Her history included pulmonary tuberculosis while pregnant with that congenitally deformed boy 4 years ago. She discontinued her antituberculous medication after 2 months when she discovered that she was pregnant. She decided herself to discontinue taking the antituberculous drugs for fear of taking medication during pregnancy. The patient looked ill, emaciated, with bruises all over her body, particularly in the upper limbs. She was not jaundiced and had no lymphadenopathy. Fine apical crepitations were heard over the right lung. Other systemic examinations were normal. The hemogram showed features of severe iron deficiency anemia with low platelets of 18,OOO/mm3 and normal white cell count. Biochemical parameters were normal. Plain chest radiography showed multiple cavitating lesions in the right upper lobe compatible with active tuberculosis. Abdominal cT showed no abnormalities. Bone

M. M. Madkour

marrow aspiration and trephine showed marked hypercellular marrow with hyperactive myeloid and erythroid series with normal maturation and an increased number of megakaryocytes. The iron store was normal. EEG and MRI of the brain were normal. Lumber puncture showed normal CSF. She was seen by our pulmonologist and started on four antituberculous antibiotics. The prednisolone dosage was gradually reduced and stopped. The patient's platelets and hemoglobin returned to normal. She had no further convulsions or bruises. Her follow-up at the chest and hematology clinic was satisfactory, and the patient had a full recovery.

19.7 Diagnosis Prenatal health care screening may help in identifying pregnant women with active pulmonary or extrapulmonary tuberculosis. Early detection of active disease may help in preventing serious consequences to the mother, fetus, and neonate. A high index of suspicion by the attending clinician is essential' particularly in endemic areas and among women at high risk for tuberculosis infection. Detailed history and clinical examination and screening investigations are required to achieve this goal. Investigations may include microbiological methods, plain chest radiography, tuberculin skin testing, and other laboratory tests as appropriate to each patient.

19.8 PPD Skin Test Earlier concepts suggested that a false-negative tuberculin skin testing might occur as a result of the suppression of cell-mediated immunity due to pregnancy (Finn et al. 1972). Pregnancy is found by controlled studies to have no demonstrable effect on tuberculin skin testing, and the test is valid at any time during pregnancy (Snider 1984; Present and Comstock 1975; Huebner et al. 1993). In endemic areas, a positive tuberculin skin test identifies individuals with previous infection by M. tuberculosis but does not indicate the state of disease activity, and a negative response may be noted in patients with active disease. HIV-infected pregnant women react to tuberculin skin testing in a similar way to nonpregnant women with HIV infection with

Tuberculosis and Pregnancy

similar rates of anergy. Anergy is not more frequent as a result of pregnancy among women with HIV infection (Mofenson et al.1995). In the USA, the recommendations of the Advisory Committee at the Center for Disease Control (CDC 1990) with regard to performing the tuberculin test for screening individuals at high risk are as follows: (a) pregnant woman with clinical features suggestive of tuberculosis, (b) women with known or suspected exposure to tuberculosis, (c) women at high risk of developing tuberculosis. A skin reaction of 15 mm in low-risk patient and 5-10 mm in immunocompromised patients is considered positive and should lead to the inclusion of chest radiography as part of the screening (Division of Tuberculosis Elimination, CDC 1991). The interpretation of the tuberculin skin test and the rationale of using various induration size measurements as a positive indication among different populations at variable risk have been the subject of debates in many recent publications. In populations at high risk of developing tuberculosis, contact with active tuberculosis patients, those with clinical or imaging evidence of tuberculosis, or patients with HIV or immunocompromised individuals, induration of at least 5 mm is considered positive and indicating infection with M. tuberculosis. For children in contact with high-risk adults, immunesuppressed patients due to other medical illness, and foreign-born persons, an induration of at least 10 mm is considered positive. In populations at low risk for tuberculosis, an induration of at least 15 mm is considered positive. There has been no classification scheme study of tuberculin induration measurements for pregnant women with or without HIV infection, nevertheless, the tuberculin skin test reaction during pregnancy is not different from that for nonpregnant women (American Academy of Pediatrics 1992; American Thoracic Society 1993; Centers for Disease Control and Prevention 1995).

19.9 Chest Radiography In the past, routine chest radiography was performed as part of screening investigations for all pregnant women (Freth 1952). This routine was found to be potentially hazardous due to irradiation of the fetus, particularly during the first trimester (Bonebrake et al. 1978). However, chest radiography can be per-

307

formed for pregnant women if active pulmonary tuberculosis is suspected particularly in endemic areas and among women at high risk. In nonendemic areas, a positive tuberculin skin test in pregnant women is an indication for chest radiography. Appropriate shielding of the abdomen will reduce irradiation to 50 millirads, which is a less hazardous dose for the fetus, and chest radiography is preferably done after the first trimester. Women with chest symptoms even with a negative tuberculin skin test should have a chest radiograph done (Swartz and Reichling 1978; Brent 1989).

19.10 Microbiology and Other Advanced Laboratory Tests The diagnosis of active tuberculosis during pregnancy may be difficult, particularly when conventional sputum smear staining is negative. Specimens from sputum, gastric or bronchial aspirates, urine and other body fluids, or tissue biopsies should be sent for culturing. Recent advances in automated culture systems such as BACTEC (Becton Dickson Diagnostic Instrument Systems, Towson, MD, USA) are now widely used in many laboratories. Immunological tests and PCR are useful tools that can be used, when available, for the diagnosis of tuberculosis during pregnancy.

19.11 Breast-Feeding and Its Contraindications Breast-feeding by mothers with newly discovered active tuberculosis, before initiating treatment, has been a subject of debate among authors in developed and developing countries. Authors from developed countries, where alternative feeding of infants is readily available, have their own views. Authors from poor, developing countries where feeding substitutes are not easily available have different views as well. To make matters worse, co-infection with HIV complicates the issue of breast-feeding in these poor countries. Transmission of HIV via breast milk to infants is a real threat, and starvation and infant death follow if breast-feeding is contraindicated in such circumstances. This issue is clearly defined in developed countries as a contraindication to breastfeeding (Oxtoby 1988).

308

Nursing mothers with active tuberculosis who are receiving antituberculous treatment should be encouraged to breast-feed their infants. Concerns about the side-effects of antituberculous drugs secreted in the mother's milk have been investigated by many authors. Rifampicin, INH, and streptomycin concentrations in breast milk have been measured after the administration of 600 mg, 300 mg, and 1 g of these drugs, respectively. Peak milk concentrations ranged between 10 and 30 mg!l when rifampicin was given in a dose of 600 mg. A concentration level of 16.6 mg!l was found 3 h after INH injection at a dose of 300 mg, while streptomycin 30 min after intramuscular injection of 1 g dose reached a concentration of 1.3 mg!I. These concentrations of antituberculous drugs in breast milk have no toxic effect on the infant (Lawrence and Lawrence 2001; Berlin and Lee 1979; Vorherr 1974; Fugimoritt and Imais 1957; Snider and Powell 1984). These antituberculous medications have been used directly and safely in infants (Snider 1984). Tuberculosis infection and active tuberculosis are considered two separate issues with regard to breastfeeding. Breast-feeding is not contraindicated in women with previous tuberculosis infection. In women with active tuberculosis, the American Academy Committee has indicated that respiratory contact puts these infants in jeopardy. Breast milk in such patients does not contain tubercle bacilli and can be pumped into bottles and fed to these infants until medication has commenced, and the mother is no longer considered infective. The committee also recommended that active tuberculosis is an indication for temporary isolation of the mother until she has received about 2 weeks of antituberculous therapy. Mothers with TB mastitis should have the milk pumped and discarded until the breast lesion has completely healed (American Academy of Pediatrics 1992). The presence of concomitant HIV and active tuberculosis in mothers living in developed countries is an absolute contraindication to breast-feeding. The rate of HIV transmission to infants via breast milk is estimated to range between 5% and 20% or higher (Lawrence 1997; Lawrence and Lawrence 2001; Oxtoby 1988). Data on freezing or heating breast milk to destroy HIV type I are sparse and insufficient (Ando et aI. 1989). In developing countries where alternative affordable infant feeding, sanitary measures, and medical resources are not available to prevent the transmission of HIV to infants, the World Health Organization, UNICEF, and the United Nations AIDS program recommend the following measures: (l) If

M. M. Madkour

an adequate and safe milk substitute is available, then breast-feeding should not be used. (2) If substitutes are not available, then women who are HIV-positive should be offered the choice of what is appropriate for their circumstances and supported in their choice (WHO 1998).

19.12 Treatment of Active T8 During Pregnancy Pregnant women with active pulmonary or extrapulmonary tuberculosis should be treated without delay. Delay in treatment poses a real threat to the pregnant women, her fetus, and the contact. Treatment should not be interrupted in women with active tuberculosis if pregnancy is discovered while she is on antituberculous medication. The only exception is streptomycin, which may cause fetal ototoxicity and should be replaced unless no alternative drugs are available (Hamadeh and Glassroth 1992). Concerns about the teratogenic effect of antituberculous drugs have been extensively studied by many authors in recent years. Isoniazid, rifampicin, ethambutol, and pyrazinamide are the most widely used and carefully evaluated drugs with no evidence of increased teratogenicity (Steen and Seainton-Ellis 1977; Snider et al. 1980; Starke 1997; Czeizel et aI. 2001). The human teratogenic potential of isoniazid, rifampicin, ethambutol, pyrazinamide, ethionamide, prothionamide, and cycloserine during pregnancy was carefully studied by Czeizel from Hungary and his colleagues from Denmark (Czeizel et al. 2001). These authors surveyed case-controlled, populationbased, congenital abnormalities from the Hungarian National Birth Registry between 1980 and 1996, regarding the safety of 7 oral antituberculous drugs used during pregnancy. These drugs were used during the second and third months of gestation to treat pregnant women with active tuberculosis (critical period for most major congenital abnormalities). The authors reported their findings as shown in their table (Table 19.1). They found no detectable teratogenic risk to the fetus; however, the number of pregnant women who were treated with these drugs during the critical period was limited (6 cases vs 21 controls). The guidelines and recommendations with regard to the choice of the antituberculous drug regimen are subject to revisions and updating depending on drug sensitivity and resistance tests. The most commonly used regimen at present involves the use of two to four or more oral drugs including isoniazid, rifam-

309

Tuberculosis and Pregnancy Table 19.1 Characteristics of the antituberculosis drugs studied, in addition to the number of cases and controls during the study period between 1980 and 1996 (reproduced with permission from Czeizel et al. 2001) Antituberculosis drugs Isoniazid Rifampicin Ethambutol Pyrazinamide Ethionamide Prothionamide Cycloserine Total

Table dose (mg) 50 150,300 250 500 250 250 250

Recommended daily treatment (mg) 50-300 450-600 15-15 mglbwkg 35 mglbw kg (1000-2000) 750-1000 500-1000 750-1000

Cases

Controls for all CAs

Crude POR

(n=22865) n (0/0)

(n=38151) n (0/0)

POR (950/0CI)

6 (0.03) 0(0.00) 4 (0.02) 0(0.00) 0(0.00) 0(0.00) 1 (0.00) 11 (0.05)

17 (0.04) 1 (0.00) 6 (0.02) 3 (0.01) 1 (0.00) 1 (0.00) 0(0.00) 29 (0.08)

0.6 (0.2-1.5) 0.6 (0.0-13.7) 1.1 (0.3-13.7) 0.2 (0.0-4.6) 0.6 (0/0-13.7) 0.6 (0.0-13.7) 5.0 (0.2-122.9) 0.6 (0.3-1.3)

POR, prevalence odds ratio; CA, congenital abnormality; CI, confidence interval; bw, body weight

picin, ethambutol, and pyrazinamide. The duration of treatment may range between 6 and 9 months. Ethambutol should be added in the first 2 months to INH and rifampicin. Alternatively, pyrazinamide can be used in the first 2 months with INH and rifampicin. Pyridoxine 50 mg daily should be added to prevent seizure in the newborn when INH is used. The dosages of these drugs are similar to those used in nonpregnant women. Streptomycin should be avoided unless no alternative antituberculous drug is available. Kanamycin and capreomycin share the same potential for producing ototoxicity as streptomycin. Successful treatment of active tuberculosis during pregnancy depends on the identification of the organisms by culture and sensitivity, the use of multiple drugs to which the organisms are sensitive, and close follow-up of the patient for treatment compliance.

19.13 Treatment of Multidrug-Resistant T8 During Pregnancy Single or multiple drug-resistant tuberculosis during pregnancy is increasing. Isoniazid-resistant tuberculosis during pregnancy can be treated with rifampicin and ethambutol for 18 months (Vallejo and Starke 1992). However, the management of pregnant women with multidrug-resistant tuberculosis is a real dilemma. Iseman recommended the use of 5-6 drugs in areas of known multidrug-resistant tuberculosis until drug sensitivity patterns are identified. This makes the treatment of pregnant women with multidrug-resistant tuberculosis extremely difficult, because some of these medications may

be contraindicated or of unknown teratogenic effect (Iseman 1993). There are no clear recommendations or guidelines to this problem because of possible serious consequences to the fetus. Good and colleagues reported their views and stated: 'it is reasonable to consider therapeutic abortion in this setting' (Good et al. 1981). Nitta and Milligan (1999) from the MDR tuberculosis unit in Los Angeles reported their experience of management of four pregnant women with multidrug-resistant pulmonary tuberculosis. MDR tuberculosis was acquired due to their nonadherence to previous regimens of antituberculous treatment. One of them chose termination of her pregnancy. In one, treatment was withheld, and only rifampicin and INH were given to prevent TB progression; another patient was allowed to continue self-administered medication during her pregnancy. Yet another patient was not treated during pregnancy. All three women who carried their gestation to full term had healthy infants. Retreatment of all four women was done using 5-6 drugs including ethambutol, cycloserine, para-aminosalicylic acid (PAS), capreomycin, ofloxacin, and clofazimine given as daily DOT for 17-24 months. The authors concluded that individualized treatment is considered according to each patient's medical and psychosocial needs. They also demonstrated that MDR tuberculosis during pregnancy can be managed safely and successfully.

19.14 Preventive Treatment During Pregnancy Pregnant women infected with tuberculosis with a positive tuberculin skin test but who are asymptomatic form

M. M. Madkour

310

a controversial issue (Vallejo and Starke 1992). Should they receive preventive treatment, and what are the guidelines in developed and developing countries? Authors from developed countries do not adopt the same policy or guidelines with regard to preventative therapy during pregnancy. Not all infected, pregnant women in developed countries have the same chance of developing active tuberculosis. In the USA, the incidence of tuberculosis infection (not disease) in the general population is approximately 7% (MedchillI999). Individuals who have a positive tuberculin test have a 5% chance of developing active tuberculosis within the first 1-2 years after exposure and can gain an additional 5% chance over the rest of their lives (Barnes and Barrows 1993). As pregnancy has no effect on the development of active tuberculosis, some clinicians may delay initiating preventive therapy until after delivery (Hamadeh et al. 1992). Starke (1997) has debated the value of initiating isoniazid treatment during pregnancy for such individuals particularly those with poor compliance to treatment. However, he structured an algorithm to serve as a guideline for clinicians in the USA to help identify those who will need treatment and when to start it (Fig. 19.2).

Starke recommended the initiation of preventive therapy to those co-infected with HIV. The cost-effectiveness of preventive therapy was reported in the USA by Medchill from Phoenix in 1999. His study was based on the data about the chance of development of active TB among those with a positive tuberculin test and found preventive therapy to be cost-effective. Isoniazid is given as a single daily dose of 300 mg for 6-12 months. Hepatotoxicity should be monitored at least monthly (Hamadeh and Glassroth 1992). In Great Britain, preventive therapy is less widely used in asymptomatic women with a positive tuberculin test but may be recommended for refugees and new immigrants (Ormerod 2001). In developing countries, preventive treatment during pregnancy is not an adopted policy as tuberculosis is highly endemic, and the prevalence of a positive tuberculin test is high. In a large study from Chile, 840 pregnant women in the third trimester were assessed by tuberculin test. Over 50% of them had a positive tuberculin test, none developed symptoms of tuberculosis during pregnancy, and 93% were followed up for 1 year with no evidence of active disease. The Chilean Ministry of Health policy is 'not to perform tuberculin testing as a means of

Positive Mantoux Sj Test During Pregnancy Chest Radiograph (abdominal shield) I Abnonnal

Nonnal

Recent High risk Exposure for progression to disease

y

Start isoniazid and monitor carefully

Consistent with "Older" infection Calcified or likely fibrotic lesion active (not active) and tuberculosis no symptoms or symptoms

I.

'd . Start Isom8Z1 After delivery

Start isoniazid after delivery if repeat chest radiograph is nonnal

I

Three sputum AFB smears and cultures

I

Start multidrug therapy (isoniazid, rifampin, ethambutol, usually pyrazinamide)

Fig. 19.2. Evaluation and treatment of a pregnant woman with a positive Mantoux skin test. AFB, acid-fast bacilli (Starke's algorithm, Starke 1997, from Clinics in Perinatology; with permission from Dr. Stark)

Tuberculosis and Pregnancy

identifying infected women and not to treat asymptomatic tuberculin-positive individuals' (Sepulveda et al. 1995).

References Adhikari M et al (1997) Tuberculosis in the newborn: an emerging disease. Pediatr Infect Dis J 16:1108-1112 Ahmed Yet al (1999) A study of maternal mortality at the university teaching hospital, Lusaka, Zambia: the emergence of tuberculosis as a major non-obstetric cause of maternal death. Int J Tuberc Lung Dis 3:675-680 American Academy of Paediatrics (1992) Committee on infectious diseases: screening for tuberculosis in infants and children. Pediatrics 93:313 American Thoracic Society (1993) Control of tuberculosis in the United States. Am Rev Respir Dis 146:1623 Ando Y et al (1989) Effect of freeze thawing breast milk on vertical HTLV-l transmission from seropositive mothers to children. Jpn J Cancer Res 80:405 Barnes PF, Barrows SA (1993) Tuberculosis in the 1990's. Ann Intern Med 19:400-410 Bazaz-Malik G et al (1983) Tuberculosis endometritis. A clinicopathological study of 1000 cases. Br J Obstet Gynaecol 90:84-88 Berlin C, Lee C (1979) Isonizid and acetylisoniazid disposition in human milk, saliva and plasma. Fed Proc 38:426 Bjerkedal T et al (1975) Course and outcome of pregnancy in women with pulmonary tuberculosis. Scand J Respir Dis 56:245-250 Bonebrake CR et al (1978) Routine chest roentgenography in pregnancy. JAMA 240:2747-2748 Brent RL (1989) The effect of embryonic and fetal exposure to x-ray, microwaves and ultrasound: counseling the pregnant and non-pregnant patient about these risks. Semin Oncol 16:346-368 Carter EJ, Mates S (1994) Tuberculosis during pregnancy: the Rhode Island experience, 1987 to 1991. Chest 106: 1466-1470 Centers for Disease Control (1990) Screening for tuberculosis and tuberculosis infection in high-risk populations. Recommendations of the Advisory Committee for Elimination of Tuberculosis. MMWR Morb Mortal Wkly Rep 39:1-7 Centers for Disease Control and Prevention (1994) COR Curriculum on tuberculosis, what the clinician should know, 3rd edn. Department of Health and Human Services, Atlanta, pp 6-7 Centers for Disease Control and Prevention (1995) Screening for tuberculosis and tuberculosis infection in high-risk populations. MMWR Morb Mortal Weekly Rep 44:19 Cohen JD et al (1952) The tuberculous mother. Am Rev Respir Dis 65:1-23 Connolly M, Nunn P (1996) Women and tuberculosis. World Health Statist Quart 49:115-119 Czeizel AE et al (2001) A population-based case-control study of the safety of oral anti-tuberculous drug treatment during pregnancy. Int J Tuberc Lung Dis 5:564-568 Division of Tuberculosis Elimination, Center for Prevention Services (1991) Center for Disease Control and American

311 Thoracic Society: core corriculum on tuberculosis. US Public Health Services, New York Dolin PJ et al (1994) Global tuberculosis incidence and mortality during 1990-2000. Bull WHO 72:213-220 Epidemiology Comments (1996) Report of the review of the tuberculosis control programme of South Africa, June 10 to 25, 1996: Department of Health, Pretoria, South Africa, vol 23, pp 2-20 Espinal MA et al (1996) The effect of pregnancy on the risk of developing active tuberculosis. J Infect Dis 173:488-491 Finn R, Hill CA et al (1972) Immunological responses in pregnancy and survival of foetal hemograft. Br Med J 3: 150-152 Freth A (1952) Routine x-ray examination of the chest at an antenatal clinic. Lancet 1:287-288 Fujimori H, Imais (1957) Studies on dihydrostreptomycin administered to the pregnant and transferred to their fetuses. Jpn Obstet Gynecol Soc 4:133-149 Fylkesnes K et al (1997) The HIV epidemic in Zambia: sociodemographic prevalence patterns and indications of trends among childbearing women. AIDS 11:339-345 Gogus S et al (1993) Neonatal tuberculosis. Pediatr Pathol13: 299-304 Good JT et al (1981) Tuberculosis in association with pregnancy. Am J Obstet GynecoI140:492-498 Hageman J (1998) Congenital and perinatal tuberculosis: discussion of difficult issues in diagnosis of difficult in diagnosis and management. J Perinatal 18:389-394 Hageman J et al (1980) Congenital tuberculosis: critical reappraisal of clinical findings and diagnostic procedures. Paediatrics 66:980-984 Hallum JL, Thomas HE (1995) Full-term pregnancy after proved endometrial tuberculosis. J Obstet Gyaecol Br Emp 62:548 Hamadeh MA, Glassroth J (1992) Tuberculosis and pregnancy. Chest 101:1114-1120 Hedvall E (1953) Pregnancy and tuberculosis. Acta Med Scand 147:1-101 Huebner RE et al (1993) The tuberculin skin test. Clin Infect Dis 17:968-975 Iseman MD (1993) Treatment of multi-drug-resistant tuberculosis. N Engl JMed 329:784-791 Kaplan C et al (1980) Placental tuberculosis in early and late pregnancy. Am J Obstet Gynecol137:858-860 Lawrence RA (1997) A review of the medical benefits and contraindications to breast-feeding in the United States. Maternal and Child Health Technical Information Bulletin. National Center for Education in Maternal and Child Health, Arlington Lawrence RM, Lawrence RA (2001) Given the benefits of breast-feeding, what contraindications exist? Pediatr Clin North Am 48:235-251 Llewelyn M et al (2000) Tuberculosis diagnosed during pregnancy: a prospective study from London. Thorax 55: 129-132 Machin GA et al (1992) Perinatally acquired neonatal tuberculosis: report of two cases. Peadiatr PathoI12:707-716 Margono F, Mroueh J, Garely A et al (1994) Resurgence of active tuberculosis among pregnant women. Obstet Gynecol 83:911-914 McKenna MT et al (1995) The epidemiology of tuberculosis among foreign-born persons in the United States, 1986 to 1993. N Engl JMed 332:1071

312 Medchill MT (1999) Prenatal purified protein derivative skin testing in a teaching clinic with a large Hispanic population. Am J Obstet GynecoI180:1579-1583 Medical Research Council Cardiothoracic Epidemiology Group (1992) National Survey of Notifications of Tuberculosis in England and Wales in 1988. Thorax 47:770-775 Miller KS, Miller JM Jr (1996) Tuberculosis in pregnancy: Interactions, diagnosis and management. Clin Obstet GynecoI39:120-142 Mofenson et al (1995) Mycobacterium tuberculosis infection in pregnant and non-pregnant women infected with HIV in the women and infants transmission study. Arch Intern Med 155:1066-1072 Nemir RL, O'Hare D (1985) Congenital tuberculosis. Am J Dis Child 139:284-287 Nitta AT, Milligan D (1999) Management of four pregnant women with multi-drug-resistant tuberculosis. Clin Infect Dis 28:1298-1304 Ormerod P (2001) Tuberculosis in pregnancy and puerperium. Thorax 56:494-499 Oxtoby MJ (1988) Human immunodeficiency virus and other viroses in human milk: placing the issue in broader perspective. Pediatr Infect Dis J 7:825-835 Present PA, Comstock GW (1975) Tuberculosis sensitivity in pregnancy. Am Rev Respir Dis 112:413-416 Rose AMC et al (2001) Tuberculosis at the end of the 20th century in England and Wales: results of a national survey in1998. Thorax 56:173-179

M. M. Madkour Schaefer G et al (1975) Pregnancy and pulmonary tuberculosis. Obstet GynaecoI46:706-715 Sepulveda RL et al (1995) The influence of BCG immunization on tuberculin reactivity in healthy Chilean women in the third trimester of pregnancy. Tuberc Lung Dis 76:28-34 Snider D (1984) Pregnancy and tuberculosis. Chest 86: 105-135 Snider DE, Powell K (1984) Should women taking anti-tuberculosis drugs breastfeed? Arch Intern Med 144:589-590 Snider DE et al (1980) Treatment of tuberculosis during pregnancy. Am Rev Respir Dis 122:65-79 Starke JR (1997) Tuberculosis, an old disease but a new threat to the mother, fetus and neonate. Clin Perinatol 24: 107-127 Steen JSM, Seainton-Ellis DM (1977) Rafampicin in pregnancy. Lancet ii:604-605 Swartz HM, Reichling BA (1978) Hazards of radiation exposure for pregnant women. JAMA 239:1907-1908 Vallejo JG, Starke JR (1992) Tuberculosis and pregnancy. Clin Chest Med 13:693-707 Vorherr H (1974). Drug excretion in breast milk. Postgrad Med J 56:97-104 Wilson EA et al (1973) Tuberculosis complicated by pregnancy. Am J Obstet GynecoI115:526-529 World Health Organization (1998) HIV and infant feeding: guidelines for healthcare managers and supervisors. World Health Organization, Geneva. Publication WHO/FRH/NUT 98.2, UNAIDS/98.4, UNICEF/PD/NUT/(J) 98.2

20 Post-primary Pulmonary Tuberculosis M. MONIR MADKOUR, Y. ABusABAAH, ALI BEN MOUSA, ALI AL MASOUD

CONTENTS 20.1 20.2 20.2.1 20.2.2 20.2.3 20.2.4 20.2.5 20.2.6 20.2.7 20.2.8 20.2.9 20.2.10 20.2.11 20.2.12 20.3 20.3.1 20.3.2 20.3.3 20.3.4 20.3.5 20.4 20.4.1

Pathogenesis and Pathology 313 Clinical Features and Complications 315 Hemoptysis in Pulmonary Tuberculosis 316 Massive Hemoptysis in Tuberculosis 316 Rasmussen Aneurysm 317 Endobronchial Tuberculosis 318 Bronchiectasis as a Complication of Post-primary Pulmonary TB 318 Pneumothorax as Complication of Post-primary Pulmonary TB 318 ARDS and Tuberculosis 319 Tuberculous Bronchopleural Fistula 319 Aspergilloma (Mycetoma) 319 Tuberculomas 320 Tuberculous Pulmonary Gangrene 320 Tuberculosis, Lung Cancer and Other Neoplasia 320 Diagnosis of Post-primary Pulmonary TB 320 Imaging Features of Post-primary Pulmonary TB 320 Microbiology of the Sputum and Bronchial Aspirate 321 Bronchoscopic Diagnosis 321 Tuberculin Skin Test 322 Other Diagnostic Investigations 322 Treatment of Post-primary Pulmonary TB 322 Response to Treatment 324 References 324

M. M. MADKouR, MD, DM, FRCP Consultant, Department of Medicine, Riyadh Armed Forces Hospital, P.O. Box 7897, C-119, Riyadh 11159, Saudi Arabia Y. ABusABAAH, ABIM Fellow, Respiratory Medicine, Department of Medicine, Riyadh Armed Forces Hospital, P.O. Box 7897, Riyadh 11159, Saudi Arabia A. BEN MousA, MD Department of Medicine, Riyadh Armed Forces Hospital, P.O. Box 7897, Riyadh 11159, Saudi Arabia A. AL MAsouD, MD Department of Medicine, Riyadh Armed Forces Hospital, P.O. Box 7897, Riyadh 11159, Saudi Arabia

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

Post-primary pulmonary tuberculosis is a chronic disease commonly caused by either endogenous reactivation of a latent infection or exogenous re-infection by Mycobacterium tuberculosis. It has other synonyms derived mostly from the route of transmission of the infection or from the age of the patient at the onset of the disease, including endogenous reactivation primary tuberculosis, exogenous re-infection pulmonary tuberculosis, or adult-onset pulmonary tuberculosis. The term being used here is 'post-primary pulmonary tuberculosis'to include both re-infection and reactivation forms. The clinical features of the disease are not specific, and the imaging features are suggestive but can simulate other diseases. The definitive diagnosis depends on the identification of M. tuberculosis bacilli, using conventional microbiological methods of sputum smear and culture or radiometric culture methods such as BACTEC or DNA probe PCR-based assays which can identify drug-resistant strains as well. Sputum smear and culture remain the most important investigative methods. Smear-negative sputum may delay the diagnosis for 4-8 weeks or longer if the culture is also negative. A presumptive diagnosis based on the clinical and radiographic features should be made with initiation of treatment after the exclusion of other possible causes of the radiographic findings. Infection with HIV is a great risk for the development of either endogenous reactivation or exogenous re-infection pulmonary disease (Millar and Horne 1979; Barnes et al. 1991; Heyderman et al. 1998). The development of drug-resistant pulmonary tuberculosis is a real global concern that indicates a failure of the tuberculosis control program. The current treatment is both toxic and expensive, and new drug development is sparse at present.

20.1 Pathogenesis and Pathology The development of post-primary pulmonary tuberculosis as a result of endogenous reactivation or exog-

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enous re-infection in low-risk and high-risk areas has been debated for many years among authors (Glynn et al. 2001). Balasubramanian and colleagues reviewed the world literature on these issues and added their own views (Balasubramanian et al. 1994). Schools of thought adopted by those researchers based on microbiological studies of tissue specimens from the lung and lymph nodes of the primary complex. Some authors quoted by reviewers suggested that the primary complex is sterile within 5 years, while other authors suggest that virulent bacilli lie dormant in a metastatic site seeded hematogenously within the vulnerable region. Cultures of apical lung lesions yielded viable bacilli in 25%-76% as reported by some of the quoted authors, and transmission via the bloodstream was suggested. Other researchers examined the sputum and urine cultures in patients living in Bangalore, India, and compared the bacilli virulence, INH sensitivity, and phage typing of the isolates and drew conclusions about the biological evidence of exogenous re-infection in that study. Epidemiologists have noted that high- or lowrisk incidence rates of infection in different areas of the world played an important role (in exogenous reinfection or endogenous reactivation). In areas with a risk greater than 1% of developing countries, with the likelihood of repeated episodes of droplet infection via the airway, the disease is more likely to be due to exogenous re-infection. In areas of low-risk (less than 0.05%), as in developed countries, endogenous reactivation is more likely to be the cause of the disease. Some other authors gave evidence of the contributions of both exogenous re-infection as well as endogenous reactivation. Balasubramanian et al. hypothesized that the implantation of the vulnerable region is directly transmitted via the airway (exogenous re-infection). They also concluded that more studies using genetic fingerprinting of Mycobacterium bacilli isolates would help in the future in disease control in endemic areas and in the development of new vaccines. Immune suppression resulting from HIV infection leads to higher rates of co-infection with tuberculosis. Recent molecular epidemiological studies have indicated that up to 40% of newly diagnosed tuberculous patients and over 70% of recurrences may be due to exogenous re-infection (Stead and Bates 2000; Bates et al. 2001). Among the immunosuppressed patients due to HIV, exogenous re-infection was the leading mechanism. Endogenous reactivation contributed to only 16% of patients in a low-risk area in developed countries and more than 70% in a high-risk area in developing countries (Alland et al. 1994; Brande et al. 1998; Small et

M. M. Madkour et aI.

al. 1994; van Rie et al. 1999; McDonough et al. 2000; Rook and Zumla 2001; Caminero et al. 2001; Bandera et al. 2001; Wallis and Johnson 2001). Caminero and colleagues (2001) reported 912 patients with culture-proved pulmonary tuberculosis between 1991 and 1996 on a Spanish island with a moderate risk rate of incidence. They were treated and followed up for at least 12 months after completing chemotherapy and were culture-negative. Twentythree patients (2.5%) became culture positive again. DNA fingerprinting results were available from 18 patients with recurrence of the disease. DNA fingerprinting was available of pretreatment and recurrent isolates and was reviewed. In 8 patients (44%), the genotype of the recurrent isolate showed a different pattern to the pretreatment isolate. These authors concluded that in 8 patients, 2 of them HIV-positive, exogenous re-infection was the cause of the recurrent pulmonary tuberculosis. Immune suppression or reduction of immune responses may also occur in certain diseases such as silicosis, diabetes mellitus, or with corticosteroid and other immunosuppressive drugs used for malignancies or connective tissue diseases. Regardless of the mode of infection (exogenous or endogenous), the apex of the lung (apical-posterior segments) is the most common site of post-primary pulmonary tuberculosis. Specific factors permitting the progression of tuberculosis in most cases are not yet known (Wallis and Johnson 2001). The host immune response and the role of the cellmediated immunity of activated macrophages and T-cells and the expression of cytokines (Garcia et al. 2002) in response to M. tuberculosis glycolipids and lipoproteins have been discussed in the pathogenesis of primary pulmonary tuberculosis in Chap. 17. Post-primary pulmonary tuberculosis commonly affects the apical and posterior segments of the upper lobe or the superior segment of a lower lobe. After its localization, inflammatory granulomatous nodular formations with cellular infiltrates, fibrosis, central necrosis, and caseation may take place. Hilar and paratracheal lymphadenitis (Woodring 1986) in post-primary tuberculosis is a rare occurrence and reported in approximately 5% of patients (see Figs. 23.18, 23.20, 23.21, 23.22, 23.39, 23.40b). Healing with fibrosis and calcification (Fig. z.25) of lung parenchymal lesion may occur, leading to traction of the trachea (Fig. 23.21, 23.22, 23.23), and in late advanced stages when the lung is destroyed and replaced by extensive fibrosis, displacement of the mediastinum may occur (Fig. 23.24). The initial upper lobe infiltration may form a pneumonic consolidation, and cavitation often

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occurs in 40%-80% of patients (Fig. 23.20, 23.26a, b) sheep with udder tuberculosis. It can also be transmit(Rohenberg and Shaw 1996). Tuberculous consolida- ted to humans from cows as an airborne infection tion with cavity formation may expand and form a (Geppert and Leff 1979; Liesegang and Cameron 1980; lung abscess discharging large numbers of the bacilli Sauret et al. 1992). The incidence ofM. bovis in humans in the sputum as was noted in one of our patients is higher in rural areas with infected herds (Moda et al. (Fig. 23.26d). Tuberculous cavities with areas of 1996). Ingestion of contaminated milk, particularly by necrosis and caseation may rupture into the pleura, young children living in developing countries, leads to leading to empyema (Fig. 23.34b) or a bronchopleu- establishment in the cervical and less frequently in the raj fistula (Fig. 23.36). Rupture of a tuberculous cavity axillary lymph nodes (scrofula). The bacilli may also into the trachea or bronchi is a common complica- affect the intestine, kidney, bones, and central nervous tion and occurs in up to 40% of patients (Rohenberg system in endemic areas with a similar pathogenicity and Shaw 1996). Bronchogenic spread of necrotic and to M. tuberculosis (Moda et al. 1996). HIV patients caseous tissue loaded with the bacilli to other parts of co-infected with M. bovis have been reported in San the lung fields on the same side or opposite lung may Diego, USA, near the border with Mexico (Dankner occur (Figs. 23.19,23.20, 23.27b,c, 23.28b,c). Infection et al.1993). Nontuberculous mycobacterial organisms starts at the newly seeded sites with nodular infiltrate may also cause a similar pulmonary infection (see bronchopneumonia or similar tissue destruction and Chap. 11). fibrosis to the lung parenchyma (Figs. 23.25, 23.26a, z.27b, c, 23.28b). A severe form of transbronchial spread of infection takes the form of dissemination in both lungs (Fig. 23.28c). 20.2 Endobronchial involvement of the bronchial wall is Clinical Features and Complications common, leading to scarring and luminal narrowing and post-stenotic emphysema (Figs. 23.22b, 23.30a, b, Post-primary tuberculosis often presents with a 23.25, 23.31b), atelectasis, and cystic or tubular bron- gradual onset of symptoms that may be tolerated by chiectasis due to traction or endobronchial fibrosis as the patient. The duration of symptoms before prea common complication of the tuberculous disease sentation may vary widely, from 3 days to 23 months process. It is often located in the upper lobes but can (Dahmash et al. 1995; Maartens and Beyers 2002). occur at any other site (Figs. 23.30a, b, 23.31a, b). Post- The presenting features may initially be related to the tuberculous bronchiectasis, although often asymp- respiratory system or present as constitutional symptomatic, may cause hemoptysis in these patients. toms or both. Cough is the most frequently reported A tuberculous cavity larger than 25 mm in diameter presenting feature. Initially, it is dry but later becomes may persist long after successful antibiotic treatment. productive. The sputum may be mucoid, muco-puruColonization with fungi forming a ball of mycetoma lent, blood-stained, or with massive hemoptysis. Chest may rarely occur (Fig. 23.26b, 23.37a,b), and hemopty- pain due to associated pleurisy or pneumothorax may sis may rarely be a presenting complaint. be a presenting symptom. Dyspnea due to tuberculous Tuberculous granulomatous tissue nodules may pneumonia or bilateral fibrocavitary disease may be be encapsulated with connective tissue during vari- the presenting symptom. Fever with sweating and able stages of disease healing and activity, leading chills are common, particularly at night. Other constito tuberculomas found in 3%-6% of patients. It may tutional symptoms including weakness, anorexia, and be single or multiple with a central area of necrosis weight loss, which are nonspecific, may also be present or calcification (Figs. 23.32a-d). Tuberculomas may (Dunlap et al. 2000; Johnson and Ellner 2000). occur in both primary and post-primary pulmonary Symptoms related to extrapulmonary tuberculotuberculosis. sis such as tuberculous monoarthritis, Pott's disease, In bovine tuberculosis, the M. bovis bacilli are genitourinary symptoms, or other organ involvebacteriologically distinctive from M. tuberculosis but ment might accompany the respiratory symptoms at otherwise cause identical pathogenesis, lung lesions, the time of presentation. We retrospectively reviewed and clinical disease. In humans, M. bovis is a zoonotic the records of 176 adult patients with post-primary disease that has been virtually eliminated in developed pulmonary tuberculosis who had a positive sputum countries and other developing countries that practice culture for M. tuberculosis. They attended our hospipasteurization of milk and immunization of dairy tal between 1998 and 2000. The frequency of history/ herds (Grange et al. 1994; Dannenberg 2001). The symptoms, physical findings, and imaging features of organism is excreted in the milk from cows, goats, and these patients are presented in Table 20.1.

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Table 20.1. Clinical features of 176 patients with culture-positive post-primary pubnonary tuberculosis No. of patients

Percentage

166 128 40 135 80 98 76 58

94.3 72.7 23.0 76.7 45.4 55.7 43.2 32.9

105 Crackles Localized wheezes 23 Bronchial sound 55 Diminished sound 66 20 Clubbing 16 Extrapulmonary 28 Bronchoscopy

59.6 13.0 31.2 37.5 11.4 9.0 16.0

Clinical features

Symptoms: Cough Expectoration Hemoptysis Fever Sweating Weight loss Dyspnea Chest pain

Signs:

The frequency of these symptoms may vary, being more intense among those co-infected with HIV (Corbett et al. 2000). The frequency of symptoms was also reported from a large tuberculosis center in Riyadh for 1566 hospitalized patients with pulmonary tuberculosis during 1983-1987. Fever and constitutional symptoms were reported in 77.7%, cough with or without expectoration in 94.3%, and hemoptysis in 40.7% (AlHajjaj et al. 1991). In another series from the south of Saudi Arabia, Al Wabel et al. (1995) reported on 190 patients with post-primary pulmonary tuberculosis who were hospitalized over a 2.5-year period. Cough was noted in 84%, expectoration in 65%, hemoptysis in 23%, fever and constitutional symptoms in over 40% of patients. Pulmonary tuberculosis in elderly patients with underlying and concomitant other chronic illnesses in 80 patients were reported from Riyadh (Dahmash et al. 1995). These patients had diabetes mellitus or malignancies, and some were on steroids, and these illnesses occurred in 86% of them, but none had HIY. Cough was noted in 85%, expectoration in 60%, fever in 66%, hemoptysis in 17.5%, anorexia, weight loss, and other constitutional symptoms in over 50%. Choyke and colleagues (1983) reported on 103 patients with adult-onset pulmonary tuberculosis: 85% were symptomatic, with fever in 40%, cough in 37%, weight loss in 23.6%, and hemoptysis in 8%. Physical examination of the chest may be normal despite the presence of pulmonary infiltrations depicted by chest radiography. Displacement of the trachea due to lung fibrosis and collapse may

be found (Fig. 23.21). Chest wall retraction due to fibrosis or prominence due to associated pleural effusion may be found. Features of consolidations with crepitation and bronchial breathing may be detected. Localized wheezes may be present, indicating endobronchial disease. Other systemic features including pallor, rarely clubbing of the fingers and toes in chronic cases, weight loss, dyspnea, and other extrapulmonary involvement may be found on physical examination. Patients with post-primary pulmonary tuberculosis may present with clinical features similar to those of community-acquired pneumonia. Al-Zeer and colleagues (1998) reported a series of 64 patients admitted to hospital during the pilgrimage season to Mecca in 1994 with an initial diagnosis of community-acquired pneumonia. All patients came from developing countries. Microbiologically proven M. tuberculosis was found in 13 patients (20.3%) and was the most common cause of pneumonia among this group.

20.2.1 Hemoptysis in Pulmonary Tuberculosis Hemoptysis is often an alarming presenting symptom in patients with tuberculosis. It may vary in severity from a slight tinge of blood mixed with the sputum, to mild, moderate, or severe, massive, lifethreatening hemoptysis. In our series of 176 patients with microbiologically proved pulmonary tuberculosis, 28 patients (16%) had slight to mild hemoptysis that was managed with chemotherapy and conservative treatment. Active pulmonary tuberculosis with or without cavitation or post-tuberculous bronchiectasis is the most common cause among these patients. Rarely, the development of bronchial carcinoma in these patients as well or mycetoma or other unrelated illnesses could be the cause of hemoptysis in tuberculous patients (Stebbings and Lim 1999; Hirshberg et al. 1997).

20.2.2 Massive Hemoptysis in Tuberculosis Life-threatening massive hemoptysis due to active tuberculosis or post-tuberculous bronchiectasis has been reported as 'common in comparison to other causes listed in many publications', as reported by Hsiao et al. (2001) from the USA. Life-threatening, massive hemoptysis is defined by most authors as

Post-primary Pulmonary Tuberculosis

expectoration of at least 200 ml of blood in 24 h, significant drop of hemoglobin requiring blood transfusion, or failure to respond to conservative treatment such as oxygen supplement, morphine, and antibiotics (Wong et al. 2002; Abal et al. 2001; Lee et al. 2000; Hsiao et al. 2001; Conlan et al. 1983). In South Africa, Conlan et al. (1983) reviewed 123 patients with massive hemoptysis due to different causes. Tuberculosis was by far the most common cause, either due to culture-proved active disease or bronchiectasis as a sequela to tuberculosis. These authors reported that active pulmonary tuberculosis as a cause of massive hemoptysis was found in 47 patients (38%),24 men and 23 women aged between 19 and 60 years. Thirty-seven patients had bronchiectasis, and 17 (45.9%) had bilateral upper lobe bronchiectasis secondary to former tuberculosis. The total number of patients with massive hemoptysis with or who had tuberculosis was 64 (52%). The remaining causes were chronic narcotizing pneumonitis in II, lung abscess in 6, lung cancer in 6, primary fungal pneumonia in 4, bronchovascular fistula in 5, and miscellaneous causes in 7 patients. In France, Mal and colleagues (1999) reported the intermediate and long-term outcome of bronchial artery embolization (BAE) performed on 46 patients with massive hemoptysis. Tuberculosis (active or sequela) was found in 23 patients (50%) as a cause of the massive hemoptysis. Idiopathic in 10, bronchiectasis in 4, lung cancer in 2, and 1 patient each due to other various causes. The outcome of BAE was favorable with an immediately successful result in stopping the bleeding, but complications were also frequent. Revascularization may occur with recurrence of hemoptysis, technical failure in BAE, spinal cord injury related to invisible anastomotic connections between the bronchial circulation and the anterior spinal artery. The authors recommended that BAE should be avoided in patients with minor hemoptysis. In the USA, Hsiao et al. (2001) from Stanford reported the assessment of modalities of investigations used for the localization of the site of bleeding in patients with massive hemoptysis. They reviewed the records of 28 patients seen between 1988 and 2000 who presented with massive hemoptysis. They found 16 patients with tuberculosis (57%), 14 with tuberculous bronchiectasis, and 2 with active disease, bronchogenic carcinoma in 2, and other causes had 1 patient each. These authors noted, 'Contrary to the statistics reported in many recent series, tuberculous bronchiectasis is the most common underlying etiology for massive hemoptysis in our patients'.

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The authors also indicated that the overall mortality of patients with massive hemoptysis was 7%-80% and operative mortality was 30%-40% as they found from reviewing the literature on the subject. These authors reported, 'The angiographic signs in hemoptysis include hyperplasia of the bronchial artery trunk and branches, bronchopulmonary anastomoses, and bronchial arterial aneurysms', which were seen on angiography of these patients. They concluded that fibroptic bronchoscopy before BAE is unnecessary in patients with hemoptysis of known origin. In Kuwait, Abal et al. (2001) prospectively studied 52 hospitalized patients with hemoptysis of variable degrees of severity over a period of 1 year. Twenty had blood-stained sputum, and 32 had frank hemoptysis including 16 with massive blood expectoration. They found that pulmonary tuberculosis (active or old) was the most common cause, found in 17 patients (32.7%). Other causes included carcinoma in 5, bronchitis in 3, 1 patient each due to other causes, and unknown cause in 13 patients. These authors managed 80.8% of their patients conservatively, and only 19% required BAE or surgery. Recurrent hemoptysis occurred in 12% at the I-year follow-up in this series. In a retrospective study of BAE for massive hemoptysis, Wong et al. (2002) from South Africa reported on 165 patients, and bilateral post-tuberculous bronchiectasis was the most common cause (75%). The short-term outcome of BAE was satisfactory in controlling hemoptysis in all patients. Thoracic aortography was done during the initial assessment, and they noted pathologic enlargement of the bronchial arteries and the presence of nonbronchial systemic collaterals with arteriovenous shunting including intercostal arteries. One patient had transient paraparesis, and the authors noted that the presence of spinal arteries was not considered a contraindication to embolization.

20.2.3 Rasmussen Aneurysm This is a rare phenomenon that can cause massive, life-threatening hemoptysis. It involves invasion of a peripheral pulmonary artery located within a tuberculous cavity often in the upper lobe. Invasion of the arterial wall by tuberculous granulation tissue leads to granulomatous vasculitis with replacement of the adventitia and media with fibrin during the process of healing. This will lead to weakening of the arterial wall with mycotic pseudoaneurysmal formation in one or more locations (see Chapter 43). Rupture of

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the aneurysm will lead to massive, life-threatening hemoptysis as reported in 5% of postmortem cases (Winer-Muram and Rubin 1990; Kim et al. 2001).

20.2.4 Endobronchial Tuberculosis Endobronchial tuberculosis is a common complication of post-primary pulmonary tuberculosis. It may occur in up to 40% of patients, and the most common source of bronchial wall infection is a contiguous tuberculous cavity (Rohenberg and Shaw 1996). Rarely, the bronchial wall may be affected by a hilar or paratracheal tuberculous caseating lymphadenitis. Hematogenous or lymphatic spread of infection to the bronchial wall may occur (Buckner and Walker 1990). The role of the bronchial tree in the spread of tuberculosis to other parenchymal segments or lobes on the same or opposite side by transbronchial spread of caseous material leading to bronchopneumonia is well recognized (1m et al.1993). Hoarseness ofvoice due to laryngeal involvement and localized wheezes due to bronchial disease in the chest are common clinical features. The imaging features of plain radiography and CT may show multiple nodular opacities, bronchial wall thickening, post-stenotic dilatation, lobar hyperinflation, pulmonary collapse, and atelectasis (Figs. 23.27 and 23.28). Endobronchial tuberculosis, its definition, epidemiology, pathogenesis and pathology, classification, clinical features, diagnosis, the role of bronchoscopy in the diagnosis and management, and the treatment are considered in a separate chapter (see Chap. 21).

20.2.5 Bronchiectasis as a Complication of Post-primary PulmonaryTB Bronchiectasis is a common sequela of pulmonary tuberculosis (primary and post-primary). It may occur primarily as a result of endobronchial tuberculosis with irreversible bronchial wall dilatation (Lee et al. 1991). Secondary tuberculous bronchiectasis occurs as a result of lung parenchymal destruction with fibrosis (traction bronchiectasis). Based on high-resolution CT, bronchiectasis was found in 27% of patients with pulmonary tuberculosis, and the upper lobes were the most common site (Cartier et al. 1999). In our series of 176 patients with pulmonary tuberculosis, 17 (9.6%, see Table 20.2) had imaging features of tuberculous bronchiectasis (Figs. 23.9, 23.27c, 23.28c, 23.29, 23.30, and 23.31). Typically, the

M. M. Madkour et al. Table 20.2. Imaging features of 176 patients with culture-positive post-primary pulmonary tuberculosis Imaging features

No. of patients Percentage

Unilateral-parenchymal 119 Bilateral-parenchymal 57 Infiltrates and consolidation 144 Cavities 61 Bronchiectasis 17 Destroyed lungs 2 Calcifications 22 (LN, parenchymal and pleural) Pneumothorax 8 Lymphadenopathy 19 (hilar and paratracheal) Lung infiltrates with pleural 46 effusion Mycetoma 2 Tuberculomas 3 Bronchopleural fistula 1

67.6 32.3 81.8 34.6 9.6 1.1

12.5 4.5 10.8 26.1 1.1 1.7 0.5

apical and posterior segments of the upper lobes are the most common sites of tuberculous bronchiectasis (Fig. 23.27c). Chest radiography may show ring shadows with occasional fluid levels (Figs. 23.9 and 23.29). Features on CT and HRCT will show the details of the bronchial wall changes (Figs. 23.28c, 23.30, and 23.31) (McAdams et al. 1995). Tuberculous bronchiectasis may also occur in the lower lobes of the lung. It is usually asymptomatic, but secondary bacterial infection or hemoptysis may be a presenting feature.

20.2.6 Pneumothorax as Complication of Post-primary PulmonaryTB Pneumothorax may occur during active post-primary pulmonary tuberculosis. Rupture of a tuberculous cavity contiguous to the pleura may result in pneumothorax. The incidence has been reported as low, ranging from 0.6% to 1% in hospitalized tuberculous patients (Wilder et al.1962; Ihm et al.I972). In our own series of 176 patients (see Table 20.2), pneumothoraxoccurred in 8 (4.5%). In 1 patient,pneumothorax failed to respond to antituberculous treatment and chest tube insertion, and a bronchopleural fistula was suspected. A fistulogram confirmed the presence of a bronchopleural fistula and active tuberculosis in the apical segment of the left upper lobe (Fig. 23.36). Pneumothorax may also occur in treated and healed pulmonary tuberculosis (Lambert 1956).

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20.2.7 ARDS and Tuberculosis

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20.2.8 Tuberculous Bronchopleural Fistula

Acute respiratory distress may occur in patients with Tuberculous bronchopleural fistula is rarely reported bilateral chronic cavitary or bronchogenic pulmo- nowadays with the recent advances in chemotherapy. nary tuberculosis with a high hospital mortality rate Most recent reports are on patients with late complicaof up to 47%. Dyer and Potgieter (1984) described tions of collapse therapy for pulmonary tuberculosis three adult patients from South Africa with adult that was done in the past (Johnson et al. 1973; Iseman respiratory distress syndrome (ARDS) due to pul- and Madsen 1991; Uchida et al. 1999; Weissberg and monary tuberculosis (nonmiliary). Weissberg 2001). It may develop after lung resection A 31-year-old woman with cough, fever, and for pulmonary tuberculosis. The lung parenchymal dyspnea lasting 2 months had bilateral pulmonary tuberculous cavity may rupture into the pleural space tuberculosis, and because of the severe dyspnea and with pneumothorax, and the diagnosis can be made the abnormal arterial blood gases, she was mechani- by fistulography (Fig. 23.36 radiology of pulmonary cally ventilated. The diagnosis of tuberculosis was TB chapter). A tract may form between the bronchus made by sputum-positive direct smear. Antituber- contiguous to the tuberculous cavity and the pleura, culous treatment was started, but the patient died. producing a bronchopleural fistula. It is estimated that Postmortem examination showed left upper and a bronchopleural fistula can occur in patients with right lower lobe cavitary tuberculosis. The second active extensive pulmonary parenchymal tuberculosis patient was a 22-year-old woman with a similar pre- in less than 1% (Miller 1981; Woodring 1986; Winersentation who died in the ICU with postmortem evi- Muram and Rubin 1990). Patients are usually sympdence of bilateral tuberculous bronchopneumonia tomatic, and sputum production may increase. Plain with a left bronchopleural fistula. The third patient chest radiography may show air in the pleural space, had a similar presentation but did not require a changing air-fluid level, and contralateral spread of ventilation and responded well to antituberculous tuberculous infiltration. CT may depict the sites of the treatment. bronchopleural fistula (Kim et al. 2001). Levy and colleagues (1987) from South Africa The management of these patients is usually reported a retrospective study of 15 patients admit- difficult. Patients with a susceptible organism may ted to the ICU between January 1982 and June 1985 respond to antituberculous treatment and intercoswith a confirmed diagnosis of pulmonary tuberculo- tal tube drainage. Patients with multidrug-resistant sis. These patients required ICU admission for respi- tuberculosis are treated with chemotherapy and ratory failure. They comprised 1.5% of 933 patients lobectomy or pneumonectomy and pleural decortiwith pulmonary tuberculosis hospitalized in Hillbow cation unless found to have respiratory insufficiency Hospital. Eleven patients required ventilation, and 5 (Iseman and Madsen 1991). Endobronchial occlusion died. Miliary tuberculosis was found in 6 patients, by coils has been found to be an effective method tuberculous bronchopneumonia in 5 patients, lobar (Uchida et al. 1999). pneumonia in 3 patients, bilateral lung parenchymal destructive disease in 2. Penner and colleagues (1995) from Canada 20.2.9 reviewed the records of 13 patients with confirmed Aspergilloma (Mycetoma) pulmonary tuberculosis (7 women and 6 men) from 1984 to 1993, and all had respiratory failure requir- A chronic tuberculous cavity may be colonized by ing mechanical ventilation. Seven patients had mili- the spores of Aspergillus fumigatus to form a fungal ary or disseminated tuberculosis and 6, tuberculous ball (Aderaye and Jajaw 1996). It may occur in 11% of pneumonia. Nine patients died, and only 4 survived. patients with a chronic tuberculous cavity, and approxM. tuberculosis was isolated in all patients from imately 25%-55% of patients with aspergilloma have respiratory or nonrespiratory sites. These authors a history of the disease (Kim et al. 2001). Patients with also quoted the work of Agarwal and colleagues aspergilloma are often asymptomatic but may present (1977) regarding 16 patients with respiratory fail- with hemoptysis (Kaestel et al. 1999). Plain radiography ure due to tuberculous pneumonia who required of the chest may depict a mobile, rounded mass with mechanical ventilation. air-crescent ring (Fig.23.26b and 23.37a,b). Surgical resection is essential if associated with hemoptysis and systemic antifungal treatment is ineffective.

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20.2.10 Tuberculomas

Solitary or multiple, round or oval, tuberculous pulmonary mass lesions may be noted on the chest radiographs in approximately 5% of patients (Kim et al. 2001; Winer-Muram and Rubin 1990). They may be the only radiographic manifestation of primary or post-primary pulmonary tuberculosis. Their diameter may range between 0.5 and 4.0 cm or larger with a smooth or sharply defined margin. Central caseation or calcifications may be found in 20%-30% of tuberculomas. Satellite lesions may be seen in up to 80% of these lesions.

20.2.11 Tuberculous Pulmonary Gangrene

An extremely rare but fatal complication of tuberculous cavitary lesion is the involvement of adjacent vessels and the development of arterial and venous vasculitis with thrombosis, leading to pulmonary gangrene (Reich 1993). Khan and colleagues (1980) from New York reported on 4 patients with pulmonary gangrene due to pulmonary tuberculosis, and only 1 survived. The first patient was a 55-year-old man who presented with fever, cough, and hemoptysis lasting 3 months. Chest radiography showed bilateral upper lobe infiltrate with cavitation and intracavitary mass. The sputum smear was positive for the bacilli. Chemotherapy was started, but the patient developed pneumothorax and died. Autopsy showed tuberculous pneumonia with extensive tuberculous arteritis and occlusion of the lumen by thrombosis. The second patient died before establishing the diagnosis, and subsequent sputum culture taken on admission grew M. tuberculosis. Autopsy showed pulmonary vasculitis in arteries and veins contiguous with the tuberculous cavity. The third patient was known to be tuberculous before and had undergone lobectomy, and now presented with fever and a large pulmonary cavity with an intracavitary mass in the right upper lobe. The sputum smear was positive, and culture grew M. tuberculosis. She responded well to chemotherapy. The fourth patient had a similar chest radiographic cavity with intracavitary mass and died. The bacilli were found at autopsy as well as lung parenchymal cavities, tuberculous granulomatous vasculitis with thrombosis of the pulmonary arteries and veins. We reviewed the world literature and found 18 previously reported patients with pulmonary gangrene mostly due to Klebsiella pneumonia and other

organisms but not due to M. tuberculosis. Lopez-Contreras et al. (1994) reported a 61-year-old alcoholic man with a 4-month history of cough, fever, and weight loss. Sputum smear and culture were positive for M. tuberculosis. Chest radiography showed a large cavity with air-fluid level and a free-floating mass. The patient died, and autopsy was denied.

20.2.12 Tuberculosis, Lung Cancer and Other Neoplasia

The relationship between pulmonary tuberculous and lung cancer has been frequently debated. Such a relationship was raised by Greenberg and colleagues (1964), indicating the co-existence of carcinoma and tuberculosis of the lung. The co-existence between bronchogenic carcinoma and tuberculosis creates a difficult diagnostic problem for radiologists as the radiographic changes may be misinterpreted as progression of tuberculosis (Kim et al. 2001; WinerMuram and Rubin 1990). Brown and Almenoff (1992) reviewed the literature of various retrospective studies on this co-existence. They reviewed other malignancies including leukemia, lymphoma, myelofibrosis, head and neck malignancies, as well as the use of immunosuppressive chemotherapy, and their relationship with the development of tuberculosis. They noted that tuberculosis was 6-9 times more common among patients with Hodgkin's disease, lung cancer, and non-Hodgkin's lymphoma than those with other malignancies. These authors noted, 'Tuberculosis was more likely to be diagnosed at the time of tumor diagnosis in patients with lung, head and neck malignancies, and disease in these patients was predominantly confined to the lungs'. Profound suppression of the cell-mediated immune response caused by malignant diseases or as a result of severe immunosuppressive chemotherapy is the most likely cause of the high risk of developing tuberculosis among these patients (Brown and Almenoff 1992).

20.3 Diagnosis of Post-primary Pulmonary T8 20.3.1 Imaging Features of Post-primary PulmonaryTB Various imaging modalities are used for the depiction of features of post-primary pulmonary

321

Post-primary Pulmonary Tuberculosis

tuberculosis. The imaging features of post-primary pulmonary tuberculosis can be broadly classified as lung parenchymal disease with cavitation, endobronchial tuberculosis, pleural extension of the disease, and other complications such as tuberculoma and mycetoma. Conventional plain chest radiography is the mainstay imaging modality in depicting pulmonary features of the disease. However, a normal chest radiograph does not exclude pulmonary tuberculosis and has been reported in approximately 10%-20% of immunocompetent and immunocompromised patients, respectively (Fitzgerald et a1.1991; Miller and Miller 1993; Greenberg et al.1994; Lee and 1m 1995). Computed tomography (CT) is useful in depicting cavitation and in patients with pleural effusion that may be masking lung parenchymal involvement on the same side (Kuhlman et aI.1990). CT is more sensitive than chest radiography (Hulnick et al. 1983; Lee et a1.1996) in depicting mediastinal and paratracheal lymphadenopathy, endobronchial tuberculosis, and dissemination to the lung parenchyma and other rare complications (Hatipoglu et al. 1996). Bronchography, now replaced by CT, is still used as the investigation of choice for the detection of bronchiectasis in poor-recourse countries of endemic areas (Fig. 23.29). Arteriography for diagnostic or therapeutic methods of bronchial artery embolization (BAE) is used for these rare but life-threatening massive hemoptysis cases. Imaging features of post-primary pulmonary tuberculosis, although suggestive, are not characteristic as they can simulate other diseases (Lee and 1m 1995). Upper lobe infiltration or consolidation should always be suspected as tuberculous. Cavitation may occur in approximately 40%, and the diagnosis of tuberculosis is usually not difficult if it is present in the upper lobe and associated with bronchogenic spread to other parts of the lung (Miller and Miller 1993). In some instances, upper lobe consolidation should always be considered to be tuberculosis until proven otherwise. The presence of lung parenchymal scarring, fibronodular or calcific changes should not be assumed as inactive, and follow-up is essential. We retrospectively reviewed the radiological records of 176 adult patients with post-primary pulmonary tuberculosis who had positive sputum culture for M. tuberculosis. They attended our hospital between 1998 and 2000, and their imaging features and frequencies are presented in Table 20.2. The imaging features of post-primary pulmonary tuberculosis have been reported by us in a separate chapter (Chap. 23).

20.3.2 Microbiology of the Sputum and Bronchial Aspirate Sputum microscopy for the detection of acid-fast bacilli by the Ziehl-Nielsen stain remains the cornerstone of rapid diagnosis of pulmonary tuberculosis (Maartens 2002). In HIV patient's sputum, microscopy is positive less often. At least 3 single specimens of sputum should be initially collected from patients with productive cough. In those who have difficulty in providing sputum, an aerosol inhalation of sterile hypertonic saline can be used to stimulate sputum production. Morning gastric aspiration, bronchoalveolar lavage, or transbronchoscopic brush or biopsies may be required. At least 5,000 to 10,000 bacilli per milliliter of sputum must be present to enable the detection of the organism by stained smear (Hobby et al. 1973). Sputum culture will require 10 to 100 bacilli to yield a positive result (Yeager et al. 1967). The American Thoracic Society (2000) reported on the diagnostic standards and classifications of tuberculosis in adult and children, and indicated that 50%-80% of patients with pulmonary tuberculosis will have positive sputum smears. Traditional culture media required 4-8 weeks to yield the bacilli, while radiometric culture methods (BACTEC) combined with a DNA probe allow identification of M. tuberculosis in 1-3 weeks. Currently, PCR-based assays for the diagnosis of tuberculosis and identification of drug-resistant strains are configured to yield results in a few hours to days (see Chapter PCR and Diagnosis of Tuberculosis by Dr. Diana L. Williams).

20.3.3 Bronchoscopic Diagnosis The use of bronchoscopy to obtain diagnostic specimens for patients with a chest radiograph suggesting tuberculosis but with negative sputum specimen has been reported (Willcox et al. 1982). Willcox and colleagues reported on 275 patients seen from 1976 to 1980, with imaging features of suspected tuberculosis and negative sputum smear. Specimens collected by bronchoscopy included bronchial brushings in 83, transbronchiallung biopsies in 18,and post-bronchoscopy sputum. Positive brushing yield was 67.5%, and transbronchial biopsies were positive in 50%. They also reported the co-existence of tuberculosis and bronchial carcinoma in 4 of their patients (4%).

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In our series of 176 patients, bronchoscopy was done on 27 patients with a chest radiograph suggesting pulmonary tuberculosis but with negative direct smear. Tuberculosis was confirmed by positive culture of bronchoscopic specimens, and no bronchial carcinoma was found. Tuberculous infection after bronchoscopy may be transmitted from patient to patient. Molecular epidemiological studies by molecular typing of DNA supported the transmission of M. tuberculosis isolates to other patients via bronchoscopic contamination (Michele et al. 1997; Argeton et al. 1997). It is recommended that the instrument be cleaned prior to its immersion in 2% aqueous solutions of glutaraldehyde for 45-min exposure times (Food and Drug Administration 1992).

20.3.4 Tuberculin Skin Test The tuberculin skin test is still widely used to identify infection with M. tuberculosis. Antigenic extracts of culture 'PPD' produces a delayed-type hypersensitivity reaction. Intradermal injection of 0.1 mg/0.1 ml of the standard 5-tuberculin unit (TU) dose (Mantoux method) is done into the volar or dorsal surface of the forearm (American Thoracic Society 2000). The test should be read between 48 and 72 h after injection. Three cut-off points have been recommended for defining a positive PPD test. A cut-off point of 2:5 mm of induration using the ballpoint pen method of Sokal is considered positive in a person with recent contact or in the presence of abnormal chest radiographs consistent with tuberculosis. A cut-off point of 2:10 mm is suggested for individuals who have normal or mildly impaired immunity and a high likelihood of being infected with the disease but without other risk factors. A cut-off point of2:15 mm for individuals with no risk factors for tuberculosis is considered positive (American Thoracic Society 2000). Tuberculin tests have several limitations including difficult administration, anergy, poor specificity, and the need for repeated testing to detect boosting (Maartens 2002).A comparative study between skin tests with PPD and measurement of the response by in-vitro culture assays measuring IFN-y production in response to tuberculin antigen stimulation is described in detail in a separate chapter. Dr. Rohit Katial has demonstrated the superiority of these assays and compared it with the PPD skin test (see Chap. 15).

20.3.5 Other Diagnostic Investigations Ultrasound or CT-guided, transthoracic, percutaneous, fine-needle aspiration (FNA) cytology may be useful in diagnosing pulmonary tuberculosis in patients initially suspected of having malignancies. Das et al. (1995) reported the use of FNA to diagnose tuberculosis in 29 patients in their series of 190 patients with malignancies and other causes. Serological tests for antimycobacterial antibodies in the serum using an ELISA immunoassay may be positive in up to 88% (Barnes et al. 1993). DNA fingerprinting PCR-based assays provide a noninvasive method of diagnosing M. tuberculosis as well as identifying drug-resistant strains, with results ready in a few hours or days (see Chap. 13). Pulmonary function tests may be required in tuberculous patients, particularly when lung surgery is required. Radionuclide studies in pulmonary tuberculosis are useful imaging tools in assessment of the disease (see Chap. 24 and 26).

20.4 Treatment of Post-primary Pulmonary T8 The history of the management of tuberculosis has been called 'the story of medical failure' (Holme 1998). 'The patients have been blamed for non-compliance with the therapeutic regimen, but sociologic studies have shown that, in most cases, the providers of health care are at fault' (Grange and Zumla 2000). The infectivity of tuberculous patients for close contacts after starting chemotherapy has been studied by several authors. Riley et al. (1962) reported that the effluent air from the rooms of patients receiving chemotherapy became noninfectious for guinea-pigs within 2 weeks. Other authors found the rapid reduction in the number of viable bacilli by 1-2 logarithmic counts within 2 weeks (Yeager et a1.1967; Hobby et al. 1973; Jindani et al. 1980). An editorial (1980) reviewed the issue of isolation of infectious patients with pulmonary tuberculosis, indicating that admission to a sanatorium was justified for supervised treatment, considering its toxicity and to safeguard their close contacts. It also referred to the work of Jenkinson et al. (1979) who found viable bacilli in the sputum of 15 patients who had received 6 weeks of treatment, and active disease was produced when injected into guinea-pigs. Studies on the duration of antituberculous treatment for patients with a positive

Post-primary Pulmonary Tuberculosis

sputum smear to achieve three consecutive negative results has been carefully studied prospectively by Telzak and colleagues (1997) from the South Bronx in New York. The study started from April 1993 to March 1995 of all patients with culture-confirmed tuberculosis. Data included the results of smears, cultures, and drug susceptibility, HIV status, CD4 cell count (for HIV-positive patients). The main objective of the study was to identify the time duration between initiating antituberculous treatment to the first of three consecutive negative sputum smears and the first of three consecutive negative sputum cultures. During the period of the study, 199 patients with culture-positive tuberculosis were diagnosed, 75% had lung parenchymal disease alone, 2% had lung and pleural abscess, 14% had pulmonary and extrapulmonary TB, 3% had only pleural disease, and 7% had extrapulmonary disease alone. They had complete information on 100 of the sputum smearpositive patients (85%). They found that the mean number of days before the first of three consecutive negative sputum smears was 33, and the median was 23 days. The mean number of days until the first of three consecutive negative sputum cultures was 32, and the median was 26 days. These authors noted that the following factors were associated with an increased number of days to achieve their objective: the high number of AFB on initial smear, the presence of cavitary disease, and no previous history of tuberculosis. They noted that HIV had no effect on the duration of treatment before achieving the study objectives. HIV-positive patients are less likely to have cavitary disease, and therefore more likely to produce few AFB. In conclusion, patients with smearpositive sputum require hospitalization and must be isolated for a mean duration of 32 days after initiating appropriate treatment or longer if the initial AFB count was high in the presence ofcavitary disease and if the patient had no prior history of tuberculosis. The aim of the appropriate chemotherapy is to use drugs to which the bacilli are susceptible, with bactericidal activity to cure the patient, reduce infectivity to contacts, and prevent the emergence of drug resistance (Centers for Disease Control 1994). Clinicians are often required to take the decision of either to initiate the treatment of smear-negative patients with a presumptive diagnosis of pulmonary tuberculosis based on the presence of clinical and imaging features, or to wait for the sputum culture results that may require 4-8 weeks to obtain and may not yield the bacilli. In a prospective study of 139 patients with a presumptive diagnosis of pulmonary tuberculosis, Gordin et al. (1989) reported their findings. The

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study was carried out in San Francisco between mid1981 to the end of 1982. The presumptive diagnosis in this series was based on the presence of clinical and radiological features suggestive of pulmonary tuberculosis with negative sputum smear. Treatment with isoniazid, rifampicin, and ethambutol was given to all patients. Positive culture was reported later in 16 patients. Among the culture-negative patients, 43 showed radiographic improvement after 3 months of initiating the treatment, clinical improvement in 7, and bronchoscopic confirmation of the diagnosis in 1 patient. There were 72 individuals with radiological stability who were considered as having inactive previous tuberculosis. The authors concluded that the treatment was appropriate in 66 of 139 (48%) of patients. The British Medical Research Council (BMRC) recommended the initiation of antituberculous treatment for such patients after other causes for abnormal chest radiography findings have been excluded (Dutt and Stead 1994; Fox et al. 1999). The modern short course of antituberculous chemotherapy, Directly Observed Therapy (DOT), is the best strategy for the treatment of post-primary pulmonary tuberculosis to achieve the three goals, that is, cure the patient, reduce infectivity to contacts, and prevent the emergence of drug resistance if appropriately adhered to. DOT is usually given as an outpatient treatment and supervised by nurses. Such visits to the outpatient facility may be difficult as it involves traveling and may be costly for patients in developing countries. Training of a family member or a community lay person to supervise the administration of DOT may be more practical in developing countries (Wilkinson 1994). WHO indicated that for the DOT strategy to be effective, it requires government commitment, the availability of microscopic and other diagnostic facilities, a continuous supply of high-quality medication, direct observation of treatment administration, and recording the response to treatment (Netto et al. 1999). DOT consists of an initial2-month phase of intensive treatment using four drugs (rifampicin, isoniazid, pyrazinamide, and either ethambutol or streptomycin) followed by a 4-month continuation phase of rifampicin and isoniazid. These drugs are usually given as daily treatment but can be given thrice weekly, either throughout or during the continuation phase, to facilitate the supervision of treatment. The isoniazid daily dose is 5 mg/kg orally or intramuscularly (maximum 300 mg), rifampicin daily dose is 10 mg/kg orally (maximum 600 mg), pyrazinamide daily dose is 15-30 mg/kg orally (maximum 2 g),

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streptomycin daily dose is 15 mg/kg intramuscularly (maximum 1 g) for persons below the age of 60 years and 10 mg/kg intramuscularly (maximum 750 mg) for persons above 60 years, ethambutol daily dose is 15-25 mg/kg orally (maximum 2-5 g). The cure rate of drug-susceptible disease when the patient completes the course of treatment is up to 98%. HIV co-infected patients have a similar outcome of tuberculosis treatment success rate (Grange and Zumla 2000). Although DOT has been successful in some countries, endemic areas with HIV and MDR tuberculosis have not achieved the WHO targets for disease control (Netto et al. 1999). Multidrug-resistant tuberculosis is a much more serious problem to treat. Drugs used for treatment are more toxic, more expensive, and require a prolonged period of up to 24 months, and surgery may be considered to decrease the load of the organisms during chemotherapy (Iseman 1993; Iseman et al.1990).

20.4.1 Response to Treatment Appropriate chemotherapy is usually associated with clinical and radiological improvements. Clinical improvement with resolution of fever occurred in 92% of patients 4 weeks after starting treatment (Teklu and AI-Wabel 1994; Vanham et al. 1997). Radiological improvement is noticed after 3 months (Gordin et al. 1989). Paradoxical worsening of the clinical and imaging responses to treatment may occur particularly in the first few weeks or months. HIV co-infected patients are more prone to paradoxical worsening after starting antituberculous treatment, and this is reported to occur in 36% (Wendel et al. 2001). In tuberculous patients without HIV, paradoxical worsening may occur in 16% (AI-Majed 1996). Paradoxical worsening after antituberculous treatment is defined as worsening of fever, cough, shortness of breath or even development of ARDS, enlargement of lymph nodes or other extrapulmonary site of the disease during appropriate treatment (Smith 1987; AI-Majed 1996; Rodriguez-Bano et al. 1997; Hung and Chang 1999; Wendel et al. 2001). Radiological worsening of the pre-existing pulmonary infiltrates, development of new lesions on the same or apposite lung, enlargement of hilar or paratracheal lymph nodes were noted in our series (Figs.23.16a-c and 23.17a-c). The pathogenesis of paradoxical worsening is not yet clear. It is believed that it may be due to enhanced immune responses (immunological rebound) with increased proliferation of

M. M. Madkour et al.

mononuclear cells and IFN-y production in response to M. tuberculosis antigens (Wendel et al. 2001). Corticosteroid therapy has been used to modify the intensity of symptoms (Rodriguez-Bano et al. 1997). There have been no controlled trials on the management of these paradoxical worsening responses.

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326 Johnson JL, Ellner 11 (2000) Adult tuberculosis overview: African versus Western perspectives. Curr Opin Pulm Med 6:180-186 Johnson TM, McCann et al (l973) Tuberculous bronchopleural fistula. Am Rev Respir Dis 107:30-41 Kaestel M, Meyer W, Mittelmeier HO et al (1999) Pulmonary aspergilloma - clinical findings and surgical treatment. Thorac Cardiovasc Surg 47:340-345 Khan FA, Rehman M et al (l980) Pulmonary gangrene occurring as a complication of pulmonary tuberculosis. Chest 77:76-80 Kim HY,Song KS et al (2001) Thoracic sequelae and complications of tuberculosis. Radiographics 21:839-860 Kuhlman JE et al (1990) CT features of thoracic mycobacterial disease. Radiographics 10:413-431 Lambert HP (1956) Spontaneous pneumothorax and pulmonary tuberculosis. Tubercle 37:207-209 Lee KS,Im JG (l995) CT in adult with tuberculosis of the chest: Characteristic findings and role of management. AJR 164: 1361-1367 Lee KS, Kim YH, Kim WS et al (l99l) Endobronchial tuberculosis: CT features. J Comput Assist Tomogr 15:424-428 Lee KS, Hwang JW, Chung MP et al (l996) Utility of CT in the evaluation of pulmonary tuberculosis in patients without AIDS. Chest 110:977-984 Lee TW, Wan S, Choy DK et al (2000) Management of massive hemoptysis: a single institution experience. Ann Thorac Cardiovasc Surg 6:232-235 Levy H, Kallenbach JM, Feldman C et al (l987) Acute respiratory failure in active tuberculosis. Crit Care Med 15: 221-225 Liesegang TJ, Cameron Douglas (l980) Mycobacterium bovis infection of the conjunctiva. Arch Ophtalmol 98:1764-1766 Lopez-Contreras JL, Ris J et al (1994) Tuberculous pulmonary gangrene: report of a case and review. Clin Infect Dis 18: 243-245 Maartens G (2002) Advances in adult pulmonary tuberculosis. Curr Opin Pulm Med 8:172-177 Maartens G, Beyers N (2002) Tuberculosis in the tropics. Clin Chest Med 23:341-350 Mal H, Rullon I, Mellot F (1999) Immediate and long-term results of bronchial artery embolization for life-threatening hemoptysis. Chest 115:996-1001 McAdams HP, Erasmus J et al (l995) Radiologic manifestations of pulmonary tuberculosis. Radiol Clin North Am 33:655-678 McDonough KA, Florczyk MA, Kress Y (2000) Intracellular passage within macrophages affects the trafficking of virulent tubercle bacilli upon reinfection of other macrophages in a serum-dependent manner. Tuberc Lung Dis 80:259-271 Michele TM, Cronin WA, Graham NMH et al (l997) Transmission of Mycobacterium tuberculosis by a fiberoptic bronchoscope: identification by DNA fingerprinting. JAMA 278: 1093-1095 Millar JW, Horne NW (l979) Tuberculosis in immunosuppressed patients. Lancet 1:1176-1178 Miller WT (l981) Tuberculosis in the adult. Postgrad Radiol 1:147-167 Miller WT, Miller WT (l993) Tuberculosis in the normal host: radiological findings. Semin Roentgenol 28:109-118 Moda G, Daborn q, Grange JM et al (l996) The zoonotic importance of Mycobacterium bovis. Tuberc Lung Dis 77:103-108

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21 Endobronchial Tuberculosis HEE SOON CHUNG

21.15.1.1 Interventional Management 343 21.15.1.2 Tracheobronchial Stent 344 21.15.1.3 Endobronchial Electrosurgery vs Laser Photoresection 346 21.15.1.4 Surgical Management 346 21.15.2 Bronchiectasis 346 21.15.3 Broncholith 346 References 347

CONTENTS 21.1 21.2 21.3 21.4 21.5 21.6 21.7

Introduction 329 Definition 330 Epidemiology 330 Pathogenesis 330 Pathology 331 Classification 332 Characteristics of the Each Subtype of Endobronchial Tuberculosis 333 21.7.1 Actively Caseating Type 333 21.7.2 Edematous-Hyperemic Type 333 21.7.3 Fibrostenotic Type 334 21.7.4 Tumorous Type 334 21.7.5 Granular Type 335 21.7.6 Ulcerative Type 335 21.7.7 Nonspecific Bronchitic Type 336 21.8 Location of Bronchial Involvement 336 21.9 Natural Course of Endobronchial Tuberculosis 21.10 Endobronchial Tuberculosis in HIV-Infected Patients 337 21.11 Clinical Features 338 21.12 Diagnosis 338 21.12.1 Clinical History 338 21.12.2 Physical Examination 339 21.12.3 Laboratory Testing 339 21.12.4 Bacteriology 339 21.12.5 Tuberculin Testing 340 21.12.6 Pulmonary Function Test 340 21.12.7 Radiology 340 21.12.7.1 Simple Roentgenograms 340 21.12.7.2 Computerized Tomography 340 21.12.8 Bronchoscopy 341 21.13 Differential Diagnosis 341 21.13.1 Pneumonia 341 21.13.2 Fungal Infection and Actinomycosis 342 21.13.3 Lung Cancer 342 21.13.4 Bronchial Asthma 342 21.14 Treatment 342 21.14.1 Anti-Tuberculosis Chemotherapy 342 21.14.2 Corticosteroid Treatment 343 21.15 Complications and Their Management 343 21.15.1 Bronchostenosis 343

21.1 Introduction

337

H. S. CHUNG, MD, FCCP Associate Professor of Medicine, Seoul National University College of Medicine and Seoul Municipal Boramae Hospital affiliated to Seoul National University Hospital, # 395 Shindaebang-2-Dong, Dongjak-Gu, Seoul, 156-707, Korea

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

Endobronchial tuberculosis is a specific form or a significant complication of pulmonary tuberculosis. It is important to remember that endobronchial tuberculosis has the following pitfalls: (1) its diagnosis is frequently delayed, since the decreased incidence itself diminishes the suspicion of tuberculosis (Greenbaum et al. 1980; Chung et al. 1991a); (2) bronchostenosis may develop as a serious complication despite efficacious antituberculosis chemotherapy (Albert and Petty 1976; Hoheisel et al. 1994; Park et al. 1997); and (3) it is often misdiagnosed as bronchial asthma (Watson and Ayres 1988; Williams et al.1988; Park et al.1995) or lung cancer (Matthews et al.1984; Smith et al. 1987). Recently there has been an unprecedented resurgence of tuberculosis, which is related to the human immunodeficiency virus (HIV) epidemic, multidrugresistant strains, poverty and homelessness, immigration, and failures in the treatment system (Millard et al. 1994; Glynn 1998; Lerner 1999). The HIV epidemic may be associated with a higher incidence of endobronchial tuberculosis (Judson and Sahn 1994; Calpe et al.1995). Therefore, endobronchial tuberculosis continues to be a health problem, though the incidence of tuberculosis affecting respiratory organs including the trachea and bronchi has been greatly reduced (Shulutko et al. 1979). Endobronchial tuberculosis should be borne in mind when patients are young female adults or adolescents who present with symptoms suggestive of asthma and/or with unusual roentgenographic patterns, or in patients with HlV infection.

330

21.2 Definition Endobronchial tuberculosis was first described by Richard Morton in 1694 (Jenks 1940), and is defined as a specific inflammation of the trachea or major bronchi caused by tubercle bacilli. Active disease can be diagnosed when certain endobronchial lesions, such as whitish gelatinous material, ulcer, tumor, stenosis or inflammation, exist on bronchoscopy and tuberculosis is proven by bronchoscopic biopsy of these lesions. Bronchial anthracofibrosis is defined as a luminal narrowing associated with anthracotic pigmentation on bronchoscopy, without a relevant history of pneumoconiosis or smoking, and may be a sign of active endobronchial tuberculosis (Chung et al. 1998; Kim et al. 2000), but histologic confirmation is necessary for definitive diagnosis (Garimella 2001). Bronchial fibrostenosis is sometimes a surprise finding in patients with a previous history of tuberculosis, which must be the presumed cause of stenosis. Since the sequela of endobronchial tuberculosis and reactivated pulmonary tuberculosis can be present coincidently, fibrotic stenosis of bronchi may be inactive lesions resulting from prior endobronchial tuberculosis even though sputum examination for acid-fast bacilli is positive. Therefore, it is necessary to obtain histologic proof of tuberculosis for a definite diagnosis of endobronchial tuberculosis. Localized tuberculous bronchitis in segmental bronchi communicating with diseased portions of lung is common in pulmonary tuberculosis (Daniel 1994). Resected lung specimens frequently show either ulceration or stenosis of the draining bronchioles or bronchi, and the same endobronchial processes may result in bronchiectasis due to destruction of the bronchial wall (Rossman and Oner-Eyuboglu 1998). Since these endobronchial lesions distal to lobar bronchi do not have clinical significance, they should be included in the disease entity of pulmonary tuberculosis rather than that of endobronchial tuberculosis.

21.3 Epidemiology Tuberculosis is still a common disease despite its great decline in recent years. In high-prevalence areas, tuberculosis afflicts chiefly young adults. In countries where HIV infection is endemic, tuberculosis is one of the most important causes of morbid-

H. S. Chung

ity and mortality in acquired immune deficiency syndrome (AIDS) patients (Daniel 1994). The incidence of endobronchial tuberculosis among tuberculous postmortem specimens was as high as 40% prior to the chemotherapy era (Wolinsky 1989). With modern treatment, endobronchial tuberculosis has been reported in about 10% of cases of pulmonary tuberculosis, when fiberoptic bronchoscopy is routinely performed (Jokinen et al. 1977). In my previous study, the incidence of endobronchial tuberculosis in pulmonary tuberculosis was 5.88 percent. However, it should be borne in mind that the actual incidence is somewhat higher than this, because bronchoscopy was not performed routinely in all tuberculosis patients but only when an endobronchial lesion was highly suspected. Endobronchial tuberculosis shows a marked preference for female patients, and the male-to-female ratio is approximately 1:5. The disease is usually detected in the third decade. The reason why endobronchial tuberculosis is more common in young females is not clear. One of the possible reasons is that organism implantation from infected sputum may occur more easily in females, especially in teenagers and those in their twenties, because they do not expectorate sputum, for sociocultural and cosmetic reasons (Chung and Lee 2000). In addition, it is well recognized that endobronchial tuberculosis frequently occurs as a part of primary pulmonary tuberculosis in young adults (Smith et al. 1987).

21.4

Pathogenesis

First infection with the tubercle bacillus is known as primary tuberculosis, and usually includes the involvement of the draining lymph nodes in addition to the initial lesion. The combination of the primary or Ghon focus and draining lymph nodes is termed the primary complex. Although primary tuberculosis was formerly relatively common in intestines or tonsils, due to infection from milk, and may occur in various other unusual sites, in the vast majority of cases the route of infection is by inhalation and, consequently, the primary lesion is pulmonary. All other tuberculous lesions are regarded as post-primary. Multiple terms have been used to describe this stage of tuberculosis - for example, chronic tuberculous postprimary disease, reinfection or recrudescent tuberculosis, adult-type progressive tuberculosis, endogenous reinfection and reactivation tubercu-

331

Endobronchial Tuberculosis

losis (Garay 1996). Regardless of the nomenclature, these tuberculous lesions are not accompanied by major involvement of the draining lymph nodes. In primary pulmonary tuberculosis, the first focus of exudative inflammation may occur in any bronchopulmonary segment, more often near the periphery in the middle or lower lung, i.e. that portion of the lung receiving the greatest ventilation, and this is where bacilli within droplet nuclei tend to be implanted. Tubercle bacilli multiply in the exudates and may be carried into some of the very abundant pulmonary lymphatics, and then to the regional lymph nodes. Hematogenous seeding to the distant organs then probably occurs with considerable frequency, either by way of lymphatic channels or more directly from smaller pulmonary veins within the exudate. However, lesions of clinical magnitude do not develop by hematogenous seeding unless native resistance is low or the number of bacilli is great. Regional lymph node involvement is a fairly consistent characteristic of primary pulmonary tuberculosis. The hilar lymph node is most commonly involved, but the paratracheal node is also frequently enlarged, and a substantial minority of cases show enlargement of both the hilar and paratracheal nodes. These nodes develop an intense cellular inflammatory response and may become so large that they compress the major bronchi, with obstructive atelectasis or obstructive pneumonitis. This phenomenon was formerly called epituberculosis. Caseation often follows in the nodes, but healing by partial resorption of the caseum, and the calcification of the lesion in the lung and lymph nodes, is the rule. However, such nodes occasionally rupture or protrude into bronchi. In children especially, rupture of the caseous glands into the trachea or major bronchi causes collapse of the lung or even sudden death by suffocation in young children. In adults, the lung component of the primary complex is usually more obvious and the nodal component may not be seen, whereas in children often only an enlarged hilar or paratracheal node is apparent (Seaton et al.1989). In post-primary tuberculosis, lymph node involvement is seldom extensive and pulmonary lesions on chest roentgenograms are usually located in the apical or subapical areas of the upper lobe. The predilection for the upper lung probably relates to the high oxygen tensions at the lung apex (Riley 1960). Even though the pathogenesis of endobronchial tuberculosis is not yet fully established, sources of endobronchial tuberculosis may include direct implantation of tubercle bacilli into the bronchus from an adjacent pulmonary parenchymal lesion,

direct airway infiltration from an adjacent tuberculous mediastinal lymph node, erosion and protrusion of an intrathoracic tuberculous lymph node into the bronchus, hematogenous spread and extension to the peribronchial region by lymphatic drainage (Myerson 1944; Smart 1951; Matthews et al. 1984; Smith et al.1987; Lee et al. 1992; Kim et al.1993). Endobronchial tuberculosis, before the era of chemotherapy, was considered a complication of advanced post-primary disease. Effective antituberculosis chemotherapy and preventive measures have reduced childhood tuberculosis exposure, which has resulted in an increase in adult primary tuberculosis with unusual clinical and roentgenographic presentations. In the 1970s and early 1980s, a number of reports concerning the so-called unusual radiographic manifestations of adult tuberculosis were published. Up to one-third of adult cases were reported to have atypical findings, such as mediastinal adenopathy, lower lung consolidation and miliary disease. However, these "unusual manifestations" are the usual manifestations of primary tuberculosis. The only unusual aspect is the increasing incidence of primary tuberculosis in adults (McAdams et al.1995). In the modern drug era, endobronchial tuberculosis is more likely to be discovered in adults with primary tuberculosis (Smith et al. 1987), whereas post-primary disease is by far the most common type of pulmonary tuberculosis.

21.5

Pathology

The pathologic changes that occur in the involved bronchi differ in primary tuberculosis from those of post-primary tuberculosis. The involvement of the trachea and bronchi in primary tuberculosis usually results from the pressure created by the enlarged lymph nodes, which may cause partial or complete bronchial obstruction, necrosis and ulceration of the bronchial wall, often in association with the rupture of caseous nodes into the bronchi. In post-primary tuberculosis, the pathogenesis differs, and bronchial lesions are usually secondary to repeated implantation of tubercle bacilli from a sloughing parenchymal source distal to the lesion (Medlar 1955). The earliest lesions often are lymphocytic infiltrations of the mucosa with or without congestion or edema. These usually clear when the parenchymal focus ceases to slough. However, bronchial lesions may progress to tubercle formation in the mucosa and submucosa. Rarely, necrosis with ulceration and sloughing may involve

332

portions of the bronchial wall, and it is this type of lesion that causes bronchial narrowing and stenosis, distal to which further bronchial inflammation may lead to obstructive pneumonitis or bronchiectasis. The healing of more extensive lesions is frequently accompanied by cicatricial stenosis (Wolinsky 1989).

21.6

Classification The clinical course of endobronchial tuberculosis is variable, not only because there are several possible pathogenetic mechanisms, but also because the interactions between the effects of mycobacteria, host immunity and antituberculous drugs is complex, and any variation in these three factors may result in an altered course (Chan and Pang 1989). Therefore, it is an oversimplification to view cases of endobronchial tuberculosis as a homogeneous group, and endobronchial tuberculosis is probably better divided into subtypes. Over the past five decades, many classifications of endobronchial tuberculosis have been published. Judd (l947) classified endobronchial tuberculosis into intrabronchial and extrabronchial types on the basis of their pathogenetic mechanisms. In 1957, the Sixth All-Union Congress of Phthisiologists adopted a classification which categorized endobronchial tuberculosis into four forms: infiltrative, ulcerative, cicatricial and fistulous (or glandular). After the introduction of the flexible bronchoscope, Oho and Amemiya (l984) suggested that endobronchial tuberculosis be classified as edematous-hyperemic, infiltrative-proliferative, ulcerative-granulative and fibrostenotic. In 1991, my colleagues and I suggested a classification of endobronchial tuberculosis which considered the above-mentioned classifications and bronchoscopic features. This classification categorized endobronchial tuberculosis into seven forms: actively caseating, stenotic without fibrosis, stenotic with fibrosis, tumorous, granular, ulcerative and nonspecific bronchitic (Chung et al. 1991a), and was partially reported at the Sixth World Congress for Bronchology (Han et al. 1989). However, the terms "stenotic without fibrosis" and "stenotic with fibrosis" were later renamed "edematous-hyperemic" and "fibrostenotic:' respectively, due to the fact that gross bronchoscopic findings cannot reflect the presence of fibrosis. As a result, the forms of endobronchial tuberculosis were classified into seven subtypes by bronchoscopic findings: actively caseating, edematous-hyperemic,

H. S. Chung

fibrostenotic, tumorous, granular, ulcerative and nonspecific bronchitic (Chung and Lee 2000). The actively caseating, edematous-hyperemic, fibrostenotic and tumorous forms of endobronchial tuberculosis have varying degrees of bronchostenosis proximal to the segmental bronchi, whereas the granular, ulcerative and nonspecific bronchitic forms do not have luminal narrowing of the bronchi. This new classification is valuable for predicting the therapeutic outcome of endobronchial tuberculosis, because it is closely related to the extent of disease progression (Chung and Lee 2000). Pathologically, the initial lesion, which presents as simple erythema and edema of the mucosa with lymphocytic infiltration of the submucosa (Medlar 1955; Shulutko et al.1979),corresponds to nonspecific bronchitic endobronchial tuberculosis. This lesion is followed by submucosal tubercle formation, which produces the erythema and granularity seen at bronchoscopy (Myerson 1944), and partial bronchial stenosis, which is caused by considerable congestion and edema of the mucosa (Medlar 1955). These are the granular and edematous-hyperemic types, respectively. At this point, the development of caseous necrosis, with the formation of tuberculous granuloma, can be found at the mucosal surface (Medlar 1955), which constitutes actively caseating endobronchial tuberculosis. However, when the inflammation erupts through the mucosa, an ulcer is seen, which may be covered by caseous material (Myerson 1944), and the disease is considered to be of the ulcerative type. Finally, the bronchial mucosal ulcer evolves into hyperplastic inflammatory polyps, and the endobronchial tuberculous lesion heals by fibrostenosis (Salkin et al. 1943; Smith et al. 1987). During this process, the lesion has moved through either the tumorous or fibrostenotic type. In addition, tumorous endobronchial tuberculosis can develop via a pathway involving erosion and later protrusion of an intrathoracic tuberculous lymph node into the bronchus (Shulutko et al.1979; Judson and Sahn 1994). This may be the principal mechanism oftumorous endobronchial tuberculosis, given that computed tomography usually reveals an endobronchial mass, as well as enlarged lymph nodes adjacent to the bronchus, and anthracotic pigment is frequently seen in biopsy specimens (Yee et al. 1985; Smith et al.1987). Interestingly, endobronchial tuberculosis in patients with HIV infection shows such bronchoscopic and computed tomography findings (Judson and Sahn 1994; Alame et al. 1995; Calpe et al. 1995; Saadoun et al.1998). In my previous study (Chung and Lee 2000), the actively caseating type was the most common form, the edematous-hyperemic, fibrostenotic, tumorous and granular types were relatively common, the non-

333

Endobronchial Tuberculosis

specific bronchitic type occurred less frequently and the ulcerative type was the rarest form (Table 21.1).

21.7 Characteristics of the Each Subtype of Endobronchial Tuberculosis

In my previous study, about a third of the cases of the edematous-hyperemic type became of the nonspecific bronchitic type and healed within three months of treatment. The remaining two-thirds became fibrostenotic within three months of drug treatment, and complete obstruction of the bronchial lumen often occurred. The prognosis of edematoushyperemic endobronchial tuberculosis is poor.

21.7.1 Actively Caseating Type Actively caseating endobronchial tuberculosis is diagnosed when the bronchial mucosa is swollen, hyperemic and diffusely covered with a whitish cheese-like material. This form is usually accompanied by luminal narrowing at diagnosis, whether granulation tissue is present or not (Fig. 21.1). In my previous study, approximately one-third of the cases of actively caseating endobronchial tuberculosis healed via the edematous-hyperemic, granular or nonspecific bronchitic types without complication. The remaining two-thirds transformed into the fibrostenotic type within three months of antituberculosis and corticosteroid treatment. The formation of granulation tissue is a poor prognostic factor, because all cases that showed granulation tissue on follow-up bronchoscopy changed into the fibrostenotic type. The prognosis of actively caseating endobronchial tuberculosis is poor.

Fig.21.1. Bronchoscopic finding of actively caseating endobronchial tuberculosis. From Chung and Lee (2000). Reproduced, with permission, from Chest 117:385

21.7.2 Edematous-Hyperemic Type In cases of edematous-hyperemic endobronchial tuberculosis, the bronchial lumen is narrowed due to severe mucosal swelling with surrounding hyperemia. However, neither caseous material nor fibrous contracture is found at diagnosis (Fig. 21.2). Table 21.1. Classification of 114 endobronchial tuberculoses by Bronchoscopic Features Type

Cases

%

Actively caseating type Edematous-Hyperemic type Fibrostenotic type Tumorous type Granular type Nonspecific bronchitic type Ulcerative type

49 16 12 12 13 9 3

43.0 14.0 10.5 10.5 11.4 7.9 2.7

From Chung and Lee (2000). Reproduced, with permission, from Chest 117:385

Fig. 21.2. Bronchoscopic finding of edematous-hyperemic endobronchial tuberculosis. From Chung and Lee (2000). Reproduced, with permission, from Chest 117:385

334

21.7.3 Fibrostenotic Type

H. S. Chung

Tumorous endobronchial tuberculosis is characterized by an endobronchial mass that has a surface often cov-

ered with caseous material, and which nearly totally occludes the bronchial lumen (Fig. 21.4). This form of endobronchial tuberculosis is frequently mistaken for lung cancer because of its bronchoscopic appearance and the fact that the computerized tomography findings mimic those of lung cancer. Anthracotic pigmentation or anthracofibrosis can appear after the endobronchial lesion has been successfully treated. If the lymph nodes caseate, they may point towards and discharge intrabronchially. Following discharge, the resultant fistulae usually heal slowly, leaving small, sometimes pigmented, pitted scars in the bronchial wall. These can be visualized as hard, depressed, black plaques by bronchoscopy, and have been observed to follow the intrabronchial perforations of tuberculous lymph nodes. The black pigment derives from the anthracotic material present in the tuberculous nodes, which is subsequently incorporated into scarred areas. In my previous study, the evolution of tumorous endobronchial tuberculosis was very complicated and unpredictable. Approximately 70% of cases eventually changed into the fibrostenotic type, which included the complete obstruction of the bronchial lumen with fibrosis. Six months after treatment, another 20% were found to exhibit impending obstruction of the left main bronchus due to a re-growing mass, although this were successfully corrected by bronchoscopic electrocautery. In 20% of cases, new tumorous lesions appeared five or six months after treatment, and anthracofibrosis or anthracotic pigmentation was

Fig.21.3. Bronchoscopic finding of fibrostenotic endobronchial tuberculosis. From Chung and Lee (2000). Reproduced, with permission, from Chest 117:385

Fig.21.4. Bronchoscopic finding of tumorous endobronchial tuberculosis. From Chung and Lee (2000). Reproduced, with permission, from Chest 117:385

Fibrostenotic endobronchial tuberculosis presents as a marked narrowing of the bronchial lumen with fibrosis. Usually) endobronchial tuberculous lesions do not encircle the bronchial mucosa and normal mucosa is partly spared, and the stenotic bronchial lumen becomes a crushed waterdrop-shape, as shown in Fig. 21.3. In some cases, the bronchial lumen is completely occluded. The edges of this stricture are avascular and pale because of dense fibrosis, and it is impossible to biopsy due to its very hard consistency. However, active tuberculosis can be diagnosed by bronchoscopic biopsy of the chronic inflamed mucosa at the periphery of the lesion, which is usually swollen and reddened. In my previous study, all cases remained in a fibrostenotic state inspite of drug therapy. In addition, roughly half of the cases showed progressive fibrostenosis and this resulted in complete obstruction of the bronchial lumen two or three months after treatment. The prognosis of fibrostenotic endobronchial tuberculosis is very poor.

21.7.4 Tumorous Type

335

Endobronchial Tuberculosis

observed in 30% of cases. The prognosis of tumorous endobronchial tuberculosis is grave. It is very difficult to analyze the evolution of tumorous endobronchial tuberculosis; this is due to the fact that the disease exhibits diverse progress and unexpected changes. However, the observations of Shulutko and coworkers (l979) are extremely valuable. In bronchoglandular tuberculosis, which is equivalent to tumorous endobronchial tuberculosis, bronchoglandular fistulas occur when the necrotic foci of tuberculous lymph nodes rupture into the bronchial lumen, extruding the lymph node contents. During this stage, bronchial stenosis is often temporary, and the bronchoglandular fistula usually heals, leaving a thin tender scar that neither deforms the wall nor narrows the lumen of the bronchus, provided endobronchial treatment (removal of caseous masses and granulations, cauterization of the fistulous opening or peribronchial blockades) is performed. However, if scarring of the bronchoglandular fistula continues, the bronchial lumen may be permanently narrowed by persistent cicatricial stenosis, or it may even be completely obliterated. Most cicatricial stenoses of endobronchial tuberculosis appear to be the sequelae of tumorous bronchadenitis, and occasionally more lymphoglandular fistulas arise near the first fistula. When the insights of Shulutko et al. were applied to my previous series, unexpected changes were no longer unexpected, but probable. In order to maintain bronchial patency, early diagnosis and efficacious treatment, including interventional

modalities (Smith et al.1987; Watson and Ayres 1988; Chung et al. 1991a), are very important in tumorous endobronchial tuberculosis.

Fig.21.5. Bronchoscopic finding of granular endobronchial tuberculosis. From Chung and Lee (2000). Reproduced, with permission, from Chest 117:385

Fig.21.6. Bronchoscopic finding of ulcerative endobronchial tuberculosis. From Chung and Lee (2000). Reproduced, with permission, from Chest 117:385

21.7.5 Granular Type Granular endobronchial tuberculosis appears macroscopically like scattered grains of boiled rice, and the underlying bronchial mucosa shows severe inflammatory change (Fig. 21.5). In my previous study, roughly 20% of the cases showed fibrostenosis of the bronchial lumen two months after treatment, and the other 80% of cases healed without endobronchial sequelae three or four months after treatment. The prognosis of granular endobronchial tuberculosis is good.

21.7.6 Ulcerative Type The appearance of the bronchial ulcer in ulcerative endobronchial tuberculosis is very similar to that of a peptic ulcer (Fig. 21.6), and it can result from the submucosal lymphatic spread of organisms from adjacent parenchymal disease or implantation. In my previous study, the prognosis of ulcerative endobronchial tuberculosis was excellent, as all cases were completely resolved within three months of

336

H. S. Chung

treatment commencement. However, the number of cases involved was too small to serve as a basis for evaluating prognosis.

21.7.7 Nonspecific Bronchitic Type In nonspecific bronchitic endobronchial tuberculosis, only mild mucosal swelling and/or hyperemia are evident by bronchoscopy (Fig. 21.7). Tuberculosis is proven by bronchoscopic biopsy of the lesions. As my previous investigation indicated, all cases of nonspecific bronchitic endobronchial tuberculosis that were studied healed within two months of treatment, suggesting that the prognosis for this disease is excellent.

Fig. 21.7. Bronchoscopic finding of nonspecific bronchitic endobronchial tuberculosis. From Chung and Lee (2000). Reproduced, with permission, from Chest 117:385

21.8 Location of Bronchial Involvement As pulmonary tuberculosis shows a right-sided predominance in most series (McAdams et al. 1995), so endobronchial tuberculosis may occur more frequently in the right side (Garay 1996). In my previous study (Chung et al. 1991a), endobronchial tuberculosis showed a mild right-sided predominance, whereas luminal narrowing of the bronchi was more frequently observed in the left. Moreover, tracheal involvement was not rare. Interestingly, the

Trachea: 17.3

Rt main B: 6.1

Cas' 48.6 E-H . 37.1 Fs : 8.6 NsB. 5.7

Cas: 56.2 E-H :18.7 Fs : 12.5 Tum: 6.3 Gra . 6.3

Lt Main B: 18.4 E-H : 35.6 Cas: 26.7 Fs : 24.4 Tum: 8.9 Gra : 4.4

Rt upper B: 17.9 Cas : 40.0 E-H : 29.3 Fs . 17.3 NsB : 6.7 Ulcer: 6.7 Rt lower B : 15.1 NsB : 55.6 E-H : 18.5 Fs : 18.5 Cas. 7.4

most common site of endobronchial tuberculous lesions was found to be the left mainstem bronchus. Lowet al. (2001) confirmed this finding. Endobronchial tuberculosis of both lower lobe bronchi and the right middle lobe bronchus was found to be mainly of the nonspecific bronchitic type, and tumorous endobronchial tuberculosis was found to occur mainly in the left mainstern bronchus. The distributions of involved sites and their types are illustrated in Fig. 21.8.

Lt upper B: 4.8 Fs : 37.5 Cas: 37.5 E-H : 25.0 Upper div: 5.8

E-H : 50.0 Cas: 25.0 Tum: 25.0 Rt middle B : 3.7 NsB Fs E-H Tum

42.8 28.6 14.3 14.3

Cas: E-H : Fs : Tum:

30.8 30.8 23.0 15.4

Lingular div: 1.2 Fs: 100.0

Lt lower B: 7.6 NsB : 84.6 Tum: 15.4

Fig. 21.8. Distributions of involved sites and their types versus their relative frequencies (%) in endobronchial tuberculosis. *Rt right, Lt left, Interm intermediate, B bronchus, div division. Cas actively caseating type, E-H edematous-hyperemic type, Fs fibrostenotic type, Tum tumorous type, era granular type, Ulcer ulcerative type, NsB nonspecific bronchitic type

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Endobronchial Tuberculosis

21.9 Natural Course of Endobronchial Tuberculosis

21.10 Endobronchial Tuberculosis in HIV-Infected Patients

The presumptive natural course of endobronchial tuberculous lesions (Fig. 21.9, dashed arrow) can be deduced by observing the healing process (Fig. 21.9, solid arrow). The desired end result of endobronchial tuberculosis is healing without significant sequelae; the other possibility is fibrostenosis. All subtypes of endobronchial tuberculosis are situated between these two conclusions, and they can transform into other subtypes during treatment. However, there is a critical point between these two extremes, the position of which is mainly determined by the extent of disease progression (Kim et al. 1993) and the formation of granulation tissue (Shulutko et al. 1979; Smith et al. 1987). Bronchial stenosis is inevitable (Albert and Petty 1976; Caligiuri et al. 1984) if the disease progresses beyond this critical point. Therefore, prompt diagnosis and efficacious treatment are of paramount importance in cases of endobronchial tuberculosis in order to minimize the resultant bronchial stenosis (Park et al. 1997). To alleviate bronchostenosis that has already developed, aggressive therapeutic modalities should be considered before dense fibrosis progresses or complete obstruction of the bronchus occurs.

In a normal host the immunologic response to infection by the tubercle bacillus provides a degree of protection against additional tubercle bacilli that may be subsequently inhaled in droplet nuclei. The likelihood of reinfection is a function of the risk of re-exposure, the intensity of such exposure, and the integrity of the host's immune system. In developed countries the risk of re-exposure to an infectious case is low. Furthermore, in the otherwise healthy, but previously infected person, any organisms deposited in the alveoli are likely to be killed by cell-mediated immune response. Mycobacterial infections have been commonly observed in patients infected with HIV. These individuals are 200 times more likely to contract tuberculosis than HIV-negative individuals (Broughton and Bass 1999). In contrast to tuberculosis infections in normal adults, tuberculosis in AIDS patients cannot be readily identified by clinical or radiological criteria. It has become apparent that infection with HIV, because of its profound suppression of normal immune response, predisposes the individual to much more severe forms of tuberculosis. In HIVinfected persons with tuberculosis, dissemination of the tubercle bacilli and a variety of extrapulmonary manifestations are common. Thus, unusual clinical

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Fig. 21.9. A scheme summarizing the observed healing process (solid arrow) and the presumptive natural course (dashed arrow) of endobronchial tuberculous lesions. From Chung and Lee (2000). Reproduced, with permission, from Chest 117:385

338

H. S. Chung

presentations of tuberculosis in HIV-infected persons present a special diagnostic challenge (American Thoracic Society 1990). Tuberculosis in HIV-infected patients may have the radiographic characteristics of primary disease. Infiltrates may appear in any lung zone, cavitation is uncommon, and mediastinal or hilar lymphadenopathy is often present (Mangura and Reichman 1989). The tumorous type of endobronchial tuberculosis predominates in patients with HIV infection, and the condition may be the result of the erosion and protrusion of a tuberculous lymph node into the bronchus, a pathogenetic mechanism of primary tuberculosis. The diagnosis of endobronchial tuberculosis in HIV patients should always be considered, since it may be more frequent than suspected (Calpe et al. 1995). Consequently, a more liberal indication of bronchoscopy helps in the early detection of endobronchial tuberculosis in patients with AIDS (Alame et al. 1995). Even if no endobronchial lesion is apparent by bronchoscopy, bronchoalveolar lavage and transbronchial biopsy are particularly useful for diagnosing HIV-related pulmonary tuberculosis, since only two-thirds to three-quarters of the patients have a positive acid-fast smear, and the tuberculin skin test is less sensitive in these patients (Rossman and Oner-Eyuboglu 1998).

A cough is the most common symptom, which has an almost imperceptible onset. Coughs slowly progress over weeks or months and become more frequent; they may be nonproductive at first, but occasionally may be associated from the onset with mucopurulent sputum or blood, and later, the expectoration of sputum usually appears. Shortness of breath frequently occurs, and may be associated with localized wheezes, stridors or the absence of a breathing sound. Fever is frequently associated with the disease, and though low-grade at the onset it may become marked as the disease progresses. Characteristically, the fever develops in the late afternoon and may not be accompanied by pronounced symptoms. With defervescence, usually during sleep, sweating occurs - the classic «night sweats." In more extensive disease, hemoptysis may occur but is seldom massive. The clinical features of endobronchial tuberculosis as detailed in several reports are summarized in Table 21.2. Symptoms are usually nonspecific and are caused mainly by the coexisting pulmonary tuberculosis. In contrast to uncomplicated pulmonary tuberculosis, hemoptysis was less frequent and dyspnea was much more common in my previous study.

21.12 Diagnosis 21.11 Clinical Features

21.12.1 Clinical History

The clinical features of endobronchial tuberculosis vary widely, depending on the site(s) and the extent of involvement, and endobronchial tuberculosis may occur in the absence of recognized symptoms.

When endobronchial tuberculosis is suspected, inquiries concerning patient exposure to a person with an open case of pulmonary tuberculosis may be helpful, especially if this contact is long-standing and close. A

Table 21.2. Clinical features of endobronchial tuberculosis as detailed in several reports Symptom and sign (%)

Song et al. (1985)

Chung et al. (1991)

Ip et al. (1986)

Hoheisel et al. (1994)

Low et al. (2001)

Cough Sputum Dyspnea Hemoptysis Chest pain Fever Absence of a BS Wheezing/Stridor Rhonchi Weight loss None

87.5 75 24 17.5 45 35 27.5 27.5

75.3 68.7 33.1 1.2

100 95 35 25 15 50

87 89

86

BS breathing sound

26.5 28.3 27.7 14.5

15

57 8 15 87 19 9 12

24 19 29

35

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past diagnosis of pneumonia that has recurred from time to time should always arouse suspicion regarding endobronchial tuberculosis. All previous chest films should be obtained. Medical conditions that increase the risk of tuberculosis (i.e. diabetes mellitus, gastrectomy, drug abuse, etc) should also be reported.

21.12.2 Physical Examination Acomplete physical examination should be performed, although an examination of the chest will usually furnish the main clues. Wheezing is frequently heard on auscultation. Persistent unilateral wheezing is more indicative of endobronchial tuberculosis, while transient wheezing due to bronchial secretions usually clears with cough. Stridor may occur with an ulceration and cicatrix of the trachea or larynx. It is nearly impossible to differentiate wheezing and stridor heard in endobronchial tuberculosis from that heard in bronchial asthma. Decreased breathing or the absence of a breathing sound is another frequent finding. When tuberculosis involves the larynx, hoarseness is usually present and is often accompanied by severe pain.

21.12.3 Laboratory Testing Routine laboratory examinations are rarely helpful in establishing or suggesting a diagnosis. A broad range of hematologic manifestations has been reported in endobronchial tuberculosis. The most common of these are increases in peripheral blood leukocyte counts and modest anemia, each of which occurs in approximately 10% of patients. WBC counts of over 20,000/f.lL suggest another infectious process, and the erythrocyte sedimentation rate is usually elevated. With endobronchial tuberculosis, HIV testing is recommended in patients who have known or suspected risk factors for the acquisition of HIV infection.

21.12.4 Bacteriology Endobronchial tuberculosis, especially the extensive form, is usually higWy infectious. In my previous study, the sputum smear for acid-fast bacilli was positive in about half of the patients, and the sputum culture for tubercle bacilli was positive in 70% or more.

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Conversely, some recent studies have found a low yield on sputum acid-fast bacilli smears. The explanation given was that the expectoration of sputum is difficult because of mucus entrapment by proximal bronchial granulation tissue (Ip et al. 1986; Lee et al. 1992; van den Brande et al. 1990). It should not be surprising that large differences are observed in the positive rates of acid-fast bacilli, because culture yield, like microscopic examination, is affected by the clinical status of patients. Sputum examination for acid-fast bacilli is much more important, since patients with endobronchial tuberculosis occasionally present with apparent acute pneumonia. In fact, the diagnosis of tuberculosis is made only on routine sputum examination or because of a failure of clinical or radiological resolution using broad-spectrum antibiotics. However, it should be noted that a positive acid-fast smear is not specific for Mycobacterium tuberculosis. Other mycobacteria, both saprophytes and potential pathogens, can be acid-fast. Thus, the only absolute way of confirming a diagnosis of M tuberculosis is by culture. FresWy expectorated sputum is the best sample to stain and culture for M tuberculosis. Twenty-four hour old sputum samples are frequently overgrown with mouth flora and are much less useful. If a patient is not producing sputum spontaneously, induced sputum is the next best specimen for study. When a patient cannot provide a spontaneous sputum sample, a gastric aspirate to obtain swallowed sputum may be useful. This sample must be obtained in the morning before the patient arises or eats. Bronchoscopy is preferable to gastric aspiration, since bronchial secretions are readily available for acid-fast smear and culture, as well as for cytologic study, and a careful evaluation of the tracheobronchial tree can be carried out at the same time. Specimens for culture should be obtained using a minimal amount of anesthesia, because the local anesthetics used for fiberoptic bronchoscopy may be lethal to M tuberculosis. The portion of the biopsy specimen to be used for culture should not be placed in formalin. Post-bronchoscopy sputum can be another valuable source of diagnostic material, and bronchoscopy may cause the patient to continue producing sputum for several days. These later specimens should also be collected and examined, as they may reveal tubercle bacilli absent from the sample taken on the day of the bronchoscopy. Newer technologies, such as radiometric technology (the BACTEC system), polymerase chain reaction and genetic probes, immunoassay of mycobacterial antigens, and the detection of biologic compounds,

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can allow an early diagnosis or improve our ability to isolate mycobacteria from clinical specimens (Glassroth 1993).

21.12.5 Tuberculin Testing The tuberculin skin test is used as an indicator of M. tuberculosis infection, and relies on a cell-mediated immune response. However, a positive delayed hypersensitivity reaction to tuberculin indicates only the occurrence of a prior primary infection and not the presence of clinically active disease. Very large reactions (greater than 25 mm of induration) are more frequently associated with active tuberculosis. However, a negative reaction to tuberculin does not rule out the diagnosis, because the patient may be anergic or have a specific anergy to tuberculin (Rossman and Oner-Eyuboglu 1998). Nevertheless, the absence of skin reactivity to tuberculin makes the possibility of tuberculosis unlikely in most situations.

21.12.6 Pulmonary Function Test Bronchial disease and pulmonary parenchymal lesions coexist in endobronchial tuberculosis. Although this may have an influence on pulmonary function, no pathognomonic pattern of physiologic disturbance exists in endobronchial tuberculosis. Nevertheless, the usual pattern is that of a predominantly restrictive ventilatory defect. The reason why endobronchial tuberculosis shows this restrictive pattern may be due to organic obstruction of the bronchial tree and chronic inflammatory or bronchiectatic changes of the lung parenchyme. The pulmonary function test may be helpful in the differential diagnosis of endobronchial tuberculosis and bronchial asthma. The results of pulmonary function testing in my previous study are illustrated in Fig. 21.10.

Pulmonary function testing is useful for the followup of endobronchial tuberculosis. Changes in pulmonary function during treatment in endobronchial tuberculosis are significantly correlated with changed bronchoscopic findings, although the indices of pulmonary function testing at diagnosis do not correlate significantly with the gross bronchoscopic findings of endobronchial tuberculosis (Chung and Lee 1996).

21.12.7 Radiology 21.12.7.1 Simple Roentgenograms

Despite the fact that roentgenographic examination itself is not diagnostic of endobronchial tuberculosis, it is a necessary procedure. A lateral chest film should be a part of every roentgenographic inquiry, since approximately 25 percent of the lung fields cannot be visualized on the conventional posteroanterior film. Endobronchial tuberculosis, as well as pulmonary tuberculosis, may produce almost any form of pulmonary radiographic abnormality. However, endobronchial tuberculosis frequently presents with unusual roentgenographic findings, such as pneumonic consolidation, lobar or segmental collapse, a mass-like lesion or hilar or paratracheal adenopathy. A normal chest radiograph cannot completely exclude endobronchial tuberculosis, because roughly 10% of patients show normal chest roentgenograms. Radiologic findings of endobronchial tuberculosis in my previous study are shown in Table 21.3. 21.12.7.2 Computerized Tomography

Special imaging techniques, such as computerized tomography and magnetic resonance imaging, may be of particular value in defining nodules, cavities, cysts, Table 21.3. Radiologic findings of 166 endobronchial tuberculoses Characteristics

Fig.21.10. The results of pulmonary function testing in 85 cases of endobronchial tuberculosis

Cases

Pneumonic patchy infiltration 42 Atelectasis or Collapse 33 Fibrostreaky densities 27 Cavitary lesion 23 Mass-like lesion 12 Bronchiectatic change 7 18 Mediastinal widening No active lesion 21

%

25.3 19.9

16.3 13.9

7.2 4.2 10.8 12.7

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calcifications, the contours oflarge bronchi and vascular details in lung parenchyma. Moreover, since the length of bronchial involvement, the thickness of bronchial wall and mediastinal lymph node enlargement can be evaluated noninvasively, computerized tomography is a useful adjunct to direct endoscopic visualization, particularly when performed at a 5-mm intervals with 5-mm slice collimation through the hila. The technique accurately depicts bronchial abnormality in 93 to 100% of all cases (McAdams et al. 1995), and it can also reconstruct three-dimensional images of the trachea and of the major bronchi (Choi et al. 2002). Computerized tomography findings of endobronchial tuberculosis include: isolated long segment bronchial narrowing with concentric wall thickening, complete endobronchial obstruction, extrinsic compression by adjacent adenopathy and even direct bronchial invasion of a caseous node. The erosion of calcified lymph nodes into adjacent bronchi, known as broncholithiasis, can also be observed, along with the resultant segmental collapse or overinflation. Computerized tomographic scans of the central airways usually show active endobronchial tuberculosis as an irregular narrowing of the airways with marked wall thickening; the scans also frequently show mediastinal lymph node enlargement, whereas fibrotic tuberculosis shows as a rather smooth narrowing of the airways with minimal wall thickening (Kim et al.1997; Moon et al.1997).

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essential that aggressive therapy be performed before the disease progresses too far and bronchostenosis becomes inevitable. Therefore, the bronchoscopic approach is mandatory not only for the prompt diagnosis of endobronchial tuberculosis, but also for the prevention of further bronchostenosis. The suspicion of endobronchial tuberculosis provides an important indication for bronchoscopy. The presence of a wheeze or of a persistent and uncontrollable cough, or the presence of tubercle bacilli in the sputum without an obvious source in the lung parenchyma, provides sufficient reason for the procedure. Roentgenographic findings of atelectasis or selective segmental or lobar collapse, unexplained shadows near the hilum, the sudden or gradual appearance of localized obstructive over-distention or ballooning cavities should also be investigated by bronchoscopy. A ballooning cavity is often referred to as the tension cavity, regardless of whether or not the intracavitary pressure is known. Ballooning cavities are frequently secondary to the involvement of bronchi in tuberculosis (Wolinsky 1989). Tuberculosis produces two main bronchoscopically visible changes: endobronchial inflammation and distortion due to extrabronchial lymph-node enlargement. One may see inflamed, swollen mucosa and purulent secretions or blood; alternatively, one may sometimes see fibrous masses ofwhite-pink color resembling cauliflower and simulating a cancerous tumor, or even ulceration, in the bronchial draining 21.12.8 lobes or segments afflicted with active tuberculosis. Bronchoscopy Acute inflammatory changes can respond rapidly to chemotherapeutic treatment, leaving normal bronBronchoscopy is the single most useful modality chi, but healing may lead to bronchial scarring and in the diagnosis of endobronchial tuberculosis, sometimes to marked contractive stenosis. whereas the chest radiograph is the most important In summary, the diagnostic use of bronchoscopy for suggesting a diagnosis of pulmonary tuberculo- in obtaining a biopsy from an area of bronchial sis. Bronchoscopy is necessary not only to make the ulceration or obstruction can clinch the diagnosis of diagnosis of endobronchial tuberculosis, but also endobronchial tuberculosis. to exclude bronchogenic carcinoma. Bronchoscopy has a unique value in the management of endobronchial tuberculosis. When the different forms of endobronchial tuberculosis are classified into seven 21.13 subtypes (actively caseating, edematous-hyperemic, Differential Diagnosis fibrostenotic, tumorous, granular, ulcerative and nonspecific bronchitic), the therapeutic outcome of 21.13.1 each subtype, except the tumorous type, can be pre- Pneumonia dicted by follow-up bronchoscopy during the initial two to three months of treatment. However, in the In contrast to endobronchial tuberculosis, in which case of tumorous endobronchial tuberculosis, close symptoms are nonspecific, the acute pneumonic and long-term follow-up is advisable, given that the patient usually has typical symptoms of fairly recent evolution of lesions during treatment is very compli- onset. If the patient is symptomatic, an oral antibicated and bronchial stenosis may develop later. It is otic should be prescribed, and if the radiographic

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342

opacities do not clear or improve in 2 to 3 weeks, then tuberculosis is a possibility. If the pneumonia is refractory to standard treatment, especially if the white count is normal, then repeated sputum specimens should be examined for acid-fast bacilli.

21.13.2 Fungal Infection and Actinomycosis Polesky et al. (1999) presented data on 38 cases of coccidioidomycosis of the airways, which included 6 cases detailed from their own experience and 32 from the literature. In histoplasmosis, regional lymph node involvement is invariable during the initial infection. The extrinsic pressure of enlarged nodes on the airways may cause obstruction and distal infection or atelectasis. Complications of histoplasmosis are similar to those of primary pulmonary tuberculosis (Fraser et al. 1994). In 1999, Lee et al. reported a case of biopsy-proven endobronchial actinomycosis. The bronchoscopic findings of this disease are very similar to those of endobronchial tuberculosis.

21.13.3 Lung Cancer This differential diagnosis occurs primarily in the middle-aged and elderly age groups. Consolidation distal to a proximal carcinoma may be cavitated and closely mimic tuberculosis. Moreover, carcinoma of the lung and tuberculosis may be present simultaneously; in fact, the frequency of coexistent lung cancer and tuberculosis is as high as 5% (McAdams et al. 1995). In cases with a simultaneous presentation of carcinoma and tuberculosis, the diagnosis of tuberculosis is frequently made first, and the carcinoma diagnosis is often delayed for several months. Thus, if the radiographic and clinical findings suggest carcinoma, but the sputum has acid-fast bacilli, further procedures to diagnose carcinoma may still be indicated (Rossman and Mayock 1988). On bronchoscopy, tuberculous granulation tissue may be observed to erupt through the bronchial mucosa to form a tumor-like mass. The caseous tracheobronchial lymph nodes can produce ominous, irregular swellings into the main bronchi or trachea that suggest the malignant invasion of lymph nodes (Stradling 1981). Bronchoscopic biopsy will reveal the true situation.

21.13.4 Bronchial Asthma Some patients with endobronchial tuberculosis show wheezing on physical examination but have normal chest films, which mimics bronchial asthma. One should always consider the possibility of endobronchial tuberculosis during the differential diagnosis of bronchial asthma if patients with wheezing show normal airway responsiveness (Park et al. 1995) or a poor response to bronchodilation (Williams et al. 1988).

21.14 Treatment 21.14.1 Anti-Tuberculosis Chemotherapy In principle, the short-course regimens are the regimens of choice for patients with endobronchial tuberculosis. Many short-course regimens have been investigated and proposed for pulmonary tuberculosis, and these can also be applied in endobronchial tuberculosis. A 6-month regimen consisting of isoniazid, rifampin and pyrazinamide for 2 months, followed by isoniazid and rifampin for 4 months, is the preferred treatment for patients with fully susceptible organisms and who can adhere to treatment. Ethambutol (or streptomycin in children too young to be monitored for visual acuity) should be included in the initial regimen until the results ofdrug susceptibility studies are available, unless there is only a small possibility of drug resistance (i.e. if there is less than 4% primary resistance to isoniazid in the community, and the patient has had no previous treatment with antituberculosis medications, is not from a country with a high prevalence of drug resistance and has no known exposure to a drug-resistant case). The four-drug,6-month regimen is effective even when the infecting organism is resistant to isoniazid. This recommendation applies for both HIV-infected and uninfected persons. However, in the presence of HIV infection, it is critically important to comprehensively assess the clinical and bacteriologic response. Any problem with the response to treatment indicates that the usual evaluation should be undertaken and the therapy possibly prolonged. Consideration should be given to treating all patients with directly observed therapy, and the duration of treatment should total at least 6 months and 3 months beyond culture conversion. Children should be managed in essentially the same ways as adults by using appropriately adjusted

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doses of the drugs. In multidrug-resistant tuberculosis (i.e. resistance to at least isoniazid and rifampin), treatment must be based on susceptibility studies (American Thoracic Society 1994). With endobronchial tuberculosis, therapy needs to be prolonged as decided on a case-by-case basis and should be individualized after considering the clinical, bacteriologic and bronchoscopic response, especially if the dominant form is of the tumorous type or if interventional management is performed.

loon dilatation, which tends to be only a temporary measure, Nd-YAG laser resection and surgical reconstructive procedures, which are generally considered to be the gold standard, although some patients will have contraindications to surgery. Stent placement, in contrast, is a new therapeutic modality. For select patients, a multidisciplinary approach, whereby pulmonologists, otolaryngologists and thoracic surgeons decide on the most appropriate use of laser resection, stent placement and surgical techniques has been advocated (Dineen et al. 2002).

21.14.2 Corticosteroid Treatment

21.15.1.1 Interventional Management

The use of corticosteroids has been and remains controversial. Nevertheless, under certain conditions corticosteroids are of benefit in patients with endobronchial tuberculosis. It appears that steroids are effective in rapidly reducing the mass effects of mediastinallymphadenopathy in patients with primary tuberculosis. Steroids may, therefore, decrease the severity of local obstructive complications (Nemir et al. 1963). Corticosteroids are more likely to be beneficial in the earlier stages of endobronchial tuberculosis, when hypersensitivity is the predominant mechanism (Dooleyet al. 1997), and they are unlikely to be helpful in more advanced cases when extensive fibrosis is present. Therefore, corticosteroids can be cautiously prescribed for actively caseating and edematous-hyperemic endobronchial tuberculosis (which occur in the earlier stages of the disease) and for tumorous endobronchial tuberculosis, which may be derived from primary tuberculosi~. The usual dose required is 40-60 mg of prednisone (or approximately 1 mg/kg ofbody weight) orally daily for 4-6 weeks, with gradual tapering over the next few weeks. It should be emphasized that before corticosteroids are prescribed, one must be confident that adequate antituberculosis chemotherapy is being given. Prompt treatment upon early diagnosis, before the formation of dense fibrosis, is a prerequisite for the prevention and amelioration of bronchostenosis (Park et al.1997).

Since bronchostenosis develops despite adequate antituberculosis therapy and/or corticosteroid treatment, more aggressive interventional management may be indicated to restore the patency of the involved bronchus in selected cases of endobronchial tuberculosis. In tumorous endobronchial tuberculosis, because the prognosis is grave if the condition is not treated aggressively, the endobronchial tumorous lesion itself should be removed by laser resection or electrosurgery to prevent further bronchostenosis. The fibrous membrane can simply be resected by laser photoresection or electrocautery (in the fibrostenotic type of endobronchial tuberculosis), if the membrane has a concentric web-like stricture (Becker et al. 1991). In cases where the fibrostenosis is relatively long, an endobronchial stent can be placed after dilatation with a high-pressure balloon catheter. Some, but not all, patients with tuberculous bronchostenosis may be provided with long-term control of their disease process by stent placement. Restenosis by granulation tissue formation can develop, but it may be successfully treated by laser ablation or electrosurgery. The therapeutic results of stent placement have been very poor in actively caseating, edematoushyperemic and tumorous endobronchial tuberculosis, which have active severe inflammation of the involved bronchus. Thus, appropriate antituberculosis chemotherapy and/or corticosteroid treatment should be administered prior to stent placement, until active inflammation disappears. This may take up to 5 months, after which, the endobronchial tuberculosis is usually of the fibrostenotic type, which is the main indication of stent placement. During drug therapy, repeated balloon dilatation may be needed to prevent complete obstruction and to maintain the patency of the narrowed bronchus (an example is shown in Figs. 21.11 and 21.12). Once active inflammation has been ameliorated by drug treatment, a

21.15 Complications and Their Management 21.15.1 Bronchostenosis Traditional strategies for repairing benign tracheobronchial stenosis include repeated endoscopic bal-

344

tracheobronchial stent can be placed, if necessary (Figs. 21.13-15}. Further chemotherapy should be given for a minimum of 3 months after the procedure to prevent recurrence. The stent may be successfully removed one year after placement, and the success rate of stenting is roughly 50% (Kim, personal communication). Granular, ulcerative and nonspecific bronchitic endobronchial tuberculosis do not indicate stent placement, because they do not involve significant bronchostenosis. 27.75.7.2

TracheobronchialStent The ideal tracheobronchial stent should possess several vital characteristics. It should be capable of establishing and maintaining airway patency; it should be easy and safe to place and (if necessary) remove;

H. S. Chung

it should be biocompatible; and, it should be flexible enough to fit appropriately in irregular anatomy. In addition, it should not cause mucosal injury or granulation tissue formation, hamper the ability to clear secretions, migrate from its desired position or obstruct otherwise patent lumens (Jantz and Silvestri 2000). As of yet, no such stent has been developed. Essentially, five types of stent have been developed and used for tracheobronchial obstructions. The earliest types were of silicone, most notably the Dumon or Endoxane stent. The next stents used were of uncovered stainless steel, such as the Gianturco Z and the Palmaz stents, which were the first stents capable of being deployed by flexible bronchoscopy. The third type were the second generation of metal stents as represented by the Wallstent and the Ultraflex. These stents are alloy-based mesh or interwoven loop stents and are also available with a polyurethane covering.

Fig. 21.11a-d. Repeated balloon dilatation of the left mainstem bronchus in a case with endobronchial tuberculosis. a At diagnosis. b At 1 month of treatment. c At 2 months of treatment; d At 3 months of treatment

Fig. 21.12a, b. Three-dimensional images of central airways in the case illustrated in Fig. 21.11. a At diagnosis. b At 2 months of treatment

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Fig. 21.13a-d. Stent placement for endotracheal tuberculosis. a Before stenting. b After stenting. c Just after stent-removal. d At 4 months after stent-removal

Fig. 21.14a, b. Three-dimensional images of the trachea in the case illustrated in Fig. 21.13. a Before stenting. b After stenting

Fig.21.15a, b. Stent placement for mainstem endobronchial tuberculosis. a Before stenting. b Just after stenting

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The polymer coating prevents the ingrowth of tumor or granulation tissue through the stent mesh framework. The fourth type of stent, the bifurcated Y-stent, was designed specifically to deal with the anatomic complexities of the central airways and the carina, and the fifth type of stent was constructed from a variety of different materials, such as polyester/silicone and nitinollsilicone. Generally, the most common complications associated with stents are stent migration, secretion retention and granulation tissue formation. Refinements in stent designs are required to improve biocompatibility and reduce migration and granulation tissue formation (Dineen et al. 2002). Overall, silicone stents have been very successful in treating benign airway obstructing lesions and may well be the gold standard for years to come. Recently, animal model trials have been reported with a bioabsorbable stent (Korpela et al. 1999). In the future, bioabsorbable stents may have a role in the management of benign airway stenoses. 21.15.1.3 Endobronchial Electrosurgery vs Laser Photoresection

Nd-YAG laser photoresection is the most effective therapy for treating tracheobronchial obstructions from benign or malignant lesions. However, the widespread use of this technique is limited by the perceived need for rigid bronchoscopy, expensive equipment and special training and fear of major complications. Advances in flexible bronchoscopy have allowed developments in other techniques directed at alleviating airway obstruction, including cryotherapy, brachytherapy and photodynamic therapy. Although costeffective, their effects are delayed and they may require repeated treatments (Coulter and Mehta 2000). Labeled "the poor man's laser:' electrosurgery offers equivalent laser-like tissue effects at a fraction of the cost. The ability to perform endobronchial electrosurgery in the outpatient setting is more accommodating for patients and time-saving for physicians, and it offers Significant cost savings. The lesions found to be most amenable to endobronchial electrosurgery are polypoid in morphology and attached to the airway by a stalk. Flat or sessile lesions can be treated by fulguration with the coagulation probe (Coulter and Mehta 2000). Endobronchial lesions in the tumorous type of endobronchial tuberculosis are good candidates for electrosurgery, because they usually present as polypoid masses or sessile lesions. Although the number of cases was small, my previous study found that electrosurgery produced successful results in this

H. S. Chung

type of endobronchial tuberculosis (Chung and Lee 2000). Granulation tissue caused by metallic stents can also be removed by endobronchial electrosurgery. Special care must be taken not to touch the wires when ablating these lesions, since electrical conduction may occur through the wire mesh. The circumferential treatment of endobronchial lesions should be avoided in endobronchial electrosurgery, as this may lead to cartilaginous damage, fibrosis and subsequent stenosis. 21.15.1.4 Surgical Management

Severe bronchostenosis with poor response to medical treatment and intervention usually requires later resection. Bronchoscopy and computed tomography are the treatments of choice in the accurate diagnosis of bronchial involvement and the assessment of surgical indications (Watanabe et al. 1997). To preserve lung function, bronchoplastic surgery is essential, especially for bronchial stricture of the trachea or larger bronchi, and appropriate antituberculosis chemotherapy should be given for 9 to 12 months perioperatively to prevent recurrence and restenosis (Hsu et al. 1997).

21.15.2 Bronchiectasis Distention by mucus, caseous tissue or secondary infection beyond a bronchial stenosis may result in bronchiectasis, especially following lobar or segmental lesions. (Seaton et al. 1989). The incidence of bronchiectasis is reduced by prompt antituberculosis chemotherapy.

21.15.3 Broncholith In primary tuberculosis, gross tracheobronchial lymph-node enlargement may take place. In many cases, these caseous nodes do not rupture but instead inspissate, contract and calcify, and occasionally such calcifications may later begin to ulcerate through the bronchial wall to produce repeated hemoptysis and eventually be extruded into a bronchus as a "broncholith:' A partially protruded broncholith can sometimes be removed bronchoscopically if not expectorated by the patient. However, attempts to remove broncholiths bronchoscopically can lead to profuse hemorrhage and, therefore, are best avoided (Stradling 1981).

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Acknowledgements. I am very grateful to Dr. Ho Joong Kim, and Miss Jin Ha Park for their generous contribution.

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347 ticosteroid therapy for tuberculosis: a critical reappraisal of the literature. Clin Infect Dis 25:872-887 Fraser RS et al (1994) Infectious disease of the lungs, chap 7. In: Fraser RS, Pare JAP, Fraser RG, Pare PD (eds) Synopsis of diseases of the chest, 2nd edn. Saunders, Philadelphia, pp 287-391 Garay SM (1996) Pulmonary tuberculosis, chap 32. In: Rom WN, Garay SM (eds) Tuberculosis. Little Brown, Boston, pp 373-412 Garimella PS (2001) Anthracofibrosis. Chest 120 [Suppl): 327s

Glassroth J (1993) Diagnosis of tuberculosis. In: Reichman LB, Hershfield ES (eds) Tuberculosis: a comprehensive international approach. Dekker, New York, pp 149-166 Glynn JR (1998) Resurgence of tuberculosis and the impact of HIV infection. Br Med Bull 54:579-593 Greenbaun M, Beyt BE, Murray PR (1980) The accuracy of diagnosing pulmonary tuberculosis at a teaching hospital. Am Rev Respir Dis 21:447-481 Han SK et al (1989) Balloon dilatation of bronchial stenosis in endobronchial tuberculosis. Program and book of abstracts. The 6th world congress for bronchology, Tokyo/ Kyoto,p 130 Hoheisel G et al (1994) Endobronchial tuberculosis: diagnostic features and therapeutic outcome. Respir Med 88:593-597 Hsu HS et al (1997) Surgical treatment of endobronchial tuberculosis. Scand Cardiovasc J 31:79-82 Ip MSM et al (1986) Endobronchial tuberculosis revisited. Chest 89:727-730 Jantz M, Silvestri GA (2000) Silicone stents versus metal stents for management of benign tracheobronchial disease-pro: metal stents. J Bronchol 7:177-183 Jenks RS (1940) Tuberculous tracheobronchitis: a review. Am Rev Tuberc 37:315-326 Jokinen K, Palva T, Nuutinen J (1977) Bronchial findings in pulmonary tuberculosis. Clin Otolaryngol 2: 139-148 Judd AR (1947) Tuberculos tracheobronchitis. J Thoracic Surg 16:512-521 Judson MA, Sahn SA (1994) Endobronchial lesion in HIVinfected individuals. Chest 105:1314-1323 Kim HY et al (2000) Bronchial anthracofibrosis (inflammatory bronchial stenosis with anthracotic pigmentation): CT findings. Am J Roentgenol 174:523-527 Kim Y et al (1997) Tuberculosis of the trachea and main bronchi: CT findings in 17 patients. Am J Roentgenol168: 1051-1056 Kim YH et al (1993) Serial fiberoptic bronchoscopic observations of endobronchial tuberculosis before and early after antituberculosis chemotherapy. Chest 103,673-77 Korpela A et al (1999) Bioabsorbable self-reinforced poly-Llactide, metallic, and silicone stents in the management of experimental tracheal stenosis. Chest 115:490-495 Lee JH et al (1992) Endobronchial tuberculosis: clinical and bronchoscopic features in 121 cases. Chest 102:990-994 Lee SH et al (1999) Endobronchial actinomycosis simulating endobronchial tuberculosis: a case report. J Korean Med Sci 14:315-318 Lerner BH (1999) Catching patients: tuberculosis and detention in the 1990 s. Chest 115:236-241 Low SY, Eng P, Hsu A (200l) Interventional bronchoscopy in tuberculous tracheobronchial stenosis. Chest 120 [Suppl): 160s Mangura BT, Reichman LB (1989) Pulmonary tuberculosis. In:

348 Pennington JE (ed) Respiratory infections: diagnosis and management, 2nd edn. Raven, New York, pp 528-543 Matthews JI, Matarese SL, Carpenter JL (1984) Endobronchial tuberculosis simulating lung cancer. Chest 86:642-644 McAdams HP, Erasmus J, Winter JA (1995) Radiologic manifestation of pulmonary tuberculosis. Radiol Clin North Am 33:655-678 Medlar EM (1955) The behavior of pulmonary tuberculous lesion: a pathological study. Am Rev Tuberc 71:132-145 Millard PS et al (1994) Rurality and tuberculosis incidence trends in North and South Carolina, 1982 to 1992. J Rural Health 10:226-236 Moon WK et al (1997) Tuberculosis of the central airways: CT findings of active and fibrotic disease. Am J Roentgenol 169:649-653 Myerson MC (1994) Tuberculosis of the trachea and bronchus. Thomas, Springfield, pp 250-275 Nemir RL et al (1963) Prednisone therapy as an adjunct in the treatment of lymph node-bronchial tuberculosis in childhood: a double-blind study. Am Rev Respir Dis 88:189-198 Oho K, Amemiya R (1984) Pathological bronchoscopic findings, chap 4. In: Oho K, Amemiya R (eds) Practical fiberoptic bronchoscopy, 2nd edn. Igaku-Shoin, Tokyo, pp 94-150 Park CS et al (1995) Bronchial hyperreactivity in patients with endobronchial tuberculosis. Respir Med 89:419-422 Park IW, Choi BW, Hue SH (1997) Prospective study of corticosteroid as an adjunct in the treatment of endobronchial tuberculosis in adults. Respirology 2:275-281 Polesky A et al (1999) Airway coccidioidomycosis: report of cases and review. Clin Infect Dis 28:1273-1280 Riley RL (1960) Apical localization of pulmonary tuberculosis. Bull Johns Hopkins Hosp 106:232-239 Rossman MD, Mayock RL (1988) Pulmonary tuberculosis, chap 7. In: Schlossberg D (ed) Tuberculosis, 2nd edn. Springer, Berlin Heidelberg New York, pp 71-76 Rossman MD, Oner-Eyuboglu AF (1998) Clinical presentation and treatment of tuberculosis, chap 162. In: Fishman AP, Elias JA, Fishman JA, Grippi MA, Kaiser LR, Senior RM

H. S. Chung (eds) Fishman's pulmonary diseases and disorders, 3rd edn. McGraw-Hill, New York, pp 2483-2503 Saadoun R et al (1998) Endobronchial tuberculosis presenting as an obstructive tumor in an HIV-l-positive patient: apropos of a case and review of the literature. Rev Med Interne 19:344-347 Salkin D, Cadden V, Edson RC (1943) The natural history of tuberculous tracheobronchitis. Am Rev Tuberc 47:351-359 Seaton A, Seaton D, Leitch AG (1989) Clinical features of tuberculosis, chap 14. In: Seaton A, Seaton D, Leitch AG (eds) Crofton and Douglas's respiratory diseases, 4th edn. Blackwell, Oxford, pp 395-422 Shulutko et al (1979) Tuberculosis. In: Lukomsky GI (ed) Bronchology. Mosby, St Louis, pp 287-305 Smart J (1951) Endobronchial tuberculosis. Br J Dis Chest 45: 61-68 Smith LS, Schillaci RF, Sarlin RF (1987) Endobronchial tuberculosis: serial fiberoptic bronchoscopy and natural history. Chest 91:644-647 Song JH, Han SK, Heo 1M (1985) Clinical observation of endobronchial tuberculosis(in Korean). Tuberc Respir Dis 4:276-284 Stradling P (1981) Inflammatory and associated changes, chap 5. In: Stradling P (ed) Diagnostic bronchoscopy, 4th edn. Churchill Livingstone, New York, pp 61-81 Van den Brande PM et al (1990) Clinical spectrum of endobronchial tuberculosis in elderly patients. Arch Intern Med 150:2105-2108 Watanabe Y et al (1997) Treatment of bronchial stricture due to endobronchial tuberculosis. World J Surg 21:480-487 Watson JM, Ayres JG (1988) Tuberculous stenosis of the trachea. Tubercle 69:223-226 Williams DJ et al (1988) Endobronchial tuberculosis presenting as asthma. Chest 93:836-838 Wolinsky E (1989) Tuberculosis, chap 26. In: Baum GL, Wolinsky E (eds) Textbook of pulmonary diseases, 4th edn. Little Brown, Boston, pp 465-520 Yee A et al (1985) Pigmented polypoid obstructive endobronchial tuberculosis. Chest 87:702-703

22 Pleural Tuberculosis M. MONIR MADKOUR, MAJDY IDREES, MONA

CONTENTS 22.1 22.2 22.3 22.4 22.5 22.5.1 22.5.2 22.5.3 22.5.4 22.5.5 22.5.6 22.5.7

Introduction 349 Epidemiology 349 Pathogenesis of Tuberculous Pleural Effusion 350 Clinical Features 351 Diagnosis of Tuberculous Pleural Effusion 352 Diagnosis 352 Pleural Fluid Examination 352 Pleural Biopsy 353 Thoracoscopy in Tuberculous Patients 354 Tuberculin Skin Test (PPD) 354 Imaging Features of Pleural Tuberculosis 355 Treatment 355 References 356

22.1 Introduction Tuberculous pleurisy is a common disease in developing countries and its incidence is increasing in developed countries. It is considered an extrapulmonary manifestation of tuberculosis despite its intimate anatomical relationship with the lung parenchyma. In the United States, because of the recent increase in the incidence of tuberculosis due to the HIV epidemic and immigrants from developing endemic countries, the incidence of pleural tuberculosis has increased in parallel with, and has been found in 20% of, AIDS patients (Ankobiah et al. 1990). Although tuberculous pleural effusion is associated with parenchymal infiltrates and cavitation in approximately 50% of patients, isolated pleural effusion without lung parenchymal disease can present M. M. MADKOUR, MD, DM, FRCP Consultant, Department of Medicine, Riyadh Armed Forces Hospital, P.O. Box 7897, C-119, Riyadh 11159, Saudi Arabia M. IDREES, MD, FRCP (C), FCCP Head, Pulmonary Function Laboratory, Division of Pulmonary Medicine, Department of Medicine, Riyadh Armed Forces Hospital, ClIO, P.O. Box 7897, Riyadh 11159, Saudi Arabia M. AL SHAHED, MBBS, FRCR Consultant Radiologist, Department of Radiology, Riyadh Armed Forces Hospital, P.O. Box 7897, Riyadh 11159, Saudi Arabia

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

AL SHAH ED

a diagnostic challenge; malignancy is of particular concern (Hunlnick et al. 1983; Hirsch et al. 1979). It is estimated that between 15 to 20% of patients with exudative pleural effusion in general are difficult to diagnose. In developing countries with poor resources, conventional methods of diagnosis by pleural fluid culture may only be positive in 25-50% of patients (Idell 1994). Presumptive diagnoses of tuberculous origin in exudative pleural effusion, based on clinical features, radiography and response to antituberculous chemotherapy in endemic countries are still adopted by many clinicians. Patients who are not treated for tuberculous pleural effusion often develop reactivation pulmonary disease (Palmer 1979). In developed countries, due to recent advances in investigative facilities, particularly in the field of molecular biology assays, the diagnosis can be made in few hours or days if other investigations are not helpful (Takagi et al.1998; Querol et al.1995; Lassence et al. 1992).

22.2 Epidemiology Pleural tuberculosis is the second commonest form of extra pulmonary parenchymal disease, after the tuberculous lymphadenitis. Pleural tuberculosis is also more common in patients that are co-infected with AIDS (11%) than among those without AIDS (6%). Other reports indicating a higher incidence of pleural tuberculosis (20%) in AIDS patients have found it to be the most common cause of pleural effusion in this patient population (Modilevsky et al. 1989; Shivaram et al.1989;Ankobiah et aI.1990). In developed countries, pleural tuberculosis is more commonly caused by post-primary disease than by primary infection. Reactivation of the disease was the cause of tuberculous pleural effusion in 64% of patients seen in Scotland and reported by Moudgil et al. (1994). Primary pleural tuberculosis was noted in 7% of patients with active pulmonary disease (Aktogu

350

et al. 1996). In young adults with HIV who are coinfected with tuberculosis, the primary disease as a cause of pleural tuberculosis was more common than reactivation (post-primary) (Sudre et al.1992; Batungwanayo et al.1993; Richter et al.1994). Seibert et al. (1991) from Alabama, USA, reviewed the medical records of 1,738 patients with tuberculosis seen between 1968 and 1988, to determine the age distribution, pleural fluid culture and frequency of pleural effusion among those with parenchymal disease, as well as the prevalence of positive tuberculin test. Pleural tuberculosis was found in 70 patients (4.0%) of all forms of the disease. The mean age was 47±17.7 years, with male predominance and pulmonary parenchymal involvement noted in 50% of patients. In Spain, two large studies of patients with pleural effusion were undertaken to determine the causes. The first series was a retrospective study of 414 patients with pleural effusion of unknown cause, who were seen between 1979 and 1986. Tuberculous cause was identified in 107 patients (28.5%) (Bueno et al. 1990). Male predominance was noted and the average age was 55 years. In the second series, 642 patients with pleural effusion were seen between 1989 and 1993. Tuberculous pleural effusion was found in 25% of these patients, similar to the earlier series, and the average age was also similar (57.1±21.1 years) with male predominance as well (Valdes et al.I996b). In Australia, Christopher et al. (1998) reported a prospective study of 27 patients with plural effusion that were hospitalized for the purpose of etiological diagnosis. Tuberculosis was found in 16 patients (59%) and was considered as the single most common cause of exudative pleural effusion in that series. In the United States, the incidence of tuberculosis as a cause of pleural effusion in AIDS patients was found to be increased. In New York, Relkin and colleagues (1994) retrospectively studied pleural tuberculosis in HIV-positive patients and found it to occur at a younger age. They found 70 patients with tuberculosis pleural effusion, including 43 HIV-positive (mean age 38±1 years) and 27 HIV-negative (mean age 52±3 years). They also confirmed previous observations that pleural tuberculosis in HIV-negative patients occurs more frequently in the older age group. In developing countries, such as some sub-Saharan African countries, the prevalence of tuberculosis has increased as a result of the HIV epidemic and the incidence of pleural tuberculosis has also increased in parallel. Richter and colleagues from Tanzania (Richter et al. 1991) prospectively studied 127 patients with pleural effusion. Tuberculosis was the

M. M. Madkour et al.

most common cause (70%) in this series. The authors also found that among the 89 patients with tuberculous pleurisy 57 (64%) were HIV-positive. In Zimbabwe where HIV is endemic, tuberculosis has become the single most likely cause of opportunistic infection (Heyderman et al. 1998). The prevalence of HIV among male factory workers was 19.4% and in females was over 30% (Mbizvo et al. 1996). In 1995, Harare provided an annual report of the incidence of tuberculosis, which was 195 cases per 100,000 population, with over 40% of the TB cases co-infected with HIV. In our series of 176 patients with culture positive sputum for M. tuberculosis, 46 patients had pleural effusion (26.1 %) - see Table 2 in the chapter on postprimary tuberculosis. The average age group was 40 years, with male predominance (75%). The majority of the patients were from the central (57%) and southern (29%) provinces of Saudi Arabia. Unlike the situation in the sub-Saharan African countries, HIV was not found to be a contributing factor for the development of tuberculous pleural effusion.

22.3 Pathogenesis of Tuberculous Pleural Effusion Tuberculous pleurisy has been described by an immunologist as an excellent model for studying the immune response in vivo. The mode of transmission of M. tuberculosis to the pleura may be hematogenous spread, as in primary tuberculosis, or it may be secondary to the direct invasion from adjacent tuberculous lymphadenitis or the rupture of subpleural tuberculous lung parenchymal cavity; it may also result from extrapulmonary disease such as spinal tuberculosis (Sahn 1988; Stevenson 1955; Mohammed et al. 1998; Maeda et al. 1993; Wallis 1996; Zhang et al. 1994; Morehead 1998). The pleura respond to the mycobacterial antigens with an extensive infiltration of mononuclear phagocytic cells and increased production of cytokines; however, the mechanisms by which these cells are recruited to the pleural space remains unclear. Several recent immunological studies have suggested that activated macrophages and CD4 lymphocytes play the most important role in cell-mediated immunity with granuloma formation against M. tuberculosis. Antigens from the wall of the bacilli have a potent stimulant effect and lead to the excessive production of cytokines (TNF-a and IFN-y) from these inflammatory cells, which in turn contribute to

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the formation of granuloma and to the defense mechanism against infection (Epstein et al. 1987; Shimokata et al. 1986; Barnes et al. 1989, 1990; Lorgat et al. 1992; Kunkel et al. 1989; Willis et al. 1990; Zhang et al. 1994; Wallis 1996). Several observations have suggested that a vigorous in-situ or "compartmentalized" intrapleural immune response with activation of cell-mediated immunity (CMI) and delayed type hypersensitivity (DTH) with cytokine production in response to the bacilli cell-wall antigens take place (Barnes et al. 1989). Mycobacterium tuberculosis bacilli contain multiple antigens, including polysaccharides (arabinogalactan and arabinomannan) and proteins (mainly glycolipids and lipoproteins). Polysaccharides from the bacilli generally do not elicit delayed type hypersensitivity (DTH) (Chaparas et al. 1971; Yamamura et al. 1968; Barnes et al. 1993). Lipoprotein and glycolipids antigens elicit DTH and stimulate T lymphocyte and cytokine production, which can be detected in high concentration in the pleural fluid. Pleural mesothelial cells are the first cells to respond to bacilli invading the pleural space. These cells are metabolically active and likely initiate and propagate an inflammatory reaction (Mohammed et al. 1998). Mesothelial cells have been found to initiate inflammation in response to various agonists by the production and release of chemokines (Boylan et al. 1992; Goodman et al. 1992; Jonjic et al. 1992).lnterleukin 12 (IL-12) cytokine has been found in high concentration in the pleural fluid of patients with tuberculous pleurisy (Zhang et al. 1994). Zhang and colleagues from California found that IL-12 play an important role in the immune response by enhancing the production of interferon-y, facilitating development of Thl cells and augmenting cytotoxicity of antigen-specific T-cells and natural killer cells. IL-12 enhances natural killer cell-mediated cytotoxicity and augments antigen-dependant proliferation by CD8+ cytotoxic T lymphocytes (Zhang et al. 1994). It has also been suggested that IL12 enhances cytotoxicity by activating CD4 + T cells against the bacilli loaded phagocytic macrophages, leading to its apoptosis and the destruction of the bacilli within it. Evidence for the excessive production ofantigen-reactive T lymphocytes,IFN-y, TNF-u and IL-12 is provided by the elevated levels of these cytokines in the pleural fluid of tuberculous patients. There is evidence that IL-12 is produced locally in the pleura in response to M. tuberculosis antigens, and that when IL-12 is experimentally suppressed, the bacilli proliferate again. These findings suggest that IL-12 contributes to lymphocyte recognition of M. tuberculosis antigens, probably by enhancing proliferation of activated T cells. The high concentration

of IFN-y and TNF-u (both have anti-mycobacterial activity) in the pleural fluid are a likely indication that they playa role in immune resistance. TNF-u augments the macrophages' capacity to phagocytose and kill the bacilli (Zhang et al. 1994). The authors conclude that IL-12 contribute to the immune response against M. tuberculosis by enhancing production of IFN-y, the T cells and orchestrating antigen-specific cytolytic mechanisms. CD4 T cells also playa critical role in the immune response to M. tuberculosis antigens. In 1996, Wallis (from Ohio), studied the response of T-cells to alpha antigen, a major protein from the wall of the bacilli, and reported the increased IFN-yproduction. As a result of the immune response and the outcome of the infection, inflammatory cellular infiltrates and granulomata formations may occur. As the infection progresses, inflammatory responses and cytokines release will lead to increased vascular permeability of the local capillaries. Subsequently, plasma protein exude fluid into the pleural space forming pleural effusion (Ellner et al. 1988). In postprimary pleural effusion, the disease may be complicated by empyema, lung parenchymal spread or bronchopleural fistula. Pleural fibrosis and calcification may occur in chronic tuberculous empyema.

22.4 Clinical Features Pleural effusion due to tuberculosis most commonly occurs 3 to 12 months, or even more, after the primary infection in adolescents and young adults, but it may occur at any time during the course of the disease (Gedde-Dhal 1952; Berger and Mejia 1973; Sahn 1988; Ansari and Idell 1998). Pleural tuberculosis, due to reactivation of the disease, may be noted in up to 50% of patients with post-primary lung parenchymal involvement, particularly with cavitations (Seibert et al. 1991). The onset of symptoms is acute in about 70% of patients with cough, fever and chest pain. Gradual onset may be noted in about 30% with dyspnea, weight-loss and weakness. The frequency of these symptoms may vary from one series to another. The presence or absence of co-infection with HIV does not change the frequency of symptoms, but non-HIV patients are more symptomatic (See Table 22.1). Non-symptomatic pleural effusion may occur in HIV co-infected patients and was reported in 4 of 21

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Table 22.1. Symptoms

Our Own Hong Kong USA Zimbabwe series (Chang et al. 1991) (Ankobiah et al. 1990) (Heyderman et al. 1998) No HIV No HIV ±HIV ±HIV

Cough 0/0 Dyspnea 0/0 Fever 0/0 Weight loss 0/0 Chest pain 0/0

63

77 86.5 90 44

71 48 71 55 53

60 38 72 59 44

HIV patients (20%) by Ankobiah et al. (1990) from New York. Clinically, sharp pain with pleural rub during deep inspiration on the affected side may be noted. The clinical features of pleural effusion may depend on its size, and are manifested as decreased chest movement, dullness of percussion, decreased breath sound or retraction of chest wall due to extensive pleural fibrosis. These features are not characteristic of tuberculous pleurisy. Pleural tuberculosis is most commonly unilateral but may be bilateral in 5% of patients (Chan et al.1991; Heyderman et al.1998). In our experience with 46 patients with proven pleural tuberculosis, 44 (96%) had unilateral pleural effusion. One patient (2%) had transudative effusion based on Light's criteria. Thirty patients (65%) had moderate effusions and 11 (24%) had massive effusions. Loculated effusion was reported in 9 patients (20%) and pleural calcification in 7 (15%).

97 82 73 51 73

cell count and bloodstained exudative effusion were the best discriminating functions in the screening for pleural tuberculosis. The diagnosis, however, can only be confirmed by the presence of M. tuberculosis determined by direct staining or by culture. The diagnosis of pleural tuberculosis has been defined for the purpose of clinical studies by several authors when one or more of the following were confirmed: (1) positive microbiological findings (smear or culture) in pleural fluid or biopsy; (2) histopathological evidence of granulomatous pleuritis with clinical andlor radiological response to anti-tuberculous treatment; (3) positive skin testing, recent conversion in young patient with a lymphocytic, exudative effusion (Ankobiah et al. 1990; Seibert et al. 1991; Morehead 1998).

22.5.2 Pleural Fluid Examination

22.5

Diagnosis of Tuberculous Pleural Effusion

22.5.1 Diagnosis The diagnosis of pleural tuberculosis begins with a high index of suspicion, clinical features, PPD skin test, imaging features and a culture of all potentially diagnostic specimens (body fluids or tissue biopsies). Screening methods used to differentiate tuberculous from non-tuberculous pleural effusion have been evaluated to identify the discriminate power of each investigative parameter. In a recent report from Spain, Carrion-Valero and Perpina-Tordera (2001) screened tuberculous pleural effusion by discriminant analysis of 189 patients. In this retrospective study, the discriminating power of routine imagining features and laboratory parameters was reviewed. Using the backward elimination method, the authors found that age, the tuberculin skin test, pleural white

Pleural fluid examination remains an important tool in the of investigation of tuberculous pleurisy. Tuberculous pleural fluid is an exudate which may be cloudy (turbid), yellow, serosanguineous or hemorrhagic in appearance. The PH usually ranges between 7.30 and 7.40 or lower, particularly among those co-infected with HIV (George et al. 1985; Pablo et al. 1997). Total WBC may range from 5,000 to 10,000/mm3, with more than 50% lymphocytes; however, polymorphs may be seen early after the onset of symptoms. Red cell count may be raised to a variable degree in the pleural fluid. Mesothelial cell count is usually less than 5% of the pleural fluid white cell count. Raised mesothelial count above 5% is considered by many authors to argue against tuberculous pleurisy (Spriggs and Boddington 1960). However, some authors have reported mesothelial cell counts above 5% in patients with tuberculous pleurisy (Hirsch et al. 1979; Lau 1989; Santos-Santre et al. 1990). Pleural fluid protein is usually greater than 3.0 Gldl, and glucose may be decreased. Pleural fluid

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lactic dehydrogenase (LDH) is usually above 200 LU.I L. Pleural fluid adenosine deaminase (ADA) measurement has been used as a biochemical parameter in an attempt to differentiate between tuberculous and other exudative non-tuberculous pleural effusions (Valdes et al. 1996). In a prospective study from India, Sharma et al. (2001) reported the diagnostic value of ADA as a marker for tuberculous pleurisy. Seventy-five patients with exudative pleural effusion were assessed. Pleural fluid ADA, as well as serum ADA, levels were significantly higher in tuberculous pleurisy compared with non-tuberculous effusions. The authors reported the sensitivity and specificity of pleural ADA at two cut-off points, 35 lUlL and 100 lUlL. At 100 lUlL, the sensitivity of ADA was 40% and the specificity was 100%. The authors suggested that using 100 lUlL pleural ADA level may spare as many as 40% of patients from having a pleural biopsy. However, ADA level estimation is complicated by false-positive and false-negative results (Yamada et al. 2001). Maartens and Bateman (1990) from South Africa found in their prospective study of 111 patients with pleural effusion that ADA did not provide a valuable diagnostic test of pleural tuberculosis as has been suggested. In recent years, the use of pleural fluid cytokines as parameters for the diagnosis of tuberculous pleurisy has been reported (Yamada et al. 2001; Pablo et al. 1997; Xirouchaki et al. 2002). In a comparative study between raised pleural levels of ADA and cytokines, interleukin-8 (IL-8), tumor necrosis factor alpha (TNF-a) and interferon gamma (IFN-y), Yamada et al. reported their findings. The study involved samples of pleural fluid obtained from 21 tuberculous, 21 inflammatoryand 18 malignancy cases. The authors indicated that IFN-y was a "very reliable marker" of tuberculous pleurisy. Xirouchaki and colleagues (2002) indicated that the measurement of pleural fluid cytokines might be helpful in differentiating malignancy from tubercu10sis in exudative pleural effusion. Methods for measuring antigens and antibodies to M. tuberculosis in the pleural fluid have been reported by many authors. It has further been reported that the sensitivity of these tests are only about 50% (Murante et al.1990; Hara et al. 1992; Caminero et al.1993). See chapter on Immunological Tests for Tuberculosis. Molecular biology techniques utilizing various PCR protocols have been developed for detecting the M. tuberculosis genome in pleural and other body fluid samples, as well as in tissue biopsies. The reported sensitivity and specificity has varied from one technique to another. Querol and colleagues (1995) from Spain reported 107 patients with pleural effusion

between 1991 and 1993. Twenty-one patients had proven tuberculosis and 86 non-tuberculous (cancer, parapneumonia, cirrhosis, heart failure, emphysema, lymphoma, SLE and non-specific pleuritis). The PCR assay was based on the detection of a 123-bp DNA segment belonging to the insertion sequence IS6100, specific for M. tuberculosis. The diagnoses of twentyone tuberculous patients were confirmed by clinical, PPD skin test, pleural ADA, cytology, microbiology and histopathology of pleural biopsies. Positive pleural biopsy with granuloma formation was found in 72%, positive culture in 67% and raised ADA activity in 86%. PCR sensitivity and specificity were found to be 81% and 100%, respectively. Other authors applied PCR to detect DNA (IS 6110) in pleural biopsy specimens (Takagi et al.1998). These authors reported PCR sensitivity and specificity of 89% and 100%, respectively, of patients, which was similar to the results of Querol and colleagues. These two studies demonstrate the excellent sensitivity and specificity of PCR using either pleural fluid or pleural tissue for rapidly diagnosing pleural tuberculosis. Pleural fluid microbiological examination (smear and culture) for M. tuberculosis may detect only 25% to 50% of patients (Idell 1994). In patients coinfected with HIV, pleural fluid cultures are more often positive than in non-HIV patients. Parenchymal lung infiltrates are more severe and depicted by various imaging modalities in HIV positive patients, suggesting more mycobacterial extension from the lung into the pleural space, in contrast to HIV negative individuals (Luzze et al. 2001). In a prospective study of 111 patients with pleural effusion, and from an area with a high prevalence of tuberculosis in South Africa, radiometric cultures using BACTEC and conventional cultures were compared (Maartens and Bateman 1990). Tuberculosis was confirmed by histopathology, microbiology or both in 62 patients (56%). Positive pleural fluid culture was found in 47%, while histology and tissue culture were positive in 84% and 71%, respectively. BACTEC was faster than conventional mycobacterial culturing, and the yield appeared after 18 versus 33 days. The incidence of a positive pleural fluid culture as reported in some series is shown in Table 22.2.

22.5.3 Pleural Biopsy Closed needle biopsy of the pleura should be considered for further evaluation if clinical features, PPD skin test, imaging findings and pleural fluid

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Table 22.2. Pleural tuberculosis in some recent reports: diagnostic procedures, % yield Series Year

Fluid culture % positive

Biopsy culture % positive

Biopsy histology % positive

PPD % positive

Maartens and Bateman (l990) Ankobiah et al. (l990) Seibert et al. (1991) Chang et al. (l991) Relkin et al. (1994) Kitinya et al. (1994) Heyderman et al. (1998) Our Own Series

47 57 58 23 83.3 28 14b (smear) 23

71 45.6 66.7 40 65.5 45.6 40 65

84 80.7 84.6 97 80 100 60 80

78 60 93 77 56 74 30' 76

'Had problem with PPD reading compliance bCulture was not reported

biochemical parameters and culture do not provide a definitive diagnosis. It is an invasive procedure with significant discomfort and potential complications (Ansari and IdellI998). Good quality single pleural biopsy sampling is sufficient to diagnose pleural tuberculosis, in contrast to the increased diagnostic yield with multiple biopsies for malignancy (Jimenez et al. 2002). Positive pleural biopsy culture was found to be higher than pleural fluid (39% versus 13%) by Bueno and colleagues (1990). Histopathological findings of granuloma in pleural biopsy may be found in up to 80% of cases. PCR of pleural tissue biopsy for M. tuberculosis was found to be rapid, sensitive and specific in 89-100% of cases for diagnosing pleural tuberculosis (Takagi et al. 1998). An audit to value the routine practice of pleural fluid aspiration and biopsy for the investigation of pleural effusion has been reported by Walshe and colleagues (1992). The authors reviewed the investigative results of pleural fluid and biopsy procedures of 112 patients. They reported that the protein content of pleural fluid was of little value as a diagnostic indicator, as it overlapped substantially between various other diagnostic groups. A low positive yield for microbiological findings was of significance. Pleural biopsy was performed only in 30% in this series. The authors, however, indicated that the practical difficulties regarding pleural biopsy included the lack of experience among junior staff, lack of pleural biopsy needles and inadequate or poor quality samples. The authors reported the rate of complications (pneumothorax and emphysema) as 2% for aspiration alone and 4% for aspiration combined with biopsy. The incidence of pleural tissue biopsies, positive cultures and the presence of granulomata on histopathological examination in different series are shown in Table 22.2.

22.5.4 Thoracoscopy in Tuberculous Patients

Thoracoscopic examination was first described by Professor Hans Christian Jabobaeus from Sweden in 1910. He inserted a cystoscope into the pleural space of two patients with exudative pleuritis (Thomas 1994). He reported his observations of patients with pulmonary tuberculosis that had been treated with pneumothorax in which there was no pleuritis. He also explored the therapeutic application of thoracoscopy in breaking adhesions in patients with pulmonary tuberculosis that were selected for lung collapse therapy. He noted the complications of thoracoscopy, including haemorrhage, pleural effusion and subcutaneous emphysema. At present, the role of thoracoscopy in obtaining pleural tissue biopsies in the diagnosis of pleural tuberculosis is restricted, as a closed-needle pleural biopsy is the most reasonable method of initially obtaining a diagnostic tissue specimen.

22.5.5 Tuberculin Skin Test (PPD)

The use ofPPD skin testing is valuable in the diagnosis of patients with pleural tuberculosis. In patients with recent conversion, pleural tuberculosis will be classified as primary tuberculous pleurisy. Patients with a past history of positive PPD or active tuberculosis will be classified as secondary (Ankobiah et al. 1990). The PPD skin test is considered positive when the induration measurement is over 9 mm, and it is found in 60 to 90% of patients with pleural tuberculosis as reported in several series (See Table 22.2). A negative PPD skin test is more frequently reported in patients with tuberculous pleurisy co-infected with

Pleural Tuberculosis

HIV than in those with negative HIV. Ankobiah and colleagues (1990) from New York found positive PPD reaction in only 12% of AIDS patients and 80% in non-AIDS patients. Relkin et al. (1994) found a similar low incidence of positive PPD in their patients with tuberculous pleurisy co-infected with HIV. compared with HIV negative ones (41 versus 76%). The high frequency of negative PPD skin tests among those co-infected with HIV reflects the alternation of delayed hypersensitivity due to HIV.

355

sion (Fig.22b in chapter 23). Bronchopleural fistula may be depicted by CT or fistulograrn (see Fig. 36 in chapter 23). Fibrothorax with diffuse pleural thickening but without effusion may be seen on CT. Ultrasonography (US) may play a role in the investigation of tuberculous pleural effusions. It may help in detecting pleural thickening, nodularity and in obtaining US-guided closed-needle pleural biopsy (Chang et al. 1991; Akhan et al. 1992). The imaging features of various modalities for pleural tuberculosis are non-specific, but may help in distinguishing tuberculous from non-tuberculous pleural disease.

22.5.6 Imaging Features of Pleural Tuberculosis 22.5.7 The imaging modalities most commonly used in Treatment tuberculous pleural disease are plain chest radiography, CT and ultrasonography. Rarely, a fistulogram Treatment of pleural tuberculosis is similar to treatfor bronchopleural fistula is used when CT localiza- ment of pulmonary disease. Full assessment is essention of the tract is not clear. CT is more sensitive tial, particularly in regard to prior treatment for TB, and useful than plain radiography in the evaluation drug susceptibility or resistance. The co-infection of pleural disease. It may show unrecognized small with HIV has to be determined. Detection of comsubpleural cavities, parenchymal lung involvement, plicated pleural effusion is essential, as it may lead lymphadenitis or rib involvement (see Figs. 36a, bin to therapeutic failure if medical treatment is used chapter on "Radiology of Pulmonary Tuberculosis") alone without surgical intervention. If left untreated, (Moon et al. 1999; Yilmaz et al. 1998; Winer-Muram pleural tuberculosis will develop into active pulmonary or extra-pulmonary disease within 5 years in at and Rubin 1990; Hunlnick et al. 1983). Unilateral, moderate or large pleural effusion can least 65% of immunocompetent patients (Roper and easily be depicted by plain radiography (see Figs. 12a, Waring 1955). Uncomplicated, HIV negative tuberculous pleub, 34b in the chapter on "Radiology of Pulmonary Tuberculosis"). Bilateral small or moderate pleural risy can be treated with a short course of 6-9 months effusions may be depicted by plain radiography and of anti-tuberculous chemotherapy. CT (see Fig. 12c in chapter 23). Imaging features of Six months of anti-tuberculous chemotherapy contiguous subpleural tuberculous cavities in the lung using two drugs for pleural tuberculosis was reported parenchyma as localized empyema may be seen on by Dutt et al. (1992). The authors used isoniazid 300 mg plain radiography or CT (see Figs. 22b, 26 in chapter 23) and rifampicin 600 mg daily for one month, followed (Seibert et al. 1991). Other imaging features of lung by twice weekly treatment with isoniazid 900 mg and parenchymal disease with bronchiectasis may be rifampicin 600 mg for five more months. This regimen noted in patients with tuberculous pleural effusion used by Dutt and colleagues on 161 patients with TB (see Fig. 30b in chapter 23). Features of large empy- pleurisy and follow-up for about 4-6 months revealed ema with increased thickness of the pleura may be no relapses. In areas with high risk for HIV infection found on plain radiography and CT (see Fig.34b in or with high incidence of drug-resistant mycobacteria, chapter 23). Tuberculous pleural empyema may be initial treatment should include at least four drugs localized with thick, calcified wall better depicted on until drug susceptibility testing is available. CT than plain chest radiography (see Figs. 13, 22b, 23, Immunosuppressed patients with pleural tuber34a, 35a in chapter 23). CT may depict focal pleural culosis should be treated for a much longer period, thickness with calcifications in the absence of fluid at least 12 months. Patients with multi-drug resistant collection (see Figs. 23, 32d in chapter 23). An asso- tuberculosis should be treated with 5-6 drugs. ciated destruction of adjacent ribs with cold abscess Complicated tuberculous pleural effusion may formation and empyema may be depicted better by CT be due to the development of loculated chronic (35a, b in chapter 23). Other calcifications in the lung empyema, drug resistance or bronchopleural fistula. parenchyma or mediastinal lymph nodes may also be Medical treatment alone will not be sufficient in such depicted in association with tuberculous pleural effu- patients and surgical intervention will be required

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(Brown and Pomerantz 1995; Iseman et al. 1991). Surgical treatment is discussed in detail in a separate chapter (see chapter XX). In a recent report from India, Lahiri et al. (1998) analyzed the surgical procedures for thoracic tuberculosis in 1655 cases seen over a 20-year period. These procedures were needed in only 2.2% of the patients, including tuberculous empyema with or without broncho-pleural fistula. Intercostal drainage with irrigation, thoracostoma and chest wall tube drainage were the most frequent minor procedures. Major procedures were less frequently required and included decortication and thoracoplasty.

References Akhan 0 et al (1992) Tuberculous pleural effusions: ultrasonic diagnosis. J Clin Ultrasound 20:461-465 Aktogu S et al (1996) Clinical spectrum of pulmonary and pleural tuberculosis: a report of 4, 480 cases. Eur Respir J 9:2031-2035 Ankobiah WA, Finch P Powell S et al (1990) Pleural tuberculosis in patients with and without AIDS. J Assoc Acad Minor Phy 1:20-23 Ansari T, Idell S (1998) Management of undiagnosed persistent pleural effusions. Clin Chest Med 19:407-417 Barnes PF, Mistry SD, Cooper CL et al (1989) Compartmentalization of a CD4+ T lymphocyte subpopulation in tuberculous pleurisy. J ImmunoI142:1114-1119 Barnes PF, Fong S-J, Brennan PJ et al (1990) Local production of tumor necrosis factor and IFN-'Yin tuberculous pleurisy. J ImmunoI145:149-154 Barnes P et al (1993) Cytokine production at the site of disease in human tuberculosis. Infect Immun 61:3482-3489 Batungwanayo J et al (1993) Pleural effusion, tuberculosis and HIV-l infection in Kigali, Rwanda. AIDS 7:73-79 Berger H, Mejia E (1973) Tuberculous pleurisy. Chest 63:88-92 Boylan AM, Ruegg C, Kim KJ et al (1992) Evidence of a role for mesothelial cell derived interleukin-8 in the pathogenesis of asbestos-induced pleurisy in rabbits. J Clin Invest 89: 1257-1267 Brown J, Pomerantz M (1995) Extrapleural pneumonectomy for tuberculosis. Chest Surg Clin North Am 5:289-296 Bueno CE et al (1990) Cytologic and bacteriologic analysis of fluid and pleural biopsy specimens with Cope's needle. Arch Intern Med 150:1190-1994 Caminero JA et al (1993) Diagnosis of tuberculosis by detection of specific IgG antigen 60 in serum and pleural fluid. Respiration 60:58-62 Carrion-Valero F, Perpina-Tordera M (2001) Screening tuberculous pleural effusion by discriminant analysis. Int J Tuberc Lung Dis 5:673-679 Chang DB et al (1991) Ultrasound-guided pleural biopsy with tru-cut needle. Chest 100:132-133 Chaparas SD, Thor DE, Hedrick SR (1971) Comparison oflymphocyte transformation, inhibition of macrophage migration and skin tests using dialyzable and nondialyzable tuberculin fractions from Mycobacterium bovis (BCG). J

M. M. Madkour et al. Immunol107:149-153 Christopher DJ, Peter JV, Cherian AM (1998) Blind pleural biop~y using a tru-cut needle in moderate to large pleural effUSIOn - an experience. Singapore Med J 39:196-199 Dutt AK et al (1992) Tuberculous pleural effusion: 6-month therapy with isoniazid and rifampicin. Am Rev Respir Dis 145:1429-1432 Ellner JJ et al (1988) The immunology of tuberculous pleurisy. Semin Respir Infect 3:335-342 Epstein DM et al (1987) Tuberculosis pleural effusions. Chest 91:106-109 Gedde-Dahl T (1952) Tuberculosis infection in the light of tuberculin maticuolation. Am J Hyg 56:139-214 George RB et al (1985) Mycobacterial, fungal, actinomycotic and nocardial infection of the pleura. Clin Chest Med 6:63-75 Goodman RB, Wood RG, Martin TR et al (1992) Cytokinestimulated human mesothelial cells produce chemotactic activity for neutrophils including NAP-lIlL-8. J Immunol 148:457-465 Hara N et al (1992) Pleural SC56-9 in differential diagnosis of tuberculous, malignant and other effusions. Chest 102: 1060-1064 Heyderman RS,Makunike R,Muza T et al (1998) Pleural tuberculosis in Harare, Zimbabwe: the relationship between human immunodeficiency virus, CD4 lymphocyte count, granuloma formation and disseminated disease. Trop Med Int Health 3:14-20 Hirsch A et al (1979) Pleural effusion: laboratory test in 300 cases. Thorax 34:106-112 Hunlnick D et al (1983) Pleural tuberculosis evaluated by computed tomography. RadioI149:759-765 Idell S (1994) Evaluation of perplexing pleural effusion. Contemp Intern Med 6:31-39 Iseman MD et al (1991) Chronic tuberculous empyema with bronchopleural fistula resulting in treatment failure and progressive drug resistance. Thorax 100:124-127 Jimenez D et al (2002) Determining the optimal number of specimens to obtain with needle biopsy of the pleura. Respir Med 96:14-17 Jonjic N, Peri G, Bernasconi S et al (1992) Expression of adhesion molecules and chemotactic cytokines in cultured human mesothelial cells. J Exp Med 176:1165-1174 Kitinya IN, Richter C, Perenboom R et al (1994) Influence pf HIV status on pathological changes in tuberculous pleuritis. Tuberc Lung Dis 75:195-198 Kunkel SL, Chensue SW, Strieter RM et al (1989) Cellular and molecular aspects of granulomatous inflammation. Am J Respir Cell Mol Bioi 1:439-447 Lassence AD et al (1992) Detection of mycobacterial DNA in pleural fluid from patients with tuberculous pleurisy by means of the polymerase chain reaction: comparison of two protocols. Thorax 47:265-269 Lau KY (1989) Numerous mesothelial cells in tuberculous pleural effusion. Chest 96:438-439 Lorgat F et al (1992) Evidence for in vitro generation of cytotoxic T-cells. PPD-stimulated lymphocytes from tuberculous effusion demonstrate enhanced cytotoxicity with accelerated kinetics of induction. Am Rev Respir Dis 145:418-423 Luzze H etal (2001) Evaluation ofsuspected tuberculous pleurisy: clinical and diagnostic findings in HIV-positive and HIV-negative adults in Uganda. Int J Tuberc Lung Dis 5:745-755 Maartens G, Bateman ED (1990) Tuberculous pleural effusion: increased culture yield with bedside inoculation of pleural

Pleural Tuberculosis fluid and poor diagnostic value of adenosine deaminase. Thorax 46:96-99 Maeda J, Ueki N, Ohkawa T et al (1993) Local production and localization of transforming growth factor-beta in tuberculous pleurisy. Clin Exp Immunol 92:32-38 Mbizvo MT et al (1996) HIV seroincidence and correlates of seroconversion in a cohort of male factory-workers in Harare, Zimbabwe. AIDS 10:895-901 Modilevsky T et al (1989) Mycobacterial disease in patients with human immunodeficiency virus infection. Arch Intern Med 147:2201-2205 Mohammed KA, Nasreen N, Ward MJ et al (1998) Mycobacterium-mediated chemokine expression in pleural mesothelial cells: role of C-C chemokines in tuberculous pleurisy. J Infect Dis 178:1450-1456 Moon WK et al (1999) Complicated pleural tuberculosis in children: CT evaluation. Pediatr RadioI29:153-157 Morehead RS (1998) Tuberculosis of the pleura. South Med J 91:630-636 Moudgil H et al (1994) Reactivation disease: the commonest form of tuberculous pleural effusion in Edinburgh. Respir Med 88:301-304 Murante T et al (1990) Antipurified protein-derivative antibody in tuberculous pleural effusion. Chest 97:670-673 Pablo AD et al (1997) Are pleural fluid parameters related to the development of residual pleural thickening in tuberculosis? Chest 112:1293-1297 Palmer PES (1979) Thoracic tuberculosis. Semin Roentegenol 14:204-243 Querol JM et al (1995) Rapid diagnosis of pleural tuberculosis by polymerase chain reaction. Am J Respir Crit Care Med 152:1977-1981 Relkin F,Aranda CP,Garay SM et al (1994) Pleural tuberculosis and HIV infection. Chest 105:1338-1341 Richter C et al (1991a) Extrapulmonary tuberculosis - a simple diagnosis? A retrospective study in Dar es Salam. Trop Geog Med 43:375-378 Richter C et al (1991b) Pleural effusion aetiology, diagnosis and clinical picture in HIV-positive and negative patients. A prospective study in Dar es Salam. Proceedings of the VIth international congress on AIDS in Africa, Dakar, Senegal, Dec 1991; WA.220 Richter C et al (1994) Clinical features ofHIV-seropositive and HIV-seronegative patients with tuberculous pleural effusion in Dar es Salam, Tanzania. Chest 106:1471-1476 Roper WH, Waring JJ (1955) Primary serofibrinous pleural effusion in military personnel. Am Rev Tuberc 71:616-635 Sahn SA (1988) State of the art - the pleura. Am Rev Respir Dis 138:184-234 Santos-Sastre et al (1990) Mesothelial cells and tuberculous pleuritis. Chest 98:518 Seibert AF et al (1991) Tuberculous pleural effusion. Twentyfive year experience. Chest 99:883-887

357 Sharma SK et al (2001) A prospective study of sensitivity and specificity of adenosine deaminase estimation in the diagnosis of tuberculous pleural effusion. Indian J Chest Dis Allied Sci 43:149-155 Shimokata K, Kishimoto H, Takagi E et al (1986) Determination of the T-cell subunit producing g-interferon in tuberculous pleural effusion. Microbiol Immunol 30:353-361 Shivaram I et al (1989) Pleural effusion in AIDS/ARC. Chest 96:2215 Spriggs AL, Boddington MM (1960) Absence of Mesothelial cells from tuberculous pleural effusions. Thorax 15:169-171 Stevenson F (1955) The natural history of pleural effusion and orthopaedic tuberculosis. J Bone Joint Surg Br 37:80-91 Sudre P et al (1992) Tuberculosis: a global overview of the situation today. Bull WHO 70:149-159 Takagi N et al (1998) Polymerase chain reaction of pleural biopsy specimens for rapid diagnosis of tuberculous pleuritis. Int J Tuberc Lung Dis 2:338-341 Takagi N, Hasegawa Y,Ichiyama S et al (1998) Polymerase chain reaction of pleural biopsy specimens for rapid diagnosis of tuberculous pleuritis. Int J Tuberc Lung Dis 2:338-341 Thomas PA (1994) A thoracoscopic peak: what did Jacobaeus see? Ann Thorac Surg 57:770-771 Valdes L et al (1996a) Adinosine deaminase (ADA) isoenzyme analysis in pleural effusion: diagnostic role and relevance to the origin of increased ADA in tuberculous pleurisy. Eur Respir J 9:747-751 Valdes L et al (1996b) The etiology of pleural effusion in an area with high incidence of tuberculosis. Chest 109:158-162 Wallis RS (1996) New approaches to identification of antigens of Mycobacterium tuberculosis. Infect Agents Dis 5: 119-125 Walshe AD, Douglas JG, Kerr KM et al (1992) An audit of the clinical investigation of pleural effusion. Thorax 47:734-737 Willis RS, Amiy-Tahmasseb M, Ellner JJ (1990) Induction of interleukin-l and tumor necrosis factor by mycobacterial proteins: the monocyte Western blot. Proc Nat! Acad Sci USA 87:3348-3352 Winer-Muram HT, Rubin SA (1990) Thoracic complications of tuberculosis. J Thorac Imag 5:46-63 Xirouchaki N et al (2002) Diagnostic value of interleukin-lalpha, interleukin-6 and tumor necrosis factor in pleural effusion. Chest 121:815-820 Yamada Yet al (2001) Cytokines in pleural liquid for diagnosis of tuberculous pleurisy. Respir Med 95:577-581 Yamamura Y, Onoue K, Azuma I (1968) Biology of the mycobacterioses. Chemical and immunological studies on peptides and polysaccharides from tubercle bacilli. Ann NY Acad Sci 154:88-97 Yilmaz MU et al (1998) Computed tomography findings of tuberculous pleurisy. Int J Tuberc Lung Dis 2:164-167 Zhang M, Gately MK, Wang E et al (1994) Interleukin 12 at the site of disease in tuberculosis. J Clin Invest 93: 1733-1739

23 Radiology of Pulmonary Tuberculosis MONA AL SHAHED, MOHAMMED ABD EL BAGI, M. MONIR MADKOUR

CONTENTS 23.1 23.2 23.2.1 23.2.2 23.2.3 23.2.4 23.2.5 23.3 23.3.1 23.3.1.1 23.3.1.2 23.3.1.3 23.3.1.4 23.3.2 23.3.3 23.3.3.1 23.3.3.2 23.3.3.3 23.3.3.4 23.3.3.5 23.3.3.6 23.4 23.5 23.6 23.6.1 23.6.2 23.6.3 23.6.3.1 23.6.3.2 23.6.3.3 23.6.3.4

Introduction 359 Imaging 359 Conventional Radiography 359 Computed Tomography (CT) 360 High Resolution Computed Tomography 360 Bronchography 360 Arteriography 360 Classification and Radiological Presentation 360 Primary Tuberculosis 360 Parenchymal Disease 361 Lymphadenopathy 362 Pleural Disease in Primary Tuberculosis 364 Miliary TB 365 Paradoxical Transient Worsening Phenomenon 366 Post Primary Tuberculosis 368 Parenchymal Disease 369 Cavitation 370 Endobronchial Disease 371 Tuberculoma 374 Pleural Disease in Post-primary Tuberculosis 375 Mycetoma Formation 378 Assessment of Activity of Pulmonary TB 379 Non-tuberculous Mycobacteria 379 Mycobaqerial Infection and Human Immunocompromised Virus (HIV) 379 Background 379 Mycobacterial Tuberculosis 380 Non-Tuberculous Infections 380 Mycobacterial Avium-intercellular Complex (MAl) 380 Mycobacterial Kansasii 381 Other Non-Tuberculous Infections 381 Non-Tuberculous Bacteria in Immunodeficiency States Other than HIV 382 References 382

M. AL SHAHED, MBBS, FRCR Senior Consultant Radiologist, Department of Radiology, Riyadh Armed Forces Hospital, P.O. Box 7897, Riyadh 11159, Saudi Arabia M. ABD EL BAGI, MB BCh, DMRD, FSRRCSI Senior Consultant Radiologist, Department of Radiology, Riyadh Armed Forces Hospital, P.O. Box 7897, Riyadh 11159, Saudi Arabia M. M. MADKOUR, MD, DM, FRCP Consultant, Department of Medicine, Riyadh Armed Forces Hospital, P.O. Box 7897, C-119, Riyadh 11159, Saudi Arabia

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

23.1

Introduction

Tuberculosis (TB) is a disease caused by infection with Mycobacterium tuberculosis and accounts for more than 95% of pulmonary mycobacterial infection. Other non-tuberculous mycobacteria, e.g. M. Kansasii, M. avium-intercellular complex and others, account for the remainder. Tuberculosis (TB) can affect virtually any organ system in the body. It is a topic of universal concern due to the recent resurgence of (TB) in both immunocompetent and immunocompromised individuals (Davis et al. 1993). Much of this increase has been ascribed to human immunocompromised virus infection (HIV), poverty and homelessness. The radiology of pulmonary (TB) reflects, and is influenced by, the immune status of the host, the virulence of the organisms, the presence of delayed hypersensitivity due to mycobacterium tuberculosis and the method of spread. Pulmonary (TB) is classically divided into primary and post primary (reactivation) disease. There is considerable overlap in the radiological manifestation of these two entities. Should primary (TB) pass into the post primary form without a break, the term progressive primary tuberculosis is used.

23.2

Imaging

23.2.1 Conventional Radiography Conventional chest radiography is the mainstay in the detection and follow up examination of patients with pulmonary TB. Good quality chest radiographs are essential and remain the first line of investigation. Normal radiographs do not exclude tuberculosis and have been reported in up to 10% of immunocompetent patients and in up to 20% of immunocompromised patients (Fitzgerald et al. 1991; Greenberg et al. 1994).

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23.2.2

23.2.4

Computed Tomography (CT)

Bronchography

Recently, conventional Computerized Tomography (CT) has been used in selected cases. It is required in many circumstances such as in the detection of cavitation and in the evaluation of the route of spread (Kuhlman et al. 1990). CT is most useful in assessing pleural disease and in patients with extensive opacification on the conventional radiographs because of the marked destruction of the lung by the disease process. CT has proven to be more sensitive than conventional radiography in detecting adenopathy, parenchymal shadowing, particularly in miliary disease, and in detecting bronchogenic dissemination. CT is used in the evaluation of complications that might occur in the process of the disease, including bronchopleural fistula formation and extension into chest wall. CT is also used to guide percutaneous intervention procedures and pre-surgical planning.

Bronchography was once the tool of choice for the detection of bronchiectasis, but it has now been replaced by HRCT.

23.2.3 High Resolution Computed Tomography High resolution CT (HRCT) is extremely useful in understanding the pathological process of the disease and route of spread; it is also useful in the evaluation of disease activity (1m et al. 1993).

23.2.5 Arteriography

Bronchial artery angiography is currently performed for therapeutic reasons in the treatment of lifethreatening haemoptysis, which is not a common presentation of bronchiectasis due to tuberculosis.

23.3 Classification and Radiological Presentation 23.3.1 Primary Tuberculosis Primary (TB) is a term used when the infected individual has not been previously exposed to M. tuberculous and lacks hypersensitivity to tuberculoprotein. Initially, primary TB was described in infants and children, in whom it remains the most common

b

a

Fig. 23.1. a Primary TB. Chest x-ray of 7 year old showing ill-defined air space consolidation (arrowheads). b CT the same patient showing dense air space consolidation with air bronchogram (arrowhead)

Radiology of Pulmonary Tuberculosis

form (Miller and Miller 1993; Lamont et al. 1986). Increasingly, however, it has been encountered in adult population, and it is now estimated to account for 23-34% of all adult cases (Buckner et al. 1990; McAdams et al. 1995; Miller and Miller 1993; Miller 1994; Woodring et al. 1986). Radiologically, primary pulmonary TB typically manifests in four major ways, singly or in aggregate: (l) parenchymal disease; (2) lymphadenopathy; (3) pleural effusion; and (4) miliary disease (Agrons et al. 1993; 1m et al. 1995; Leung et al. 1992; Palmer 1979; Stansberry 1990). Ten percent (lO%) of all cases of primary TB progress directly into the chronic form, which is indistinguishable from reactivation (Gepport and Left 1979). Moreover, the result of a chest radiograph may be normal in 15-50% of cases (McAdams et al. 1995; Miller and Miller 1993; Woodring et al.1986). 23.3.7.7

ParenchYn1alDisease By radiological examination, parenchymal shadowing is commonly manifested as homogenously dense air space consolidation with ill-defined margins, frequently segmental or lobar in distribution (Fig. 23.1a). Expansion of a consolidated lobe may occur (Fig. 23.2). The focal parenchymal lesion may be mass-like, and in adults it may be confused with neoplasia (Fig. 23.3). It is usually unilateral and single, but multilobar consolidation can be seen in up to 25% of cases (Leung et al. 1992; Woodring et al. 1986). A tendency to favor the right lung has

Fig. 23.2. Chest x-ray demonstrating dense air space consolidation with expansion of right upper lobe in 10 years old child with primary tuberculosis.

361

emerged in several series (Lamont et al. 1986; Leung et al. 1992; Weber et al. 1968). This was also noted in our patients. No consensus has been reached as to regional preference within the lung. Upper lobe predominance (Weber et al. 1968; Nagakura 1960; Joffe 1960; Choyke et al. 1983), mid and lower lobes predominance (Woodring et al. 1986; Choyke et al. 1983) and no anatomic bias (Lamont et al.1986) have each been reported. Cavitation may occur in primary TB (Fig. 23.4). The incidence varies from 10% (Choyke et al. 1983) to 30% (Woodring et al. 1986). It is more common in infants and children raised in communities in which TB has been introduced comparatively recently (Weizman et al. 1980). At Computed Tomography (CT), primary TB typically manifests as dense hemogenous air space consolidation with well-defined margins (Harishigani et al. 2000) (Fig. 23.1b). Parenchymal shadowing usually resolves with no radiological sequelae over 6-24 months. Some may be left with residual scarring or a calcified focus (Ghon focus). This is seen in up to 20% of patient (Fig. 23.5). Occasionally during the first three months of treatment, worsening of parenchymal shadowing occurs despite appropriate therapy, a phenomenon referred to as paradoxical transient worsening (see below). Single or multiple tuberculomas may develop in primary TB, but they are seen much less frequently than in post primary TB.

Fig.23.3. Chest x-ray of a 35-year old female with primary tuberculosis presenting with a focal lung lesion (arrow), right paratracheal and left hilar lymph adenopathy (arrowhead)

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b

a Fig. 23.4. a Chest x-ray showing cavitation within tuberculous consolidation in the right upper lobe. b The lesion has resolved with minimal residual scaring after the completion of antituberculous treatment

Fig.23.5. Chest x-ray showing foci of the calcification in the right perihilar region (arrowhead) a stigma or previous tuberculous infection

23.3.1.2 Lymphadenopathy

Lymphadenopathy is the hallmark of primary TB, with or without concomitant parenchymal abnormality. Age stratification qas been identified in many series (Lamont et al. 1986; Leung et al. 1992; Weber et al. 1968), with a higher prevalence of lymphadenopathy in children under 3 years of age than in

older children and adults with primary tuberculosis (McAdams et al.1995; Woodring et al.1986). It can be the only manifestation in young children (Campbell and Dyson 1977). Any lymph node group may be involved, but the patterns commonly seen are unilateral hilar, unilateral hilar plus right paratracheal or isolated right paratracheal adenopathy (Fig. 23.6). Right paratracheal nodal involvement predominates in our experience, similar to the experience of others (Amorosa et al. 1978; Rottenberg and Shaw 1996; Weber et al.1968). Bilateral adenopathy has also been described in up to 32% of cases (Leung et al. 1992); when present, it is almost always asymmetrical and can be strikingly extensive, resembling lymphoma, metastatic disease and sarcoidosis (Fig. 23.7). CT demonstrates lymphadenopathymore accuratelythan chest radiographs. Characteristically, on post-contrast studies the nodes larger than 2 cm in diameter consistently display a low density center, 40-50 HU, with enhancing peripheral rims (Harishigani et al. 2000) (Fig. 23.8), and hence citing dissimilarity to lymphoma, sarcoidosis or histoplasmosis. Lymphadenopathy usually resolves at a slower rate than parenchymal lesions. Nodal calcification occurs 6 months or more after infection and is more frequently seen than parenchymal calcification; it is encountered in up to 35% of all cases (Weber et al. 1968; Leung et al. 1992). There are significant differences in the distribution and pattern of calcification of lymph nodes in TB and sarcoidosis, which can be explained by the route of lymphatic drainage and the

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a Fig.23.6. Primary tuberculous presenting with isolated right paratracheallymphadenopathy in 12-year old male patient

b

Fig. 23.8. Post contrast CT of the chest demonstrating characteristic appearance of tuberculous lymphadenopathy with low density centre and enhancing peripheral rim (arrowheads)

Fig. 23.7. a Frontal and lateral. Chest x-ray of primary tuberculosis presenting with extensive lymphadenopathy resembling lymphoma. Note large hilar (arrow) and bilateral paratracheal (arrowhead) lymph node involvement. b Lateral x-ray of the same patient demonstrating hilar adenopathy (arrows)

caseating nature of tuberculous granulomas. When hilar node calcification is present, it is more likely to be unilateral in TB and bilateral in sarcoidosis. A focal pattern of calcification is more common in sarcoidosis, while complete nodal calcification is common in TB (Fig. 23.9). Nodal pressure and/or erosion into adjacent structures may lead to the following complications: (1) Obstruction of airways leading to over-inflation and/or segmental/lobar collapse, usually in the anterior segment of the right middle lobe; (2) Perforation into an airway, leading to Widespread bronchogenic dissemination. The healing of these

lesions, though occasionally without sequelae, often results in various combinations of bronchostenosis, bronchiectasis, parenchymal fibrosis and loss of lung volume; (3) Haematogenous spread from infected nodes, which can lead to "metastatic" lesions such as soft tissue abscesses. These "metastatic" foci may lie dormant for years before they become active, manifesting as bone, joint or renal TB; (4) Erosion of the node into the pericardium, leading to tuberculous pericarditis. Pericarditis can also be a complication of miliary TB. Involvement of the pericardium can present in the form of pericardial effusion (Fig. 23.10) or

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Fig. 23.10. Chest x-ray demonstrating cardiac enlargement due to pericardial effusion caused by tuberculous pericarditis Fig.23.9. Chest x-ray demonstrating complete lymph node calcification typical of tuberculosis (arrowhead). Note extensive cystic bronchiectasis changes in the right middle and lower lobes (arrows), some showing air fluid level (small arrows). Also node calcined granuloma in the left mid zone (short arrow)

in the form of constrictive pericarditis, with or without calcification (Fig. 23.11). Other complications of nodal involvement include erosion into oesophagus, phrenic and recurrent laryngeal nerve paresis, superior vena cava obstruction and fistula formation. 23.3.1.3 Pleural Disease in Primary Tuberculosis

Pleural effusion is fairly common, occurring in up to 25% of cases. Unlike lymphadenopathy, it is seen more in adults than in children (Weber et al. 1968; Stead et al. 1968; Derham 1956). The effusions are generally unilateral, the exception being when the disease is a complication of miliary TB. Associated pulmonary parenchymal lesions or adenopathy may be radiologically occult. Tuberculosis should be considered in any young patient with moderate size or large unilateral pleural effusion in the absence of demonstrable pulmonary disease (Fig. 23.12a, b). Pleural effusion in primary tuberculosis can be self-limiting, or it can lead to serious disease years later. The effusions are usually painless and can be very large at presentation. The majority of these effusions are reactive in nature, rather than due to direct pleural involvement

Fig. 23.11. Lateral chest x-ray showing pericardial calcification as sequelae to tuberculous pericarditis (arrowheads)

by tuberculosis. Therefore, mycobacterium bacilli are rarely isolated from culture of the pleural fluid. The diagnosis is best established by pleural biopsy. CT is more sensitive than plain radiographs in depicting associated pulmonary infiltrate and adenopathy in addition to pleural fluid (Fig. 23.12c, d). CT will also demonstrate evenly thickened parietal pleura, which will enhance when contrast material is used. Com-

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a

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d Fig. 23.12. a Chest x-ray demonstrating left sided pleural effusion with no visible parenchymal lesion or adenopathy in a young patient presenting with fever, night sweat, loss of weight and high ESR. Pleural biopsy confirms the diagnosis. b Post enhanced CT of the chest of the same patient demonstrating right sided simple effusion (arrow). c Thoracic post-enhanced CT of another patient presented with fever and weight loss showing thin bilateral pleural effusion (arrowheads) and lymph nodes (arrows). d CT scan of the same patient at lower level showing posterior mediastinal adenopathy. No parenchymal lesions were seen Bronchial aspirate was positive for tuberculosis

plete resolution is the usual sequelae to antituberculous treatment. Incompletely resolved effusions will commonly develop into secondary disease (Palmer 1979). Tuberculous empyema is a less common form of pleural disease in primary tuberculosis, resulting from discharge of mycobacterium bacilli into pleural space (Fig. 23.13). It is usually seen in post primary cases (see below). 23.3.7.4 Miliary 18

Miliary TB results from haematogenous dissemination of the organisms and is seen in both primary and reactivation tuberculosis. It is increasingly encountered in adults, particularly the immunosuppressed, in whom it has been reported in up to 13% of cases

(Lee and 1m 1995). It is associated with a very high mortality if untreated, respiratory failure being the major cause of death. The characteristic radiologiCal appearance consists of Widespread nodular shadows measuring 2-3 mm in diameter and randomly distributed throughout the parenchyma (Fig. 23.14). In approximately 50% of cases the initial radiographs appear normal. Ill-defined haze can be an early manifestation before the characteristic miliary pattern became discernable. High resolution CT (HRCT) can detect diffuse lung changes where the initial radiographic appearance is normal or undetermined (Fraser et al. 1989). Miliary TB at HRCT manifests as numerous fine, discrete nodular or reticulonodular shadows. An associated nodular appearance of the interlobular septa and vessels may also be seen (McGuinness et al. 1992) (Fig. 23.15). Miliary tuber-

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culosis differs from bronchogenic spread in its even distribution throughout the lung and its uniform size. Diseases which have a similar appearances to that of miliary TB are varicella pneumonia, sarcoidosis, histoplasmosis, metastasis, pneumoconiosis and haemosiderosis. The resolution of these nodules is

Fig. 23.13. Tuberculous empyema as a complication of pleural disease. Note the presence of irregular pleural calcification (arrowheads)

a

usually slow and complete, with no residual calcification after treatment. Radiological improvement can be seen within 3 weeks of starting therapy.

23.3.2 Paradoxical Transient Worsening Phenomenon Paradoxical transient worsening of the radiographic findings, both parenchymal and extraparenchymal, is common in the first three months following the initiation of therapy (Akira et al. 2000; Amodio et al. 1986; Bobrowitz 1980; Campbell and Dyson 1977; Lamont et al. 1986; Matthay et al. 1974; Weber et al. 1968). Paradoxical response refers to progression of the original lesions or development of new ones during apparently adequate antituberculous treatment (Bobrowitz 1980), usually regresses without a change in the initial drug regimen. As we and others have observed (Akira et al. 2000), progression often manifests as enlargement of the original parenchymal shadowing. Areas of ground glass opacities, new areas of consolidations ipsilateral or contralateral to the initial lesion and new macronodules in the ipsilateral site were also encountered; none were with cavitations (Figs. 23.16, 23.17). It is important to recognize this transient benign phenomenon to avoid unnecessary invasive procedures or changes of appropriate therapy. The mechanisms of these clinically and radiologically impressive changes remain unclear. Several hypotheses have been considered,

Fig. 23.14. a Chest x-ray of a child presenting with miliary tubeculosis. Note widespread nodular shadowing involving both lung fields. b Miliary tuberculosis in another child presenting with massive mediastinal adenopathy (arrowheads) and superadded consolidation in the right middle lobe (arrow)

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a Fig. 23.15. a CT scan of the chest demonstrating numerous fine discrete nodular shadow. Note the nodular appearance of the interlobular septa (arrows). b CT scan of same patient more caudally showing the miliary pattern of tuberculosis. Note the nodular irregular outline of the blood vessels (arrows)

b

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Fig. 23.16. a Paradoxical transient worsening: A young female patient presented with malaise, fever, weight loss and night sweats. Chest x-ray showed right paratracheal adenopathy (arrow) and ill-defined consolidation in the right perihilar region (arrowhead). Tuberculosis was diagnosed based on positive bronchial aspirates and was started on antituberculous treatment. b Chest x-ray 8 weeks after initiation of antituberculous treatment showed progression of the parenchymal lesion with development of new macronodular lesions (arrowheads). Note significant regression of the right paratracheal adenopathy. c Chest x-ray demonstrates complete resolution after completion of antituberculous treatment

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Fig.23.17. a Paradoxical transient worsening: A middle aged male patient with positive bronchial aspirate. Initial chest x-ray showed patchy infiltrates in the right lower lobe. b Six weeks after initiation of antituberculous treatment a new lesion with thick wall developed in the right upper lobe (arrowhead). Note resolution of the initial changes. c Chest x-ray 6 months after initiation of treatment showing almost complete resolution

a

b

including enhanced focal immune responses (Iwai et al. 1979; Marshall and Chambers 1988), local hypersensitivity to sudden destruction of the bacilli and tuberculoprotein (Onwubalili et al. 1986) and local hypersensitivity to drug reaction (Akira et al. 2000). Interestingly, new pulmonary lesions during therapy for extrapulmonary TB have been reported by Sze-chunhung et al. (Hung and Chang 1999). Transient paradoxical worsening should be differentiated from true worsening of tuberculous lesions, complication by bacterial and fungal infection and drug reaction. Thin-cut CT in this aspect may playa role. In a study by (Akira et al. 2000), the dominant CT findings of transient progressions were ground glass opacities and/or consolidation, whereas the dominant CT findings of true worsening of TB were macronodules and centrilobular nodules, often with cavitations. Currently, the American Thoracic Society

and Centers for Disease Control recommend a radiographic evaluation at 2-3 months after initiation of therapy (Bass et al. 1986). Parenchymal abnormalities can then be evaluated every 2-3 months until they clear, and lymphadenopathy at yearly intervals until radiographically stable (Abernathy 1989).

23.3.3 Post Primary Tuberculosis The term post-primary TB is used to describe tuberculosis in patients who have acquired tubercula protein hypersensitivity from a previous infection or BCG vaccination. Other terminology used include: reactivation, secondary, reinfection or adult tuberculosis. Postprimary disease results from reactivation of a previously dormant primary infection in 90% of

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cases, and as extension of primary TB in 10% of cases (Woodring et al. 1986). It is a disease of adolescence and adulthood characterized by its chronicity, strong site preference, cavitation and fibrosis. Radiologic features of postprimary TB can be broadly classified as lung parenchymal disease with cavitation, endobronchial airway disease, tuberculoma, pleural extension and other complications. 23.3.3.1

ParenchYlnalDisease The earliest radiological manifestation is the development of exudative lesions of patchy ill-defined segmental or subsegmental infiltrations in typical anatomic regions: apical and posterior segments of an upper lobe or a superior segment of a lower lobe in 95% of patients. This site of preference has been attributed to the oxygen tension being relatively high, and to lymphatic drainage being relatively ineffective in these areas. The lesions consist of peripheral consolidation, often patchy and frequently associated with accentuated bronchovascular markings, extending to the ipsilateral hilar region (Fig. 23.18). Widespread bronchopneumonia is usually a result of endobronchial seeding (Spencer et al. 1990). Despite this strong site preference, no portion of the lung is immune; isolated anterior and basal involvement have been reported (Woodring et al. 1986). Pulmonary TB presenting as segmental consolidation has similar radiological appearances as non-tuberculous segmental pneumonia. Park et al. (1999) have shown

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that CT findings of fluid-bronchogram, in an area of consolidation, bronchial dilatation and proximal bronchial wall thickening is significantly more prominent in tuberculous pneumonia than in nontuberculous, non obstructive pneumonia (Fig. 23.19, 23.24b). Hilar and mediastinal lymph node involvement is veryrare,being reported in only5% ofcases (Woodring et al. 1986) (Fig. 23.20). The initial exudative infiltrates will be replaced by a more sharply defined nodular pattern (acinar nodules), interspersed with reticular opacities of fibroproductive lesions (Fig. 23.21). The

Fig. 23.19. CT chest demonstrating dense consolidation with fluid-bronchogram (arrowheads), and evidence of endobronchial spread (small arrows). The posterior mass (large arrows) is due to enlarged lymph nodes

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b Fig. 23.18. a Chest x-ray of an adult female showing patchy consolidation with element of collapse in the right upper lobe. Note bilateral hilar calcification as evidence of previous tuberculous infection (arrowheads). b Chest x-ray of an adult male showing consolidation in the apical segment of both upper lobes. Note calcification of the hilar lymph nodes (arrows)

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Fig.23.20. Chest x-ray of 40 year old male presented with fever and malaise, chest x-ray showed upper lobe and lower lobe consolidation with associated paratracheal adenopathy

(arrowheads)

b

Fig.23.21. Post primary TB. Chest x-ray demonstrating noduloreticular opacities in the apical segment of the right upper lobe with element of fibrosis. Note shifting of the trachea to the ipsilateral site

majority of patients show both patterns. Marked tissue destruction may occur at this stage, with cavitation and necrosis. Healing may occur by fibrosis, resulting in cicatrization, considerable loss of lung volume, traction bronchiectasis and atelectasis. Scattered calcification may also be seen (Fig.23.22) (Lee et al. 1991). Secondarily, compensatory signs include elevation of ipsilateral hilum, over-infiltration of adjacent lung tissue and bullate formation (Figs. 23.23, 23.24). Extensive fibrosis and bullae formation with scattered

Fig. 23.22. a Post primary TB. Chest x-ray demonstrating fibrotic changes with cicatrization, deviation of trachea to the right indicating loss of lung volume in the right upper lobe (black arrowheads). Bronchial distortion is also present (white arrowhead). b CT of different patient with post primary TB showing evidence of fibrosis and thickened septi in the left upper lobe and scattered calcific densities (arrows). Patchy emphysematous changes (white arrowhead) and thickened pleura (black arrowheads). Note complete calcification of lymph nodes (large black

arrowhead)

macronodular shadows are seen in end-stage pulmonary tuberculosis (Fig. 23.25). 23.3.3.2 Cavitation Cavitation is a distinct feature of postprimary TB and is of considerable diagnostic significance, since it indicates the likelihood of activity (1m et al. 1993). It is seen in up to 40-80% of patients with postpri-

Radiology of Pulmonary Tuberculosis

Fig. 23.23. Post primary TB. Chest x-ray demonstrating fibrotic changes with considerable loss of lung volume of the right upper lobe. Note deviation of trachea to the ipsilateral site, elevation of right hilum, (small arrow) and compensatory hyperinflation of right lower lobe (large arrow). Pleural thickening and calcification (arrowheads)

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Fig. 23.24. Post primary TB chest x-ray demonstrate end stage tuberculous changes involving the right lung with extensive fibrosis, loss of lung volume, deviation of the mediastinum, bullae formation (arrowheads) and hyperinflation of the left lung

mary TB (Rottenberg and Shaw 1996). Cavities tend to occur in the areas of consolidation. They have no diagnostic features and may be single or multiple, small or large, thin or thick-walled (McAdams et al. 1995). Air fluid level may be present, but it is uncommon and usually indicates superadded infection (Fig. 23.26). Spontaneous pneumothorax may be seen (Woodring et al. 1986). A residual tuberculous cavity may lead to endobronchial spread or become a site for the development of mycetoma. Rasmussen aneurysm is a rare but a life-threatening complication of cavitary lesion involving the wall of the pulmonary artery, and may lead to massive haemoptysis if ruptured. 23.3.3.3

Endobronchial Disease Endobronchial disease is a common complication seen in up to 40% of patients with active TB. The source of bronchogenic spread is usually from an adjacent tuberculous cavity or tuberculous lymph node containing liquefied materials rich in tuberculous bacilli (Smith and Schillaci 1987; McLoud and Naidich 1992). The spread through peribronchial lymphatic channels or directly via infected sputum are less common routes (Collins et al. 1998; Rottenberg and Shaw 1996). Rarely, the airways can be involved through a haematogenous route via bronchial arteries (Auerbacho 1949; Buckner and Walker

Fig.23.25. Post primary TB. Chest x-ray showing end stage tuberculous changes with extensive fibrosis, macro noduloreticular shadows, hyperinflation and bullae formation involving both lung fields. Note scattered calcifications

(arrowheads)

1990). Bronchogenic spread can be ipsilateral or contralateral, and bilateral dissemination can also occur. (see chapter 21, Endobronchial Tuberculosis) The radiological manifestations of bronchogenic spread include multiple small nodular opacities that

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a

d

c Fig. 23.26. a Post-primary TE. Chest x-ray demonstrating a large thick wall cavity in a consolidated left upper lobe with an air fluid levels (arrow). Patchy infiltrate with macronodular shadows in the right lower lobe (small arrowheads) indicating bronchogenic spread. Note two nodular opacities in the left midzone representing tuberculous granuloma (open arrows). b CT chest of a different patient demonstrating thick-walled subpleural tuberculous cavity with air fluid level. Note localized empyema as a complication (arrowheads). c Tomography of the chest demonstrates a thin-wall tuberculous cavity (arrow). d Tuberculous abscess. Chest x-ray of a female patient with bilateral thin wall cavities demonstrating air fluid level (arrowheads)

may later become confluent (Fig. 23.27). Bronchial wall thickening, post-stenotic dilatation, lobar hyperinflation, persistent pulmonary collapse, obstructive pneumonia and mucoid impaction are other radiological features of bronchogenic disease. HRCT is more sensitive than conventional radiographs in demonstrating early endobronchial spread. The most common findings are the formation of 2-4 mm centrilobular nodules and branching linear structures ((tree-on bud" appearance), which represent caseation necrosis within and around the bronchioles. The centrilobular nodules are well defined and of high attenuation, a finding which is unusual in other

causes of bronchopneumonias (1m et al. 1993, 1995) (Fig. 23.28). Other findings include ill defined 8 mm centrilobular nodules, lobular consolidation, thickened interlobular septa and long segment narrowing with acentric wall thickening of the bronchi (1m et al. 1993; Lee et al.I993). Bronchiectasis is a common complication of endobronchial TB (Lee et al. 1991). It is defined as the irreversible dilatation of a bronchial tree. It is typically secondary to pulmonary destruction and fibrosis (traction bronchiectasis). It may also result from central bronchostenosis (Fig. 23.27c). Since the vast majority of post primary TB affects apical and

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b

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Fig. 23.27. a Endobronchial tuberculosis: chest x-ray showing multiple small nodular opacities (arrows). b Endobronchial TE. Chest x-ray showing consolidation of the left upper lobe with large cavity with irregular outline and an intracavitary mass, mycetoma (arrowheads). Multiple macronodular shadows are seen bilaterally (arrows) indicating bronchogenic spread. Note hyperinflation of the right upper lobe and the paraspinal tuberculous abscess (curved arrows). c Endobronchial tuberculosis: chest x-ray demonstrates extensive bronchiectasis and cavitation in the right upper lobe with multiple bilateral basal nodular and bronchial linear shadows of indicating bronchogenic spread (arrows)

posterior segments of the upper lobes, facilitating bronchial drainage, bronchiectasis is usually asymptomatic. Chest radiographic findings include tram line opacities (dilated thickened wall bronchi with loss of normal tapering) and ring shadows, occasionally with air-fluid levels (Fig. 23.9). Bronchography was until recently the investigation of choice for the diagnosis of bronchiectasis (Fig. 23.29). CT, particularly HRCT, has replaced bronchography in the diagnosis of bronchiectasis in the recent years (Park et al.1999), with sensitivity up to 82-97% (Munroe et al. 1990; Grenier et al. 1986). Features on HRCT include uniform bronchial dilatation extending to the lung periphery without tapering (Fig. 23.28a), bronchial wall thickening and ring shadows representing markedly dilated bronchi (Fig. 23.30). HRCT is able to demonstrate the lobular distribution of airway abnormalities in early bronchiectasis

not seen using conventional x-ray or conventional CT. Features include subpleural nodules and branching linear structures ("tree-on-bud" appearance) corresponding to impacted bronchioles (Fig. 23.28c) (Davis et al. 1993; Moon et al. 1997). Hypertrophy of bronchial arteries, secondary to bronchiectasis, is demonstrated on contrast enhanced CT. With effective treatment, most of the changes of endobronchial spread resolve over time; residual fibrosis, bronchiectasis and emphysematous changes are invariably seen. The latter is believed to result from traction by adjacent fibrosis, from paracicatricial emphysema, and from bronchial stricture (1m et al. 1993). CT after treatment will demonstrate the residual changes of fibrosis, bronchiectasis and emphysema. Lobular emphysematous changes will give rise to a mosaic pattern (Fig. 23.31) (Eber et al. 1993; Martin et al. 1986).

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Fig.23.28. a Endobronchial tuberculosis: HRCT scan showing irregular bronchial wall thickening, loss of tapering (long arrow), multiple scattered linear branching densities, tree-on-bud (small arrow), and macronodular shadows. b CT of the same patient at lower level showing widespread macronodular and linear branching shadows of endobronchial spread (arrowheads). Note solid consolidation in the left lower lobe and massive adenopathy (arrow). c CT scan of the same patient at lung bases demonstrating impaction of the peripheral bronchioles with infective material resulting in extensive linear and nodular shadows (arrowheads)

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23.3.3.4 Tuberculoma

Fig.23.29. Bronchogram demonstrating both cystic (arrowheads) and tubular (arrows) dilatation of the lower lobe bronchial tree

A tuberculoma is a focus of acid-fast bacilli that is encapsulated by connective tissue. It can be a manifestation of either primary or secondary TB, and it is believed to represent localized parenchymal disease that alternately activates and heals. Tuberculoma always carry a potential risk of cavitation and dissemination. They are seen in 3-6 % of cases, can be multiple and may be associated with satellite nodules (Leung 1999). Tuberculoma, by radiographic investigation, appears as a well-defined, round or oval masslike lesion (Fig. 23.32a). Most tuberculoma are <3 cm in size (range 0.5-5 cm) (Lee et al. 1991). The majority of these lesions remains stable for a long time; 20-30% may calcify. CT shows them as low attenuation masses that do not enhance with contrast media (Gawne-Cain and Hansell 1996) (Fig. 23.32b-d).

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a b Fig. 23.30. a CT chest showing multiple ring shadows of cystic bronchiectasis in the superior segment of the right upper lobe. b CT scan of patient presented with post-primary TB showing extensive cystic bronchiectatic changes as complication of endobronchial disease. Note fluid levels (arrows). Pleural effusion was due to cardiac failure

b Fig. 23.31. a CT scan demonstrating change of fibrosis with residual bronchiectatic changes m the left upper lobe. Note the mosaic pattern in the lung fields due to lobular emphysematous changes (arrowheads). b CT demonstrating end result of endobronchial disease. There is evidence of traction bronchiectasis (arrowheads), bullae (open arrow) and tubular bronchial dilatation (arrow). Note pleural thickening in the right apical zone. Note mosaic appearance in the left upper lobe from lobular emphysema

23.3.3.5

Pleural Disease in Post-primary Tuberculosis The pleural effusion accompanying post primary TB is usually an empyema, and it carries a worse prognosis than does effusion in primary TB. When present, the condition is invariably associated with parenchymal disease. Radiologically, it appears as lobulated pleural collections associated with pleural calcification (Figs. 23.13, 23.33). Presence of air fluid level (hydropneumothorax) usually indicates presence of

bronchopleural fistula. CT demonstrates the pleural disease to better advantage than ordinary radiography (Fig. 23.34) (Hulnick et al.1983). CT is also more sensitive in demonstrating associated parenchymal lesions and peripheral subpleural cavitary lesions, which could be the cause of empyema formation (Fig. 23.26b); CT is also more sensitive in demonstrating associated complications such as bronchopleural fistula, rib destruction and cold abscess (empyema necessitatis) (Fig. 23.35). Fistula can also be demonstrated by fistulogram (Fig. 23.36).

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Fig.23.32. a Chest x-ray of an adult showing well-defined round lesion with central lucency representing tuberculoma (arrow). Two other nodular opacities are seen in the right lower lobes representing multiple tuberculomas. b CT of the same patient in prone position showing the tuberculoma of soft tissue density and central lucency (arrow). c CT at lower level demonstrating two other tuberculomas presenting as homogenous round tissue opacities (arrowheads). d CT chest of another patient showing single tuberculoma in the left lower lobe with central focal calcification (small arrowhead) Note the fibrotic band extending to an area of focal pleural thickening (large arrowhead)

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a

Fig. 23.33. Chest x-ray demonstrates extensive pleural disease caused by previous tuberculous infection. There is considerable pleural thickening and calcification causing fibrothorax (arrowhead). Note compensatory emphysema of the right upper and middle lobe b

Fig. 23.34. a CT of the chest demonstrating tuberculous empyema (arrow) manifesting as localized collection of high density fluid associated with pleural thickening (arrowheads). b CT of the chest showing a large empyema with associated thickening of parietal pleura (large arrowheads). Note fluid bronchogram in collapsed consolidated apical segment of the left upper lobe (small arrowheads)

b

a Fig. 23.35. a CT chest showing pleural thickening (short arrows), localized collection with irregular calcification (large arrow) associated with rib destruction and localized cold abscess appearing as low density area within the intercostal muscles (arrowheads). Note localized pleural thickening with calcification on the left. b Chest x-ray of the same patient later after completion of antituberculous treatment showing resolution of the pleural pathology demonstrated on a and residual changes in the affected ribs (arrowheads)

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Fig.23.36. Fistulogram demonstrate pleuro bronchial fistula caused by tuberculous changes in the apical segment of the left upper lobe (arrowheads)

23.3.3.6 Mycetoma Formation

Pulmonary mycetomas are masses of Aspergillus hyphae matted together to form a fungus ball. The fungi colonize a pre-existing cavity in the lung, usu-

ally tuberculous in origin, but can also develop in sarcoidosis, emphysematous bullae, histoplasmosis and in cavitary bronchial carcinoma. Approximately 15% of tuberculous cavitary lesions larger than 25 mm in diameter become colonized by Aspergillus Fumigatus (Research Committee 1970). Fungal ball develops in both tuberculous cavities as well as in areas of cystic bronchiectasis. The majority of mycetomas are found in the upper lobes and superior segments of the lower lobes. The majority are asymptomatic. Haemoptysis, although uncommon, being the most important complication that may warrant surgical resection or bronchial artery embolization. When haemoptysis is a presenting symptom, differentiation between mycetoma formation, reactivation of tuberculosis and development of bronchial carcinoma becomes difficult. The radiographic findings include demonstration of a mass within a cavity. Air crescentic sign, an air rim between the wall of the cavity and the fungal ball, is highly suggestive but not specific (Fig. 23.37). The wall of the cyst is usually thickened, and an associated adjacent pleural reaction is not uncommon; osteomyelitis of the adjacent rib can also occur. Right and left lateral decubitus films may show the mobile nature of the fungal ball. Immature mycetoma is seen as an irregular spongework of soft tissue containing air spaces and obliterating the cavity (Rottenberg and Shaw 1996). HRCT aids in the diagnosis of mycetoma as well as in pre-operative assessment (Kuhlman et al. 1990).

a Fig.23.37. a Mycetoma. Chest x-ray demonstrates a large cavity in the left upper lobe with a fungal ball (arrow). (Courtesy of Dr. M. Mutairi) b Localized view of this region shows the characteristic appearance of crescentic sign (arrow). (Courtesy of Dr. M. Mutiari)

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23.4 Assessment of Activity of Pulmonary T8 Chest radiography plays an important role in the diagnosis of pulmonary TB, both assessing the activity and monitoring the response to treatment. Inactivity cannot be reliably diagnosed on a single radiograph, and serial radiographs are required. Tuberculous foci, which appear inactive over an extended period, such as extensive calcification and pulmonary fibrosis, can harbour active disease with the potential to break down under certain favorable circumstances. Features that suggest active disease are ill-defined air space shadowing, miliary nodulation and cavitation. CT is more sensitive in the detection of miliary disease, cavitation and lymphadenopathy. HRCT has been proven to playa role in the early detection of endobronchial spread and in the determination of disease activity. The presence of branching centrilobular lesions without evidence of fibrotic bronchovascular distortion are highly suggestive of active disease (1m et al. 1995). Conventional radiographs are used to follow up patients once treatment has started. Radiographic resolution of pulmonary changes can take from 6 to 24 months. Complete resolution is seen in two-thirds of patient (Lee et al. 1991). Radiographic worsening can be seen despite appropriate therapy "transient radiographic progression" and should be differentiated from true worsening (see text). In patients with HIV, assessment of disease activity is less sensitive as the possibility of secondary infection and other pulmonary complications are common and should always be considered (Barnes et al. 1991).

23.5 Non-tuberculous Mycobacteria One to three percent of mycobacteria other than M. tuberculosis have been identified as causes of pulmonary infection (Woodring and Vandiviere 1990). These include M. kansasii, M. avium-intercellular complex, M. fortuitum and M. gordonae. These are free-living sporocyte. Infection is acquired by inhalation or ingestion from the environment. Non-tuberculous mycobacterial infections have a predilection for individuals with pre-existing chronic obstructive pulmonary disease, underlying debilitating disease, a previous tuberculous infection and patients who are immunocompromised. Males are more commonly affected than females, and tuberculin skin tests are usually negative or weakly positive. Radiological fea-

tures of non-tuberculous mycobacterial infections are in general indistinguishable from post primary TB and have similar site preferences: posterior segments of the upper lobes and the superior segments of the lower lobes. Cavitation is a distinct feature, occurring in up to 96% of cases. Cavities tend to be multiple (Abelda et al. 1985; Erasmus et al. 1999). CT findings of non-tuberculous mycobacteria ranges from small to large nodular infiltrates, consolidation, cavitations and bronchiectasis (Hartman et al. 1993).

23.6 Mycobacterial Infection and Human Immunocompromised Virus (HIV) 23.6.1 Background Mycobacterial infection is an important cause of morbidity and mortality in immunocompromised patients, particularly those infected with HIY. The association between HIV and tuberculosis has been observed since 1984 (Barnes et al. 1991; Greenberg et al. 1994). Pulmonary TB occurs in 4-21 % of patients with acquired immunocompromised syndrome (AIDS) (Davis et al.1993), and it was declared to be an AIDS-defining disease in 1993. The increased susceptibility of these patients to tuberculosis is best explained by their altered immunity function. The T-helper lymphocyte (CD 4 Tcell) and to lesser extent macrophage depletion and dysfunction process are central to the HIV disease rendering these patients particularly susceptible to tuberculous infection. Both M. tuberculosis and non-tuberculous mycobacteria have become a serious problem in patients infected with HIY. Noninvasive diagnostic methods, such as sputum stain and culture, are less effective in the immunocompromised host. Moreover, other infections and non-infectious disease processes are common in these patients and there is considerable overlap in radiological manifestation, making accurate diagnosis more difficult. Clinicians are often forced to choose between the use of invasive techniques to determine the exact cause of the pulmonary disease or an empirically chosen therapy (McLoud 1989; McLoud and Naidich 1992). The role of radiology in this setting is important and involves not only detection of abnormalities on chest radiographs or CT, but also analysis of these changes with regard to the possible diagnosis and choice of an appropriate interventional technique, e.g. percutaneous needle biopsy and aspiration. The role of radiology

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disease and in the identification and characterization of lymphadenopathy. HRCT is also helpful in demonstrating parenchymal lesions in patients whose chest radiographs are normal (Leung etal. 1996).

23.6.2 Mycobacterial Tuberculosis Reactivation is the primary mechanism of infection. Rapid progression of newly acquired infection has also been described (Small et al. 1994). Clinical and radiological features depend on the degree of cellular immune compromise, especially CD 4 T-cell count. In early stages of HIV disease (CD 4 count>200 cell/mm\ radiological findings are typical of post primary TB, especially apical cavitary disease and bronchogenic spread. Skin testing to tuberculin is usually positive at this stage. With a greater degree of immunocompromise (CD 4 count <200 cell/mm\radiographs typically show a pattern more consistent with primary TB, including hilar and mediastinal adenopathy, non-cavitary infiltrates equally distributed in both upper and lower lobes, multiple nodules, miliary disease and unilateral and bilateral pleural effusion (Figs. 23.38,23.39). However, normal radiographs have been reported in up to 15% of cases (Greenberg et al. 1994). Skin testing at this stage is positive in only 20-40% of patients, similarly bronchoalveolar lavage is positive in only 20% of cases. In contradistinction, chest radiographic abnormalities can be identified in up to 85% of cases, making accurate interpretation imperative, as therapy with antituberculous drugs are usually effective (Barnes et al.1991; Leung 1999; Greenberg et al. 1994). HRCT is helpful, especially in the evaluation of miliary

Fig.23.38. Atypical mycobacteria. Chest x-ray of immunocompromised patient presented with miliary pattern. Note the diffuse fine nodular opacities in both lung fields from MAl infection

23.6.3 Non-Tuberculous Infections 23.6.3.1 Mycobacterial Avium-intercellular Complex (MAl) The incidence of (MAl) in patients with AIDS has risen since pneumocystis prophylaxis has been widely instituted (Hoover et al. 1993). Unlike infection with M. tuberculosis, pulmonary disease is relatively uncommon in patients infected with MAL Significant radiographic abnormalities occur in approximately 5% of cases and then only late in the course of HIV disease (Horsburgh 1991). Infection with MAl typically causes disseminated extrapulmonary disease, presumably due to the fact that the main route of entry is the gastrointestinal tract. There are no distinctive pulmonary radiographic abnormalities in patients with MAl infection and AIDS; moreover, other associated opportunistic diseases are common. The radiographic pulmonary findings described in the literature range from normal chest x-rays to mediastinal adenopathy, pulmonary infiltrates, diffuse nodules, miliary spread and pleural effusion (Fig. 23.40). Localized pulmonary disease is uncommon, occurring in less than 5% of patients (Horsburgh 1991), and cavitation is rare. MAl is very resistant to antituberculous drugs, and no treat-

Fig.23.39. Post renal transplant patient presented with respiratory failure. Chest x-ray show extensive consolidation, macronodular pattern and massive mediastinal adenopathy (arrowheads). Lung biopsy confirmed MAl infection

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b

a

Fig.23.40. a Chest x-ray of an adult patient with atypical mycobacterium MAl infection demonstrating consolidation, patchy infiltration and bronchiectatic changes in the right middle lobe (straight arrow). Note cavitation (curved arrow) and pleural effusion (arrowhead). (Courtesy of Dr. M. Enani). b CT scan of the same patient showing macro-nodular opacities in the right lower lobe (arrows), consolidation in the middle lobe c pleural thickening and effusion (small arrowhead), and adenopathy (large arrowhead). (Courtesy of Dr. M. Enani). c CT scan of the same patient at higher cuts showing bronchiectatic changes in the right middle lobe and medial basal segment of the right lower lobe (arrows)

ment regimen has proven entirely satisfactory. Because of the poor outcome of treatment, prophylaxis is recommended in patients with CD4 count <50 celI/mm 3• 23.6.3.2 Mycobacterial Kansasii

M. Kansasii is second only to M. tuberculosis in the frequency with which it causes pulmonary disease. Radiographic manifestation mimics post primary tuberculosis, including upper lobe cavitary infiltrates, endobronchial lesions and lymphadenopathy (Bamberger et al.1994; Christensen et al.1978, 1981; Connolly et al. 1993). Normal chest radiographs have also been reported (Fishman et al. 1997).

c

23.6.3.3 Other Non-Tuberculous Infections

Virtually all atypical mycobacterial infections that complicate HIV infection have been caused by MAl and M. Kansasii. M. gordonae, M. fortuitum, M. chelonei, M. haemophilum, M. malmoense and M. terrae are extremely rare causes and usually manifest as disseminated disease (Fakih et al. 1996; Saubolle et al. 1996; Carbonara et al. 2000). Radiological manifestations are nonspecific, ranging from normal radiographs to focal and diffuse infiltrates. Prognosis is generally poor, as most of these organisms are resistant to antituberculous treatment.

382

M. Al Shahed et al.

a Fig. 23.41. Post enhanced CT of the chest for a 67-year-old female patient with hairy cell leukemia. a Mediastinal setting at the level of aortic arch showing multiple enlarged lymph nodes (arrowheads). b Lung window setting at the same level demonstrates ill-defined increased parenchymal densities and macronodular shadows (arrows)

23.6.3.4 Non-Tuberculous Bacteria in Immunodeficiency States Other than HIV Malignancy and immunosuppressive therapy for organ transplantation (steroid and chemotherapy) can predispose patients to infection with non-tuberculous mycobacteria. Among malignancies, there is a particular strong association with hairy cell leukemia (Fig. 23.41) (Libshitz et al. 1981; Weinstein et al. 1981). A review of the literature points to the prevalence of MAl infection in these patients and to the fact that the disease is more common than was previously thought. Pulmonary involvement, according to multiple reports, is most often a manifestation of disseminated infection rather than a primary lung disorder. Reported radiographic manifestations include normal chest radiographs, single or multiple pulmonary nodules and masses, lymphadenopathy and patchy alveolar infiltrates with or without cavitation (Albelda et al. 1985; Bamberger et al. 1994; Long et al. 1991).

References Abernathy RS (1989) Tuberculosis in children and its management. Semin Respir Infect 4:232-242 Agrons G A, Markowitz RI, Kraner SS (1993) Pulmonary tuberculosis in children. Semin RoentgenoI2:158-172 Akira M. Sakatani M, Ishikawa H (2000) Transient radiographic progression during initial treatment of pulmonary tuberculosis: CT findings. J Comput Assist Tomogr 24:426-431

Albelda SM, Kern JA, Marinelli DL, Miller WT (1985) Expanding spectrum of pulmonary disease caused by nontuberculous mycobacteria. Radiology 157:289-296 Amodio J, Abramson S, Berdon W (1986) Primary pulmonary tuberculosis in infancy: a resurgent disease in urban United States. Paediatr RadioI16:185-189 Amorosa JK, Smith PR, Cohen JR (1978) Tuberculous mediastinallymphadenitis in the adult. Radiology 126:365-368 Auerbacho (1949) Tuberculosis of trachea and major bronchi. Am Rev Tuberc 60:604-606 Bamberger DM, Driks MR, Gupta MR et al. (1994) Mycobacterium kansasii among patients infected with human immunodeficiency virus in Kansas city. Kansas city AIDS Research Consortium. Clin Infect Dis 18:395-400 Barnes PF, Bloch AB, Davidson PT, Snider DE (1991) Tuberculosis in patients with human immunodeficiency virus infection. N Engl J Med 324:1644-1650 Bass JB, Farer LS, Hopewell PC et al (1986) Treatment of tuberculosis and tuberculosis infection in adults and children. Am Rev Respir Dis 134:355-363 Bobrowitz D (1980) Reversible roentgenographic progression in the initial treatment of pulmonary tuberculosis. Am Rev Respir Dis 121:735-742 Buckner CB, Walker CW (1990) Radiologic manifestation of adult tuberculosis. J Thorac Image 5:28-37 Campbell lA, Dyson AJ (1977) Lymphnode tuberculosis: a comparison of various methods of treatment. Tuberculosis 58:171-179 Carbonara S, Tortoili E, Costa D et al (2000) Disseminated Mycobacterium terrae infection in a patient with advanced human immunodeficiency virus disease. Clin Infect Dis 30: 831-835 Christensen EE, Dietz GW, Ahn CH et al (1978) Radiographic manifestations of pulmonary mycobacterium kansasii infections. AJR 131:985-993 Christensen EE, Dietz GW, Ahn CH et al (1981) Initial roentgenographic manifestation of pulmonary M. tuberculosis, M. kansassi, M. intercellularis infections. Chest 80: 132-136

Radiology of Pulmonary Tuberculosis Choyke PL, Soskman HD, Curtis AM et al (1983) Adult onset tuberculosis. Radiology 148:357-362 Collins J, Blankenbaker D, Stern E (1998) CT patterns ofbronchiolar disease: what is tree-in-bud? AJR 171:365-370 Connolly MG Jr, Baughman RP, Dohn MN (1993) Mycobactrium kansasii presenting as an endobronchial lesions. Am Rev Respir Dis 148:1405-1407 Davis SD, Yankelevits DF, Williams T et al (1993) Pulmonary tuberculosis in immunocompromized hosts: epidemiological, clinical and radiological assessment. Semin Roentgenol 28:119-130 Derham RJ (1956) Post primary intrathoracic tuberculosis in childhood with special reference to its sequelae. Taxes J Med 52:583-585 Eber CD, Stark P, Bertozzi P (1993) Bronchiolitis obliterans on high resolution CT: a pattern of mosaic oligemia. J Comput Assist Tomogr 17:853-856 Erasmus JJ, McAdams HP, Farrell MA et al (1999) Pulmonary non-tuberculous mycobacterial infection: Radiologic manifestations. Radiographics 19:1487-1503 Fakih M, Chapalamadugu S, Ricart A, Corriere N Amsterdam D (1996) Mycobactrium malmoense bacteremia in two AIDS. J Clin MicrobioI34:731-733 Fishman JE, Schwartz DS, Sais GJ (1997) Mycobacterium kansasii pulmonary infection in patients with AIDS: spectrum of chest radiographic findings. Radiology 204:171-175 Fitzgerald JM, Gizybouski S, Allen EA (1991) The impact of human immunodeficiency virus infection on tuberculosis and its control. Chest 100:191-200 Fraser RG, Pare JAP, Pare PD et al (1989) Infectious diseases of the lung. In: Diagnosis of diseases of the chest, vol 2, 3rd edn. Saunders, Philadelphia pp 882-940 Gawne-Cain ML, Hansell DM (1996) The pattern and distribution of calcified mediastinal lymph nodes in sarcoidosis and tuberculosis: A CT study. Clinical Radio 51:263-267 Gepport EF, Left A (1979) The pathogenesis of pulmonary and miliary tuberculosis. Arch Intern Med 139:1381-1383 Greenberg SD, Frager D, Suster B, Walker S, Stavropoulos C, Rothpeal A (1994) Active pulmonary tuberculosis in patients with AIDS: spectrum of radiographic findings (including a normal appearance). Radiology 193:115-119 Grenier P, Maurice F, Musset D et al (1986) Bronhiectasis: assessment by thin section CT. Radiology 161:95-99 Harishigani M, Mcloud T, Shepard J, Ko J et al (2000) Tuberculosis from head to toe. Radiographics 20:469-470 Hartmann TE, Swensen SJ, Williams DE (1993) Mycobactrium avium-intercellulare complex: evaluation with CT. Radiology 187:23-26 Hoover DR, Saah AJ, Bacellar H et al (1993) Clinical manifestation of AIDS in the era of pneumocytis prophylaxis. N Engl J Med 329:1922-1926 Horsburgh CR Jr (1991) Mycobacterium avium complex infection in the acquired immunodeficiency syndrome. N Engl J Med 324:1332-1338 Hulnick DH, Naidich PD, McCauley DL (1983) Pleural tuberculosis evaluated by computed tomography. Radiology 1489:759-765 Hung S, Chang S (1999) New pulmonary lesions during therapy for extrapulmonary tuberculosis. Chest 116: 1794-1797 1m JG, Hoh H, Shim YS, Lee JH,Ahn J, Han MC, Noma S (1993) Pulmonary tuberculosis: CT findings early active disease and sequential change in antituberculous therapy. Radiology 186:653-660

383 1m JG, Itoh H, Han MC (1995) CT of pulmonary tuberculosis. Semin Ultrasound CT/MR 16:420-434 Iwai K, Kiao C, Tsuchiya S, Kita R, Kinoshita T (1979) Histological observation on the tuberculous lesions aggravated during rifampicin treatment (in Japanese). Kekkaku 54: 473-478 Joffe N (1960) Cavitating primary pulmonary tuberculosis in infancy. Br J Radiol 33:430-433 Kuhlman JE, Deutsch JH, Fishman EK et al (1990) CT features of thoracic mycobacterial disease. Radiographics 10: 413-431 Lamont AC, Cremin BJ, Pelleret RM (1986) Radiological patterns of pulmonary tuberculosis in paediatric age group. Pediatr RadioI16:2-7 Lee KS, 1m JG (1995) CT in adults with tuberculosis of the chest: characteristic findings and role in management. AJR 164:1361-1367 Lee KS, Kim YH, Kim WS, Hwang SH et al (1991) Endobronchial tuberculosis: CT features. J Comput Assist Tomogr 15:424-428 Lee KS, Song KS, Lim TH, Kim PN et al (1993) Adult onset pulmonary tuberculosis; findings on chest radiographs and CT scans. AJR 160:753-758 Leung AN, Millet NL, Pired PR et al (1992) Primary tuberculosis in childhood. Radiographic manifestations. Radiology 182:87-91 Leung NA (1999) Pulmonary tuberculosis: the essentials. Radiology 210:307-322 Leung NA, Brauner MW, Gamus G et al (1996) Pulmonary tuberculosis: comparison of CT findings in HIV-seropositive and HIV-seronegative patients. Radiology 198: 687-691 Libshitz HI, Shuman LS, Gresik MV (1981) Pneumonia in hairly cell leukemia Radiology 139:19-24 Long R, Maycher B,Scaicini M et al (1991) The chest roentgenogram in pulmonary tuberculosis patients seropositive for human immunodeficiency virus type 1. Chest 99:123-127 Marshall BG, Chambers MA (1988) Central nervous system tuberculosis: the paradox of host immune response. J Infect 36:3-4 Martin KW, Sagel SS, Siegel BA (1986) Mosiac oligemia stimulation pulmonary infiltrates on CT. AJR 147:670-673 Matthay RA, Neff TA, Iseman MD (1974) Tuberculous pleural effusion developing during chemotherapy for pulmonary tuberculosis. Am Rev Respir Dis 109:469-472 McAdams HP, Erasmus J, Winter JA (1995) Radiologic manifestations of pulmonary tuberculosis. Radiol Clin North Am 33:655-678 McGuinness F, Naidich DP, Jagirdar J, Leitman B, Mc Cauley DL (1992) High resolution CT findings in miliary lung disease. J Comput Assist Tomogr 16:384-390 McLoud TC (1989) Pulmonary infections in the immunocompromised host. Radiol Clin North Am 27:1059-1062 McLoud TC, Naidich DP (1992) Thoracic disease in the immunocompromised patient. Radiol Clin North Am 30: 525-554 Miller WT (1994) Tuberculosis in the 1990s. Radio Clin North Am 32:649-661 Miller WT, Miller WT (1993) Tuberculosis in the normal host: radiological findings. Semin Roentgenol 28:109-118 Moon Wk, 1m JG, Yeon KM et al (1997) Tuberculosis of the central airways: CT findings of active and fibroxic disease. AJR 169:649-653

384 Munroe NC, Cooke JC, Currie DC et al (1990) Comparison of thin section computed tomography with bronchography for identifying bronchiectatic segments in patients with chronic sputum production. Thorax 45:135-139 Nagakura Y (1960) Pathologic-anatomic studies or resected lungs of younger patients with pulmonary tuberculosis. Clin Resp Organs (Tokyo) 15:462 Onwubalili JK, Scott GM, Smith H (1986) Acute respiratory distress related to chemotherapy of advanced pulmonary tuberculosis; a study of two cases and review of the literature. Q J Med 59:599-610 Palmer PES (1979) Pulmonary tuberculosis usual and unusual radiographic presentations. Semin RoentgenoI14:204-242 Park S, Hong YK, Joo SH, Choe KO, Cho SH (1999) CT findings of pulmonary tuberculosis presenting as segmental consolidation. JComput Assist Romogr 23:736-742 Research committee of the British Thoracic and Tuberculosis Association (1970) Aspergilloma and residual tuberculous cavities: the result of survey. Tubercle 51 :227- 245 Rottenberg GT, Shaw P (1996) Radiology of pulmonary tuberculosis. Br J Hosp Med 56: 195-199 Saubolle MA, Kiehn TE, White MH, Rudinsky MF, Armstrong D (1996) Mycobacterium haemophilum: microbiology and expanding clinical and geographic spectra of disease in humans. Clin Microbiol Rev 9:435-447 Small PM, Hopewell PC, Singh SP et al. (1994) The epidemiology of tuberculosis in San Francisco. A population based

M. Al Shahed et al. survey using conventional and molecular methods. New Engl J Med 330:1703-1709 Smith LS, Schillaci RF (1987) Endobronchial tuberculosis: serial fibroptic bronchoscopy and natural history. Chest 91:644-647 Spencer D, Yagan R, Blinkhorn R, Spagnuolo PJ (1990) Anterior segment upper lobe tuberculosis in the adult. Occurrence in primary and reactivation disease. Chest 97:384-388 Stansberry SD (1990) Tuberculosis in infants and children. J Thorac Imag 5:17-27 Stead WW, Kerby GR, Schuleter DP et al (1968) The clinical spectrum of primary tuberculosis in adults: confusion with reinfection in the pathogenesis of chronic tuberculosis. Ann Intern Med 68:731-737 Weber AI, Bird KT, Janower ML (1968) Primary tuberculosis in children with particular emphasis on changes affecting the tracheobronchial tree. AJR 103:123-132 Weinstein RA, Golomb HM, Grumet G et al (1981) Hairy cell leukemia: association with disseminated atypical mycobacterial infection. Cancer 48:380 Weizman Z, Shvi Y, Ayalon A (1980) Primary cavitary tuberculosis in an infant chest 77:578-581 Woodring JH, Vandiviere HM (1990) Pulmonary disease caused by non tuberculous mycobacteria. J Thorac Imag 5:64-76 Woodring JH, Vandiviere HM, Fried AM et al (1986) Update: the radiographic feature of pulmonary tuberculosis. AJR 146:497-506

24 Pulmonary Function Test and Tuberculosis MAJDY M. IDREEs, SIRAJ

0 WALl, ABDULLA AL-AMOUDI

CONTENTS 24.1 24.1.1 24.2 24.2.1 24.2.2 24.2.3 24.2.4 24.3 24.3.1 24.3.2 24.4 24.5 24.6 24.7 24.8

Pulmonary Function Abnormalities in Tuberculosis 385 Historical Aspect 385 TB and Restrictive Lung Disease 385 Parenchymal Lung Disease 385 Pleural Disease and Fibrothorax 386 Endobronchial Tuberculosis 386 Surgical and Collapse Procedures 386 TB and Obstructive Lung Disease 387 Endobronchial Tuberculosis 387 Bronchiectasis 388 TB and Mixed Pattern of Obstructive and Restrictive Abnormality 389 TB and Respiratory Failure/Hemodynamics Preoperative Evaluation 390 Case Illustration 391 Discussion 392 References 392

389

24.1 Pulmonary Function Abnormalities in Tuberculosis 24.1.1 Historical Aspect Tuberculosis (TB) is an ancient disease. It has been found in the spines of Egyptian mummies. Drawings of persons with Potts's disease have been found on the walls of Egyptian tombs. Hippocrates (460-370 B.C.) called the disease "phthisis," and Varro (116-28 B.C.) conceived the notion that organisms too small to be seen by the naked eye might be causing the disease. M. M. IDREEs, MD, FRCP (C), FCCP Head, Pulmonary Function Laboratory, Division of Pulmonary Medicine, Department of Medicine, Riyadh Armed Forces Hospital, ClIO, P.O. Box 7897, Riyadh 11159, Saudi Arabia S. O. WAll, MD, FRCP (C), FCCP Head, Division of PulmonaryMedicine,Department of Medicine, King Khalid Hospital, National Guard, Jeddah, Saudi Arabia A. AL-AMOUDI, MD, FRCP (C) Deputy Head, Department of Medicine, King Faisal Specialist, Hospital & Research Center, Jeddah, Saudi Arabia

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

Before the availability of chemotherapy, pulmonary function assessment was frequently performed in patients with pulmonary tuberculosis. In 1846, Hutchinson suggested a correlation between the severity of the reduction in vital capacity and the extent of the parenchymal disease. There are no characteristic pulmonary function abnormalities in patients with pulmonary tuberculosis. Restrictive, obstructive or mixed pattern can present, depending on the extent, chronicity and the location of the disease (see below). However, in most patients with mild to moderate disease, the pathological abnormality is transient and complete recovery in pulmonary function tests takes place after completion of therapy. As an infection control measure, in our lab a pulmonary function test is not performed until three sputum samples have stained negative for acid-fast bacilli (AFB).

24.2 T8 and Restrictive Lung Disease Both complications and therapeutic measures for controlling tuberculosis can result in restrictive lung disease.

24.2.1 Parenchymal Lung Disease The pulmonary tissue response to the inhalation of Mycobacterium tuberculosis is characterized by hypersensitivity leading to necrosis that is surrounded by inflammatory cells. These cells form a fibrotic tissue encompassing the area involved in the inflammatory process, isolating it from the remaining lung parenchyma. Limitation of the infection to this stage has no significant effect on pulmonary function or gas exchange abnormality. Decreased static and dynamic lung volume, reduced forced expiratory volume in one second (FEV!) propor-

M. M. Idrees et aI.

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tionally to forced vital capacity (FVC) and reduction in the diffusion capacity (DLco) can result from necrotizing tuberculous pneumonitis. In massive pneumonia, severe hypoxemia and widening of the alveolar-arterial oxygen gradient (A-a 02) take place. This is related to the low V/Q ratio and the development of venous admixture. In the absence of coexisting significant airway obstructions, hypercapnia is rarely observed. Tuberculosis is an uncommon, but treatable, cause of Acute Lung Injury I Acute Respiratory Distress Syndrome ALIIARDS that might develop as a complication of tuberculous pneumonitis. The exact pathogenesis of ALII ARDS in TB is unclear. Massive release of mycobacteria into pulmonary circulation with secondary hyperimmune and inflammatory reaction leading to infiltrative and obliterative endarteritis, basal membrane thickness and vascular and endothelial leakage is the postulated mechanism. Whether partial or complete resolution of the lung function abnormalities will take place depend on the extent of scarring and fibrous tissue deposition after the acute injury. Most patients who survive the acute attack will have a mild degree of parallel reduction in both FEVI and FVC three months after hospital discharge that will continue to improve during the first year. A subset of survivors might end with permanent residual abnormality manifested by low diffusion capacity. In a group of 73 patients with cavitary disease and 27 patients with non-cavitary disease, Marcus and colleagues reported an average vital capacity of 67% and a diffusing capacity of 63% of that predicted at baseline (Marcus et al. 1963). In contrast, Malik and Martin reported an average arterial oxygen tension (Pa02) of 76 mmHg at baseline in 104 patients with tuberculosis, but the number of cavities was not specified (Malik and Martin 1969). More recently, Long and coworkers reported milder changes in pulmonary function in these patients. They prospectively studied 25 patients with pulmonary tuberculosis. Pulmonary function tests were performed at baseline, 1 and 6 month intervals. Patients with non-cavitary disease (15 cases) had virtually normal lung function, while those with cavitary disease (10 cases) had very mild restrictive changes (vital capacity and diffusing capacity averaging 88 and 85%, respectively, of that predicted) and trivial hypoxemia with Pa02 averaging 85 mmHg. In the same study, some correlation of lung function with structure (number of cavities) was found (Long et al. 1998). This may explain why patients in earlier studies had inferior values, i.e. they had more disease or pre-existing lung function abnormalities.

24.2.2 Pleural Disease and Fibrothorax Pleural involvement is very common in tuberculous infection. It usually occurs through direct extension from a subpleural focus. Tuberculous pleural effusion and residual pleural thickness may occur in up to 50% of patients (Barbas et al.I991). The exact pathogenesis behind the development of pleural thickness is probably related to a delayed hypersensitivity reaction, rather than to an inflammatory response to the infection. The role of corticosteroids in reducing the risk of pleural thickness is controversial. Recent reports suggest no beneficial effect (Lee et al. 1988; Senderovitz and Viskum 1994). The coexistence of empyema thoracis may complicate the clinical picture, leading to grossly thickened pleura with loculated pleural fluid. Once extensive, this process can result in trapped lung syndrome and a variable degree of volume loss leading to significant restrictive lung disease. This is manifested by low TLC and a proportional reduction in both FEVI and FVC. DLco may also be reduced, resulting in a variable degree of gas exchange abnormalities. Shunting and venous admixture may take place at the atelectatic lobes, leading to a significant degree of widening of A-a 02 gradient and hypoxemia.

24.2.3 Endobronchial Tuberculosis Endobronchial tuberculosis will be discussed in detail as a cause of obstructive lung disease (see below). It should be noted, however, that a restrictive pattern is not uncommon in patients with endobronchial TB. Post obstructive pneumonitis, atelectasis or coexisting parenchymal or pleural disease are likely causes for restrictive lung disease in this patient population.

24.2.4 Surgical and Collapse Procedures The need for collapse procedures such as thoracoplasty, pneumothorax, pneumoperitoneum and phrenic nerve crush has been virtually eliminated by the great success of anti-TB chemotherapy. However, excisional surgery can still be called upon to deal with complications, such as bronchopleural fistula, persistent empyema, significant hemoptysis from bronchiectasis or aspergilloma or excision of a lobe

Pulmonary Function Test and Tuberculosis

or segment infected by multi-drug resistant organisms. These "volume reduction" procedures result in a variable degree of restriction. In addition, a mixed obstructive-restrictive pattern has been observed. The obstructive element in these patients may be related to the development of compensatory hyperinflation of the lung postoperatively. It has also been suggested that airway obstruction may be related to the alteration of the bronchial caliber, coexisting cigarette smoking or endobronchial location of specific inflammation (Marino and Giuliano 1998). DLco may be normal when compared to residual alveolar volume. The net effect on gas exchange and pulmonary circulation hemodynamics depend upon the integrity of the residual pulmonary tissues.

24.3 18 and Obstructive Lung Disease Obstructive airway disease came to be recognized as a complication of advanced pulmonary tuberculosis within a few years after the advent of effective chemotherapy.Anno and Tomaschefskyin 1955 reported pulmonary function studies in 25 selected patients with proven pulmonary tuberculosis. They demonstrated that airway obstruction and pulmonary hyperinflation were more common in far advanced than in less advanced disease (Anno and Tomaschefsky 1955). Hallet and Martin (1961) reported on 710 patients with pulmonary tuberculosis admitted to the Firland Sanitarium. The obstructive pattern was found in 34% of these patients and occurred more frequently in men than in women, although the difference was not statistically significant. The incidence of the obstructive abnormality increased with advanced age. The duration of smoking appeared to influence the incidence of obstructive disease; however, when the age factor was controlled, the smoking relationship was no longer significant (Hallet and Martin 1961; Martin and Hallet 1961). The failure to show a very strong association between smoking and airway obstruction in patients with pulmonary tuberculosis is an interesting observation that is difficult to explain. It may be related to the predominant effect of tuberculosis on the airways and the subsequent damage, irrespective of the smoking status of the patient. However, current data suggest an additive effect of smoking with tuberculosis in producing airway obstruction. The mechanisms of airway obstruction in pulmonary tuberculosis remain largely speculative.

387

Obstructive lung disease might be due to tuberculous involvement of the bronchial tree. Sub-mucosal tuberculous involvement and nonspecific inflammation are frequently observed in resected specimens of bronchi from tuberculous patients (Thompson and Kent 1958). Bronchial obstruction and dilatation can complicate lymph node involvement of the primary infection. In chronic post primary tuberculosis, severe bronchiectasis may result from the involvement of the tuberculous lesion in specific segments of the bronchial tree (see below). Chronic bronchitis, emphysema and bronchial asthma may develop as purely coincidental phenomena, especially in patients with atopy or a history of heavy smoking. The specific pathological entities involved in pulmonary tuberculosis presenting with obstructive pulmonary insufficiency will be discussed in detail below.

24.3.1 Endobronchial Tuberculosis Endobronchial tuberculosis (EBTB) is most often a complication of primary pulmonary tuberculosis in children, although it may also occur in adults. The prevalence of EBTB varies among studies, ranging from 10-50%, probably reflecting the heterogeneity of the studies' population and design. In the authors' experience of 98 adults with proven pulmonary TB, 12 (12%) were found to have endobronchial disease (unpublished data); 10 (10%) of them had submucosal infiltration and hyperemia and 2 (2%) had a polypoid tumor. Bronchoscopically, EBTB may present as an endobronchial mass lesion (either polypoid or ulcerative granuloma), submucosal infiltration, hyperemia with edema and fibrostenosis. In one study, 50 EBTB cases were diagnosed by bronchial biopsy, bronchial fine needle aspiration and washing. Mass lesions were found in 31 cases (62%),21 of which were ulcerous granulomas and 10 polypoid masses, while 11 cases (22%) were of submucosal infiltrative, 16 (32%) fibrostenosis and 5 (10%) hyperemia and edema (Altin et al.1997). The pathogenesis of EBTB is not yet completely understood, and the course of EBTB differs according to the type. The pathogenesis, presentation, treatment and prognosis of EBTB are discussed in detail in the chapter on Endobronchial TB. The prognosis of the actively caseating and edematous-hyperemic types is poor, resulting in fibrostenosis in two-thirds of patients. Granular and non-specific bronchitic types have a more favorable prognosis (Shim 1996).

388

Clinically,cough, mostly nonproductive,is invariably present and usually persistent. General symptoms, such as fever, anorexia and weight loss, usually predominate over specific pulmonary symptoms. However, dyspnea, wheeze and strider may be the prominent features and mimic other conditions such as asthma. A variety of lung function abnormality patterns are recognized by PFT in patients with EBTB. They include: iP Pure, restrictive defect as manifested by a proportional reduction of FVC and FEV1, with normal FEVlIFVC % ratio. (Post obstructive pneumonitis, atelectasis or coexisting parenchymal or pleural disease are likely causes for restrictive lung disease in EBTB.) lIIil Pure obstructive pattern defined as FEV1/FVC % ratio is less than 70%, with a low FEVI value. (This is usually caused by the generalized spread of the disease endobronchially to large and small airways.) (I Possible increased airway hyperresponsiveness. One study, however, looked at this particular issue by comparing the provocation concentrations of histamine required to reduce FEVI by 20% (PC 20) of the pre-challenge baseline between patients with EBTB, symptomatic asthmatics and normal healthy controls. PC 20 in EBTB patients and normal controls was significantly higher than in asthmatics. Furthermore, PC 20 was not affected by disease location within the bronchial tree and did not correlate with FEVI or FVC (Park et al. 1995). .. Abnormal inspiratory curve of the flow volume loop, indicating a variable upper airway (Le. extrathoracic) obstruction (Fig. 24.1) leading to inspiratory flow reduction. This might occur secondary to the involvement of the extrathoracic upper airway, typically found in extensive laryngeal tuberculosis (LTB). LTB can result from the direct spread of contaminated sputum to the larynx, or it can be a secondary manifestation of hematological spread. .. Fixed large airway obstruction, characterized by equally reduced inspiratory and expiratory flow (Fig.24.2). This can be a direct result of large airway stenosis secondary to EBTB. Hoheisel and coworkers found that 7% of their patients had a total occlusion of their airways secondary to EBTB, 13% had less than total, 13% had significant,45% minor and 22% had no residual stenosis (Hoheisel et al. 1994).

M. M. Idrees et al. FIoWI~J

FNex

6

8

10

Fig. 24. I. FIV loop: variable extrathoracic obstruction

AawIVa)

FNex

10

5 10 FN~

Fig. 24.2. FIV loop: fixed obstruction

24.3.2

Bronchiectasis

The pathogenesis of bronchiectasis in tuberculosis is multifactorial. Bronchial stenosis secondary to EBTB can result in post obstructive pneumonitis with a secondary bacterial infection. Exogenous compression of the bronchial lumen by enlarged lymph node produces results similar to endobronchial obstruction. In both situations, the inflammatory destruction of the bronchial lumen and the subsequent dilatation of the bronchi is mainly caused by a mixed bacterial infection and purulent bacterial secretion, with an exaggerated local immune reaction, rather than by the local spread of M. tuberculosis. Pulmonary function abnormalities in this situation can show pure obstruction, pure restriction or a combination of both abnormalities, depending on the type and extent of the involvement and the degree of residual damage. In extensive disease, both DLco and lung compliance are reduced, indicating a significant degree of gas exchange abnormality, with venous admixture and increased lung stiffness. The

Pulmonary Function Test and Tuberculosis

A-a 02 gradient is widened, and, at a more advanced stage, chronic hypoxemia and respiratory failure can develop. Chronic corpulmonale may develop secondarily to a persistent increase in pulmonary artery pressure. The physical destruction of the pulmonary vessels by the inflammatory process may play an important role in the development of pulmonary hypertension, but this is unlikely to be the major cause. Hypoxemia, active immune modulators and cytokines release are more likely to be the most important factors in the development of full-blown pulmonary hypertension and corpulmonale.

389

13 patients with pulmonary tuberculosis requiring mechanical ventilation. Seven patients had miliary tuberculosis and six had tuberculosis pneumonia. Eight had ARDS and another two had probable ARDS. The mortality rate of these patients was 69%, which is almost twice that of the hospital mortality for non-tuberculosis pneumonia requiring mechanical ventilation (36%) (Penner et al. 1995). Circulatory disturbance characterized by septic shock is a rare syndrome which has been reported in patients with disseminated tuberculosis (Gachot et al. 1990; Piqueras et al. 1987; Sandoval et al. 1991). In recent years, the occurrence of extra-pulmonary and disseminated tuberculosis has been increasing, especially among HIV patients and intravenous drug 24.4 users, and the incidence of septic shock complicating T8 and Mixed Pattern of Obstructive disseminated tuberculosis is expected to be on the and Restrictive Abnormality rise as well. Pulmonary hypertension (PHT) is a known sequela In miliary TB, the reported physiological changes are of complicated pulmonary tuberculosis. The exact of an obstructive-restrictive pattern. In a group of 33 pathophysiology for PHT is not clear. However, various patients with miliary TB, pulmonary function test- mechanisms have been attributed to the development ing was performed in 31 patients and arterial blood of PHT and corpulmonale in tuberculosis, including gases were analyzed in 13 patients (Shama et al.1992). chronic hypoxia and a reduced pulmonary capillary The physiologic abnormalities observed suggested a bed, caused either by the disease itself or as a result mild to moderate restrictive defect (vital capacity of surgical therapy (Ershov et al. 1996). Sandoval and of 56% of that predicted, ±14), with impairment of colleagues studied the hemodynamic behavior of pulpulmonary diffusing capacity (68±2l) and arterial monary circulation in both anatomical and functional hypoxemia (Pa02 of 75 mmHg ±12), and widening settings. Six patients with miliary tuberculosis were of the A-a 02 gradient. In addition, there was a mild studied. Cardiac catheterization, with subsequent reduction in the flow rates, based on reduced mid- hemodynamic measurements, was performed at rest expiratory flow and increased residual volume-to- and during exercise. The mean values of the baseline total lung capacity. This suggests peripheral airway pulmonary function testing, expressed as percentage involvement and subsequent gas trapping. These of the predicted value, showed a vital capacity of 62%, changes are consistent with the diagnosis of inter- FEVI of 50%, FEVlIFVC 76% and TLC of 79.5%. The stitial lung disease and peripheral airway dysfunc- resting pulmonary artery pressure, cardiac index, tion. With treatment, however, there was significant pulmonary vascular resistance and the PAd-PWP improvement in gas exchange (mean Pa02 increased (pulmonary diastolic minus pulmonary wedge pressignificantly, P value of <0.03), but no change in pul- sure) were all within normal limits. As a group, the monary function abnormality (Shama et al. 1992). hemodynamic response to exercise was characterized Other pathological entities causing mixed obstruc- by an increase in both the mean pulmonary artery tive-restrictive abnormalities are EBTB and post pressure and cardiac index, while pulmonary vascular resectional surgeries (see above). resistance remained within the normal range. At rest, hypoxemia (Pa02 59±3 mmHg) without hypercapnia and normal pH were found in the group as a whole. The alveolar arterial oxygen gradient and the dead 24.5 space (VDIVT) ratio increased. During exercise, no T8 and Respiratory Failure/Hemodynamics significant changes occurred in the gas exchange variables, except for oxygen consumption, respiratory rate Tuberculosis is an uncommon primary cause of and minute ventilation (Sandoval et al.199l). respiratory failure requiring mechanical ventilaThe correlation between survival and pulmonary tion. In a retrospective study that extended over a hypertension in patients with sequelae of pulmonary lO-year period, Penner and colleagues reported only tuberculosis was also studied. Twenty-one patients

390

with a past history of treated pulmonary tuberculosis and a mean Pa02 of 59 mmHg and PaC02 of 51 mmHg were included in the study. Spirometry showed a mean vital capacity of 44% of that predicted and a FEVI of 66%. Twenty patients had an mPAP greater than 30 mmHg, and 18 received home oxygen therapy. Among those patients who required home oxygen therapy, blood gases and pulmonary hemodynamics did not vary significantly between those who died within 2 years (short-term survivors) and those who lived for more than 5 years (long-term survivors). However, lung function parameters (FVC and FEV!) were significantly lower in the short-term vs.long-term survivors, suggesting that the principle prognostic determinant for long-term survival in patients with post tuberculosis sequelae is the degree of restrictive pulmonary abnormality, and not PHT or the severity of gas exchange abnormalities (Sasaki et a1.1998).

24.6 Preoperative Evaluation Preoperative pulmonary function testing emerged in the 1950s as an appealing approach for predicting complications after thoracotomy. The goals of preoperative evaluation are to: • Identify patients at risk • Assess the degree of risk for post operative complications • Identify factors associated with increased risk • Keep both morbidity and mortality low In a retrospective analysis of 454 patients who underwent thoracic surgery, age (greater than 65 years), obesity and hypocapnia (PaC02 less than 31 mm Hg) were found to be associated with increased morbidity and mortality (Beaufils et al. 1992). In patients undergoing lung resection for pulmonary tuberculosis, mortality was as high as 40% among those with maximum voluntary ventilation (MVV) less than 50% of the predicted and FVC less than 70%. Other parameters associated with poor outcome included age older than 70 and FEVI less than 21 (Gaensler et aI.1995). More recent studies confirmed the correlation between MVV and poor postoperative outcome. Olsen and coworkers (1975) reported that 5 out of

M. M. Idrees et aI.

6 patients deemed inoperable by pulmonary artery pressure and perfusion scan-predicted FEVI measurement had MVV less than 50% of the predicted outcome, whereas only 2 out of 23 patients who were deemed operable had low MVV. FEV1 is also frequently measured to assess the risk of resection surgery for multi-drug resistant tuberculosis or other indications, such as lung cancer. Preoperative FEVI has been used in conjunction with perfusion lung scan to estimate postresectional FEVl. Based on data extrapolated from COPD patients, estimated postoperative FEVI (FEVI-PPO) less than 0.8 I, or 30% of the predicted, has been considered the threshold below which resection is considered prohibitive. When this criterion was used to determine operability in high-risk lung resection patients, denying surgery to patients with an FEVI-PPO less than 0.81 defined a group having a 20% postoperative mortality rate (Olsen et aI, 1975). More recently, Melendez and Fischer divided the preoperative tests into three predictive value groups: lljl Spirometry, blood gas analysis and stair climbing tolerance are helpful for screening but not very discriminating. This group had a poor outcome predictive value. " An intermediate predictive value was achieved using diffusion capacity, exercise-induced decrease in oxygen saturation and exercise pulmonary vascular resistance. G A high predictive value was achieved by the full cardiopulmonary exercise test for the measurement of the oxygen consumption (V02) at 40 watts of exercise, or V02 max (Melendez and Fischer 1997). Richter and coworkers also evaluated the best predictor of postoperative morbidity and mortality for thoracic resection surgery. In all, they prospectively evaluated 97 patients. All patients had preoperative maximal exercise testing and dynamic spirometry. Logistic regression showed maximum preoperative workload to be the only predictor of cardiopulmonary complications. Maximum oxygen consumption (V02 max) was predictive of cardiopulmonary death. V02 max of less than 50% of the predicted value was associated with a high risk of death from cardiopulmonary causes. However, both FEV 1 and V02 max were predictive of postoperative complications. Finally, V02 max was correlated with long-term survival, while spirometric variables were not (Richter et al. 1997).

Pulmonary Function Test and Tuberculosis

391

Recently, the role of cardiopulmonary exercise testing in the preoperative evaluation for thoracic resection surgery has become the subject of great interest. It has been recommended that patients with FEV1-PPO of less than 40% of predicted values should be exercised to assess oxygen transport and consumption. Patients with FEVI-PPO greater than 30% of predicted values and peak exercise V02 greater than 15 mllkg/min should be offered surgery with the goal of resecting the smallest volume of tissue that would be compatible with a cure (Gilbreth and Weisman 1994).

monary illness and no contact with sick people. She has no pets, nor had she recently traveled. She was given a three-day course of azithromycin by her GP with no significant response. Clinically, she looked ill and mildly distressed. Temperature was 37.8 0c. She had very audible wheezes all over the lung fields. Chest-x-ray showed mild degree hyperinflation, but was otherwise unremarkable.

24.7 Case Illustration N.S.S is a 54-year-old woman, with no previous illness aside from mild rhinitis. She presented with a 3-week history of low-grade fever, cough, shortness of breath and wheeze. She is a non-smoker and had no family history of atopy. There was no occupational risk factor for pul-

FNa

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Arterial blood gases on room air were: iii

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24.8 Discussion Pulmonary function testing showed a moderate degree of obstruction. The borderline FEVl/FVC ratio was related to incomplete exhalation and underestimation of FVC. Total lung capacity was normal, but both residual volume (RV) and RV% TLC were high, indicating gas trapping. There was a significant response to bronchodilator. Arterial blood gases showed a mild degree of hypoxemia and widening of the A-a 02 gradient. The patient was treated initially as a case of bronchial asthma/bronchitis. Steroids, bronchodilator and antibiotics were started with partial initial response followed by deterioration. Three sputum samples for AFB were negative. Bronchoscopy was done and an endobronchial mass lesion in the left main stem bronchus was found. This was associated with generalized airway hyperemia. Anti-TB chemotherapy was started and the patient subsequently improved.

References Altin S, Cikrikcioglu S, Morgul M et al (1997) 50 endobronchial tuberculosis cases based on bronchoscopic diagnosis. Respiration 64:162-164 Anno H, Tomaschefsky JF (1955) Studies on the impairment of respiratory function in pulmonary tuberculosis. Am Rev Tuberc 71:333 Barbas CSV, Cukier A, de Varvalho CRR et al (1991) The relationship between pleural fluid finding and the development thickening in patients with pleural tuberculosis. Chest 100:1264-1267 Beaufils LC, Brachet A, Manuelian M et al (1992) Preoperative evaluation of respiratory function in thoracic surgery. Do reliable predictive criteria exists in that type of surgery. Agressologie 33:15

M. M. Idrees et al. Ershov AL, Evstaf'ev IuA, Sobkin AL et al (1996) The significance of exacerbations of lung diseases in the development of chronic corpulmonale and their treatment. Probl Tuberk 4:14-16

Richter LK, Svendsen UG, Milman N et al (1997) Exercise testing in the preoperative evaluation of patients with bronchogenic carcinoma. Eur Respir J 10:1559 Gachot B, Wolff M, Clair B (1990) Severe tuberculosis in patients with human immunodeficiency virus infection. Intensive Care Med 16:491-493 Gaensler EA, Cugell DW, Lindgren I et al (1995) The role of pulmonary insufficiency in mortality and invalidism following surgery for pulmonary tuberculosis. J Thorac Cardiovasc Surg 29:163 Gilbreth EM, Weisman 1M (1994) Role of exercise stress testing in preoperative evaluation of patients for lung resection. Clin Chest Med 15:389 Hallet WY, Martin q (1961) The diffuse obstructive pulmonary syndrome in a tuberculosis sanatorium. Etiological factors. Ann Intern Med 54:1146 Hoheisel G, Chan BK, Chan CH et al (1994) Endobronchial tuberculosis: diagnostic features and therapeutic outcome. Respir Med 88:593-597 Lee CH, Wang WJ, Lan RS et al (1988) Corticosteroids in the treatment of tuberculous pleurisy: a double blind, placebocontrolled, randomized study. Chest 94:1256-1259 Long R, Maycher B, Dhar A et al (1998) Pulmonary tuberculosis treated with directly observed therapy. Chest 113: 933-943

Malik SK, Martin q (1969) Tuberculosis, corticosteroid therapy, and pulmonary function. Am Rev Respir Dis 100:13-18 Marcus H, Yoo OH,Akyol T et al (1963) A randomized study of the effect of corticosteroid therapy on healing of pulmonary tuberculosis as judged by clinical, roentgenographic and physiologic measurements. Am Rev Respir Dis 88:55-64 Marino de Rosa, Giuliano C (1998) Respiratory function impairment in pulmonary tuberculosis. Rays 23:87-92 Martin q, Hallet WY (1961) The diffuse obstructive pulmonary syndrome in a tuberculosis sanatorium. Incidence and symptoms. Ann Intern Med (Chic) 54:1156 Melendez JA, Fischer ME (1997) Preoperative pulmonary evaluation of the thoracic surgical patient. Chest Surg Clin North Am 7:641 Olsen GN, BlockAJ, Swenson EW et al (1975) Pulmonary function evaluation of the lung resection candidate: a prospective study. Am Rev Respir Dis 111:379 Park CS, Kim KU, Lee SM et al (1995) Bronchial hyperreactivity in patients with endobronchial tuberculosis. Respir Med 89:419-422 Penner C, Robert D, Kunimoto D et al (1995) Tuberculosis as a primary cause of respiratory failure requiring mechanical ventilation. AJRCCM 151:867-872 Piqueras AR, Marrueces L, Artugas A (1987) Miliary tuberculosis and adult respiratory distress syndrome. Intensive Care Med 13:175-182 Sandoval J, Cicero R, Seoane M et al (199l) Behavior of the pulmonary circulation at rest and during exercise in miliary tuberculosis. Chest 99:152-154 Sasaki Y, Yamagishi F, Suzuki K et al (1998) Survival and

Pulmonary Function Test and Tuberculosis pulmonary hemodynamics in patients with sequelae of pulmonary tuberculosis who received anti-tuberculosis chemotherapy and home oxygen therapy. Nihon Kokyuki Gakkai Zasshi 36:934-938 Senderovitz T, Viskum K (1994) Corticosteroids and tuberculosis. Respir Med 88:561-565 Shama SK, Pande JN, Singh YN et al (1992) Pulmonary func-

393

tion and immunologic abnormalities in miliary tuberculosis. Am Rev Respir Dis 145:1167-1171 Shim YS (1996) Endobronchial tuberculosis. Respirology 1: 95-106 Thompson JR, Kent G (1958) Occult tuberculous endobronchitis in surgically resected lung specimens. Am Rev Tuberc 77:931

25 Thoracic Surgery for Tuberculosis YUJI SHIRAISHI

CONTENTS 25.1 History of Thoracic Surgery for Tuberculosis 395 25.1.1 Role of Surgery in the Pre-Rifampin Era 395 25.1.2 Post-Rifampin Era and Emergence of Drug-resistant Tuberculosis 396 25.2 Surgery for Multidrug-Resistant Pulmonary Tuberculosis 396 25.2.1 Background 396 25.2.2 Preoperative Medical Treatment 396 25.2.3 Indications for Surgery 399 25.2.4 Preoperative Evaluation 399 25.2.5 Surgical Technique 399 25.2.6 Postoperative Care 400 25.2.7 Types of Operative Procedures 400 25.2.8 Operative and Late Mortality 401 25.2.9 Postoperative Complications 401 25.2.10 Cure Rate of Surgical Treatment 402 25.2.11 Surgical Treatment Other than Pulmonary Resection 402 25.3 Surgery for Tuberculous Infection of the Pleural Space 403 25.3.1 Clinical Manifestations and Diagnosis 403 25.3.2 Medical Therapy 403 25.3.3 Surgical Treatment 405 References 407

25.1

History of Thoracic Surgery for Tuberculosis

25.1.1 Role of Surgery in the Pre-Rifampin Era Thoracic surgery began when the specialty was "chest" surgery for treating tuberculosis. Our hospital was established as a sanatorium owned by the Japan Anti-Tuberculosis Association. The Section of Chest Surgery began to operate on patients with pulmonary tuberculosis in 1948. At first, most patients underY. SHIRAISHI, MD Head, Section of Chest Surgery, Fukujuji Hospital, 3-1-24 Matsuyama Kiyose, Tokyo 204-8522, Japan

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

went thoracoplasty. However, pulmonary resection, such as lobectomy, pneumonectomy or segmentectomy, soon became the predominant operation. The number of pulmonary resections performed annually reached around 240 in 1954. On the other hand, the number of cases treated with collapse therapy decreased (Fig. 25.1). Until the advent of antituberculous chemotherapy in the 1940s, pulmonary resection frequently resulted in high mortality because of bronchial failure or poor wound healing due to uncontrolled tuberculous infection. Therefore, rather than resectional surgery, collapse therapy, especially thoracoplasty, was the primary operation for the management of tuberculosis (Pomerantz and Mault 2000). The concept behind collapse therapy involves compressing the cavities, which prevents oxygen from entering them, causing aerobic tubercle bacilli to die from suffocation (Pomerantz and Brown 1995). Other examples of collapse therapy, which are less frequently performed, include plombage, therapeutic pneumothorax, pneumoperitoneum and phrenic nerve crush. Under the auspices of adequate chemotherapy, pulmonary resection became safer and thus was performed more frequently in the 1950s and 1960s. Collapse therapy eventually yielded to pulmonary resection. However, with the introduction of rifampin, almost all patients with tuberculosis could be successfully treated with medication alone. Even the removal of cavities persisting after medical treatment proved unnecessary. The need for surgery, therefore, markedly diminished and sanatoriums in many countries were closed down. In our hospital, the number of operations performed for tuberculosis decreased year by year. Eventually, fewer than 20 operations were performed for tuberculosis in 1975 (Fig. 25.1). In the late 1970s and early 1980s, indications for the surgical treatment of tuberculosis were limited to the following: massive hemoptysis, bronchopleural fistula, bronchial stenosis, a trapped lung and the need to rule out cancer (Pomerantz and Mault 2000).

396

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(van Leuvan et al. 1997), South Korea (Sung et al. 1999), Turkey (Kir et al. 1997), and the United States (Treasure and Seaworth 1995; Pomerantz et al. 2001). Exceptions are France (Mouroux et al. 1996; Souilamas et al. 2001) and Hungary (Furak et al. 2001), where surgery for tuberculosis is seldom performed for multidrug-resistant strains.

-----"---------"'-------'-----'---.::....::...---" 1955

1960

1965

1970

1975

Year - - Pulmonary resection - ..-. Thoracoplasty

Fig. 25.1. The number of operations performed for pulmonary tuberculosis annually at Fukujuji Hospital between 1948 and 1975. At first, the number of thoracoplasty was higher than that of pulmonary resection, but soon the situation was reversed. Pulmonary resections were most frequently performed in the late 1950s and early 1960s

25.1.2 Post-Rifampin Era and Emergence of Drug-resistant Tuberculosis Unfortunately, during the last five decades of the chemotherapy era, certain strains of Mycobacterium tuberculosis have acquired resistance to various antituberculous drugs. Particularly, multidrug-resistant strains, which are defined as resistant to isoniazid and rifampin, have emerged. These organisms are often resistant to other first-line drugs (ethambutol, streptomycin, and pyrazinamide) and also to some of the other less efficacious drugs. The emergence of multidrug-resistant tuberculosis has posed a major problem in antituberculous therapy (Iseman 1993). Medical therapy alone has been associated with high rates of relapse or treatment failure and a mortality rate of approximately 50% (Goble et al. 1993). Patients with such resistant strains invariably have either a thick-walled cavitary disease or a destroyed lobe or lung (Figs. 25.2-25.4). Cavities contain from 107 to 4 109 organisms compared with 10 2 to 10 in nodules (Canetti 1965). Thus, the removal of this heavy bacterial burden by pulmonary resection may enhance the efficacy of medical treatment. A destroyed lobe or lung acts similar to a cavitary disease. Therefore, the surgeon's role has recently come back to the armamentarium in the treatment of tuberculosis (Pomerantz and Brown 1995). Currently, multidrug-resistant tuberculosis is the most common indication for surgery for tuberculosis in many countries. Examples are Italy (Rizzi et al. 1995, 1997), Japan (Nakajima 1997), South Africa

25.2 Surgery for Multidrug-Resistant Pulmonary Tuberculosis 25.2.1 Background A team at the National Jewish Center for Immunology and Respiratory Medicine in the United States at Denver, Colorado, is a pioneer of the surgical treatment for multidrug-resistant tuberculosis. Between the 1970s and early 1980s, pulmonary resection was still infrequently performed for multidrug-resistant tuberculosis at the National Jewish Center. Only nine (5.3%) of 171 patients with multidrug-resistant tuberculosis underwent surgery from 1973 to 1983 (Goble et aI.1993). However, the center has employed resectional surgery aggressively over the last two decades, due to the fact that even the best medical regimens available have been associated with unacceptably high rates of treatment failure, whereas surgical treatment has proved safe and efficacious (Iseman et al. 1990). Beginning with lobectomies in patients having abundant respiratory reserve, the National Jewish Center group has progressed to pneumonectomies or bilateral resections in patients with very marginal cardiopulmonary reserve. In contrast with the earlier series (Goble et al. 1993), out of 109 patients treated between 1983 and 1993 and eligible for long-term follow-up, 62 (57%) underwent pulmonary resections (Iseman 2000).

25.2.2 Preoperative Medical Treatment Patients with multidrug-resistant tuberculosis initially should be administered the best antituberculous chemotherapy possible based on drug sensitivity tests. The recommended regimen consists of at least four drugs to which the organism is sensitive, two of which have not been used previously in the patient. Resectional surgery should be performed only after approximately

Thoracic Surgery for Tuberculosis

397

a

c Fig. 25.2a, b. A 59-year-old man had bilateral cavitary diseases in the both upper lobes (a, b). His tubercle bacilli were resistant to isoniazid, rifampin, and streptomycin. The patient was treated with chemotherapy employing ethambutol, pyrazinamide, cycloserine, kanamycin, ethionamide, and levofloxacin. After six months of chemotherapy, cavities shrunk, but still remained (c). He underwent staged bilateral upper lobectomies (d). Latissimus dorsi muscle flaps were used to cover the both bronchial stumps

a

b Fig. 25.3a, b. A 48-year-old man had multiple cavitary diseases in the upper and lower lobes of the right lung (a, b). The left lung was intact. His tubercle bacilli were resistant to seven drugs: isoniazid, rifampin, ethambutol, streptomycin, cycloserine, paraaminosalicylcclic acid, and ethionamide. After being treated with isoniazid, rifampin, kanamycin, ethionamide and levofloxacin, he underwent a right pneumonectomy. The bronchial stump was reinforced with the latissimus dorsi

398

Y. Shiraishi

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a

b

c

d Fig. 25.4a-d. A 59-year-old man having the destroyed left upper lobe (a, b) was infected with tuberculosis resistant to isoniazid, rifampin, ethambutol, streptomycin, cycloserine, ethionamide, and levofloxacin. He was treated with pyrazinamide, kanamycin, and para-aminosalicylcclic acid, and then underwent a left upper lobectomy with a superior segmentectomy of the lower lobe. The latissimus dorsi was used, but air leakage prolonged (c). Thoracoplasty removing from the second to the seventh ribs was performed on postoperative day 35, resulting in the obliteration of residual space (d)

three months of intensive medical treatment, and when the lowest bacterial count possible is achieved in the sputum smear and culture results. This may decrease the incidence of postoperative complications. Attempting resection without establishing antituberculous control poses an increased risk of bronchial stump or chest wall wound dehiscence. It is ideal if the sputum smear and culture of the patient becomes negative at the time of operation. This has been possible, however, in only about half

of the patients with multidrug-resistant tuberculosis, even those treated with appropriate antituberculous regimens (Pomerantz et al. 2001). The analysis of the 1973-1983 series at the National Jewish Center revealed that the median time for cultures to become negative was two months, with the great majority becoming negative at four months (Goble et al.I993). Therefore, if the patient remains culture positive after three or four months of chemotherapy, the patient is unlikely to be cured with medication alone

399

Thoracic Surgery for Tuberculosis

and should be considered for surgery if feasible. Improvement in pulmonary hygiene by pulmonary rehabilitation is essential during the preoperative period. Nutritional support is also important during both the medical treatment phase before surgery and the postoperative period.

25.2.3 Indications for Surgery

The following indications for surgery proposed by Iseman (2000) have been widely accepted. (A) The patient is persistently culture positive for multidrugresistant tuberculosis despite extended drug retreatment. (B) Patterns of drug resistance are so extensive as to be likely to be associated with the risk of treatment failure or relapse with additional resistance. (C) The patient has localized cavitary or necrotic/destructive disease in a lobe or region of the lung that is amenable to resection without producing respiratory insufficiency and/or severe pulmonary hypertension. Surgery is sometimes performed on patients who have achieved negative sputum cultures with chemotherapy but are at high risk of relapse because of cavitary diseases or a destroyed lung and extensive patterns of resistance. Pulmonary resection is also performed on patients with anticipated noncompliance and on those with little or no medical options if the current treatment fails. Contraindication to surgery is bilateral disease that is so extensive that resection is not feasible.

25.2.4 Preoperative Evaluation

Patients undergoing pulmonary resection for multidrug-resistant tuberculosis should be carefully evaluated in order to keep morbidity and mortality rates low. Preoperative evaluation should include standard chest x-rays, computed tomography (CT) scan of the chest, pulmonary function tests and a ventilation perfusion scan. These studies are necessary to assess the extent of the disease and to determine the acceptable resection based on anticipated postoperative pulmonary reserve. Bronchoscopy should also be performed if there is hemoptysis or a possibility of bronchostenosis. When pulmonary hypertension is suspected, right heart catheterization should be performed to determine whether the patient is suitable for resectional surgery. A mean pulmonary artery pressure of 25 mmHg or greater often precludes pneumonectomy (Pomerantz and Brown 1997).

The purpose of surgery for patients with multidrug-resistant tuberculosis is to remove all gross lesions. This requires the removal of all cavitary diseases as well as the destroyed lung. Scattered nodular lesions may remain because their mycobacterial burden is low. Indications for a pneumonectomy, in contrast to a lesser procedure, include destruction of an entire lung, multiple cavities in one lung (Fig. 25.3), stenosis of the main stem bronchus, infection involving more than one lobe of the lung and tuberculosis associated with a chronic empyema.

25.2.5 Surgical Technique

At the beginning of the surgery, bronchoscopy is performed to cleanse the airway in order to prevent spread to other portions of the lung. A double-lumen endobronchial tube, which prevents intraoperative contamination of the contralateral lung, is routinely used to achieve lung isolation. A posterolateral thoracotomy incision is routinely used, and the fifth or sixth rib is usually removed. When the chest cavity is entered, dense adhesions are usually found over the upper lobe and often over the superior segment of the lower lobe. Dissection of adhesions may be done intrapleurally or extrapleurally. However, extrapleural dissection has been recommended whenever the pleural space is obliterated to prevent the operative field from being contaminated with tubercle bacilli (Brown and Pomerantz 1995; Conlan et al. 1995). During extrapleural dissection, hemostasis should be achieved using electrocautery and/or bipolar scissors (PowerStar Bipolar Scissors; Ethicon, Somerville, NJ) to minimize blood loss. Special care must be taken to avoid spillage of the contents of cavities into the operative field. Frequently, once pneumolysis is completed, the hilar structures can be isolated without difficulty. However, in the case of a completion pneumonectomy, pulmonary arteries and veins may have to be dissected within the pericardium. The bronchial stump is covered with muscle flaps or omentum if indicated. Bronchial closure can then be done either by suture or with staples. The liberal use of muscle and omental flaps in combinationwith pulmonaryresection for multidrug-resistant tuberculosis has been advised in order to decrease the incidence of postoperative complications (Pomerantz et al. 1991; Treasure and Seaworth 1995). Indications for using these flaps include a positive sputum culture preoperatively, a preoperative bronchopleural fistula, polymicrobial contamination of the pleural space and

Y. Shiraishi

400

anticipated space problems after lobectomy (Pomerantz and Brown 1997). The choice of muscle flap is the latissimus dorsi. The technique for harvesting the latissimus dorsi has been well described previously (Pairolero et al.1983). The flap is sutured to the mainstem bronchial stump, in the case of a pneumonectomy, and used to cover the hilum. When a lobectomy is performed, the flap is sutured to the bronchial stump and also placed at the top of the remaining lung. Other flaps less frequently used include the pectoralis major muscle, the serratus anterior muscle and the intercostal muscle. An omental flap is used when a previous thoracotomy precludes the mobilization of a muscle flap (Pomerantz and Brown 1997). It is also used when a left or right pneumonectomy is performed in the presence of massive contamination. These flaps may be unnecessary despite positive sputum in middle lobe and lingula resections, lower lobectomies and segmental resections. Hemostasis then should be achieved carefully, occasionally with the argon beam coagulator. The chest cavity is thoroughly irrigated and drained. If a muscle flap has been used, a suction drain should be placed below the skin flap and left until drainage becomes less than 25 mllday. On completion of the surgery, bronchoscopy is usually done to cleanse the tracheobronchial tree of secretions that may result from manipulation of the lung during resection. Pomerantz (2000) has advocated that an Eloesser's procedure (Eloesser 1935) be done for patients with extensive contamination after completion of a pneumonectomy. The Eloesser is closed 4 to 6 weeks later with a Clagett procedure (Clagett and Geraci 1963).

25.2.6 Postoperative Care Postoperative care is usually the same as that for pulmonary resection for lung cancer. It should be emphasized that surgery is an adjunct to medical therapy.

Therefore, the patient should be kept on antituberculous medication for 12 to 24 months postoperatively, depending on the bacteriologic and radiographic findings. Stopping antituberculous drugs too soon leads to further resistance or mycobacterial spread.

25.2.7 Types of Operative Procedures Since it is crucial to resect all grossly diseased areas of the lung, the rates of pneumonectomy have been high in some reports (Table 25.1). Kir and colleagues (1997) reported an extremely high rate of pneumonectomy. Out of 27 operations, 20 (74%) were pneumonectomies. Van Leuvan and associates (1997), Pomerantz and coworkers (2001) and Treasure and Seaworth (1995) reported pneumonectomy rates of 56 to 42%. When a lobectomy or an operation that is more than a lobectomy, but less than a pneumonectomy, is performed, the right upper lobe is most commonly involved. In a report by Pomerantz and associates (2001), 55 of 93 patients undergoing lobectomy had the right upper lobe, or the right upper lobe in combination with another portion of the lung, resected. In patients with pulmonary tuberculosis, the destruction of the lung requiring a pneumonectomy occurs more frequently on the left than on the right side. This is revealed by the fact that 73% of all pneumonectomies were on the left in a series by Pomerantz and colleagues (2001). Van Leuven and associates (1997) reported a similar incidence (80%) ofleft-sided pneumonectomies. Similarly, in a report by Kir and colleagues (1997), 75% of pneumonectomies were performed on the left side. Ashour (1997) reported that 16 (80%) of 20 pneumonectomies were done on the left side when pneumonectomy was performed for patients with post-tuberculosis lung destruction. The reasons for this left-sided predominance remain unclear. Ashour and associates (1990) postulated that the predilection for left-lung destruction might be

Table 25.1. Types of pulmonary resections for multidrug-resistant tuberculosis Reference Treasure and Seaworth (1995) Kir et aI. (1997) Van Leuvan et aI. (1997) Nakajima (1997) Sung et aI. (1999) Pomerantz et al. (2001)

No. of Pneumonectomy operations 19 27 62 40 27 180

8 20 (right 5, left 15) 35 (right 7, left 28) 14 9 82 (right 22, left 60)

Lobectomy Segmental resection 9

2

7 26 24 16 93

1 2 2 5

401

Thoracic Surgery for Tuberculosis

related to the smaller caliber of the left main stem bronchus, a tight mediastinum through which the left main stem bronchus traverses and the more horizontal course of the left main stem bronchus.

25.2.8 Operative and Late Mortality In general, pulmonary resection for multidrugresistant tuberculosis can be performed with low mortality. Operative mortality rates ranging from zero to 3.3% have been reported (Table 25.2). Causes of operative deaths described in the reported series include postpneumonectomy pulmonary edema, pulmonary embolism, bronchopleural fistula with respiratory failure, myocardial infarction and a cerebral vascular accident. Operative survivors have seldom died from the progression of multidrug-resistant tuberculosis. Pomerantz and colleagues (2001) reported that 11 late deaths occurred but only three were caused by multidrug-resistant tuberculosis. Of the three patients, one patient had his antituberculous medication stopped inexplicably in the postoperative period, a second had cavitary disease on the other side and refused a second operation and a third died from progressive tuberculosis in spite of continued chemotherapy. Other causes included respiratory failure, a self-induced drug overdose, myocardial infarction, renal failure and unknown causes.

25.2.9 Postoperative Complications Although operative mortality has been acceptably low, postoperative complication rates have been high. Morbidity rates have ranged from 12 to 26% (Table 25.2). Complications described after pulmonary resection for multidrug-resistant tuberculosis are summarized in Table 25.3. These complications occur more com-

Table 25.2. Morbidity and mortality after pulmonary resections for multidrug-resistant tuberculosis Reference Treasure and Seaworth (1995) Kir et al. (1997) Van Leuvan et al. (1997) Sung et al. (1999) Pomerantz et al. (2001)

No. of Mortality Morbidity operations (No.) (No.) 19 27 62 27 180

0% (0)

21% (4)

0% (0) 1.6% (1) 0% (0) 3.3% (6)

19% (5) 23% (14) 26% (7) 12% (20)

Table 25.3. Complications after pulmonary resections for multidrug-resistant tuberculosis Reference

Complications (no. of patients)

Kir et al. (1997)

Revision because of hemorrhage (2); bronchopleural fistula (2); apical residual space (1) Van Leuvan et al. (1997) Postoperative hemorrhage (5); postpneumonectomyempyema (4); wound infection (2); pneumonectomy stump fistula (2); postpericardiotomy syndrome (1); respiratory failure (1); space problem (1) Sung et al. (1999) Prolonged air leakage (3); reoperation due to bleeding (2); bronchopleural fistula (1); reversible blindness (1) Pomerantz et al. (2001) Respiratory failure (6); bronchopleural fistula (5); wound infection (3); postoperative hemorrhage (3); recurrent nerve injury (2); intrathoracic bowel herniation (1)

monly after surgery for tuberculosis because of the adhesive nature of the disease process, as well as the debilitated catabolic condition of the patient. A bronchopleural fistula is a dreaded complication after surgery for mycobacterial infections. Factors adversely affecting the incidence of bronchopleural fistula include right pneumonectomy, positive sputum at the time of surgery, significant polymicrobial contamination, diabetes and prior chest wall irradiation (Pomerantz 2000). Although some investigators have not used muscle flaps to cover the bronchial stump (Kir et al. 1997; van Leuvan et al. 1997; Sung et al. 1999), the use of muscle flaps has been advocated to decrease the incidence of bronchopleural fistula (Treasure and Seaworth 1995; Pomerantz et al. 2001). Bronchopleural fistula is rarely encountered after resection of the middle lobe, lingula, lower lobe or segment. When resections less drastic than pneumonectomies are performed, the inability of the remaining lung to fill the pleural space has occasionally resulted in a chronic space problem (Fig. 25.4). Thoracoplasty has been used to treat space problems (Pomerantz and Mault 2000). However, Pomerantz and coworkers (1991) have recommended using muscle flaps to prevent this complication and to avoid thoracoplasty. While operative morbidity and mortality are the obvious disadvantages of pulmonary resection, overall mortality is reduced, compared with simple medical treatment, and the patient's opportunity to rejoin society outweighs the risk.

402

25.2.10 Cure Rate of Surgical Treatment

The combination of pre- and postoperative antituberculous medications and pulmonary resection has resulted in high cure rates in patients with multidrugresistant tuberculosis. Iseman and colleagues (l990) noted that 92% of patients remained sputum-culture-negative for tuberculosis a mean of 39 months after resection. Recent studies around the world have also demonstrated that cure can be obtained in more than 80% of the surgical cases (Table 25.4). Although no randomized study has been done to compare the cure rates of medical treatment plus surgical treatment with those of medical treatment alone, the overall cure rate during the surgical era is substantially higher than that in the previous era (81 vs. 56%) (Iseman 2000). In a recent report from Denver, the largest of all reported series, 172 patients with multidrug-resistant tuberculosis underwent 180 pulmonary resections over a 17-year period (Pomerantz et al. 2001). Despite the fact that one half (911172) of the patients had positive sputum at the time of the operation, the sputum remained positive in only four patients (2%) after the operation. In another report, also from the United States, 17 (89%) of 19 patients with drug-resistant tuberculosis remained sputum-negative up to 12 months after resection (Treasure and Seaworth 1995). A study from Turkey achieved an overall success rate of 89% in patients undergoing surgery (Tahaoglu et al. 2001). Of 158 patients with multidrug-resistant tuberculosis, 122 were treated with chemotherapy alone and 36 underwent resectional surgery in addition to chemotherapy. Of the 36 patients undergoing surgery, 21 (58%) had cures and 11 (31 %) had probable cures. In contrast, the success rate for patients with chemotherapy alone was 73%. In another study from Turkey, 27 human immunodeficiency virusnegative patients with multidrug-resistant tuberculosis underwent resectional surgery (Kir et al. 1997). In all patients but one, negative cultures were obtained prior to operation, and only one patient (4%) developed a relapse after operation. A group in South Africa performed pulmonary resections on 62 patients (van Leuven et al. 1997). Of these, 38 patients were sputum negative at the time of surgery. Of the remaining 24 patients with positive sputum culture at the time of surgical treatment, 18 (75%) converted to sputum negative immediately afterward. For all patients who were sputum negative after the surgery, the actuarial relapse-free rate was 80% beyond 36 months postoperatively. Failure to

Y. Shiraishi Table 25.4. Success rates of pulmonary resections for multidrug-resistant tuberculosis Reference

No. of patients Success (no. of operations) rate

Treasure and Seaworth (1995) Kir et aI. (1997) Van Leuvan et aI. (1997) Nakajima (1997) Sung et al. (1999) Tahaoglu et al. (2001) Pomerantz et al. (2001)

19 27 62 37 (40) 27 36 172 (180)

89% 96% 80% 89% 96% 89% 98%

convert to negative sputum cultures was considerably less likely after pneumonectomy than it was after lobectomy or segmentectomy. In a report from our hospital, 37 patients with multidrug-resistant tuberculosis underwent 40 pulmonary resections (Nakajima 1997). Excluding two patients who died postoperatively, 38 cases were available for evaluation. Bacteriological relapses were confirmed in seven cases of the 38. Of these seven cases, two underwent completion pneumonectomy, achieving complete cure. Thus, the ultimate cure rate after pulmonary resection was 89% (31135). The South Korea group demonstrated that sputum negative conversion was achieved in 22 patients (81.5%) initially, out of 27 patients undergoing pulmonary resection (Sung et al. 1999). Furthermore, continued postoperative chemotherapy could convert to negative in another four patients (14.8%) and an overall success rate of 96%.

25.2.11 Surgical Treatment Other than Pulmonary Resection As mentioned above, pulmonary resection in combination with chemotherapy is an effective treatment for patients with multidrug-resistant tuberculosis. However, not all patients are eligible for resectional surgery. Extensive bilateral diseases and/or poor cardiopulmonary function may preclude pulmonary resection. For these high-risk patients, several alternative surgical approaches have been recommended. Jouveshomme and colleagues (l998) revisited the efficacy of collapse therapy with plombage for the treatment of patients with multidrug-resistant mycobacteria. Out of seven patients undergoing this surgery, four were infected with multidrug-resistant tuberculosis. Collapse therapy with insertion of five to nine spheres resulted in long-standing bacterio-

Thoracic Surgery for Tuberculosis

logical conversion in all four patients. Jouveshomme and colleagues concluded that collapse therapy with plombage is a safe alternative therapy in patients with multidrug-resistant tuberculosis at high risk for drug treatment failure but considered unsuitable for pulmonary resection. Tseng and associates (2000) used cavernostomy combined with intrathoracic muscle flap transposition to treat patients with fibrocavernous pulmonary tuberculosis. Using this relatively simple operative procedure, they intended to prevent massive blood loss during pulmonary resection and to preserve pulmonary function. Ten patients were treated with this technique, including three patients with multidrug-resistant tuberculosis. However, cavernostomy combined with intrathoracic muscle transposition resulted in failure in all three patients with multidrugresistant tuberculosis. They concluded that patients with multidrug-resistant tuberculosis were probably not suitable for this procedure.

25.3 Surgery for Tuberculous Infection of the Pleural Space

403

tional symptoms, such as fatigue and weight loss, and also manifest low-grade fever and increasing dyspnea with or without chest pain. However, once a bronchopleural fistula has developed, the patients become extremely ill and sometimes moribund. They may present with acute fever, dyspnea and production of abundant purulent sputum. This not only identifies the disease, it also increases the risk of spread of the tubercle bacilli through contaminated sputum. In addition, the pleural space is frequently contaminated with one or more pyogenic organisms, which results in a mixed tuberculous/pyogenic empyema. The typical finding of tuberculous empyema on chest radiography is a moderate to large pleural effusion and calcified pleura (Figs. 25.5,25.6).An air-fluid level is often observed, representing a bronchopleural fistula (Fig. 25.6). CT scan shows a thick fibrous peel, calcification of parts of, or all of, the rim of the fibrous peel and loculated pleural fluid between the parietal and the visceral peel (Figs. 25.5,25.7). The underlying lung is usually entrapped. A destroyed lobe or lung is also observed in many cases (Fig. 25.7). Thoracentesis yields grossly purulent fluid whose smear is positive for acid-fast bacilli and whose culture is subsequently positive for Mycobacterium tuberculosis. The fluid should be routinely examined for aerobic, anaerobic and fungal cultures.

25.3.1 Clinical Manifestations and Diagnosis Tuberculous infection of the pleural space can occur in patients with a primary parenchymal infection and in patients with postprimary tuberculosis. Pleural tuberculosis may also occur as sequelae of collapse therapy for tuberculosis. Pleural involvement by tuberculosis presents numerous and diverse clinical aspects. Barker and Shields (1994) classified pleural tuberculosis into four manifestations: (1) pure pleural tuberculosis, (2) pure pleural disease with mixed tuberculous/pyogenic infection, (3) pleuroparenchymal tuberculosis and 4) mixed tuberculous/pyogenic pleural disease with parenchymal infection. They recommended that the term, "tuberculous empyema:' be discarded. However, the term "tuberculous empyema" is still used by many investigators (Elliott et al. 1995; Ali et al. 1996; Bai et al. 1998; Sahn and Iseman 1999; AI-Kattan 2000; Massard and Wihlm 2000). Usually, patients with chronic tuberculous empyema have been asymptomatic for years before coming to clinical attention, because the markedly thickened pleura virtually isolates the tubercle bacilli into the empyema cavity. Some patients may have constitu-

25.3.2 Medical Therapy Like parenchymal disease, antituberculous chemotherapy forms the basis of the therapy for pleural tuberculosis (Sahn and Iseman 1999). When tuberculous infection is associated with mixed pyogenic infection of the pleural space, proper antibiotic therapy should be added. Drug-sensitive tuberculous strains should be treated with multidrug regimens containing isoniazid, rifampin and ethambutol to prevent acquired resistance. Resistant organisms may require as many as five drugs, including streptomycin, pyrazinamide, cycloserine, and so on, to achieve bacteriologic control. Antituberculous chemotherapy should be continued for at least three months, and sputum conversion should be achieved before considering any major surgical intervention. It should be noted, however, that in chronic empyema associated with thickening and calcification of the pleura, the inability to achieve therapeutic drug levels in the pleural fluid can lead to drug resistance. Iseman and Madsen (1991) reported five patients with chronic pleural tuberculosis and bronchopleu-

404

Y. Shiraishi

b

a Fig. 25.5a, b. A 62-year-old man had tuberculous infection of the pleural space. The pleural fluid was positive for Mycobacterium tuberculosis. Although he was treated with isoniazid, rifampin, and ethambutol, pleural tuberculosis resulted in an entrapped lung (a). The underlying lung was not destroyed, and no bronchopleural fistula was observed (b). He underwent decortication and transposition of the latissimus dorsi

b

a

Fig.25.6a-c. A 69-year-old man who had a history of pleuritis had drug-sensitive pleuroparenchymal tuberculosis. The pleural fluid was positive for Mycobacterium tuberculosis, and a regimen employing isoniazid, rifampin, and ethambutol was started. During chemotherapy, he developed a bronchopleural fistula. An apparent air-fluid level was seen on the chest radiograph (a). At first, he was treated by open window thoracostomy (b). Purulent contents in the pleural space were positive for Aspergillus flavus. After 261 days of open drainage, he underwent decortication, transposition of the latissimus dorsi and the serratus anterior, and thoracoplasty (c). He has had no relapse of tuberculosis and empyema since the operation

c

Thoracic Surgery for Tuberculosis

405

b

ANT R

L

c Fig. 25.7a-d. A 72-year-old man having undergone therapeutic pneumothorax 48 years ago had a chronic empyema complicated with minor bronchopleural fistula (a). He presented with increasing hemoptysis. The left lung was destroyed (b), and blood flow going into the left lung was markedly diminished in ventilation perfusion scan (c). He underwent extrapleural pneumonectomy and had the bronchial stump reinforced with a latissimus dorsi muscle flap (d). Operative time was 8 h, 5 min. Intraoperative blood loss was 1,180 mI, and four units of packed red blood cells were transfused. His postoperative course was uneventful

ral fistula in whom chemotherapy was complicated by the evolution of drug resistance. Thickened and calcified empyema walls might have limited the penetration of drugs into the infected empyema space, resulting in suboptimal drug concentrations and the acquisition of drug resistance. Elliott and associates (1995) demonstrated a patient with drug-resistant chronic tuberculous empyema in whom substantial differences between achievable serum and pleural fluid drug concentrations were displayed. The case strongly suggested that subtherapeutic drug concentrations in the pleural fluid might have contributed to the acquisition of drug resistance.

25.3.3 Surgical Treatment

The initial step for the surgical treatment of pleural tuberculosis is adequate pleural space drainage (Sahn and Iseman 1999). This can be achieved either with chest tube thoracostomy or with open window thoracostomy. Once the pleural space has been cleansed, a definitive operation for empyema should be performed if feasible. The goal of the operation is either to obliterate the pleural space completely or to remove the empyema space with the underlying diseased lobe or lung. These goals cannot usually

406

be achieved with drainage alone, due to thickened and calcified pleura and an entrapped lung. Bai and associates (1998), however, reported that 19 of 27 patients with tuberculous empyema were treated successfully with chemotherapy and repeated thoracentesis, or with closed-tube thoracotomy. Ali and coworkers (1996) reported interesting cases with tuberculous empyema, where, using open drainage and antituberculous chemotherapy, "entrapped" lungs which had totally collapsed expanded to fill the entire pleural space. Definitive operations include decortication, decortication limited to the parietal sides of the empyema wall, thoracoplasty, transposition of extrathoracic muscle flaps and resection of the empyema along with a lobe or a lung. Choosing the most suitable operation based on the extent of the disease is of paramount importance, and this often requires a thoracic surgeon's expertise. CT scan of the chest is useful in differentiating parenchymal and pleural involvement and in evaluating the status of the underlying lung, such as whether it contains cavitary lesions, bronchiectasis or has been destroyed. When the underlying lung is expected to be re-expandable, the procedure of choice may be decortication (Thurer 1996; Katariya and Thurer 1998; Massard and Wihlm 2000; AI-Kattan 2000). In patients with pure pleural tuberculosis, a pleural residual occupying one-fourth to one-third of the hemithorax three months after antituberculous chemotherapy requires that decortication be carried out to avoid undue delays in resolution (Langston et al. 1967; Barker and Shields 1994) (Fig. 25.5). Massard and associates (1995) performed decortication liberally after collapse therapy for tuberculosis, even on patients with late empyema, and reported favorable outcomes. The postoperative course after decortication may be complicated, due mainly to the pleural space problem. Prolonged air leaks eventually seal with prolonged drainage, provided that the lung is completely re-expanded. Residual pleural spaces after decortication may be managed either with transposition of muscle flaps or with thoracoplasty (Massard and Wihlm 2000). Chronic tuberculous empyema is commonly associated with the underlying lung that cannot be re-expanded to fill the pleural space. Should CT scan demonstrate cavitary disease, large cystic bronchiectasis or destroyed lesions in the underlying lung, re-expansion of the lung obviously cannot be anticipated. In this instance, the use of a modified decortication procedure has been advocated. Iioka and colleagues (1985) described a technique involving

Y. Shiraishi

decortication of the visceral peel and obliteration of the dead space by collapsing the parietal wall without rib resection (Fig. 25.8). The goal of treatment may also be achieved using either muscle or omental flaps, or using thoracoplasty. Garda-Yuste and colleagues (1998) demonstrated a dual-procedure technique, involving preparatory open window thoracostomy and subsequent thoracomyoplasty, which achieved satisfactory results. Using this technique, once the pleural cavity is stabilized, intrathoracic transposition of the extrathoracic skeletal muscle is performed to obliterate the space (Fig. 25.6). Other investigators have reported the use of thoracoplasty for the treatment of tuberculous empyema (Hopkins et al. 1985; Horrigan and Snow 1990; Peppas et al. 1993). When the underlying lung has been extensively destroyed, extrapleural pneumonectomy should be considered (Sarot 1949). Surgical success is anticipated on exchanging an actively infected pleural space for a merely contaminated one. However, extrapleural pneumonectomy for a destroyed lung associated with empyema is considered a high-risk procedure (Okano and Walkup 1958; Langston et al. 1967; Odell and Henderson 1985; Massard et al.1995; Massard and Wihlm 2000). In a report by Massard and colleagues (1996), the incidence of empyema or bronchopleural fistula after pneumonectomy (or chronic infection is higher in patients with sequelae of tuberculosis. Halezeroglu and associates (1997) also reported that the combined morbidity and mortality rate after pneumonectomy for a destroyed lung is significantly higher in patients with preoperative empyema. Rather than performing extrapleural pneumonectomy, Odell and Henderson (1985) invented the technique of pneumonectomy through an empyema. As reported by Odell and Buckels (1999), however, postpneumonectomy empyema developed in 45.7% of the survivors. Blyth (2000) also performed pneumonectomy through empyema, resulting in a similar incidence (44%) of postpneumonectomy empyema. Even though there have been admonitions against using extrapleural pneumonectomy, our group (Shiraishi et al. 2000) has performed this high-risk procedure on 94 patients with chronic empyema (Fig. 25.7). In our study, operative mortality was 8.5%, and 89% of the operative survivors were free of empyema at 5 years. Langston and coworkers (1967) found that complications following extrapleural pneumonectomy were more likely to occur in patients who had had drainage used as a preliminary measure and who still had a sinus tract at the time of the operation. As a result of this finding, Barker and Shields (1994) as

407

Thoracic Surgery for Tuberculosis

a

b

c

d

Fig. 25.8a-d. A 26-year-old man infected with drug-sensitive tuberculosis (a) was complicated with secondary pneumothorax (b). The pleural fluid was positive for Mycobacterium tuberculosis. He was treated with isoniazid, rifampin, and ethambutol. Despite chest tube drainage, the complete re-expansion of the right lung could not be achieved (c). Rupture of cavities might have been responsible for air leakage. He underwent decortication of the visceral peel and obliteration of the dead space by collapsing of the parietal wall without rib resection (d)

a rule do not recommend preoperative pleural drainage prior to extrapleural pneumonectomy. In contrast, our study demonstrated that preoperative chest tube drainage and/or open-window thoracostomy did not adversely affect the incidence of postoperative empyema. It must be emphasized, however, that surgery for pleural tuberculosis is extremely complicated and formidable, and should only be performed by experienced thoracic surgeons.

References AI-Kattan KM (2000) Management of tuberculous empyema. Eur J Cardio Thorac Surg 17:251-254 Ali SM, Siddiqui AA, McLaughlin JS (1996) Open drainage of massive tuberculous empyema with progressive reexpansion of the lung: an old concept revisited. Ann Thorac Surg 62:218-224 Ashour M et al. (1990) Unilateral post-tuberculous lung destruction: the left bronchus syndrome. Thorax 45: 210-212

408 Ashour M (1997) Pneumonectomy for tuberculosis. Eur J Cardio Thorac Surg 12:209-213 Bai K-J et al (1998) Tuberculous empyema. Respirology 3: 261-266 Barker WL, Shields TW (1994) Tuberculous and fungal infections of the pleura. In: Shields TW (ed) General thoracic surgery, 4th edn. Williams and Wilkins, Baltimore, pp 701-709 Blyth DF (2000) Pneumonectomy for inflammatory lung disease. Eur J Cardio Thorac Surg 18:429-434 Brown J, Pomerantz M (1995) Extrapleural pneumonectomy for tuberculosis. Chest Surg Clin North Am 5:289-296 Canetti G (1965) Present aspects of bacterial resistance in tuberculosis. Am Rev Respir Dis 92:687-703 Clagett aT, Geraci JE (1963) A procedure for the management of postpneumonectomy empyema. J Thorac Cardiovasc Surg 45:141-145 Conlan AA et al (1995) Elective pneumonectomy for benign lung disease: modern-day mortality and morbidity. J Thorac Cardiovasc Surg 110:1118-1124 Elliott AM et al (1995) Failure of drug penetration and acquisition of drug resistance in chronic tuberculous empyema. Tuberc Lung Dis 76:463-467 Eloesser L (1935) An operation for tuberculous empyema. Surg Gynecol Obstet 60:1096-1097 Funik J et al (2001) Surgical intervention for pulmonary tuberculosis: analysis of indications and perioperative data relating to diagnostic and therapeutic resections. Eur J Cardio Thorac Surg 20:722-727 Garcia-Yuste M et al (1998) Open-window thoracostomy and thoracomyoplasty to manage chronic pleural empyema. Ann Thorac Surg 65:818-822 Goble M et al (1993) Treatment of 171 patients with pulmonary tuberculosis resistant to isoniazid and rifampin. N Engl J Med 328:527-532 Halezeroglu S et al (1997) Factors affecting postoperative morbidity and mortality in destroyed lung. Ann Thorac Surg 64:1635-1638 Hopkins RA et al (1985) The modern use of thoracoplasty. Ann Thorac Surg 40:181-187 Horrigan TP, Snow NJ (1990) Thoracoplasty: current application to the infected pleural space. Ann Thorac Surg 50: 695-699 Iioka S et al (1985) Surgical treatment of chronic empyema: a new one-stage operation. J Thorac Cardiovasc Surg 90: 179-185 Iseman MD (1993) Treatment of multidrug-resistant tuberculosis. N Engl J Med 329:784-791 Iseman MD (2000) Drug-resistant tuberculosis. In: Iseman MD (ed) A clinician's guide to tuberculosis. Lippincott Williams and Wilkins, Philadelphia, pp 323-354 Iseman MD, Madsen LA (1991) Chronic tuberculous empyema with bronchopleural fistula resulting in treatment failure and progressive drug resistance. Chest 100:124-127 Iseman MD et al (1990) Surgical intervention in the treatment of pulmonary disease caused by drug-resistant Mycobacterium tuberculosis. Am Rev Respir Dis 141:623-625 Jouveshomme S et al (1998) Preliminary results of collapse therapy with plombage for pulmonary disease caused by multidrug-resistant mycobacteria. Am J Respir Crit Care Med 157:1609-1615 Katariya K, Thurer RJ (1998) Surgical management of empyema. Clin Chest Med 19:395-406

Y. Shiraishi Kir A et al (1997) Role of surgery in multi-drug-resistant tuberculosis: results of 27 cases. Eur J Cardio Thorac Surg 12:531-534 Langston HT, Barker WL, Graham AA (1967) Pleural tuberculosis. J Thorac Cardiovasc Surg 54:511-519 Massard G, WihIm J-M (2000) Tuberculous and fungal infections of the pleura. In: Shields TW, loCicero J III, Ponn RB (eds) General thoracic surgery, 5th edn. Lippincott Williams and Wilkins, Philadelphia, pp 717-727 Massard G et al (1995) Decortication is a valuable option for late empyema after collapse therapy. Ann Thorac Surg 60: 888-895 Massard G et al (1996) Pneumonectomy for chronic infec· tion is a high-risk procedure. Ann Thorac Surg 62: 1033-1037 Mouroux J et al (1996) Surgical management of pleuropulmonary tuberculosis. J Thorac Cardiovasc Surg Ill: 662-670 Nakajima Y (1997) Surgical treatment of multidrug resistant pulmonary tuberculosis cases (in Japanese). Kekkaku 72: 25-34 Odell JA, Buckels NJ (1999) Techniques of pneumonectomy: pneumonectomy through an empyema. Chest Surg Clin North Am 9:369-378 Odell JA, Henderson BJ (1985) Pneumonectomy through an empyema. J Thorac Cardiovasc Surg 89:423-427 Okano T, Walkup HE (1958) Some problems in extrapleural pneumonectomy for tuberculous empyema and destroyed lung. J Thorac Surg 35:523-531 Pairolero PC, Arnold PG, Piehler JM (1983) Intrathoracic transposition of extrathoracic skeletal muscle. J Thorac Cardiovasc Surg 86:809-817 Peppas G et al (1993) Thoracoplasty in the context of current surgical practice. Ann Thorac Surg 56:903-909 Pomerantz BJ et al (2001) Pulmonary resection for multidrug resistant tuberculosis. J Thorac Cardiovasc Surg 121: 448-453 Pomerantz M (2000) Surgery for the management of Mycobacterium tuberculosis and nontuberculous mycobacterial infections of the lungs. In: Shields TW, LoCicero JIII, Ponn RB (eds) General thoracic surgery, 5th edn. Lippincott Williams and Wilkins, Philadelphia, pp 1066-1075 Pomerantz M, Brown J (1995) The surgical management of tuberculosis. Semin Thorac Cardiovasc Surg 7:108-111 Pomerantz M, Brown JM (1997) Surgery in the treatment of multidrug-resistant tuberculosis. Clin Chest Med 18:123-130 Pomerantz M, Mault JR (2000) History of resectional surgery for tuberculosis and other mycobacterial infections. Chest Surg Clin North Am 10:131-133 Pomerantz M et al (1991) Surgical management of resistant mycobacterial tuberculosis and other mycobacterial pulmonary infections. Ann Thorac Surg 52:1108-1111 Rizzi A et al (1995) Results of surgical management of tuberculosis: experience in 206 patients undergoing operation. Ann Thorac Surg 59:896-900 Rizzi A et al (1997) Modern morbidity following pulmonary resection for postprimary tuberculosis. World J Surg 21: 488-491 Sahn SA, Iseman MD (1999) Tuberculous empyema. Semin Respir Infect 14:82-87 Sarot IA (1949) Extrapleural pneumonectomy and pleurectomy in pulmonary tuberculosis. Thorax 4: 173-223 Shiraishi Yet al (2000) Morbidity and mortality after 94 extra-

Thoracic Surgery for Tuberculosis pleural pneumonectomies for empyema. Ann Thorac Surg 70:1202-1206

Souilamas R et al (2001) Surgical treatment of active and sequela forms of pulmonary tuberculosis. Ann Thorac Surg 71:443-447 Sung S-W et al (1999) Surgery increased the chance of cure in multi-drug resistant pulmonary tuberculosis. Eur J Cardio Thorac Surg 16:187-193 Tahaoglu K et al (2001) The treatment of multidrug-resistant tuberculosis in Turkey. N Engl J Med 345:170-174

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Thurer RJ (1996) Decortication in thoracic empyema. Chest Surg Clin North Am 6:461-490 Treasure RL, Seaworth BJ (1995) Current role of surgery in Mycobacterium tuberculosis. Ann Thorac Surg 59:1405-1407 Tseng Y-L et al (2000) Intrathoracic muscle flap transposition in the treatment of fibrocavernous tuberculosis. Eur J Cardio Thorac Surg 18:666-670 Van Leuven M et al (1997) Pulmonary resection as an adjunct in the treatment of multiple drug-resistant tuberculosis. Ann Thorac Surg 63:1368-1372

26 Radionuclides in Pulmonary and Extra-Pulmonary Tuberculosis DAVID HAMILTON

and

JAWDA AL-NABULSI

CONTENTS 26.1 26.2 26.2.1 26.2.2 26.2.3 26.2.4 26.2.5 26.2.6 26.2.7 26.3 26.3.1 26.3.2 26.3.3 26.3.4 26.3.5 26.4 26.5 26.5.1 26.5.2 26.5.3 26.5.4 26.5.5 26.6 26.6.1 26.6.2 26.6.3 26.6.4

Introduction 411 Pulmonary Tuberculosis 411 67Gallium Citrate (67 Ga) 412 201Thallium Chloride e01Tl) 414 99Technetiumm (99Tc m ) Radiopharmaceuticals 414 lllIndium (lllIn) Radiopharmaceuticals 415 Sodium 123Iodide (1231) 415 18Fluorodeoxyglucose Positron Emission Tomography 415 Alteration of Normal Physiology 415 Soft Tissue Tuberculosis 416 67Gallium Citrate (67 Ga) 416 Leukocytes 418 99Technetiumm (99Tc m ) Radiopharmaceuticals 418 18Fluorodeoxyglucose Positron Emission Tomography 418 Alteration of Normal Physiology 419 Renal Tuberculosis 419 CNS Tuberculosis 420 67Gallium Citrate (67 Ga) 420 99Technetiumm (99Tc m ) Radiopharmaceuticals 420 201Thallium Chloride e01Tl) 420 18Fluorodeoxyglucose Positron Emission Tomography 421 Partition Test 421 Bone and Joint Tuberculosis 422 99Tc m Polyphosphonate 422 67Gallium Citrate (67 Ga) 425 lllIn Leukocytes 427 18Fluorodeoxyglucose Positron Emission Tomography 427 References 428

D. HAMILTON, PhD, FIPEM Department of Nuclear Medicine, Riyadh Armed Forces Hospital, P.O. Box 7897, Riyadh 11159, Saudi Arabia J. AL-NABULSI, DMRD, MSc NM Department of Nuclear Medicine, Riyadh Armed Forces Hospital, P.O. Box 7897, Riyadh 11159, Saudi Arabia

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

26.1 Introduction Radionuclide investigation is a sensitive, but generally non-specific, indicator of the presence and the extent of tuberculosis; proving valuable in differentiating active from inactive disease. It also provides a method of revealing reactivation of the disease, estimating the therapeutic response, and assessing consequential alteration of normal physiology. Experience extends over 40 years but in the last 10 years, with the resurgence of the disease, new radiopharmaceuticals and imaging techniques have been added to the armamentarium. Also in this period, radionuclides have increasingly been focused on detecting the opportunistic infection complications associated with human immunodeficiency virus (HIV}-infected patients. The non-specificity of imaging using radionuclides, particularly in this disease, must be emphasized. In vivo distribution of radiopharmaceuticals demonstrates characteristics that are common to many pathologies and interpretation must be undertaken with extremely careful consideration of the clinical environment. Most experience in tuberculosis has been gained using planar imaging, and this remains adequate for the majority of investigations. With the increasing sophistication of single photon emission tomography (SPET) technology, however, this type of acquisition is being increasingly utilized to improve detection, particularly for small, deep lesions. Positron emission tomography (PET) has recently provided an alternative perspective to the functional imaging of this disease.

26.2 Pulmonary Tuberculosis A number of radiopharmaceuticals have been used in the evaluation of pulmonary tuberculosis. Their main contribution to clinical investigation is the ability to

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differentiate active from inactive disease, thus enabling evaluation of therapeutic response and revelation of reactivation. In patients with acquired immune deficiency syndrome (AIDS), in particular, nuclear medicine procedures are more sensitive than morphologic imaging modalities in localizing sites of pulmonary tuberculous infection (Abdel-Dayem et al. 1997).

26.2.1 67Gallium Citrate (67Ga) Early studies were performed primarily using 67Ga (Siemsen et al. 1978), and this remains the most widely used (Gulaldi et al. 1995; Onsel et al. 1996; Utsunomiya et al. 1997; Degirmenci et al. 1998) and best radiopharmaceutical for imaging mycobacterial infections (McAfee 1996). It is a "catch-all" radiopharmaceutical that demonstrates accumulation in infection, inflammation, and neoplasm, but requires a delay of 24-72 h between administration and imaging (Gulaldi et al.1995; Onsel et al.1996; Utsunomiya et al. 1997; Degirmenci et al. 1998; O'Doherty et al. 1997; Lin and Hsieh 1999) because of prolonged blood clearance and biliary excretion (Gulaldi et al. 1995). However, the relatively long half-life of the radionuclide facilitates protracted imaging protocols that accommodate slow accumulation in chronic and indolent infections. An advantage of using 67Ga to investigate suspected infection is its ability to image the whole body. This may give rise to incidental findings (Grieff and Lisbona 1991; Lin and Hsieh 1999), and also facilitates determination of the most appropriate biopsy site by exposing involved accessible peripheral nodes (Goldfarb et al. 1997). The accumulation of gallium in tuberculous lesions is complex, but is thought to result from transcapillary exudation of transferrin-bound gallium with subsequent binding to leukocytes or bacteria (Moody and Delbeke 1992; Brophey et al. 1995b). It is affected by malnutrition (Walsh et al. 1985), but not by the impaired cellular immunity in patients with AIDS (Lee et al. 1994). The distribution pattern of the radiopharmaceutical alone can be useful to differentiate different types of pulmonary infections (Lee et al. 1994). It can, however, be similar to the pattern demonstrated by other pathologies and therefore, differentiation may be difficult in the absence of a consideration of the clinical environment (Abdel-Dayem et al. 1995). Generally, the distribution tends to be asymmetric and irregular (Fogelman et al. 1994), mainly at the upper lobes {Goldfarb et al.1995).As with lymphoma,

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focal uptake at the hila, mediastinum, and throughout the lung parenchyma is also expected (Ganz and Serafini 1989; Lee et al. 1994). As noted in sarcoidosis, hilar or diffuse lung involvement is most often seen (Fogelman et al. 1994). Pneumocystis pneumonia (PCP) usually shows bilateral and diffuse uptake, and bacterial pneumonia tends to show segmental or lobar uptake (Lee et al. 1994). Atypical mycobacterial infections present more frequently with extra hilar nodes (Ganz and Serafini 1989). In miliary disease, 67Ga primarily demonstrates a diffuse bilateral pattern (Winzelberg 1981) that is similar to the pattern demonstrated by diffuse pulmonary metastases (AbdelDayem et al. 1995). The intensity of the accumulation is usually similar to or slightly less than that in the liver. Intensity greater than that in the liver is reported in only 12% of patients (Kao et al. 1993). Localized accumulation occurs less frequently (Moody and Delbeke 1992; Kao et al. 1993; Malhotra et al.1985). In pulmonary tuberculosis associated with AIDS, typical distribution patterns differ significantly from those seen in "classical" tuberculosis. The traditional upper lobe presentation is the exception rather than the rule; lower lobe disease and adenopathy are more common (Goldfarb et al. 1995, 1997; Abdel-Dayem et al. 1997). Parenchymal lesions are more heterogeneously distributed than would be expected in traditional pulmonary tuberculosis (Goldfarb et al. 1995), and it becomes difficult to differentiate other opportunistic infections on the basis of the 67Ga distribution alone. Differentiation with PCP would usually be possible by relying on the characteristic diffuse distribution demonstrated by this infection (AbdelDayem et al. 1997). However, this pattern can vary in AIDS patients and become more heterogeneous, ill-defined, and peri-hilar, causing problems in interpretation. Also, there tends to be localized uptake in bacterial pneumonia, and ill-defined, peri-hilar uptake in cytomegalovirus (CMV) infection (Kramer et al. 1989). Lymph node accumulation occurs in the majority of cases, however (Goldfarb et al. 1995; Abdel-Dayem et al. 1997). This forms the basis of a more definite differentiation from other opportunistic infections. The presence of lymph node uptake, in the presence or absence ofparenchymal uptake, raises the possibility of tuberculous involvement; whereas a lack of uptake in the lymphoid regions suggests that the disease is unlikely (Goldfarb et al. 1995, 1997; Parmett et al. 1995; Santin et al. 1995; Abdel-Dayem et al. 1997). Such lymph node accumulation does, however, make differentiation from lymphoma more difficult because of the similar presentation of these two entities (Kramer et al. 1989).

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Imaging with 67Ga is a very sensitive indicator of the presence of active tuberculosis (Siemsen et al. 1978; Moody and Delbeke 1992; Kao et al. 1993) and seems more accurate than physical examination of the neck or plain X-rays of the chest (Goldfarb et al. 1997). Active disease results in a positive image in up to 97% of patients (Siemsen et al. 1976, 1978; Walsh et al. 1985; Lin and Hsieh 1999). 67Ga is extremely valuable in differentiating active disease from established scarring, since inactive disease results in a negative image in up to 100% of patients (Siemsen et al. 1978; Kao et al. 1993). False negative results do occur, however. Conditions that can cause this include anti-tuberculous treatment (Kao et al. 1993) and malnutrition (Walsh et aI.1985). Less commonly, a false negative image can arise in association with drug interference or leukopenia as a result of chemotherapy (Kao et aI.1993). In patients with AIDS, 67Ga scintigraphy is also a very sensitive technique for localizing sites of tuberculous infection (Palestro et al. 1991; Santin et al. 1995; Abdel-Dayem et al. 1997; Goldfarb et al. 1997). A normal 67Ga distribution is very suggestive of an absence of active disease (Lee et al. 1994; Santin et al. 1995), but cannot exclude the possibility completely (Utsunomiya et al. 1997). In terms of opportunistic infections other than tuberculosis, anti-tuberculous treatment can increase the false negative rate of the 67Ga investigation (Goswami et al. 2000). 67Ga scintigraphy is complementary to chest X-ray for determining the activity of disease (Gulaldi et al. 1995; Onsel et al. 1996) because this is difficult to diagnose solely morphologically, in the presence of extensive fibrotic areas (Loken 1987). There is a correlation between the extent of 67Ga accumulation and the extent of radiographic abnormalities but often, the 67Ga uptake is greater than the extent of disease shown on the chest X-ray (Siemsen et al. 1978; Walsh et al. 1985). Also, abnormal patterns of 67Ga accumulation may be seen earlier than radiographic abnormalities (Walsh et al. 1985; Moody and Delbeke 1992). In miliary disease, both 67Ga scintigraphy and chest X-rays are mandatory for reliable diagnoses, especially in high-risk patients. Some lesions may be missed when only one of the modalities is used (Kao et al. 1993). 67Ga images may be positive in the presence of normal chest radiographs (Walsh et al. 1985) even when the accumulation is localized (Kao et al. 1993; Grieff and Lisbona 1991). In AIDS, 67Ga scintigraphy and chest X-rays are again complementary and mandatory techniques (Parmett et al. 1995; Goldfarb et al. 1997), achieving a combined sensitivity of 96% (AbdelDayem et al. 1997). 67Ga is much more sensitive than

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chest X-rays when only lymph node accumulation is present (Goldfarb et al. 1997). Chest X-rays are even less likely to demonstrate abnormality when there is only peripheral node 67Ga uptake than when intrathoracic uptake is present (Santin et al. 1995). Imaging with 67Ga is better than conventional chest radiography in establishing reactivation of the disease, again, because 67Ga uptake is rarely observed in inactive tuberculosis (Siemsen et al. 1978; Moody and Delbeke 1992). Because of the high sensitivity and specificity, abnormal 67Ga accumulation, even in the presence of a normal chest X-ray and negative sputum smears, suggests active disease. This helps to justify further diagnostic procedures and early implementation of empiric therapy (Walsh et al. 1985; Grieff and Lisbona 1991). Such a regimen is also true in HIV-positive patients, especially in areas with a high prevalence of tuberculosis infection, and can be very useful in those patients from whom a biopsy is difficult to obtain. Because the diagnosis of tuberculosis is unlikely when the 67Ga scan does not show nodal uptake (Santin et al. 1995); in those patients suspected of having active tuberculosis, but whose chest X-ray is not suggestive of this, the presence of intrathoracic lymphadenopathy on 67Ga scintigraphy heightens suspicion of the disease (Parmett et al. 1995; Santin et al. 1995). 67Ga scintigraphy is better than morphological radiology for assessing the response of the disease to therapy (Siemsen et al. 1978; Kao et al. 1993). 67Ga uptake decreases with the duration of therapy, indicating a decrease in disease activity that is generally consistent with clinical findings. The uptake increases as the disease worsens (Utsunomiya et al. 1997). Successful treatment results in a marked reduction of 67Ga accumulation within a few months of initiation (Siemsen et al. 1978). In patients with AIDS, as well as providing an indicator of therapeutic response, 67Ga scintigraphy can be used to help determine the point at which medication may be stopped, as it is more reliable than clinical symptoms or the findings on chest radiography (Bekerman et al.1980; Abdel-Dayem et al.1997). 67Ga scintigraphy suffers from three main disadvantages in its use. It produces images of poorer quality than some other radiopharmaceuticals; it requires a protracted delay of 48-72 h between administration and imaging; and it may require cleansing of the bowel to ensure accurate diagnostic information. Also, the specificity of 67Ga is poor because it is a "catch-all" radiopharmaceutical, which demonstrates increased accumulation in infection, inflammation, and neoplasm (Walsh et al. 1985). The specificity in patients with AIDS, in particular, is poor because other oppor-

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tunistic infections such as PCP or CMV can cause difficulty in the interpretation (Abdel-Dayem et al.1997). There are a number of radiopharmaceuticals that can be used as alternatives to 67Ga and that show similar patterns of distribution. Unlike 67Ga, scintigrams obtained with these radiopharmaceuticals can be obtained within a few hours of administration and require little patient preparation.

26.2.2 201Thallium Chloride (20'TI) 20ln scintigraphy, undertaken soon after administration, might be more useful than 67Ga scintigraphy for the evaluation of active disease (Utsunomiya et al. 1997; Degirmenci et al. 1998). 20lTI was first used for this purpose following incidental imaging of active pulmonary tuberculosis on cardiac studies (Lee et al. 1994; Burke 1995) and observation of diffusely increased accumulation in miliary tuberculosis (Abdel-Dayem et al.1995). The uptake of tracer in an infected area is variable immediately after injection (Lee et al. 1994), but a high lesion to normal tissue ratio is normally obtained at 15 min (Utsunomiya et al. 1997). Patients in whom pulmonary tuberculosis is inactive should have negative findings on 20ln scintigraphy (Lee et al. 1994). Even patients who showed improvements on other investigations but in whom subsequent inadequate treatment allowed recurrence of tuberculous lesions showed slight 20lTI uptake. In view of these observations, the possibility of recurrence should be considered in patients who show any abnormal 20ln accumulation, even in the presence of normal clinical data (Utsunomiya et al. 1997). 20ln scintigraphy is also possibly more useful than 67Ga for the evaluation of therapeutic response. 20lTI accumulation decreases with duration of therapy, indicating a decrease in disease activity that is consistent with clinical findings. The uptake increases as the condition worsens. The retention of 201n, over several hours seems to suggest whether healing is underway rather than reflecting the level of disease activity. It decreases significantly in patients showing improvement after therapy and increases in patients experiencing deterioration (Utsunomiya et al.1997). As with 67Ga, the specificity of 20lTI imaging early after administration is poor. Tuberculosis cannot be differentiated from certain tumors (Utsunomiya et al. 1997) for which 201T1 also shows high avidity (Lee et al.1994).A major problem in the follow up of AIDS patients using nuclear medicine is the inability to differentiate among mycobacterial infections, lymphoma,

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and Kaposi sarcoma (KS) (Lee et al.1994). The specificity of scintigraphy can be improved using sequential 20lTI and 67Ga imaging. Both infection and lymphoma generally result in a positive 67Ga image, whereas a negative 67Ga image in the presence of a positive early (less than 15 min after injection) 20lTI image has a high specificity for the diagnosis of KS (Lee et al. 1994; Abdel-Dayem et al. 1996). Differentiation with lymphoma, which demonstrates the same concurrent 67Ga and early 20ln accumulation as tuberculosis, remains difficult. In infection, the increased 20ln accumulation decreases relatively rapidly, whereas lymphoma retains 20lTI much longer. Delayed 201Tl scintigraphy, at 3-4 h following administration, therefore, enables differentiation between the two entities. Local mismatch on sequential delayed 201 Tl and 67Ga images is reported to be highly specific for AIDS-related mycobacterial infections (Lee et al. 1994); but correct results are not always achieved (Abdel-Dayem et al. 1994, 1996; Gomez et al.1996). Other opportunistic infections may show a better clearance of 2ol TI than tuberculosis. In pCP,201n accumulation is seen only in the early images; delayed images show significant clearance. In miliary tuberculosis, however, although the increased accumulation is seen predominantly in the early images, the clearance in the delayed images is not as significant as in PCP and both early and delayed 20lTI images showed diffuse uptake with no significant clearance in the delayed images (Abdel-Dayem et al. 1995).

26.2.3 99Technetium rn (99Tcrn ) Radiopharmaceuticals Tuberculosis generally shows considerable methoxyisobutylisonitrile (MIBI) uptake, which is most probably related to disease activity. It can be used to evaluate therapeutic response, showing a decrease in accumulation with regressing disease and an increase with worsening disease, and can reveal reactivation of previously treated disease. The extent of abnormal MIBI accumulation in positive images generally exceeds the area of chest X-ray abnormalities. The main problem with MIBI is its inability to differentiate tuberculosis from other benign and malignant disease processes. Another drawback is its extensive usual distribution, which can compromise disease detection. For instance, normal skeletal muscle uptake of the thorax and lower neck can mask abnormal accumulation in the apical regions, particularly for small lesions (Onsel et al. 1996). Tetrofosmin (Myoview) behaves in a manner similar to MIBI. It may be more sensitive than sputum smear

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tests and gives clinically useful information until results of sputum cultures are available. It can contribute to the evaluation of the response to therapy. As with MIBI, specificity of tetrofosmin is poor; differential diagnosis between tuberculosis and tumor is difficult because of marked uptake in both (Degirmenci et al.1998). Pentavalent dimercaptosuccinic acid [(V) DMSAj may perform similarly to 67Ga for assessment of the extent and activity of tuberculosis. Citrate does not appear useful in this disease (Gulaldi et al. 1995). Although glucoheptonate (GH) is less expensive and more convenient to use than 67Ga, and although the results are similar using both radiopharmaceuticals, GH is not considered an adequate substitute for 67Ga (Vorne et al. 1988; Braga et al. 1998). Two radiopharmaceuticals that have been used successfully in infection imaging, human polyclonal immunoglobulin G (HIG) and nanocolloid, do not seem appropriate in this disease. Both showed an absence of accumulation in patients with active disease in whom MIBI demonstrated positive results. They also showed an absence of uptake in patients previously treated and in patients with a suspicion of relapse (Onsel et al. 1996).

26.2.4 llllndium (111 In) Radiopharmaceuticals Somatostatin analogue (octreotide and pentetreotide) scintigraphy may be of value in detecting the presence and assessing the extent of active disease (Ozturk et al. 1994; Vanhagen et al. 1994) because of the presence, in granulomatous lesions, of activated lymphocytes that have somatostatin receptors (Ozturk et al. 1994). Accumulation is not specific to tuberculosis, however, since patients with sarcoidosis also show increased uptake (Vanhagen et al. 1994), albeit not focal (Ozturk et al. 1994). Also, normal as well as activated lymphocytes and macrophages have been shown to express somatostatin receptors (Vanhagen et al. 1994). Leukocytes radiolabeled with III In have been used extensively in the imaging of infection but do not seem appropriate in this disease, particularly when it is associated with AIDS (Fineman et al. 1989; Palestro et al. 1991). Although experimental studies with radiolabeled monoclonal antibodies appear promising for the specific localization of tuberculosis (Lee et al. 1992), no human trials have been undertaken thus far (Onsel et al. 1996). The high cost of these studies, the development of the HAMA response, and the lack of experience in clinical studies have limited routine application (Degirmenci et al.1998).

26.2.5 Sodium 12310dide (1231) 1231 is not suggested as a radiopharmaceutical for detecting tuberculosis; it may, however, be compromised in its ability to detect malignant disease by previously treated pulmonary tuberculosis (Bakheet et al. 1999).

26.2.6 18Fluorodeoxyglucose Positron Emission Tomography Focal accumulation of 18fluorodeoxyglucose (l8FDG) occurs in active tuberculosis (Patz et al. 1993; Knight et al. 1996; Bakheet et al. 1998; Goo et al. 2000), albeit sometimes mildly (Patz et al. 1993), and this has caused false-positive results in the detection of malignant disease (Bakheet et al.1998).As with previous radiopharmaceuticals, specificity is poor, showing little differentiation with malignancy (Goo et al. 2000). In comparison with 67Ga, 18FDG seems more sensitive for the detection of opportunistic infections other than tuberculosis in the presence of anti-tuberculous therapy (Goswami et al. 2000).

26.2.7 Alteration of Normal Physiology Alteration of normal physiology, as a result of tuberculous infection, can be demonstrated using several radiopharmaceuticals. Changes to the distribution of pulmonary blood flow, consequential to altered ventilation, can be documented using 99Tc ffi macroaggregated albumin. Typically, a patchy distribution of reduced accumulation is obtained. When compared with X-ray findings, previous tuberculosis may lead to disproportionately large defects on lung perfusion scintigraphy (Fogelman et al. 1994). The same perfusion pattern would also be obtained in pulmonary embolism, however. This low specificity can be improved by imaging the ventilation pattern as well. A concurrent pattern of hypoventilation, indicated as areas of reduced tracer accumulation, suggests a primary ventilation defect causing a perfusion abnormality rather than an embolism. In the presence of corroborative clinical information, such a concurrence can implicate an infective process. Regional patterns of hypoventilation are readily demonstrable using radioactive gases

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b

a m

Fig. 26.1a,b. a Posterior lung perfusion using 99Tc macroaggregated albumin. The image shows multiple large areas of hypoperfusion in the right lung of a patient with pulmonary tuberculosis. These areas correspond with fibrotic changes seen on the chest X-ray (b)

The alternative gas, xenon in the form of 127Xe or 133Xe, does not produce as good an image as 81 Kr m and suffers from further degradation of image quality because of scatter from the perfusion phase, if this is performed concurrently. This gas requires the patient to perform breathing maneuvers during imaging to obtain a ventilation image. These restrict the ventilation views, usually to only the posterior orientation. Radio-aerosols allow multiple images of ventilation to be obtained without imaging maneuvers having to be performed. They are, however, labeled with 99Tc m which, being the same radionuclide as is used in the perfusion phase, precludes concurrent imaging. Sequential imaging, in which the perfusion phase is undertaken approximately 2 h after the radio-aerosol study, is usual.

Fig. 26.2. Posterior lung perfusion, undertaken 22 months later, on the patient presented in Fig. 26.1. The image shows a worsening in the perfusion of both lungs, with disease progression

or radio-aerosols. Of all the options, 81Krm is the best, allowing ventilation images to be obtained during equilibrium breathing concurrently with the perfusion imaging and in the same imaging orientations. The specificity of the full ventilation-perfusion test, using 81 Kr m for differentiating between airways disease and pulmonary embolism, is extremely high.

26.3 Soft Tissue Tuberculosis 26.3.1 67Gallium Citrate (67 Ga) 67Ga is presently the best radiopharmaceutical for imaging mycobacterial infections in soft tissue (McAfee 1996). The technique is very sensitive (Sarkar and Ravikrishman 1978; Sarkar et al. 1979; Lin and Hsieh 1999; Yang et al. 1992) and has proven useful

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a Fig. 26.3a,b. Posterior lung ventilation using 81Kr"', undertaken at the same time as (a) the image in Fig. 26.1a and (b) the image in Fig. 26.2. The images show multiple large areas of hypoventilation corresponding with the areas of hypoperfusion previously described

in the identification of distant sites of tuberculous involvement (Kattapuram et al. 1979; Moody and Delbeke 1992), presenting as a single focus or diffuse area of increased accumulation, or as multiple foci arranged in a random distribution. The progression of the disease can be followed by identifying an enlargement of a focus or an increase in number of foci (Shih et al. 1986; Schmidt and Rebarber 1994; Lin and Hsieh 1999). 67Ga scintigraphy is also useful in assessing the response to therapy (Pettengell et al. 1990; Moody and Delbeke 1992). A number of cases of abnormal 67Ga accumulation occurring at a single site in the abdomen have been reported (Lin and Hsieh 1999). These have included a focus in the intestine (Yang et al. 1992; Lin and Hsieh 1999), two foci in the liver (Ohta et al. 1996), and three foci in the spleen (Kao et al. 1996). Diffusely increased tracer accumulation throughout the abdomen has been shown in tuberculous peritonitis (LaManna et al. 1984; Sumi et al. 1999). Decreased hepatic accumulation is also associated with this. The scintigraphic findings of tuberculous peritonitis are not specific; many intra-abdominal processes present with similar features. Nevertheless, if 67Ga scintigraphy shows diffuse abdominal uptake with decreased hepatic accumulation, tuberculous peritonitis should be considered in the differential diagnosis (Sumi et al. 1999). Other examples of diffuse areas of abnormality at a single site have included infection in the peritoneum at the base of the pelvis detected on whole body imaging

as diffuse abdominal uptake and linear uptake along the bottom of the pelvic cavity (Hashimoto et al. 2000) and tuberculous enteritis (Pettengell et al. 1990). After 24 h, the fecal route predominates, thus making the interpretation of uptake in the abdominal region somewhat difficult. In spite of this drawback, the possibility of involvement of the GI tract by infection or tumor may be suspected if excessive GI activity is seen in the early scans (e.g., in a 24 h image), or if the intensity of GI uptake on the 48-72 h image is equal to or greater than the liver activity (Beckerman and Bitran 1988). Bowel cleansing and changes in the location and/or configuration of the intestinal activity from one scan to another have been used for distinction of physiologic bowel excretion from pathologic changes (Beckerman and Bitran 1988; Yang et al.1992; Lin and Hsieh 1999). However, uptake due to diffuse inflammation or due to neoplastic involvement of the intestinal wall may change location and configuration in two consecutive scans, thus diminishing the reliability of such a "change shape/location" sign (Beckerman and Bitran 1988). Asymmetric 67Ga accumulation in lymph nodes or salivary glands is an unusual finding and suggests the need for more aggressive diagnostic investigation (Kattapuram et al. 1979; Bihl and Maier 1987; Moody and Delbeke 1992). Disseminated tuberculosis presents as abnormal 67Ga accumulation in numerous organs (Moody and Delbeke 1992), for instance, in the kidney and peritoneum (Sarkar and Ravikrish-

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man 1978; Sarkar et al. 1979). Lymph node accumulation has been reported in the mediastinum, left lung hilus and retroperitoneum (Prat et al. 1991); in esophageal and supraclavicular regions (Young et al. 1996); and in tuberculous salpingitis, endometriosis, and both kidneys (Leventhal et al.1981). The differential diagnosis of increased 67Ga uptake includes both infective/inflammatory and malignant processes, and 67Ga alone is thus not specific enough to provide pathognomonic signs for tuberculosis (Bihl and Maier 1987; Dhekne et al. 1987; Gomez et al. 1996). In tuberculosis associated with AIDS, it is reported that sequential delayed 20ln and 67Ga scintigraphy allows differentiation between infection and malignancy because, in infection, there is clearance of 20lTI on delayed images (Lee et al. 1994). This finding has been disputed, however. In a patient with HIV and tuberculous lymphadenopathy, both delayed 20lTI and 67Ga images showed increased uptake. This suggests that caution must be exercised when differentiating between malignancy and infection/ inflammation in HIV-positive patients using delayed 20ln and 67Ga scans, and that careful microbiological and clinical investigation is still necessary to exclude AIDS-related mycobacterial infections (Gomez et al. 1996).

26.3.2 Leukocytes Although increased accumulation is seen on both lllIn leukocyte and 67Ga images (Schmidt and Rebarber 1994), generally leukocytes are less sensitive for the detection of tuberculosis (Brophey et al. 1995b). In tuberculosis enteritis there is a slight, statistically significant, superiority of67Ga over leukocyte imaging, partly because it does not rely on vigorous leukocyte migration to the area of disease for its success. There is positive scintigraphy with leukocytes despite prolonged treatment, indicating that leukocyte recruitment may continue for several weeks despite optimum anti-tuberculous treatment. However, it is not certain that serial scans are of benefit in the assessment of treatment (Pettengell et al. 1990). Mixed results have been obtained with leukocytes labeled with 99Tc ffi • On the positive side, leukocyte scintigraphy showed increased ileocecal accumulation in disseminated tuberculosis (Prat et al. 1991). On the negative side, an absence of uptake occurred in a paravertebral abscess (Hovi et al. 1993) and in a number of patients with extensive tuberculous lesions (Brophey et al. 1995b).

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26.3.3 99'fechnetium m(99'fem) Radiopharmaceuticals Methoxyisobutylisonitrile (MIBI) has been shown to accumulate in a tuberculous lesion in the female breast and indicates that tuberculosis must be added to the differential diagnosis of breast uptake of MIBI (Ohta et al. 1998). In comparison with 67Ga, (V) DMSA will reveal an inflammatory lesion as a wider area of less well-defined and lower uptake because it detects the relatively hypervascular and hypermetabolic tissue surrounding such a lesion. Thus, intense 67Ga accumulation in association with moderate, poorly defined, and wider (V) DMSA uptake suggests a marked inflammatory reaction in a lesion. Such a pattern was shown in solitary muscular involvement by tuberculosis. Otherwise, in a large proportion of malignant soft tissue tumors, 67Ga accumulation is relatively fainter than that of (V) DMSA (Kobayashi et al. 1995). As in pulmonary tuberculosis, HIG does not seem appropriate in this disease. Neither increased accumulation nor cold lesions were revealed in a patient with spondylitis and a paravertebral abscess (Hovi et al. 1993). Hydroxymethylene diphosphonate, generally regarded as purely a skeletal imaging pharmaceutical, can reveal tuberculous lesions in soft tissue. It showed a large and well-delineated area of increased uptake in extraskeletal tissue corresponding to a tuberculous abscess (Tamgac et al. 1995). Pyrophosphate is used as a myocardial radiopharmaceutical for evaluation of myocardial infarcts. It also seems to be useful for the detection of early tuberculous pericarditis and showed abnormal uptake along the lateral portion of the left ventricle in a case of tuberculous pericarditis. Although no calcification was proven on biopsy, the abnormal uptake of pyrophosphate along the left ventricle was considered to be caused by early calcifying inflammatory changes in the pericardium (Ishino et al. 1992).

26.3.4 18Fluorodeoxyglucose Positron Emission Tomography As in pulmonary disease, moderate or intense accumulation of 18FDG occurs in active soft tissue tuberculosis. It presents as focal uptake at single (Bakheet et al. 2000) or multiple sites (Bakheet et al. 1998) or as diffuse accumulation (Braga et al. 2001).

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Moderate, diffuse, and homogeneous accumulation was documented as corresponding to tuberculous involvement of the spinal cord (Braga et al. 2001). In one patient, PET imaging showed very intense focal 18PDG accumulation in the breast, which responded to anti-tuberculous drugs and was regarded as tuberculous mastitis (Bakheet et al. 2000). Intense multifocal 18PDG accumulation was documented in two patients with widespread tuberculous lymphadenitis (Bakheet et al. 1998). However, specificity is poor and PET imaging alone cannot differentiate acute or chronic infection or inflammation from malignancy (Bakheet et al. 1998,2000; Cook et al. 1996).

26.3.5 Alteration of Normal Physiology Alteration of normal physiology can be detected during active infection or in inactive disease as a result of altered anatomy. 99Tc ffi pertechnetate sialogram studies in two patients with unilateral tuberculosis in parotid and submandibular glands showed normal radionuclide uptake. One patient showed blocked excretion in the distended parotid after administration of a gustatory stimulus. The other patient demonstrated a normal excretion phase (Bihl and Maier 1987). Superior vena cava (SVC) obstruction developed from progressive enlargement of mediastinal tuberculosis, which was demonstrated on consecutive 67Ga scans. An initial 99Tc ffi pertechnetate SV cavagram showed no definite evidence of obstruction and an initial sulfur colloid scintigraphy showed normal tracer distribution throughout the liver. A follow-up radionuclide SV cavagram, 4 months after the initial study, demonstrated interruption of flow in the SVC and development of collateral circulation in the right anterior chest wall. A follow-up 99Tc ffi sulfur colloid scintigraphy showed two hot spots in the liver (Shih et al. 1986) 3 weeks later. An abdominal cerebrospinal fluid (CSP) pseudocyst associated with tuberculous peritonitis involving the peritoneal end of a ventriculoperitoneal shunt was detected using intrathecal administration of III In diethylenetriamine pentaacetic acid (DTPA) to assess the patency of the shunt. A study of the shunt revealed tracer flowing freely through the shunt but a loculated collection of activity was seen at the peritoneal end of the shunt catheter. Tuberculous peritonitis was considered to be the cause of the failure of CSP resorption from the peritoneal cavity and the formation of a thick-walled cystic lesion (Suga et al. 2000).

Alteration of normal physiology in the liver and spleen can be revealed using 99Tc ffi sulfur colloid. Photopenic areas demonstrate an absence of function, such as multiple discrete defects in the spleen (Kattapuram et al. 1979) or as diffuse hepatocellular dysfunction with marked splenomegaly (Winzelberg 1981). Two patients with pseudotumor of the liver showed 67Ga uptake, which corresponded to a relatively larger cold defect seen on a simultaneously obtained liver-spleen scan (Dhekne et al. 1987). Three focal areas increased 67Ga accumulation at the left upper abdominal quadrant showed three photondeficient areas on sulfur colloid scintigraphy in the spleen corresponding to the 67Ga distribution (Kao et al. 1996). The effect of tuberculous thyroiditis can produce the same 131Iodine (1 31 1) distribution as occurs in malignancy. In a patient with this disease, scintigraphy initially indicated a reduced 131 1 uptake with enlarged gland and well-defined area of absent accumulation. Both uptake and distribution showed significant improvement 3 months following initiation of anti-tuberculous therapy. This improvement continued at 6 months, by which time the thyroid uptake had returned to within normal limits (Wang et al. 1972).

26.4 Renal Tuberculosis Renal tuberculosis has been particularly extensively studied since the 1960s, with almost all of the early contribution originating from Russia. The function of the kidney can be investigated from three perspectives: static parenchymal imaging, dynamic renography, and absolute function. Scarring is readily demonstrable by parenchymal imaging using DMSA. Lesions appear as areas of reduced tracer accumulation, indicating non-functioning parenchyma. Small scars are sometimes only detectable using SPET. The effect of such scarring on perfusion, function, and excretion throughout the kidneys can be revealed using renography with hippuran, DTPA, or betiatide MAG3. Due to its dynamic nature, this imaging is undertaken from one orientation only, usually posterior.Abnormalities will present as reduced perfusion, function, or excretion, but activity-time curves may be needed to accurately assess any such deterioration. Because progressive fibrosis may occur, followup renograms are recommended initially at about

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1 month and then at 3-6 month intervals depending on the site of tuberculosis in the renal tract (Sweny et al. 1989). Confirmation of the non-functioning of a kidney and the compensatory hypertrophy of the contralateral kidney with dilated upper ureter was shown on a DTPA renogram (Taher 1998). The absolute effect of the disease on renal function can be assessed by estimating glomerular filtration rate (GFR), using SlCr edetic acid or 99Tc rn DTPA. Abnormalities will be revealed by a reduction (in mllmin) compared with normal ranges. The test is one of overall renal function and cannot provide an indication of whether one kidney is more severely affected than the other. GFR is the best single parameter for the assessment of absolute renal function (Brochner-Mortensen 1978; Groth 1984; Picciotto et al. 1992; Piepsz et al. 1994). It is measured in mllmin corrected for body surface area, using blood samples usually taken between 2 hand 4 h after administration. Its sensitivity can be appreciated by the example of a 65-year-old man who presented with tuberculosis of the urinary tract. The initial GFR was 66 mllmin/1.73 m 2 compared with a normal range of 73-116. This had reduced to 29/min/1.73 m 2 compared with a normal range of 71-112 with disease progression, 16 months later.

26.5

eNS Tuberculosis Meningitis caused by tuberculosis has been studied, most recently, using imaging techniques which are very different from the older non-imaging partition test. In contrast to structural imaging techniques, functional methods can detect brain alterations before morphological damage occurs (Villringer et al. 1995). If the intracranial lesions are large and relatively superficially located, planar imaging might be adequate to make the diagnosis, but for most lesions the use of SPET is necessary (Kim et al. 1995; Lee et al. 1999).

26.5.1 67Gallium Citrate (67Ga) Although useful for most presentations of tuberculosis, 67 Ga scintigraphy is of limited use in the detection of tuberculous meningitis. It is postulated that the blood-brain barrier mechanism of the central nervous system (CNS) plays a role in this low detection rate (Lin and Hsieh 1999).

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L

Fig. 26.4. 99Tc m diethylenetriamine pentaacetic acid scintigraphy demonstrating non-functioning left kidney

26.5.2 99'fechnetium rn (99'fc rn ) Radiopharmaceuticals Autologous leukocytes labeled with 99Tcrn can be used to diagnose tuberculous meningitis (Kim et al.1995). Data on perfusion imaging in tuberculous meningitis are lacking but this has recently been studied using ethylene cystine dimer (ECD). The ECD studies were more frequently abnormal compared with computed tomography (CT) but did not correlate with the severity or stage of meningitis, or clinical outcome (Misra et al. 2000).

26.5.3 201Thallium Chloride (l01TI) Because brain involvement due to opportunistic infections or primary CNS lymphoma is a common complication of HIV infection and early diagnosis is important for therapy strategies and prognosis, much work has been concentrated in this area (Villringer et al. 1995). In patients with AIDS, 201Tl can be used to differentiate lymphoma from tuberculosis in lesions identified on CT/magnetic resonance imaging (MRI) (Lorberboym et al. 1998; Lee et al. 1999). This radiopharmaceutical concentrates in many tumors, but more importantly, its concentration in infectious and inflammatory foci is relatively low (Lee et al. 1999). The absence of accumulation on images, early after

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pharmaceutical but DTPA has the advantage of easier availability (von Wenzel et al. 1989). Following intravenous or oral administration (Wiggelinkhuizen and Mann 1980), the ratio of the activity in the blood to that in the CSF is measured at 48 h for 82Br (Girgis et al. 1990) and at 24 h for DTPA (von Wenzel et al. 1989). In normal subjects, the concentration in plasma is 2.5-3.5 times that in lumbar CSF and 3-5 times that in ventricular CSF. The concentration gradient between plasma and CSF appears to be maintained by an active transport system in the choroid plexus, and proximity to the plexus probably accounts for the differences in the levels in lumbar and ventricular CSF. The radiopharmaceuticals cross the blood-brain barrier to a greater extent in patients with meningitis, more so in tuberculous than in viral (Wiggelinkhuizen and Mann 1980). Both tracers thus yield decreased serum to CSF concentration ratios in patients with tuberculous meningitis (von Wenzel et al. 1989; Girgis et al. 1990). A low ratio, below 1.6, is strong support for a diagnosis of tuberculous meningitis and one above 1.6 is against the diagnosis (Wiggelinkhuizen and Mann 1980; Daniel 1987). The depression of the ratio is independent of the stage of the untreated disease and the prognosis, however (Wiggelinkhuizen and Mann 1980). The sensitivity of the test approximates to 90% 26.5.4 (Wiggelinkhuizen and Mann 1980; Daniel 1987). The 18Fluorodeoxyglucose Positron Emission results for DTPA are not quite as good as 82Br. The Tomography accuracy for distinguishing among tuberculous and viral and septic meningitis, was found to be 86.9% Primary CNS lymphomas are known to be meta- using DTPA compared with 90.9% using 82Br (von bolically very active tumors, even if the patients Wenzel et al. 1989). It is possible that the number of are receiving steroids. This high metabolism of CNS false-negative results could be kept to a minimum lymphomas was also found in HIV-infected patients by performing the test as soon as anti-tuberculous (Villringer et al.1995). Many infectious foci are 18FDG therapy is started and by avoiding, if possible, the avid, which is useful in detecting both infections and use of corticosteroids until the test is complete malignancy, but it is of limited value in distinguish- (Wiggelinkhuizen and Mann 1980). These reintegrate ing between them (O'Doherty et al. 1997), although the blood-brain barrier and cause very dramatic differentiation has been reported in one patient with changes to the penetration of compounds into the tuberculoma (Villringer et al. 1995). spinal fluid (Buchanan 1981). The test has also been reported to be an indicator of the development of permanent sequelae (Girgis et al.1990). 26.5.5 A low ratio, of 1.6 or less, is not specific for tubercuPartition Test lous meningitis (Wiggelinkhuizen and Mann 1980). Although the partition test can differentiate among The partition test is particularly useful in distinguish- those patients with encephalitis and those with mening early tuberculous meningitis from viral meningitis ingitis (Buchanan 1981), false-positive results occur (Wiggelinkhuizen and Mann 1980). The partition of in both pyogenic (Wiggelinkhuizen and Mann 1980) certain ions between serum and CSF after a loading and aseptic meningitis and, although the specificdose reflects the integrity of the blood-brain barrier ity approximates to 90%, concern remains that the (Daniel 1987). Both ammonium 82Bromide (82 Br) and test may not have the very high specificity that is 99Tcffi DTPA can be used. 82Br is the traditional radio- necessary for detecting this disease (Daniel 1987).

administration, at the site of a CT/MRI abnormality excludes the diagnosis of lymphoma with a high degree of confidence (Lorberboym et al.1998). In the presence of abnormal early 20lTl uptake, it is essential to perform delayed imaging, at approximately 3 h after injection, to distinguish tuberculosis from lymphoma (Lorberboym et al. 1998; Lee et al. 1999). This is because an infectious process can sometimes show early accumulation, which then clears relatively quickly in comparison with neoplastic lesions (Lee et al. 1999). Although most reports have referred to extracranial lesions to differentiate between tuberculosis and KS or infarct in patients with AIDS, sequential delayed 20lTl and 67Ga imaging can be undertaken. Both lymphomas and infection are 67Ga avid. Lymphoma would show a positive 20lTl pattern whereas tuberculosis would show an absence of 20lTI accumulation. KS and infarct show an absence of 67Ga accumulation. An absence of 201Tl uptake would suggest infarct. A pulmonary lesion with a 20lTI positive and 67Ga negative pattern would indicate KS. Since KS is extremely rare in the CNS, such a pattern would be unexpected. In practice, therefore, 67Ga scanning is probably unnecessary if brain lesions are 20lTl avid (Lee et al.1999).

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In particular, the differentiation between tuberculous meningitis and partially treated bacterial meningitis remains elusive (Buchanan 1981). Little is known about the duration of the depression of the ratio in treated tuberculous meningitis, but specific antituberculous therapy does not affect the ratio in the first few weeks (Wiggelinkhuizen and Mann 1980). The rise in serum to CSF ratio following therapy could be used, however, to distinguish bacterial from tuberculous meningitis (Girgis et al. 1990). There is no relationship between the ratio and the severity of the meningeal inflammatory response (Wiggelinkhuizen and Mann 1980).

26.6 Bone and Joint Tuberculosis Radioisotope imaging is usually more sensitive than plain radiography in the detection of bone and joint tuberculosis (Dickinson et al. 1996), as an uncertain time interval can exist between the onset ofthe clinical presentation and the radiological diagnosis (Everaert et al. 1997). There is a possibility of false negative results however and, if there is a strong clinical suspicion of skeletal tuberculosis, further investigations should be performed even if the nuclear medicine studies are normal (Pui et al. 1986). Nuclear medicine techniques may be more useful when the diagnosis has been made and when an assessment of the extent of involvement is required, particularly to detect asymptomatic lesions (Dickinson et al. 1996), many of which are unsuspected clinically (Rust et aI.1981). A whole body survey in a patient with extra-pulmonary tuberculosis is important because multiple lesions are not uncommon. Both phosphonate bone and 67 Ga scans facilitate such whole body screening to detect multiple sites of involvement (Muradali et al. 1993; Lin et al.1998; Lin and Hsieh 1999) and they reveal sites for further detailed evaluation by other modalities (Lin et al. 1998; Lin and Hsieh 1999).

26.6.1

"Tem Polyphosphonate Tuberculous infection of bone has been investigated extensively since the 1960s, when radioactive strontium was used. The present mainstay of investigation is the polyphosphonate scan, which was introduced in the early 1970s (Fanning et al. 1974). Bone scintigraphy is an excellent test for detecting disseminated

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tuberculosis of the skeleton (Boumpas et al. 1987; Lin et al. 1998; Dickinson et al. 1996), both in making the diagnosis and in localizing further areas of increased uptake (Dickinson et al. 1996). It can be used as a relatively inexpensive investigation to decide which patients are likely to benefit from MRI, particularly at the stage when X-rays are normal (Desai 1994). The investigation comprises three phases: perfusion, blood pool, and late. Although infections are usually apparent on all three, in indolent infections like tuberculosis, often only the third phase is positive. The lesions appear either as a single focus or as multiple foci in a random pattern. Pulmonary involvement need not be present and involvement is not limited to the axial skeleton (Muradali et al.1993). The lesions usually show increased radionuclide accumulation, reflecting increased osteoblastic activity. Less commonly, they show decreased uptake due to interference with the blood supply by inflammatory products (Pui et al. 1986) or fibrous replacement of the osteoid upon healing, which results in lack of bone imaging agent uptake and a consequential area of photopenia (Rust et al.1981). Single focus examples include abnormality at tibia and pubic bone (Abdelwahab et al. 1991), rib (Muradali et al. 1993), and hip joint, more intense at the periphery, affecting both the femoral head and acetabulum (Greenspan and Stadainik 1995). Many examples ofmultiple,scattered,focal areas ofaccumulation are reported (Boumpas et al. 1987; Dickinson et al. 1996). Particular sites have included: ribs, thoracic and lumbar spine, shoulder girdle (Rust et al. 1981); ribs, spine, appendicular skeleton (Nocera et al. 1983); sternum, clavicle, ribs, thoracic and lumbar spine, iliac crest, tibia, sacroiliac joints, acetabulum (Muradali et al. 1993); elbow, lumbar and thoracic spine, shoulder, maxilla, temporomandibular joint, as well as faint sternal uptake (Hardoff et al. 1995). Bone scintigraphy is a sensitive technique for detecting active skeletal tuberculosis (Lisbona et al. 1993; Desai 1994). False normal bone imaging can occur, however, particularly in low-grade, indolent (Dickinson et al. 1996; Pui et al. 1986), or severely destructive osteomyelitis (Pui et al. 1986; Lisbona et al. 1993). The results of bone scintigraphy must be interpreted in the context of the clinical situation; a negative result does not exclude tuberculous bone infection (Muradali et al. 1993). The technique is reasonably sensitive in spinal tuberculosis (Desai 1994), but false negative results do seem to be found more frequently in this presentation. The reasons for this are unknown (Lisbona et al. 1993) but are likely to be due to the indolent nature of the infection

Radionuclides in Pulmonary and Extra-Pulmonary Tuberculosis

423 Fig.26.5a-c. 99Tc rn methylene diphosphonate bone scintigraphy in a patient with multi-focal tuberculous osteomyelitis. a Posterior blood pool showing a focus of slightly increased accumulation in the region of the left first rib. b Anterior skull showing focus of increased accumulation in the right frontal bone. c Right anterior oblique head and neck showing foci of increased accumulation at C3 and the left first rib

a

b

c

Fig. 26.6. Lateral cervical spine X-ray, corresponding to Fig. 4c, showing destruction of C3

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a

c

Fig. 26.7. A case of spinal tuberculosis involving thoracic vertebrae 8-11. a Late phase 99Tc rn bone scintigraphy showing a complete absence of accumulation in T9 with increased accumulation in T8 and TIO and slightly increased uptake in TIL Loss of height at 11 is apparent. b Blood pool image showing only slightly reduced activity in the region of T9 and only slightly increased activity in the region of T8 and TIO-l1. c Lateral magnetic resonance image with contrast, showing destruction at the T9level that is enhancing. Also shown is a paraspinal abscess not revealed by the bone scintigraphy

(Pui et al. 1986). Bone scintigraphy is usually more sensitive in detecting tuberculous osteomyelitis and shows abnormality earlier than conventional radiographs (Nocera et al. 1983; Pui et al. 1986; Lisbona et al. 1993; Muradali et al. 1993). It is not specific for tuberculous lesions (Lin et al. 1998) and will demonstrate non-specific findings, which may be seen in other conditions (Sharif et al. 1989; Greenspan and Stadainik 1995). The presentation may mimic malig-

nancy (Rust et al. 1981; Nocera et al. 1983; Boumpas et al. 1987; Muradali et al. 1993; Hardoff et al. 1995) because multiple asymmetrical areas of increased uptake are often regarded as being virtually diagnostic of metastases (Dickinson et al. 1996). Experience indicates, however, that any confusing bone lesion in an "at risk" patient may prove to be tuberculous (Abdelwahab et al. 1991) and may create confusion about the diagnosis (Nocera et al. 1983).

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Fig. 26.8. a Diffusely increased accumulation at the distal half of the right femur on 99Tc m bone scintigraphy. Two months after anti-tuberculous therapy, b the accumulation in the femur has reduced but c there is increased uptake at the distal end of the left humerus

a

b

c

Serial bone scintigraphy can be used to assess the response to treatment (Dickinson et al. 1996). It can remain positive for a prolonged period after initiation of anti-tuberculous therapy (Sarkar et al. 1979), but generally returns to normal in 3-6 months (Rust et al. 1981; Nocera et al. 1983; Boumpas et al. 1987). The assessment can encompass the effect of interrupted treatment (Rust et al. 1981).

26.6.2

67Gallium Citrate (67Ga) 67 Ga

scintigraphy has an advantage over 99Tcffi phosphonate bone scintigraphy in that it detects soft tissue as well as bone infections (Pui et al. 1986; Lisbona et al. 1993; Hardoff et al. 1995; Lin et al. 1998). In the spine, in particular, it highlights distant septic foci in the soft tissues or skeleton, which are more

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a

Fig. 26.9a-c. 99Tcm methylene diphosphonate bone scintigraphy undertaken 11 months after the scintigraphy presented in Fig. 26.5, showing disease regression. a Anterior blood pool showing no evidence of the focus of slightly increased accumulation in the region of the left first rib. b Anterior skull showing no evidence of the focus of increased accumulation in the right frontal bone. c Right lateral head and neck showing no evidence of the foci of increased accumulation at C3 and the left first rib

c

amenable to biopsy than the spine itself (Lisbona et al. 1993). Skeletal uptake of 67Ga is related to both reticuloendothelial activity and to bone turnover. Lesions appear as focal areas of increased accumulation, and may be solitary or appear as multiple foci in a random distribution. Although the pattern is not characteristic only of tuberculosis, it must be considered when this pattern is observed (Hardoff et al.1995). Pulmonary involvement need not be present (Lisbona et al. 1993). The detection sensitivity of 67Ga scintigraphy is high for skeletal tuberculosis (Lin et al. 1998; Lin and Hsieh 1999). It seems more sensitive than 99Tc ffi phosphonate bone scintigraphy (Lisbona et al. 1993). It also seems more sensitive in spinal lesions (Sarkar

and Ravikrishman 1978; Sarkar et al. 1979; Lisbona et al. 1993; Hardoff et al. 1995; Everaert et al. 1997; Lin and Hsieh 1999). As with 99Tc ffi phosphonate bone scintigraphy, false-negative results do occur in spinal tuberculosis and with a greater frequency than in other parts of the skeleton (Pui et al. 1986; Lin et al. 1998; Lin and Hsieh 1999) and 67Ga citrate images are insensitive in low-grade, indolent, or severely destructive osteomyelitis (Pui et al. 1986; Lin et al. 1998). Sequential 67Ga scanning offers the opportunity to monitor response to therapy (Lisbona et al. 1993), particularly in the spine (Everaert et al. 1997); since abnormally increased 67Ga accumulation resolves within months of initiation of anti-tuberculous therapy (Pui et al. 1986).

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Radionuclides in Pulmonary and Extra-Pulmonary Tuberculosis

67Ga scintigraphy is frequently performed in AIDS patients with fever of unknown origin to identify a site for a more invasive investigation. In these patients, however, disseminated mycobacterial infection also alters the usual 67Ga distribution in the bone marrow. This is assessed by measuring the skull uptake, chosen because of the absence of overlapping structures, which may be a sign of peripheral marrow activation and could reflect the presence of expanded bone marrow. Abnormal skull uptake appears to be a sensitive and specific indicator of disseminated tuberculous infection in HIV-infected patients (Gomez et al.1995). 67Ga scintigraphy is more sensitive than X-rays for the detection of active tuberculous osteomyelitis (Lisbona et al. 1993). Specificity of 67Ga scintigraphy is poor, the distribution pattern being characteristic not only of tuberculosis. It is unable to differentiate between tuberculous and pyogenic osteomyelitis (Lisbona et al. 1993), an ' ',creased uptake occurs in malignancy (Hardoff et, '995). Combined 99Tcffi phos) mate bone and 67Ga scintigraphy can improve th{ ecificity for evaluation of skeletal tuberculosis, 67C..l scintigraphy ascribing a septic origin to the less specific increased uptake seen on 99Tc ffi phosphonate bone scintigraphy (Lisbona et al. 1993; Dickinson et al. 1996). However, there have been few reports where both radiopharmaceuticals are used (Lin et al. 1998). Both 99Tcffi phosphonate bone and 67Ga scintigraphy generally show concurrent accumulation in tuberculous osteomyelitis (Brophey

et al. 1995a). However, the uptake is more intense with 67Ga, and its distribution extends beyond the 99Tcffi phosphonate distribution, consistent with the soft tissue component of the lesions (Hardoff et al. 1995). A combination protocol improves sensitivity in comparison with single radiopharmaceutical investigation (Lin et al. 1998). Abnormal 67Ga accumulation can resolve within months ofinitiation of anti-tuberculous therapy (Sarkar et al. 1979), but significant uptake can persist. 67Ga scintigraphy, 2 months after initiating anti-tuberculous therapy, demonstrated abnormal residual uptake in both bone and soft tissue (Boumpas et al. 1987). 20lTl is reported to accumulate avidly in tuberculous osteomyelitis, but it is not clear whether this is on early or delayed scintigraphy. Comparative scintigraphy showed marked localized hyperemia and intense focal osteoblastic activity with 99Tcffi phosphonate, but only a moderate degree of 67Ga uptake. The combined scan appearance favored a primary bone neoplasm; chronic osteomyelitis being less likely since 20lTl avidity in the lesion was so much greater than that of 67Ga, but a biopsy confirmed tuberculous osteomyelitis with no evidence of malignancy (Mansberg et al.1997). Other radiopharmaceuticals have been used, in combination with 99Tcffi phosphonate bone scintigraphy. In two patients with tuberculous spondylitis, 99Tcffi phosphonate bone scintigraphy gave positive results. However, scintigraphy with HIG and monoclonal antibodies gave false-negative findings, as did the blood pool phase of the phosphonate scintigraphy (Sciuk et al. 1991). In tuberculous lesions, l1lIn chloride bone marrow scintigraphy shows areas of decreased accumulation corresponding to areas of increased 99Tcffi phosphonate bone uptake. It is postulated that the photopenic areas represent bone marrow replacement by the tuberculous inflammatory process (Nocera et al.1983).

26.6.3 1111n Leukocytes In tuberculous osteomyelitis, I11In labeled leukocytes show increased accumulation, concurrent with increased 67Ga uptake (Schmidt and Rebarber 1994).

Fig. 26.10. 67Ga scintigraphy undertaken 6 weeks after the 99Tc m methylene diphosphonate bone scintigraphy shown in Fig. 26.9. Right lateral showing slight residual increased accumulation in the region of C3

26.6.4 1sFluorodeoxyglucose Positron Emission Tomography 18 FD G

is useful for assessing the process of inflammatory activity in tuberculous osteomyelitis by

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quantifying the pathologic increase in the glucose metabolism of the inflammatory processes (Kalicke et al. 2000; Schmitz et al. 2000). Compared with 99Tc ffi phosphonate bone scintigraphy, soft tissue changes can also be observed, including lung involvement. The reason for this is the high spatial resolution compared with single photon scintigraphy, which enables differentiation between osteomyelitis and infection of surrounding soft tissue (Schmitz et al. 2000). There is significantly increased 18FDG uptake in malignant tissue, as a result of which differentiation between infection and metastases is difficult. However, in fractures and pseudarthroses only very low 18FDG uptake is observed, which means that it is possible to differentiate these from infection (Kalicke et al. 2000). Although it is thought to act mainly as a tumor-imaging agent (O'Doherty et al. 1997) because malignant cells demonstrate higher glucose metabolic activity than benign lesions do (Goo et al. 2000), 18FDG PET also shows the increased glucose metabolism of activated inflammatory cells, such as leukocytes, granulocytes and macrophages (Bakheet et al. 1998; Kalicke et al. 2000; Schmitz et al. 2000). Therefore, 18FDG uptake in tuberculosis is not unexpected (Bakheet et al.1998). There is overlap between 18FDG uptake of malignant lesions and some infectious processes (Knight et al. 1996) mainly due to the presence of macrophages, but early reports indicate that 18FDG is a promising technique to differentiate tumors from infections (O'Doherty et al.1997). Early after surgical intervention, however, it is not possible to differentiate between post-surgical reactive changes and further infection because of non-specific tracer uptake (Kalicke et al. 2000). The progress of therapy can be clearly shown (Kalicke et al. 2000). In comparison with 67Ga, it is likely that the superior resolution of PET cameras and the biokinetic distribution of 18FDG will provide enhanced diagnostic capability, and the time saved by getting a diagnostic result may be put to appropriate use for the treatment or further investigation of the patient. The other area that is of potential use is the absolute quantification of uptake, which could be used in the assessment of response to therapy at an early stage of treatment (O'Doherty et al. 1997).

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D. Hamilton and J. Al-Nabulsi Abdel-Dayem H et al (1995) Diffuse TI-201 uptake in the lungs. Etiologic classification and pattern recognition. Clin Nucl Med 20:164-172 Abdel-Dayem HM et al (1996) Evaluation of sequential thallium and gallium scans of the chest in AIDS patients. J Nucl Med 37:1662-1667 Abdel-Dayem HM et al (1997) Sites of tuberculous involvement in patients with AIDS. Autopsy findings and evaluation of gallium imaging. Clin Nucl Med 22:310-314 Abdelwahab IF et al (1991) Atypical skeletal tuberculosis mimicking neoplasm. Br J RadioI64:551-555 Bakheet SM et al (1998) F-18-FDG uptake in tuberculosis. Clin Nucl Med 23:739-742 Bakheet SM et al (1999) Radioiodine uptake in inactive pulmonary tuberculosis. Eur J Nucl Med 26:659-662 Bakheet SM et al (2000) F-18 FDG uptake in breast infection and inflammation. Clin Nucl Med 25:100-103 Bekerman C, Bitran J (1988) Gallium-67 scanning in the clinical evaluation of human immunodeficiency virus infection: indications and limitations. Semin Nucl Med 8:273-276 Bihl H, Maier H (1987) Unilateral gallium-67 uptake in primary tuberculosis of the major salivary glands. Clin Nucl Med 12:650-653 Boumpas DT et al (1987) Skeletal tuberculosis resembling metastatic disease on bone scintigraphy (letter). J Nucl Med 28:1507-1509 Braga FJHN et al (1998) 99mTc-gluco-heptonate scintigraphy in lung tuberculosis patients: initial results (abstract). Eur J Nucl Med 25:1125 Braga FJHN et al (2001) Neural tuberculosis detected by F-18 FDG positron emission tomography. Clin ~ucl Med 26: 706 Brochner-Mortensen J (1978) Routine methods and their reliability for assessment of glomerular filtration rate in adults. Dan Med Bull 25:181-202 Brophey M et al (1995a) The scintigraphic presentation of Pott's disease. Clin Nucl Med 20:191-193 Brophey Met al (1995b) Prominent small bowel Ga-67 uptake associated with Yersinial and tuberculous enterocolitis. Clin Nucl Med 20:107-110 Buchanan N (1981) Radioactive bromide partition test in the diagnosis of tuberculous meningitis (letter). J Pediatr 99:506 Burke T (1995) TI-201 uptake in pulmonary Mycobacterium avium complex infection. Clin Nucl Med 20:835-836 Cook GJ, Fogelman I, Maisey MN (1996) Normal physiological and benign pathological variants of 18-fluoro-2-deoxyglucose positron-emission tomography scanning: potential for error in interpretation (review). Semin Nucl Med 26: 308-314 Daniel TM (1987) New approaches to the rapid diagnosis of tuberculous meningitis. J Infect Dis 155:599-602 Degirmenci B et al (1998) Technetium-99m-tetrofosmin scintigraphy in pulmonary tuberculosis. J Nucl Med 39: 2116-2120 Desai SS (1994) Early diagnosis of spinal tuberculosis by MRI. J Bone Joint Surg [Br] 76B:863-869 Dhekne RD et al (1987) Tuberculous pseudotumor of the liver. Clin Nucl Med 12:816-819 Dickinson FL, Finlay DB, Belton IP (1996) Multifocal skeletal tuberculosis: bone scan appearances. Nuc1 Med Commun 17:957-962 Everaert H et al (1997) Ga-67 uptake in a case of tuberculous spondylitis. Clin Nucl Med 22:403-404

Radionuclides in Pulmonary and Extra-Pulmonary Tuberculosis Fanning A, Dierich H, Lentle B (1974) Bone scanning with technetium 99mTc polyphosphate in tuberculous osteomyelitis. Tubercle 55:227-230 Fineman DS et al (1989) Detection of abnormalities in febrile AIDS patients with In-Ill-labeled leukocyte and Ga-67 scintigraphy. Radiology 170:677-680 Fogelman I,Maisey MN, Clarke SEM (1994) An atlas of clinical nuclear medicine, second edition. Dunitz, London Ganz WI, Serafini AN (1989) The diagnostic role of nuclear medicine in the acquired immunodeficiency syndrome. J Nucl Med 30:1935-1945 Girgis NI et al (1990) The use of the bromine partition test in the diagnosis and prognosis of tuberculous meningitis. East Afr Med J 67:404-406 Goldfarb CR et al (1995) Ga-67 scintigraphic appearances of tuberculosis in the 'new' tuberculosis (abstract). J Nucl Med 36:23P Goldfarb CR et al (1997) Gallium scanning in the 'new' tuberculosis. Clin Nucl Med 22:470-474 Gomez MV et al (1995) Abnormal gallium-67 skull uptake: a sign of peripheral marrow activation in HIV-positive patients with disseminated mycobacterioses. J Nucl Med 36:2211-2213 Gomez MV et al (1996) Identification of AIDS-related tuberculosis with concordant gallium-67 and three-hour delayed thallium-201 scintigraphy. Eur J Nucl Med 23:852-854 Goo JM et al (2000) Pulmonary tuberculoma evaluated by means ofFDG PET: findings in 10 cases. Radiology 216:117-121 Goswami GK et al (2000) Discrepancy between Ga-67 citrate and F-18 fluorodeoxyglucose positron emission tomographic scans in pulmonary infection. Clin Nucl Med 25: 490-491 Greenspan A, Stadainik RC (1995) Increased uptake around the hip joint. Semin Nucl Med 3:283-286 Grieff M, Lisbona R (1991) Detection of miliary tuberculosis by Ga-67 scintigraphy. Clin Nucl Med 16:910-912 Groth S (1984) Calculation of 51Cr-EDTA clearance in children from the activity in one plasma sample by transformation of the biexponential plasma time-activity curve into a monoexponential with identical integral area below the time-activity curve. Clin PhysioI4:61-74 Gulaldi NC et al (1995) The visualization of pulmonary tuberculosis with Tc-99m (V) DMSA and Tc-99m citrate in comparison to Ga-67 citrate. Clin Nucl Med 20:1012-1014 Hardoff R, Efrat M, Gips S (1995) Multifocal osteoarticular tuberculosis resembling skeletal metastatic disease. Evaluation with Tc-99m MDP and Ga-67 citrate. Clin Nucl Med 20:279-281 Hashimoto T et al (2000) Peritoneal linear uptake of Ga-67 caused by tuberculous peritonitis. Clin Nucl Med 25:214-215 Hovi I et al (1993) Technetium-99m-HMPAO-labeled leukocytes and technetium-99m-labeled human polyclonal immunoglobulin G in diagnosis of focal purulent disease. J Nucl Med 34:1428-1434 Ishino Y, Shiozaki H, Nakata H (1992) Positive Tc-99m pyrophosphate myocardial scintigraphy in a patient with tuberculous pericarditis. Clin Nucl Med 17:515-517 Kalicke T et al (2000) Fluorine-18 fluorodeoxyglucose PET in infectious bone diseases: results of histologically confirmed cases. Eur J Nucl Med 27:524-528 Kao C-H et al (1993) Usefulness of gallium-67 citrate scans in patients with acute disseminated tuberculosis and comparison with chest x-rays. J Nucl Med 34:1918-1921

429 Kao P-F et al (1996) Accumulation of Ga-67 citrate in a tuberculous splenic abscess. Report of a rare case. Clin Nucl Med 21:49-52 Kattapuram SV, Lee VW, Shapiro JH (1979) Primary tuberculosis diagnosed by gallium scan. Clin Nucl Med 4:238-239 Kim DG et al (1995) 99mTc_HMPAO labeled leukocyte SPECT in intracranial lesions. Surg Neurol 44:338-345 Knight SB et al (1996) Evaluation of pulmonary lesions with FDG-PET. Comparison of findings in patients with and without a history of prior malignancy. Chest 109:982-988 Kobayashi H et al (1995) Solitary muscular involvement by tuberculosis: CT, MRI and scintigraphic features. Comput Med Imag Graph 19:237-240 Kramer EL et al (1989) Diagnostic implications of Ga-67 chestscan patterns in human immunodeficiency virus-seropositive patients. Radiology 170:671-676 LaManna MM et al (1984) Gallium localization in peritonitis. Two case reports. Clin Nucl Med 9:25-27 Lee JD et al (1992) Immunoscintigraphy in the detection of tuberculosis with radiolabelled antibody fragment against Mycobacterium bovis bacillus Calmette-Guerin: a preliminary study in a rabbit model. Eur J Nucl Med 19:1011-1015 Lee VW et al (1994) Pulmonary mycobacterial infections in AIDS: characteristic pattern of thallium and gallium scan mismatch. Radiology 193:389-392 Lee VW et al (1999) Intracranial mass lesions: sequential thallium and gallium scintigraphy in patients with AIDS. Radiology 211:507-512 Leventhal WD,Gordon L,Hotchkiss S (1981) Ga-67-citrate and ultrasonographic visualization of genitourinary tuberculosis. Clin Nucl Med 6:504-505 Lin W-Y, Hsieh J-F (1999) Gallium-67 citrate scan in extrapulmonary tuberculosis. Nuklearmedizin 38:199-202 Lin W-Y et al (1998) Diagnostic value of bone and Ga-67 imaging in skeletal tuberculosis. Clin Nucl Med 23:743-746 Lisbona R et al (1993) Gallium-67 scintigraphy in tuberculous and nontuberculous infectious spondylitis. J Nucl Med 34: 853-859 Loken MK (1987) Pulmonary nuclear medicine. Appleton and Lange, California Lorberboym M et al (1998) Thallium-201 retention in focal intracranial lesions for differential diagnosis of primary lymphoma and nonmalignant lesions in AIDS patients. J Nucl Med 39:1366-1369 Malhotra CM et al (1985) Ga-67 studies in a patient with acquired immunodeficiency syndrome and disseminated mycobacterial infection. Clin Nucl Med 10:96-98 Mansberg VJ, Murray IP, Rossleigh MA (1997) Complementary scintigraphy in tuberculous osteomyelitis. Clin Nucl Med 22:776-778 McAfee JG (1996) Editorial comment on Brophey et al1995b. The Year Book of Nuclear Medicine. Mosby, St Louis Misra UK, Kalita J, Das BK (fOOO) Single photon emission computed tomography in tuberculous meningitis. Postgrad Med J 76:642-645 Moody EB, Delbeke D (1992) Nuclear medicine case of the day. Case 1: miliary tuberculosis. Am J Roentgenol 158:1382-1386 Muradali D et al (1993) Multifocal osteoarticular tuberculosis: report of four cases and review of management. Clin Infect Dis 17:204-209 Nocera RM et al (1983) Tc-99m MDP and indium-Ill chloride scintigraphy in skeletal tuberculosis. Clin Nucl Med 8:418-420

430 O'Doherty MI et al (1997) PET scanning and the human immunodeficiency virus-positive patient. I Nucl Med 38: 1575-1583 Ohta H et al (1996) Liver tuberculoma detected by Ga-67 imaging. Clin Nucl Med 21:577 Ohta H et al (1998) Tc-99m sestamibi uptake in tuberculosis of the breast. Clin Nucl Med 23:106-108 Onsel C et al (1996) Technetium-99m-MIBI scintigraphy in pulmonary tuberculosis. I Nucl Med 37:233-238 Ozturk E et al (1994) The visualization of granulomatous disease with somatostatin receptor scintigraphy. Clin Nucl Med 19:129-132 Palestro CJ et al (1991) Relative efficacy of In-III leukocyte and Ga-67 imaging in HIV (+) patients (abstract). I Nucl Med 32:1003 Parmett SR et al (1995) Utility of Ga-67 scintigraphy in detecting radiologically negative tuberculosis in HIV-positive patients (abstract). I Nucl Med 36:207P-208P Patz EF et al (1993) Focal pulmonary abnormalities: evaluation with F-18-Fluorodeoxyglucose PET scanning. Radiology 188:487-490 Pettengell K et al (1990) Radionuclide scintigraphy in tuberculous enteritis. Gastrointest RadioI15:148-150 Picciotto G et al (1992) Estimation of chromium-51 ethylene diarnine tetra-acetic acid plasma clearance: a comparative assessment of simplified techniques. Eur I Nucl Med 19:30-35 Piepsz A, Pintelon H, Ham HR (1994) Estimation of normal chromium-51 ethylene diamine tetra-acetic acid clearance in children. Eur I Nucl Med 21:12-16 Prat L et al (1991) Ga-67 citrate and Tc-99m HMPAO leukocyte scanning in extrapulmonary tuberculosis. Clin Nucl Med 16:865-866 Pui MH, Chin-Sang HR, Rubenstein ID (1986) False-normal bone imaging in spinal tuberculosis. Clin Nucl Med II: 245-248 Rust RI, Park HM, Robb IA (1981) Skeletal scintigraphy in miliary tuberculosis: photopoenia after treatment. Am I Radiol 137:877-879 Santin M et al (1995) Utility of the gallium-67 citrate scan for the early diagnosis of tuberculosis in patients infected with the human immunodeficiency virus. Clin Infect Dis 20:652-656 Sarkar SD, Ravikrishman KP (I978) Gallium-67 citrate scanning in extra-pulmonary tuberculosis (abstract). I Nucl Med 19:734 Sarkar SD et al (1979) Gallium-67 citrate scanning-a new adjunct in the detection and follow-up of extrapulmonary tuberculosis: concise communication. I Nucl Med 20:833-836 Sciuk I et al (1991) Comparison of technetium-99m polyclonal human immunoglobulin and technetium-99m monoclonal antibodies for imaging chronic osteomyelitis. First clinical results. Eur I Nucl Med 18:401-407 Schmitz A et al (2000) Use of fluorine-18 fluoro-2-deoxy-Dglucose positron emission tomography in assessing the process of tuberculous spondylitis. I Spinal Disord 13: 541-544

D. Hamilton and

I. Al-Nabulsi

Schmidt U, Rebarber IF (1994) Tuberculous pericarditis identified with gallium-67 and indium-III leukocyte imaging. Clin Nucl Med 19:146-147 Sharif HS et al (1989) Brucellar and tuberculous spondylitis: comparative imaging features. Radiology 171:419-425 Shih WI et al (I986) Progression of mediastinal tuberculosis and superior vena caval obstruction demonstrated by gallium-67 citrate and radiocolloid liver scintigraphy. Clin Nucl Med II:126-128 Siemsen IK et al (1976) Gallium-67 scintigraphy of pulmonary diseases as a complement to radiography. Radiology II8: 371-375 Siemsen IK, Grebe SF, Waxman AD (1978) The use of gallium67 in pulmonary disorders. Semin Nucl Med 8:235-249 Suga K et al (2000) Findings on radionuclide cisternography in a large abdominal cerebrospinal fluid pseudocyst associated with tuberculous peritonitis. Clin Nucl Med 25: 1063-1065 Sumi Yet al (1999) Tuberculosis peritonitis: gallium-67 scintigraphic appearance. Ann Nucl Med 13:185-189 Sweny P, Farrington K, Moorhead IF (1989) The kidney and its disorders. Blackwell, Oxford Taher MA (1998) Nuclear scan and sonogram in renal tuberculosis (letter). I Assoc Physic India 46:401-402 Tamgac F et al (1995) Extraskeletal accumulation of Tc-99m HMDP in a tuberculous cold abscess. Clin Nucl Med 20:1092 Utsunomiya K et al (1997) Clinical significance of thallium201 and gallium-67 scintigraphy in pulmonary tuberculosis. Eur I Nucl Med 24:252-257 Vanhagen PM et al (1994) Somatostatin analogue scintigraphy in granulomatous diseases. Eur I Nucl Med 21:497-502 Villringer K et al (1995) Differential diagnosis of CNS lesions in AIDS patients by FDG-PET. I Comput Assist Tomogr 19: 532-536 Von Wenzel KS, Klopper IF, Wasserman HI (I989) The technetium-99m DTPA partition test in the diagnosis of tuberculous meningitis. South Afr Med I 20:488-489 Vorne M, Sahlstrom K, Alanko K (1988) Poor accumulation of technetium-99m glucoheptonate in sarcoidosis and other diffuse infiltrative lung diseases as compared with gallium67 citrate. Clin Nucl Med 13:107-109 Walsh TI et al (1985) The value of gallium-67 scanning in pulmonary tuberculosis. Am Rev Respir Dis 132:746-747 Wang Y, Sabow LT, Dee WF (1972) 131-1 study of thyroid tuberculosis mimicking thyroid carcinoma. CRC Crit Rev Radiol Sci 3:101-103 Wiggelinkhuizen I, Mann M (1980) The radioactive bromide partition test in the diagnosis of tuberculous meningitis in children. I Pediatr 97:843-847 Winzelberg GG (1981) Radionuclide evaluation of miliary tuberculosis. Clin Nucl Med 6:330-331 Yang S-O et al (1992) Detection of extrapulmonary tuberculosis with gallium-67 scan and computed tomography. I Nucl Med 33:2II8-2123 Young T-H et al (1996) Esophageal tuberculosis with supraclavicular lymph node involvement demonstrated by Ga-67 imaging. Clin Nucl Med 21:344

27 Tuberculosis of the Heart and Pericardium ERNESTO E. SALCEDO and AHMAD S. OMRAN

CONTENTS 27.1 27.2 27.2.1 27.2.2 27.2.2.1 27.2.2.2 27.3 27.3.1 27.3.1.1 27.3.1.2 27.4 27.4.1 27.4.1.1 27.4.1.2 27.4.1.3 27.5 27.5.1 27.5.1.1 27.5.1.2 27.6 27.6.1 27.6.1.1 27.6.1.2

Introduction 431 Tuberculous Pericarditis 431 Clinical Pathophysiology 431 Acute Pericarditis 432 Diagnosis 432 Management 432 Pericardial Effusion and Cardiac Tamponade 433 Clinical Pathophysiology and Epidemiology 433 Diagnosis 433 Management 434 Constrictive Pericarditis 435 Pathophysiology and Epidemiology 435 Diagnosis 436 Diagnostic Tests 436 Management 439 Tuberculous Endocarditis 439 Clinical Pathophysiology 439 Diagnosis 440 Management 440 Tuberculous Myocarditis 440 Clinical Pathophysiology 440 Diagnosis 441 Management 441 References 441

cal mycobacterium infections should now be included, by the astute clinician, in the differential diagnosis of chronic infections or obscure clinical processes. The heart and pericardium can be infected by the tuberculous mycobacterium via hematogenous spread occurring during the primary tuberculous infection, but also by direct, peribronchial or lymphatic dissemination (Table 27.1). The most common form of cardiac involvement by tuberculosis is as pericarditis, with the long-term development of calcific constrictive pericarditis. Other forms of cardiac involvement in tuberculosis are quite rare and include myocarditis and endocarditis. In this chapter we review the important issues regarding the clinical presentation, diagnostic procedures and contemporary medical management of patients with cardiac tuberculosis. Table 27.1. Mycobacterium routes to heart and pericardium

Hematogenous During primary tuberculous infection

Lymphatic Lung Bronchial Mediastinal nodes

27.1 Introduction Tuberculosis remains a considerable public health problem in non-industrialized countries. In industrialized countries, with the recent epidemic of human immunodeficiency virus (HIV) infection and immunocompromised hosts, tuberculosis has resurfaced as an important disease process. Typical as well as atypi-

Peribronchial Contiguous Mediastinal nodes Pleural

27.2 Tuberculous Pericarditis 27.2.1 Clinical Pathophysiology

E. E. SALCEDO, MD Head Non-invasive Laboratories, King Abdulaziz Cardiac Center, National Guard Hospital, P.O. Box 22490, Riyadh 11426, Saudi Arabia A. S. OMRAN, MD Consultant Cardiologist, King Abdulaziz Cardiac Center, King Abdulaziz Medical City, National Guard, Riyadh, P.O. Box 22490, Riyadh 11426, Saudi Arabia

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

Pericardial involvement by mycobacterium represents the most frequent form of cardiac tuberculosis. Clinically, tuberculous pericarditis can present as acute pericarditis, pericardial effusion, cardiac tamponade and constrictive pericarditis (Table 27.2). Tuberculosis remains an uncommon cause of large

432

E. E. Salcedo and A. S. Omran

Table 27.2. Classification of tuberculous pericardial involvement

Acute pericarditis Pericardia I effusion Without tamponade and with tamponade

Constrictive pericarditis Acute Sub acute Chronic

Pericardial calcification Without hemodynamic consequences With hemodynamic consequences

pericardial effusion and cardiac tamponade is distinctly rare. However, constrictive pericarditis is a common long-term sequelae of tuberculosis.

27.2.2

Acute Pericarditis The infectious pericarditis include viral pericarditis, bacterial suppurative pericarditis, fungal pericarditis and tuberculous pericarditis. Tuberculous pericarditis is a rare form of acute pericarditis, but needs to be considered in the differential diagnosis in immunocompromised patients and in areas of the world where tuberculosis is still endemic. Subclinical pericarditis has also been recognized in patients with pulmonary tuberculosis (Kishk et al. 1998). 27.2.2.1 Diagnosis

In contradistinction with acute viral or bacterial pericarditis, where there is usually an abrupt initiation of symptoms, tuberculous pericarditis has a much more insidious beginning. The usual symptoms of an acute febrile episode followed by chest pain with pleuritic exacerbation and constitutional symptoms are usually lacking. A more common clinical scenario is that of presentation as fever of unknown origin. Immunocompromised patients and children do present with the more typical picture of acute pericarditis. The presence of a pericardial friction rub is the most reliable clinical marker for the diagnosis of pericarditis. During the acute episode of pericarditis, the pericardial friction rub may come and go, and its recognition may require having the patient sit up and lean forward. With chronic pericarditis, such as with tuberculosis, the pericardial friction rub may also wax and wane depending on the degree of inflammation and the presence and size of a pericardial effusion.

The characteristic electrocardiogram findings of pericarditis can also be expected to wax and wane in tuberculous pericarditis, depending on the severity of the inflammatory process. These ECG changes include diffuse ST elevation without reciprocal changes, T wave inversion, and PR segment deviations. Acute phase reactants such as sedimentation rate and C-reactive protein, markers of an acute inflammatory process, are less likely to be elevated in tuberculous pericarditis than in the more common forms of acute viral pericarditis. Elevation of cardiac enzymes during acute pericarditis is the result of associated myocarditis or extension of the inflammatory process into the myocardium from the visceral pericardium. In tuberculous pericarditis, elevation of cardiac enzymes is distinctly rare and its presence should raise the question of associated myocarditis. The chest X-ray, besides demonstrating the pulmonary evidence of tuberculosis, offers little help in the diagnosis of acute pericarditis. A left pleural effusion is commonly associated with pericarditis, but is a non-specific finding. The cardiac silhouette remains normal, unless there is associated pericardial effusion. The typical calcification of the pericardium does not appear until late in the course of the illness, and is not expected to be present during the acute tuberculous pericarditis phase. The echocardiogram, as will be discussed later, is of great value in assessing the presence and size of pericardial effusion, the presence and degree of pericardial thickening and in demonstrating the characteristic hemodynamic changes of constriction and tamponade by Doppler techniques. During the acute pericarditis phase, when there is no or little pericardial effusion, the echocardiogram may be normal. When a small fibrinous pericardial effusion is present during the acute pericarditis process, a partially echo-free space may be seen surrounding the heart. In the presence of a pericardial effusion, the echocardiogram can be used to guide a pericardiocentesis needle for diagnostic purposes. Although nuclear imaging with Gallium-67 has been found to be useful in demonstrating the inflammatory process in acute pericarditis (Spodick 1997), its use in tuberculous pericarditis has not been described. 27.2.2.2 Management

The management of acute tuberculous pericarditis is no different than that of the more common forms of acute pericarditis. The treatment is directed to the

Tuberculosis of the Heart and Pericardium

control of symptoms and, as much as possible, to the eradication of the etiological agent. Ibuprofen is the preferred nonsteroidal anti-inflammatory drug at doses of 300-800 mg every 6-8 h. Steroids are contraindicated in acute tuberculous pericarditis, unless the patient is well covered with appropriate antimycobacterial therapy. The effectiveness of corticosteroids to prevent the eventual development of constriction is at most limited (Chen et al. 1996). The management of pericardial effusion in patients with tuberculous pericarditis is discussed in the following section.

27.3 Pericardial Effusion and Cardiac Tamponade 27.3.1 Clinical Pathophysiology and Epidemiology Acute pericarditis from infective or inflammatory processes, or from physical and immunologic origin, can lead to pericardial effusion. A variety of other conditions such as myxedema, renal failure, pregnancy and malignancy can produce pericardial effusion (Table 27.3). The cause of the pericardial effusion can frequently be inferred from the underlying clinical problem (Sagrista-Sauleda et al. 2000). If the pericardial effusion is found as an incidental finding and it is small, no further work-up or treatment may be necessary. However, if the pericardial effusion is moderate or large, every effort should be made to identify its cause. As has been previously discussed, in industrialized countries the incidence of tuberculous pericarditis has declined over the past several decades. However, in Africa, Asia and East Europe where tuberculosis is still endemic, tuberculous pericarditis and effusion are more common. As can be seen from Table 3, the etiology of a moderate to large pericardial effusion varies from country to country. In the patients reported by Cheema (Cheema et al. 1999) from Saudi Arabia, the incidence of pericardial effusion related to tuberculosis was much higher (20%), than those reported by SagristaSauleda (2%) from Spain and by Colombo (O%) from the United States. In addition, tuberculous pericarditis is more prevalent in immunocompromised patients and, in particular, in patients with the acquired immunodeficiency syndrome. In one series from Africa, of 37 patients

433 Table 27.3. Etiology of moderate-large pericardia! effusions Cheema Colombo Sagrista-Sauleda n Tamponade Idiopathic Neoplastic Uremia Iatrogenic Post-acute myocardial infarction Pyogenic Collagen disease Tuberculosis Other

43 23% 40% 2% 26% 0% 0%

25 44% 32% 36% 20% 0% 8%

322 37% 20% 13% 6% 16% 8%

9% 0% 20% 3%

0% 0% 0% 4%

0% 5% 2% 30%

Adapted from Cheema et al. (1999); Colombo et a!. (1988); Sagrista-Sauleda et al. (1988)

with effusive pericarditis, 32 (86%) were associated with tuberculosis and 30 (81 %) were HIV positive (Haas and Des Prez 1995) Tuberculosis remains an uncommon cause of cardiac tamponade. It has been reported in disseminated tuberculosis with myocarditis and pericarditis (Afzal et al. 2000). In addition, in a series of 231 patients with pericardial disease, three of nine patients with tuberculous pericarditis initially manifested as tamponade, and only 7% of all tamponade patients had tuberculous pericarditis (Permanyer-Miralda et al. 1985). 27.3.1.1

Diagnosis The diagnosis of pericardial effusion is straightforward when using two-dimensional echocardiography. An "echo-free" space is visualized surrounding the heart; the size of this echo-free space is related to the volume of the pericardial fluid. Normally there is only about 20-30 cc of pericardial fluid in the pericardial space. In this situation, there is virtually no separation between the visceral and parietal pericardium layers, and there is absence of the echo-free space surrounding the heart. With a small pericardial effusion (less than 100 cc) there is about 1 cm of echo-free space around the heart. With a large effusion (>500 cc), the echo-free space increases to over 2 cm. The confirmation for the clinical diagnosis of cardiac tamponade is based on the echocardiographic demonstration of a pericardial effusion, usually but not necessarily large in size (Fig.27.l), and by the characteristic hemodynamics shown by Doppler

434

E. E. Salcedo and A. S. Omran Fig.27.1. Two-dimensional parasternal long axis (a) and short axis (b) views in a patient with very large pericardial effusion and cardiac tamponade

a

b

echocardiography or catheterization. The most useful echocardiographic signs of cardiac tamponade are inspiratory shift of the ventricular septum toward the left ventricle (Fig. 27.2), right ventricular diastolic collapse and right atrial compression. Doppler echocardiography provides additional information regarding increased intrapericardial pressure (Fig. 27.3). There is a significant accentuation of the normal transvalvular flow velocities. The normal inspiratory decreases of about 10-20% of mitral and aortic flow are accentuated to 30-40% with tamponade. Parallel to this there is a dramatic increment of tricuspid and pulmonary flow velocities by up to 80%. Although the demonstration of the presence of pericardial effusion and tamponade is fairly straightforward by echo-Doppler techniques, the demonstration that tuberculosis is the cause of the pericardial effusion is more complex. Less than half of patients with tuberculous pericarditis have evidence of pulmonary tuberculosis (Sagrista-Sauleda et al. 1988). Because of the slow growth of Mycobacterium tuberculosis there is usually a delay of about 5 weeks between admission and diagnosis (Sagrista-Sauleda et al. 1988). Sputum cultures are positive in about 50%, gastric aspirate cultures and acid fast stains are positive in about 15-20% and in 30-75% of pericardial aspirate cultures (Gooi and Smith 1978). Other tools that assist in the diagnosis of tuberculosis as the cause of pericardial effusion include serodiagnosis (Ng et al.1995), the polymerase chain reaction, testing for adenosine deaminase activity, and activity of interferon level (Woods and Goldsmith 1989; Seino et al.1993; Koh et al.1994; Shah et al.1998).

Fig.27.2. M-mode echocardiogram in same patient as in Fig. 27.7 showing inspiratory shift of the ventricular septum toward the posterior ventricular wall. This is characteristic of cardiac tamponade

27.3.1.2 Management

Antibiotic therapy is similar to that used in pulmonary tuberculosis. Resolution occurs in 2-3 months in about 80% of patients. A form of sub-acute constriction occurs in 20% of patients, resolving in several months in half of them, but requiring eventual pericardiectomy in about 10% (Strang 1997). Corticosteroids can be used to control fluid accumulation, to reduce the need for repeated pericardiocentesis and to control impending cardiac tampon-

Tuberculosis of the Heart and Pericardium

Fig. 27.3. Mitral (a) and tricuspid (b) inflow pattern obtained by transthoracic echo in a patient with cardiac tamponade. There is reduction in the mitral inflow velocity after inspiration and the velocity increases after expiration. Opposite changes are seen in the tricuspid inflow as the velocity increases with inspiration

435

especially in areas of the world where tuberculosis is still endemic. Cardiac tamponade in the early clinical stage of Tuberculous pericarditis has been found to be the most predictive factor in the subsequent development of constrictive pericarditis (Suwan and Potjalongsilp 1995). Constrictive pericarditis is caused by pericardial fibrosis and calcification with typical histological features (Figs. 27.4, 27.5). These processes compromise the filling of the heart during diastole and eventually produce right-sided heart failure. The rigid pericardium restricts the inflow of blood into the ventricles; a high driving pressure across the atrio-ventricular valves results in early rapid diastolic filling and an abrupt increase in ventricular pressure. Flow is terminated early in diastole, and there is marked elevation of pressure in all four heart chambers. As a consequence of this, a dip and plateau pattern is seen on the ventricular pressure curves, and a restrictive filling pattern is seen in the Doppler tracings. These findings will be illustrated on the next section. Figure A Causes of Constrictive Pericarditis 5Or-----

ade (Strang et al. 1988). Additionally, large doses of prednisolone (60 mg/day for 4 weeks and 15 mg/day for 2 weeks) has been shown to decrease mortality from 11 % to 4% (Strang et al.I987). In the rare instances of overt tuberculous cardiac tamponade, emergent pericardiocentesis may be life saving. If there is recurrence of pericardial effusion with unstable hemodynamics, a subxiphoid pericardial window may be required.

--~

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27.4

Constrictive Pericarditis 27.4.1 Pathophysiology and Epidemiology

(Adapted Irom Ling LH, 1999)

Figure B Etiology of Infective myocarditis and Pericarditis 80

-

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----

50

Constrictive pericarditis is a serious sequelae of tuberculous pericarditis and an important determinant of patient outcome. Since surgery may be the only viable therapeutic option, its recognition is of great importance. The clinical spectrum of constrictive pericarditis has changed over the years (Ling et al. 1999), and its etiology has shifted from infectious diseases to postoperative and post-radiation causes (Fig. 27.A). Tuberculosis remains an important cause of constriction;

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Fig. 27.4. Histological pericardial section obtained at time of pericardiectomy. The pericardium is thickened and chronically inflamed. The inner surface is covered with a thick layer of fibrin, several granulomas are found

E. E. Salcedo and A. S. Omran

of tuberculosis in other organs or the patient lives, or comes from, an endemic area of tuberculosis. As the survival of immunocompromised patients improves, it is expected that long-term complications of tuberculosis, such as constriction, will also increase. Again, in these patients a great degree of suspicion will assist the clinician in arriving at the correct diagnosis. Patients will seek medical attention because of peripheral edema, ascites with abdominal discomfort and fatigue. Shortness of breath with dyspnea on exertion and orthopnea are not uncommon. These symptoms, more commonly seen with "left heart failure;' are seen in patients with constrictive pericarditis because of a fixed cardiac output, associated pleural effusions, and elevated diaphragms from the ascites. On physical exam, jugular venous distention with sharp x and y descents are quite noticeable. Paradoxical systolic retraction of the apical impulse is another hallmark of constrictive pericarditis. Other physical findings include the Kussmaul's sign (inspiratory swelling of the neck veins) and a pericardial knock, which occurs at the time of a third heart sound, but is of higher frequency and intensity. 27.4.1.2

Diagnostic Tests Chest X-Ray

Fig. 27.5. Higher magnification histological specimen from the same patient as Fig. 27.1. A granuloma composed of epithelioid cells and also showing caseation necrosis and multinucleated giant cells of the Langhans type are demonstrated

27.4.1.1

Diagnosis History and Physical Findings A high degree of suspicion is required to consider constrictive pericarditis in the differential diagnosis of patients with right heart failure. This is particularly the case when the signs and symptoms for right heart failure are out of proportion to the degree of pulmonary disease or left sided pathology. Tuberculous constrictive pericarditis needs to be considered if there is evidence

The cardiac silhouette on chest X-ray is usually normal, and the pulmonary vasculature is indistinct. Evidence of pulmonary tuberculosis mayor may not be evident. Bilateral pleural effusions are common, and frequently there is upper pulmonary flow redistribution and Kerley B lines may be present. Dilation of the superior vena cava and azygos vein may be evident. Calcification of the pericardium is the hallmark of tuberculous constrictive pericarditis (Fig. 27.6). Although sometimes it is apparent in the PA view, calcification in the pericardium is much easier to visualize from the lateral projection and is very evident with fluoroscopy. A rim of calcium appears surrounding the heart, with preference over the right atrium, right ventricle, and the diaphragmatic wall. Calcification of the pericardium occurs in about 50% of patients with constrictive pericarditis (Rienmuller et a1. 1993). Other potential causes of cardiac calcification need to be considered in the differential diagnosis. These include calcified left ventricular aneurysm, calcified intracardiac thrombus, coronary calcifications and valvular calcifications. Therefore, although non pathognomonic, calcifica-

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Fig. 27.6. PA and lateral chest X-ray in a patient with tuberculous calcific constrictive pericarditis. The cardiac silhouette is somewhat generous. The pulmonary vasculature is normal. A rim of calcium is seen affecting mainly the apex and the distal posterior wall. Note that the calcium is better appreciated in the lateral projection

tion around the pericardium is a very useful and cost-effective finding in patients suspected of having tuberculous constrictive pericarditis. Chest Computed Tomography Computed tomography (CT) is the diagnostic tool of choice to evaluate pericardial thickness (Fig. 27.7) and presence and severity of pericardial calcification. High spatial resolution sectional pictures that provide exquisite anatomic detail have now replaced the blurred images initially obtained with conventional CT imaging. Associated findings, such as dilated superior vena cava and lateral bowing of the interatrial septum, can be clearly demonstrated by high resolution CT imaging. The pericardial thickness measured by CT has been found to correlate extremely well with pathologic specimens (Grover-McKay et al. 1991). In addition, CT can localize areas of the pericardium that are more or less thickened, and as such serve as a tool for surgical planning by assisting the surgeon in choosing the optimal surgical approach. The value of CT in providing prognostic information in patients with constrictive pericarditis has been described (Rienmuller et al. 1985). These authors found that all 5 of 16 patients with non-detectable poster lateral wall died at or soon after pericardiectomy. They concluded that myocardial fibrosis or atrophy provoked the non-visualization of myocardium, and defined patients at high surgical risk. Magnetic Resonance Imaging Magnetic Resonance Imaging (MRI), also allows for excellent imaging of the pericardium. The normal pericardium appears on MRI as a low intensity line not exceeding 3 mm in width (Stark et al. 1984). MRI can readily demonstrate the presence and extent of pericardial thickening. However, it should be remem-

Fig. 27.7. High resolution chest computed tomography in the same patient as in Fig. 27.3. There is a small pericardial effusion (PE) and the thickened pericardium is seen surrounding both the left ventricle (LV) and right ventricle (RV). The thickness of the pericardium varies from a few millimeters to 1 em

bered that a thickened pericardium could be seen in conditions other than constrictive pericarditis. Pericardial thickening has been noted by MRI after open heart surgery (Sechtem et al. 1986) and in uremic or infectious pericarditis. MRI has also been used to differentiate constrictive pericarditis from restrictive cardiomyopathy (Soulen et al. 1985). In contrast to restrictive cardiomyopathy, in constrictive pericarditis, MRI will demonstrate a thickened pericardium and an associated conical or tubular narrowing of non-hypertrophied ventricles (White 1998). MRI allows for demonstration of asymmetric pericardial thickening and compression, assisting the surgeon in planning for the best surgical window

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E. E. Salcedo and A. S. Omran

(D'Silva et al. 1992). The disadvantages of MRI over CT for the evaluation of pericardial thickening and constriction include its longer scan time and its inability to reliably detect pericardial calcification (Sechtem et al. 1986). Cardiac Catheterization The classical hemodynamic findings of constrictive pericarditis include a large and rapid Y descent in the right atrial waveform and diastolic equalization of pressures in the four cardiac chambers (Fig. 27.8). Unfortunately, these abnormalities are not exclusively seen in constrictive pericarditis. For example, a large Y descent is seen in patients with right ventricular infarction. Diastolic equalization on the cardiac chambers can also be seen in restrictive cardiomyopathy. Since constrictive pericarditis usually requires pericardiectomy as the definite form of therapy, and surgery is of no use (and actually is detrimental on patients with restrictive cardiomyopathy), a clear differentiation between both disease processes is essential. The most valuable hemodynamic method to differentiate constrictive physiology from restrictive physiology employs the principle of discordance of right ventricular and left ventricular systolic pressure during respiration. In constrictive pericarditis, at end inspiration the left ventricular systolic pressure decreases whereas the right ventricular systolic pressure increases. In restrictive cardiomyopathy, both the right ventricular and left ventricular systolic pressure decrease at end-inspiration (Hurrell et al. 1996).

-t

-----------

PACW

2e

Echocardiography and Doppler Studies M-mode echocardiography in constrictive pericarditis demonstrates normal left ventricular size and systolic function and mild left atrial enlargement. Abnormalities of septum and posterior wall motion are also frequently present. A sudden anterior displacement of the septum followed by a brisk posterior rebound is noted. Evaluation of pericardial thickness by m-mode echocardiography is limited because the pericardial signal is significantly affected by gain and gray scale settings. On two-dimensional echocardiography, the thickened pericardium can be somewhat better appreciated than by m-mode echocardiography. In addition, one will observe small ventricular cavities, normal systolic function, bilateral atrial enlargement and increased vena cava diameter and hepatic veins. The variation in intracardiac flow velocities produces an expiratory septal bulge toward the left ventricle, which is fairly characteristic of constrictive physiology. Transesophageal echo (TEE) provides an adequate means of detecting pericardial thickening (Fig. 27.9). An excellent correlation between pericardial thickness by TEE and CT has been described (Ling et al. 1997). TEE provides the means of evaluating not only the pericardial thickness but also the means to fully evaluate, through Doppler methods, the hemodynamics of constriction. Doppler echocardiography via transthoracic or transesophageal methods allows for detailed characterization of the hemodynamic alterations seen in constrictive pericarditis (Hurrell et al. 1996). Fur-

.--_tee_---------------PA

2e

Fig. 27.8. Pressure tracings in a patient with constrictive pericarditis. There is diastolic equalization of pressures in the left atrium as seen through the capillary wedge pressure (PACW), the pulmonary artery (PA), and the right ventricle (RV). In addition, a dip and plateau or "square root" sign can be appreciated in the RV tracing

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439

Fig. 27.9. A transesophageal echocardiogram in a patient with constrictive pericarditis showing a thickened calcified pericardium surrounding the right atrium (RA), and the right ventricle (RV). The left atrium (LA) is not well seen from this projection

thermore, Doppler is of great value in distinguishing constrictive pericarditis from restrictive cardiomyopathy (Hatle et al.I989). The characteristic Doppler findings of constrictive pericarditis include an expiratory increase in the mitral inflow E velocity of equal or greater than 25% than on inspiration. In addition, there is a reciprocal decrease in the tricuspid velocity of 40% or more (Fig. 27.10). Further, the isovolumic relaxation time decreases during expiration by a mean of 20%. Respiratory alterations in pulmonary venous flow velocities by TEE have permitted the differentiation of constrictive pericarditis from restrictive cardiomyopathy (Klein et al.I993). Using the combination of pulmonary venous systolic/diastolic flow ratio of 0.65 or more in inspiration, and a percentage increase of peak diastolic flow during expiration of 40% or more, Klein was able to correctly distinguish constrictive pericarditis from restrictive cardiomyopathy in 86% of 31 patients with diastolic dysfunction. 27.4.1.3 Management

The medical management of tuberculous constrictive pericarditis is directed toward eradication of the infective organism by appropriate antibiotic therapy to decrease the inflammatory process when present and to the management of right heart failure. Most patients will require increasing doses of diuretics as the hemodynamic compromise worsens.

Fig.27.10. Transesophageal Doppler flow velocities showing respiratory variation of mitral (A), and tricuspid (B) inflow pattern in a patient with constrictive pericarditis. During inspiration there is a noticeable drop in the mitral inflow velocity with reciprocal changes in the tricuspid inflow

In the management of patients with known or suspected constrictive pericarditis, it is imperative to make a clear distinction between the constrictive process and a possible restrictive component. This differentiation, at times, is not easy and requires detailed echo/Doppler hemodynamic evaluation as well as right heart catheterization, as previously discussed. Eventually most patients with significant constrictive pericarditis will require surgical intervention, as discussed in a following chapter.

27.S Tuberculous Endocarditis 27.5.1 Clinical Pathophysiology Endocardial tuberculosis is extremely rare, found in only 0.14% (19 of 13,658 autopsies) of cases by Rose (1987). The endocardial involvement can be either miliary with multiple small tuberculi (less than 3 mm

440

in diameter) or nodular formed by confluent foci of tuberculi. Endocardial involvement by tuberculous infection may affect the valvular surfaces creating the picture typical of valvular infective endocarditis, or it can involve the endothelial surfaces of the cardiac chambers or great vessels. When granulomas due to Mycobacterium tuberculosis are found in valvular structures, they are usually seen in immunocompromised patients with disseminated tuberculosis. However, valvular tuberculous endocarditis in an immunocompetent patient has been described (Klinger et al. 1998). This particular patient had severe mitral regurgitation secondary to perforation of the anterior mitral leaflet. Another potential valvular involvement from tuberculosis includes the formation of subvalvular left ventricular aneurysms. Deshpande reported 19 subvalvular aneurysms seen in 16 patients. There were 12 isolated subaortic aneurysms, three isolated submitral aneurysms and one patient with a subaortic and submitral aneurysm. He described an association between infective endocarditis and the subvalvular aneurysms and showed a strong association between the submitral aneurysms and tuberculosis (Desphande et al. 2000). Extension of tuberculoma into the left ventricular free wall with pseudoaneurysm formation and successful repair of rupture has been described (Halim et al. 1985). Other clinical presentations of endocardial tuberculosis include pulmonary vein obstruction from left atrial tuberculoma, right ventricular outflow tract obstruction, and superior vena cava obstruction (Chang et al.1999). 27.5.1.1 Diagnosis

As described above, endocardial involvement by tuberculosis may present in different forms and a clinical diagnosis is certainly difficult. This is made even more problematic because endocardial tuberculosis is, as previously noted, quite rare. Nevertheless, in any patient with tuberculosis (especially miliary) or in any immunocompromised patient with cardiovascular symptoms, the possibility of endocardial tuberculosis needs to be raised. Physicians should perform a detailed cardiovascular history and examination in patients with tuberculosis, in searching for symptoms suggestive of cardiac arrhythmias or heart failure, and in the presence of new or changing heart murmurs. If endocarditis is

E. E. Salcedo and A. S. Omran

suspected, an echocardiogram should be performed in search of vegetations, regurgitant lesions and subvalvular aneurysms. Occasionally, a large tuberculoma with the appearance of a cardiac tumor may be formed in one of the cardiac chambers or great vessels. In these cases, a cardiac MRI may further clarify the nature of the cardiac mass. A heightened degree of clinical suspicion and echocardiography remain the main tools for the diagnosis of tuberculous endocarditis. 27.5.1.2 Management

As with all forms of tuberculosis, appropriate antimicrobial therapy remains the fundamental form of therapy. Because of this, a prompt and correct diagnosis is mandatory. A case of miliary tuberculosis with aortic valvulitis, which resolved with antituberculous therapy, has been reported (Cope et al. 1990). This case emphasizes the central role of antimicrobials in the management of tuberculous endocarditis. In addition to the antimicrobial therapy, patients with valvular tuberculous endocarditis may benefit from valve surgical procedures with valvular repair or replacement. A successful surgical repair of tuberculous aortic insufficiency has been described (Soyer et al.I981). It has been noted that tuberculosis is a rare complication of valve replacement. The majority of mycobacterial infections occurring after valve surgery have, for some unknown reason, the nontuberculous forms of M. chelonae and Mfortuitum (Grange 1992). These mycobacteria have a very poor response to therapy, so prevention by avoidance of contamination of all surgical materials is of great importance. Surgical excision of large endocardial tuberculomas needs to be considered if they produce obstruction to normal flow or have the potential of major embolic event.

27.6 Tuberculous Myocarditis 27.6.1

Clinical Pathophysiology As with tuberculous pericarditis, the myocardium can be reached by the mycobacteria by either direct extension, lymphangitic spread or by the hema-

441

Tuberculosis of the Heart and Pericardium

togenous route. In contrast to the common pericardial involvement with tuberculosis, myocardial involvement is quite rare. Before the introduction of specific antituberculous medications, myocardial involvement by mycobacteria was reported in only less than 0.30% of patients dying from tuberculosis (Horn and Saphir 1935). Although rare, it is important to recognize tuberculosis as a cause of myocarditis because it has the potential of presenting as sudden death (Dada et al. 2000; Alkuja and Miller 2001), particularly with miliary tuberculosis (Chan and Dickens 1992). The organisms reported to cause infective myocarditis and pericarditis as reported by the Public Health Laboratory Service of the United Kingdom are shown in Figure B, and demonstrate the paucity of cardiac involvement by mycobacteria (Fairley et al. 1996).

(Diaz-Peromingo et al. 2000) This represents another potential source of lethal arrhythmias in patients with cardiac tuberculosis. 27.6.1.2 Management

Since the ante mortem diagnosis of tuberculous myocarditis is rare, the chances of managing patients with this process are also rare. A high index of suspicion is required, especially in the presence of immunocompromised patients or in the presence of miliary tuberculosis. The main goal is to provide prompt and effective antimicrobial therapy. Darwish et al. (1998) reported a patient with tuberculous pancarditis who presented with atrial flutter and converted to normal sinus rhythm after initiation of antituberculous therapy. Resolution of ventricular tachycardia and endocardial tubercu27.6.1.1 loma following antituberculous therapy has been Diagnosis reported (O'Neill et al. 1991). Other considerations that need to be considered Since most cases of myocardial tuberculosis are clini- when treating patients with known or suspected cally silent, the recognition of myocardial involvement myocardial tuberculosis are the avoidance of any in patients with tuberculosis is frequently made only medications that may prolong the QT interval of the during post-mortem examination. Rose (1987), electrocardiogram. As described above, prolongation encountered myocardial tuberculosis in 19 patients of the QT interval has been described in tuberculous (0.14%) at autopsy over a 27 year period. Myocardial myocarditis, and any situation or medication that tuberculosis was diagnosed ante mortem in only further prolongs the QT interval should be avoided. one patient. There have been occasional reports of If there is associated pericarditis and nonsteroidal pre-mortem diagnosis, but this represents more the anti-inflammatory drugs are to be used, ibuprofen exception than the rule. It is possible that with the would be preferred over indomethacin, as the former increased clinical use and the high resolution of MRI increases coronary flow and the latter decreases it. and TEE, more patients with either nodular or miliary Patients with tuberculous myocarditis have potential forms of tuberculous myocarditis will be recognized foci for arrhythmias and they would be placed in furante mortem. ther jeopardy by decreasing their coronary flow with Dahar (1998) described the chest X-ray and chest indomethacin. CT of a patient in whom at autopsy the apical myocardium revealed myocardial tubercula, and at histology granulomas with giant cells. The chest X-ray showed a right pleural effusion, increased cardiac silhouette References and perihilar edema. A chest CT showed thickened Afzal A, Keohane M, Keeley E et al (2000) Myocarditis and pericardium and a small pericardial effusion. pericarditis with tamponade associated with disseminated There have been isolated reports on electrocartuberculosis. Can TCardioI16:519-521 diographic abnormalities and cardiac arrhythmias Alkuja S, Miller A (2001) Tuberculosis and sudden death: a in patients with myocardial involvement in tubercase report and review. Heart Lung 30:388-391 culosis. Doherty et al. (1996) described a patient Chang BC, Ha TW, Kim TT et al (1999) Intracardiac tuberculoma Ann Thorac Surg 67:226-228 that developed infection of a pacemaker pulse-generator pocket and died from ventricular fibrilla- Chan AC, Dickens P (1992) Tuberculous myocarditis presenting as sudden cardiac death. Forensic Sci Int 57:45 tion. At autopsy, she was found to have Widespread Cheema MA, Ghalib MB, Shatoor AS, Suliman FA, Al-Hroub miliary tuberculosis, including myocardial tissue SS, Kardash M, Ahmed MK (1999) Pattern of pericardial involvement. Prolonged QT syndrome in a patient disease in the Asir region of Saudi Arabia. Ann Saudi Med 19:171-173 with tuberculous myocarditis has been described

442 Chen WT, Chen CC, Yu FC et al (1996) Clinical response of tuberculous pericarditis to medical treatment: a retrospective survey. Chin Med J 58:7-11 Colombo A, Olson HG, Egan J et al (1988) Etiology and prognostic implications of a large pericardial effusion in men. Clin Cardiol11:389-394 Cope AP, Heber M, Wilkins EG (1990) Valvular tuberculous endocarditis: a case report and review of the literature. J Infect 21:293-296 Dada MA, Lazarus MG, Kharsany AB, Sturn AW (2000) Sudden death caused by myocardial tuberculosis: case report and review of the literature. Am J Forensic Med Pathol 21: 385-388 Darwish Y, Mushannen B, Hussain KM, Dadkah S, Atkinson J, Zar F, Kogan A (1998) Pancardiac tuberculosis-a case report. Angiology 49:151-156 Deshpande J, Vaideeswar P, Sivaraman A (2000) Subvalvular left ventricular aneurysms. Cardiovasc Pathol 5:267-271 Diaz-Peromingo JA, Marino-Callejo AI, Gonzalez-Gonzalez C, Garcia-Rodriguez et al (2000) Tuberculous myocarditis presenting s long QT syndrome. Eur J Intern Med 11:340-342 Doherty JG, Rankin R, Kerr F (1996) Miliary tuberculosis presenting as infection of a pacemaker pulse-generator pocket. Scott Med J 41:20-21 D'Silva SA, Nalladaru ZM, Dalvi BV et al (1992) MRI as guide to surgical approach in tuberculous pericardial abscess. Case report. Scand J Thorac Cardiovasc Surg 26:229-231 Fairley CK, Ryan M, Wall PG, Weinberg J (1996) The organisms reported to cause infective myocarditis and pericarditis in England and Wales. J Infect 32:223-225 Gooi HL, Smith JM (1978) Tuberculous pericarditis in Burmingham. Thorax 33:94-96 Grange JM (1992) Mycobacterial infections following heart valve replacement. J Heart Valve Dis 1:102-109 Grover-McKay M, Burke S, Thompson SA et al (1991) Measurement of pericardial thickness by cine computed tomography. Am J Card Imaging 5:98-103 Haas DW, Des Prez RM (1995) Tuberculous pericarditis. In: Mandell GL, Bennett JE, Dolin R (eds) Mandell, Douglas and Bennett's principles and practice of infectious disease, vol 2, 4th edn Halim MA, Mercer EM, Guinn GA (1985) Myocardial tuberculoma with rupture and pseudoaneurysm formation-successful surgical treatment. Br Heart J 54:603-604 Hatle LK, Appleton CP, Popp RL (1989) Differentiation of constrictive pericarditis and restrictive cardiomyopathy by Doppler echocardiography. Circulation 79:357-370 Horn H, Saphir 0 (1935) The involvement of the myocardium in tuberculosis: a review of the literature and report of three cases. Am Rev Tuberc 32:492-506 Hurrell DG, Nishimura RA, Higano ST et al (1996) Value of dynamic respiratory changes in left and right ventricular pressures for the diagnosis of constrictive pericarditis. Circulation93:2007- 2013 Kishk YT, Allam MH, Abdel-Wahab AM (1998) Subclinical pericarditis in 289 patients with pulmonary tuberculosis; further indirect evidence by analysis of 53 patients with pericardial disease. J Am Coil CardioI31:220-230 Klein AL, Cohen Gl, Pietrolungo JF et al (1993) Differentiation of constrictive pericarditis from restrictive cardiomyopathy by Doppler Transesophageal echocardiographic methods of respiratory variations of pulmonary venous flow. J Am Coil CardioI22:1935-1943

E. E. Salcedo and A. S. Omran Klinger K, Brandi 0, Doerfler M, Schluger N, Rom WN (1998) Valvular endocarditis due to Mycobacterium tuberculosis. Int J Tuberc Lung Dis 2:435-437 Koh KK, Kim EJ, Cho CH et al (1994) Adenosine deaminase and carcioembrionic antigen in pericardial effusion diagnosis, specially in suspected tuberculous pericarditis. Circulation 89:2728-2735 Ling LH, Oh JK, Tei C et al (1997) Pericardial thickness measured with Transesophageal echocardiography: feasibility and potential clinical usefulness. J Am Coil Cardiol 29: 1317-1323 Ling LH, Oh JK, Shaff HV, Danielson JK, Mahoney WV, Seward JB, Tajik AJ (1999) Constrictive pericarditis in the modern era. Evolving clinical spectrum and impact on outcome after pericardiectomy. Circulation 100:1380-1386 Ng TTC, Strang JIC, Wilkins EGL (1995) Serodiagnosis of pericardial tuberculosis. Q J Med 88:317-320 O'Neill PG, Rokey R, Greenberg S, Pacifico A (1991) Resolution of ventricular tachycardia and endocardial tuberculoma following antituberculosis therapy. Chest 100:1467-1469 Permanyer-Miralda G, Sagistra-Sauleda J, Soler-Soler J (1985) Primary acute pericardial disease: a prospective study of 231 consecutive patients. Am J CardioI56:623-630 Rana BS, Jones RA, Simpson IA (1999) Recurrent pericardial effusion: the value of polymerase chain reaction in the diagnosis of tuberculosis. Heart 82:246-247 Rienmuller R, Doppman JL, Lissner J et al (1985) Constrictive pericardial disease:prognostic significance of a non visualized ventricular wall. Radiology 156:753-755 Rienmuller R, Gurgan M, Erdman E et al (1993) CT and MR evaluation of pericardial constriction: a new diagnostic and therapeutic concept. J Thorac Imaging 8:108-121 Rose AG (1987) Cardiac tuberculosis: a study of 19 patients. Arch Pathol Lab Med III :442-446 Sagrista-Sauleda J, Permanyer-Miralda G, Soler-Soler J (1988) Tuberculous pericarditis: ten year experience with a prospective protocol for diagnosis and treatment. J Am Coil Cardiol11:724-728 Sagrista-Sauleda J, Merce J, Permanyer-Miralda G et al (2000) Clinical clues to the causes of large pericardial effusion. Am J Med 109:95-101 Sechtem U, Tscholakoff D, Higgins CB(1986) MRI on the abnormal pericardium. Am J RoentgenoI147:245-252 Seino Y, Ikeda U, Kawaguchi K et al (1993) Tuberculous pericarditis presumably diagnosed by PCR analysis. Am Heart J 126:249-251 Shah S, Miller A, Mastellone A et al (1998) Rapid diagnosis of tuberculosis in various biopsy and body fluid specimens by the AMPLICOR Mycobacterium tuberculosis polymerase chain reaction test. Chest 113:1190-1194 Soulen RL, Stark DD, Higgins CB (1985) Magnetic resonance imaging of constrictive pericardial disease. Am J Cardiol 55:480 Soyer E, Brunet E, Chevalier B, Leroy J, Morere M, Redonnet M (1981) Tuberculous aortic insufficiency: report of a case with successful surgical treatment. J Thorac Cardiovasc Surg 82:254-256 Spodick DH (1997) Acute, clinically noneffusive ("dry") pericarditis. In: Spodick DH (ed) The pericardium: a comprehensive textbook. Dekker, New York, pp 94-113 Stark DD, Higgins CB, Lanzer P et al (1984) Magnetic resonance imaging of the pericardium: normal and pathologic findings. Radiology 150:469-474

Tuberculosis of the Heart and Pericardium Strang JIG (1997) Tuberculous pericarditis. J Infect 35: 215-219

Strang JIG, Kakasa HHS, Gibson DG et al (1987) Controlled trial of prednisolone as adjuvant in treatment of tuberculous constrictive pericarditis in Transkei. Lancet 2:1418-1422 Strang JIG, Kakasa HHS, Gibson DG et al (1988) Controlled clinical trial of complete open surgical drainage and of prednisolone in the treatment of tuberculous pericardial effusion in Transkei. Lancet 2:759-764

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White RD (1998) Magnetic resonance imaging. In: Topol EJ (ed) Texbook of cardiovascular medicine. Lippincott Raven, Philadelphia Woods GL, Goldsmith JC (1989) Fatal pericarditis due to mycobacterium avium intracellulare in acquired immunodeficiency. Chest 1355-1357

28 Mycobacterial Lymphadenitis M. MONIR MADKOUR and RASHID AL-KUHAYMI

incidence of lymph node tuberculosis remained constant (Rieder et al. 1990; Cowie and Sharpe 1997; Geldmacher et al. 2002). The clinical features of tuberculous lymphadenitis may mimic other benign and malignant diseases and may present as a diagnostic dilemma.

CONTENTS 28.1 28.2 28.3 28.4 28.5 28.6 28.7 28.8 28.9

Epidemiology 445 HIV and Tuberculous Lymphadenitis 446 Pathogenesis 446 Clinical Features 447 Diagnosis 448 Histology and Cytology and Microbiology Findings 448 Polymerase Chain Reaction 450 Imaging Findings 450 Treatment of Mycobacterial Lymphadenitis References 452

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28.1 Epidemiology

Tuberculosis and its extrapulmonary manifestations, particularly of the lymph nodes, are re-emerging as a Cervical tuberculous lymphadenitis was, perhaps, major problem in the developed western industrialfirst described by the ancient Egyptians in 1534 B.C. ized world. Several contributing factors to such a rise The medical papyrus of Ebers (Ebers papyrus 1875) in incidence may include the immigration of indicomprises no pages and contains the description of viduals from endemic areas, overcrowding, the rise two cases of tuberculosis of the cervical lymph nodes. in homelessness, the relative difficulties with accesThese medical papyri were purchased in Luxor by sibility to medical care facilities and infection with Edwin Smith in 1862 and are now in the university human immunodeficiency virus (HIV) (Bloch et al. library of Leipzig (see Chap. 1). Cervical lymph node 1987; Rieder et al. 1990; Shriner et al. 1992; Cantwell tuberculosis is commonly known as scrofula, a Latin et al. 1994; Butt 1997). In the United States, tuberculous lymphadenitis term for "glandular swelling" or from the French "full necked sow". occurs in 2-5% of all patients with tuberculosis and in It was also called "king's evil" during the European 30.9% of extra-pulmonary disease (Appling and Miller Middle Ages or Dark Ages and was believed to be 1981; Shikhani et al' 1989; Rieder et al' 1990). Rieder cured by the "king's touch". Surgical excision, as a and colleagues (1990) noted the increased number of treatment method, was first described by Abu'l-Qasim patients (22,764) with tuberculosis in the USA in 1986, Khalaf Ibn-Abbas AI-Zahrawi, known as Albucasis as reported by the Centers for Disease Control (CDC). (936-1013), in his book entitled, Practica - Surgery Ofthese patients, 17.5% had extra-pulmonary manifestations, and the lymph nodes were involved in 30.9%. and Instruments. (see Chap. 2 - Historical Aspects) Tuberculosis of the lymph nodes is the most The demographic data of patients with extra-pulmocommon extra-pulmonary manifestation of the nary tuberculosis were related to age, ethnic origin disease. Despite the reduction in the incidence of and gender. Age groups younger than 15 years were pulmonary tuberculosis in developed countries, the more likely to have tuberculous lymphadenitis. Racial and ethnic minorities, foreign-born, black and Asians were more likely than non-Hispanic white patients to M. M. MADKOUR, MD, DM, FRCP have tuberculous lymphadenitis. The author noted Consultant, Department of Medicine, Riyadh Armed Forces female predominance among those with adenitis. Hospital, P.O. Box 7897, C-119, Riyadh 11159, Saudi Arabia In Great Britain, Thompson et al. (1992) reported 67 R. AL KUHAYMI, FRCS patients with peripheral tuberculous lymphadenitis Director of Surgery, Riyadh Armed Forces Hospital, who attended Leicestershire group of teaching hospiP.O. Box 7897, Riyadh 11159, Saudi Arabia M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

446

tals between 1979 and 1989. The majority of patients [54 (81%)] were from the Indian subcontinent (India, Pakistan or Bangladesh) and only 13 (19%) were of white ethnic origin. Female predominance was noted in both ethnic groups and the incidence of family history was higher in the Indian group. In Germany, Geldmacher et al. (2002) reviewed the data of 60 hospitalized patients with tuberculous lymphadenitis aged 12 years or more over an 8-year period (1992-1999). Tuberculous lymphadenitis occurred in 5.1 % of all patients with tuberculosis hospitalized during the same period. Immigrants from Afghanistan, India and Pakistan were more affected with adenitis than native German patients (70% versus 30%). Female predominance was noted in both groups. The mean age of native patients was significantly higher than of the immigrants (53.8 years versus 35.5 years). Infection with HIV was present in only one patient. In Western Australia, Pang (1992) reported 172 patients with culture-positive mycobacterial lymphadenitis over an 18-year period (1972-1989). Tuberculosis lymphadenitis was found in 53 patients and non-tuberculous mycobacterial lymphadenitis in 119. Female predominance was noted in both groups. Tuberculous adenitis was found in 71 % of adult Asian migrants while non-tuberculous adenitis was found in 92% of non-Aboriginal Australian children.

28.2 HIV and Tuberculous Lymphadenitis Several authors have indicated that extra-pulmonary tuberculosis was more frequent in patients with HIV than pulmonary involvement and, therefore, extrapulmonary tuberculosis became synonymous with HIV infection (Shafer et al. 1991; Barnes et al. 1991; Onorato and McCray 1992; Rosenblum et al. 1994). Shriner et al. (1992) compared the incidence of mycobacterial infection of lymph nodes in 11 HIV-seropositive patients with 29 HIV-seronegative patients. They noted that mycobacterial lymphadenitis was an uncommon manifestation of HIV infection. The incidence of mycobacterial adenitis primarily depends upon the endemicity of M. tuberculosis. In high endemic areas, in HIV-infected patients; lymph node infection is caused by M. tuberculosis. In USAborn, HIV-infected patients, adenitis is more likely caused by non-tuberculous mycobacteria. In Canada, the high frequency of extra-pulmonary tuberculosis was not attributable to HIV infec-

M. M. Madkour and R. AI-Kuhaymi

tion. Cowie and Sharpe (1997) from Alberta, Canada reported their findings in a prospective populationbased study on 351 patients with tuberculosis diagnosed during a 5-year period (1990 to 1994). Extra-pulmonary tuberculosis was diagnosed in 160 (46%) patients, of whom 79 had superficial lymph node involvement. Patients of Asian ethnic origin accounted for 82% of those with adenitis with female predominance (71 %) and immigration from an Asian country was considered a major risk factor for tuberculosis lymphadenitis. Although lymph node tuberculosis is recognized by many authors to occur in a younger age, in this study, the Asian-born group was older than other groups. The prevalence of HIV infection was reported as 1.4%, and the authors concluded that it was not contributing to the high incidence of extra-pulmonary tuberculosis. The high incidence of extra-pulmonary tuberculosis in the Indian subcontinent patients was suspected to be due to the reduced immunocompetence against tuberculosis as a result ofVitamin D deficiency caused by reduced exposure to sunlight (Davies 1985). In India, Arora and Kumar (1999) reported a prospective study of 190 patients with HIV co-infected with tuberculosis, and extra-pulmonary tuberculosis was found in 46 patients (24.2%). Tuberculous lymphadenitis was found in 27 (58.7%) patients with extra-pulmonary tuberculosis. Tuberculous cervical lymphadenitis was found to be the most common cause of cervical lymph node enlargement. In Singapore, Chao et al. (2002) reported 72 patients with inflammatory cervical lymphadenitis, and 25 (33.8%) of these were due to tuberculosis. In Saudi Arabia, tuberculous lymphadenitis was found to be the most common cause of cervical lymph node enlargement in approximately 45% of patients (Thabet et al. 1984; Abba et al. 2002). The incidence of tuberculous lymphadenitis in patients with extra-pulmonary disease in Saudi Arabia ranged between 22.2% and 54.4% (Froude and Kingston 1982; Mokhtar and Salman 1983). It is more common among the age group of 20-30 years with female predominance (Thabet et al. 1984; Ibekwe et al.1997; Abba et al. 2002).

28.3 Pathogenesis Tuberculous lymphadenitis is the most common manifestation of non-respiratory tuberculosis worldwide. It is often caused by M. tuberculosis but M. bovis

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was found to be the cause in 2.8% of a series of 2272 nodes within a group. Adhesion to the overlying skin mycobacterial isolations from tuberculous lymph- may occur, resulting in induration and development adenitis in South East England (Grange et al. 1982). of a purplish discoloration. The center ofthe enlarging mass lesion becomes soft It is considered that tuberculous lymphadenitis is a local manifestation of a systemic disease (Kent 1967). and caseous; material may rupture into the surroundNon-tuberculous lymphadenitis is a localized disease ing tissue or through the skin with a sinus formation. caused by environmental mycobacteria found in the If untreated, discharging sinus may remain unhealed soil, animals, raw milk, natural and artificial water for years, but healing may take place with scarring, and systems (Dunn and Hodgson 1982; Pang 1992). The calcification may also occur. Tuberculous mediastinal infection is transmitted by drinking untreated water, lymph adenitis may enlarge and cause compression of milk, via oropharyngeal mucosa, salivary glands, ton- major blood vessels, phrenic or recurrent laryngeal sils or by skin injuries from contaminated objects or nerves or cause erosion of a bronchus or the pericaranimals, particularly in children and in immuno- dium (see Chap. 17 and 20 - Primary & Post-Primary compromised adults, particularly with HIV infection Pulmonary Tuberculosis). Asymptomatic intestinal or (Shriner et al. 1992; Pang 1992). M. avium complex hepatic tuberculosis may spread via lymphatic drainis more often the cause than other non-tuberculous age to the mesenteric, hepatic or peripancreatic lymph mycobacteria such as M. malmoense, M. kansasii, M. nodes (Brizi et al.1998). chelonei, M. fortuitum and M. scrofulaceum. Axillary lymph node tuberculosis may occur in up Tuberculous lymphadenitis may occur during to 1% of children following recent vaccination with primary tuberculous infection or as a result of reacti- BCG (Mori et al.1996). Inguinal lymph node tuberculovation of a dormant foci or by direct extension from sis may occur as a result of tuberculosis of the external a contiguous focus. In primary pulmonary tubercu- genitalia and may present with discharging inguinal losis, the bacilli enters the body via inhalation and sinuses (see chapter on tuberculosis of the skin). bacteremia may occur. Hilar, mediastinal and paratracheal lymph nodes are the first site of spread of infection from the lung parenchyma. The infection may then spread via the lymphatics to 28.4 the nearest cervical lymph nodes. However, sub-clinical Clinical Features pulmonary disease with no apparent imaging sequelae may be a focus of dissemination to the surrounding The main presenting features of tuberculous lymphlymphatic. Supraclavicular lymph node involvement adenitis as reported by most authors are palpable may reflect the lymphatic drainage routes for lung masses in approximately 75% of patients without parenchyma mycobacterial disease (Shriner et al. constitutional symptoms in about two-thirds of them 1992). Cervical tuberculous lymphadenitis may repre- (see Table 28.1). Cervical lymph nodes are the most sent a spread from the primary focus of infection in the common site of involvement and reported in 60% to tonsils, adenoids, sinonasal or osteomyelitis of the eth- 90% of patients (Manolides et al. 1993). The incidence moid bone (Wadman et al. 1981; Dandapat et al. 1990; of fever, weight loss and night sweating varied widely in different series and ranged from 10% to 100% of Johnson et al.1995; Jha et al. 2001; Jang et al. 2001). Tuberculous lymphadenitis most frequently patients. The duration of symptoms before diagnosis involves the cervical lymph nodes followed in fre- may range from a few weeks to several months (Geldquency by mediastinal, axillary, mesenteric, hepatic macher et al. 2002; Aggarwal et al. 2001; Memish et al. portal, peripancreatic and inguinal lymph nodes 2000; Fain et al. 1999; Chen et al. 1992; Thompson et al. (Krishnaswamy et al. 1972; Thompson et al. 1992; 1992; Pang 1992). Lymph node enlargement is usually painless with Freixinet et al. 1995; Mori et al. 1996; Baran et al. 1996; Brizi et al. 1998; Arora and Kumar 1999; Ayed matting due to periadenitis and adhesion to a surand Behbehani 2001; Jang et al. 2001; Geldmacher rounding structure at a single site in 50-70% of patients et al. 2002). In the initial stage of superficial lymph (Memish et al. 2000; Dandapat et al.1990; Krishnaswamy node involvement, progressive multiplication of the et al.1972; Deital et al.1989; Hooper 1972). Multiple sites tubercle bacilli, the onset of delayed hypersensitivity involvement may occur in up to 35% of patients (see is accompanied by marked hyperemia and swelling, Table 28.1). Complications may be noted at the time of necrosis and caseation of the centers of the nodes. presentation in 10% to 20% of patients, including skin This may be followed by marked perinodal inflam- inflammation, abscess formation or cutaneous dismation, progressive swelling and matting with other charging sinus (Pang 1992; Aggarwal et al. 2001).

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M. M. Madkour and R. Al-Kuhaymi

Table 28.1. Symptoms and sites of tuberculous lymphadenitis (in various series). ND not described Series

Geldmacher et al. (2002) Fain (1999) Thompson et al. (1992) Chen et al. (1992) Pang (1992) Oandapat et al. (1990) Ayed and Behbehani (2001)

Number of patients

Symptoms %

Sites %

Fever Weight Sweating

Cervical Mediastinal Axillary Inguinal Multiple sites

60 59 67

NO 30.3 11.9 14.1 NO 40 41

63.3 73.1 85 91.5 80 70 NO

71

53 80 34 all mediastinal

100 47.5 14.9 9.9 NO 85 35

100 22 10.4 NO NO 37 NO

The clinical features of non-tuberculous mycobacteriallymphadenitis are localized to the site involved and are more rapidly growing with rarity of associated systemic manifestations (Spyridis et al. 2001; Flint et al. 2000; Pang 1992). Localized complications at the site of lymph nodes involvement, such as skin inflammations, abscess formation and discharging cutaneous sinuses, are much more frequent than in tuberculous lymphadenitis. Pang (1992) found these complications in 52 of the 119 patients (43.7%) with non-tuberculous mycobacterial lymphadenitis.

28.5 Diagnosis Tuberculous lymphadenitis remains the most common cause of cervical lymphadenopathy in developing countries and reported in about 40% of cases (Thabet et al. 1984; Abba et al. 2002). The differential diagnosis is extensive and includes infection (bacteria, virus, fungi), neoplasms (lymphoma, metastatic carcinoma, Hodgkin's disease, sarcoma), sarcoidosis, non-specific reactive hyperplasia and drug reactions. Medical and social history, particularly of contact with tuberculous patients, and chest radiograph may be helpful. Tuberculin skin testing may be positive in over 85% of patients (Ibekwe et al. 1997; Lee et al.1992; Dietel et al.I989). Tuberculin test may be negative in patients with non-tuberculous mycobacterial lymphadenitis or in patients with HIV co-infection. Most patients with cervical tuberculous lymphadenitis have normal chest radiographs (58% to 86%) (Ibekwe et al. 1997; Lee et al. 1992; Thompson et al. 1992; Dietel et al. 1989). Histopathological or cytological diagnosis can be obtained by lymph nodes tissue biopsies or by fine-needle aspiration (FNA). The detection of epithelioid cells and granuloma is highly suggestive of tuberculosis, but other

26.7 NO NO NO 3.7 NO 34

8.3 15.4 10.4 12.7 13.2 6 NO

1.7 9.6 4.5 7 3.7 9 NO

35 15.3 NO 25.4 24.5 15 NO

diseases may produce similar findings. The confirmation of the diagnosis can be achieved by identifying the acid-fast bacilli (AFB) by Ziehl-Neelsen (Z-N) staining of lymph nodes aspirates or biopsies or by positive cultures from these specimens. Positive cultures of surgical biopsies are reported in 62-79% in different series (Krishnaswamy et al. 1972; Campbell and Dayson 1977; Dandapat et al. 1990). The diagnosis of tuberculous lymphadenitis can be achieved with diagnostic accuracy in 76-97% of cases by the combination of FNA cytology, AFB smear and culture (Bailey et al. 1985; Das et al. 1990; Das Gupta et al. 1994). They will also differentiate between lymphadenitis caused by M. tuberculosis and those caused by non-tuberculous mycobacterial infection. Lymph node biopsies may be necessary if FNA was not helpful. Mycobacterial culture required for the confirmation of the diagnosis is time consuming. A rapid and accurate laboratory method of diagnosis with ability to predict the presence of multi-drug resistance may be achieved by polymerase chain reaction (PCR) and PCR-single strand conformational polymorphism (SSCP) (Gong et al. 2002).

28.6 Histology and Cytology and Microbiology Findings Excisional biopsy of lymph nodes remains a common method of obtaining tissue specimen in developing countries for histological and microbiological examinations. Abba et al. (2002) from Saudi Arabia retrospectively reviewed the clinicopathological features in 258 patients with cervical lymphadenopathy. All patients had excisional biopsies from the lymph nodes and tuberculous granulomata were found in 98 (37.9%). In western Australia, Pang (l992) performed excisional biopsies on 151, by needle aspirations in seven and

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by sterile swab obtained at incisional drainage in ten. All had culture-positive results as well as histological features of granulomas. Al-Hadrani et al. (2000) from Yemen reported 302 patients with peripheral tuberculous lymphadenitis prospectively studied between January 1995 and December 1997. All patients underwent lymph node biopsy by surgical excision for histological examination, and 284 (94%) had histological findings consistent with tuberculosis. The authors noted that mycobiological examinations were not useful as only 5 cases of 17 had positive cultures. During the past two decades, FNA has been used more by several authors as the initial technique for the diagnosis of mycobacterial lymphadenitis, and if cytological findings are uncertain, tissue biopsies by surgery are usually advisable (Geldmacher et al. 2002; Pang 1992; Lau et al. 1990, 1991; Kamboj et al. 1994; Shaha et al. 1986; Khan et al. 1994; Chao et al. 2002; Dandapat et al. 1990; Qadri et al. 1991). The sensitivity and specificity of FNA cytology in the diagnosis of tuberculous lymphadenitis were 88% and 96%, respectively, as reported by Chao et al. (2002). Lau et al. (1990) reported the results of a consecutive series of 1349 FNA biopsies from the head and neck region of 1193 patients and found that 108 patients showed granulomatous changes. Only 68 of them had subsequent surgery with histological diagnosis, and tuberculous lymphadenitis was confirmed in 63. The authors indicated that the specificity of FNA in diagnosing granulomatous lymphadenitis in their series was 63/68 (93%). Smears from 52 patients stained with the Z-N technique showed AFB in 19 (37%). Of the AFB-positive smears, 13 and six were associated with granulomatous and non-specific inflammatory cytological findings, respectively. Of the smears of the same 52 patients, nine had positive culture of mycobacterial tuberculosis. The authors indicated that the overall sensitivity of FNA in diagnosing tuberculous cervical lymphadenopathy was 77%. Cultures of the specimen obtained by excisional biopsy showed Mycobacterium tuberculosis in 80% of cases. In Saudi Arabia, the specificity of FNA was found to be 93%. Qadri et al. (l991) described the sensitivity and specificity of FNA in the diagnosis of mycobacterial lymphadenitis. The authors reported positive smear staining in 23% while cultures were positive in 53%. Khan et al. (1994) from Saudi Arabia had similar results of FNA microbiological findings and reported AFB-positive smear staining in 25% and cultures in 62%. Dandapat et al. (1990) from India reported that FNA cytology was positive in 83%, culture of surgical biopsies were positive in 65% and noted that "In our practice, biopsy in always undertaken to confirm the diagnosis". In India, Prasoon (2000) used FNA cytology for evaluation of

449

783 patients who presented with lymphadenopathy due to various causes over a 4-year period (1994 and 1998), and 213 (27.2%) were tuberculous. Cytological patterns included epithelioid cell granulomas alone with coexistence of necrosis, AFB or both, and necrosis with AFB. The author noted that the chance of finding AFB was highest in patients presenting with cold abscess. The presence of granuloma and of AFB had an inverse relationship. Geldmacher et al. (2002) found that both FNA and lymph node excisional biopsies were similarly effective methods in obtaining sufficient lymph node tissue for histological and microbiological examinations. The cytological and histological analyses were equally positive and revealed epithelioid cells in 88.3%, giant cells in 55% and caseation in 43.3%. Microbiological confirmation by cultures was equally positive in 40% by FNA or biopsies. Z-N staining was positive in 13.3% in both FNA and excisional biopsies. Lymph node samples obtained by FNA can provide sufficient collection of material for cytological and bacteriological examination and is considered as an alternative and easy procedure. Gupta et al. (1993) from Kuwait reported the cytodiagnostic and microbiological confirmation findings by FNA on 102 patients with tuberculous lymphadenitis. Patients were diagnosed by FNA cytological examination with tuberculous lymphadenitis. They were subjected to mycobacterial examination by Z-N staining and by culture of direct or of concentrated smear materials. Z-N staining for AFB was positive in 29.5%. The cultures for mycobacteria were positive in 49%. The authors concluded that cytodiagnosis supplemented with AFB smear staining and culture helped in establishing a definite diagnosis in 56.9% of cases. There are only few comparative studies on the diagnostic characteristics of mycobacterial lymphadenitis among patients co-infected with HIV and those without HIY. Shriner et al. (1992) from California reported a 16-year experience of 40 patients with tuberculous lymphadenitis of whom 11 were HIV-seropositive and 29 were HIV-seronegative. Positive AFB stain was significantly higher in HIV-seropositive than seronegative patients (72.7% versus 14.8% respectively). Positive FNA culture was significantly higher in HIVseropositive than seronegative patients (100% versus 12.5% respectively). Similar comparative diagnostic studies were reported by Finfer et al. (199l) from New York. In a total of 30 patients with tuberculous lymphadenitis; 13 were with AIDS or ARC and 17 were without AIDS. Positive smear stain for AFB was found in 9 of 13 patients with AIDS and ARC, but found in only 1 of 10 non-AIDS patients.

450

Isolated tuberculous mediastinal and hilar lymphadenopathy in the absence of parenchymal lung disease may present as a diagnostic challenge (Ayed and Behbehani 2001; Domingo 1996; Julia et al. 1990; Dhand et al. 1979; Liu et al. 1978). Several diagnostic methods that require procedures such as fiberoptic bronchoscopy, transthoracic image guided FNA using computed tomography (CT), magnetic resonance imaging, fluoroscopy and ultrasound are well established for the diagnosis of mediastinallymphadenopathy. Mediastinoscopy or thoracotomy may rarely be performed when other procedures are not diagnostic or if lymphoma is suspected (Khan et al. 1994; Ayed and Behbehani 2001; Zwischenberger et al. 2002). Ayed and Behbehani (2001) reported 34 patients with isolated mediastinal tuberculous lymphadenitis with no parenchymal lung and all had bronchoscopy and mediastinoscopy lesions. Bronchoscopy showed endobronchial hyperemia in seven patients (21 %); of them, three had positive culture for Mycobacterium tuberculosis, while granulomatous inflammation was found in all. Mediastinoscopy confirmed that diagnosis in all 34 [100% patients, granuloma in 100%, and positive microbiological features in 30 patients (88.2%)]. Baran et al. (1996) reported their findings on 17 patients with isolated tuberculous mediastinal lymphadenitis without parenchymal lung lesions. All patients had bronchoscopy and 15 had endobronchial abnormalities and biopsies were obtained. Bronchoscopy yielded the diagnosis in nine patients (53%). Mediastinoscopy or thoracotomy was performed on six patients that were not diagnosed by bronchoscopy and the diagnosis was confirmed in 100% of them.

28.7 Polymerase Chain Reaction Detection of Mycobacterium tuberculosis DNA from FNA material using polymerase chain reaction (PCR) assays has been extensively reported (Kim et al.I996). Conventional utilization of Z-N staining requires a high bacillary load of 10,000-100,000 per ml of aspirate material to be able to detect it. Various series have reported a wide range of AFB smear positivity, from 0% to 75% (Arora and Arora 1990; Das Gupta et al. 1994; Ellison et al. 1999; Harrison and Jayasundera 1999; Ibekwe et al. 1997; Kumar et al. 1998). The molecular basis of mycobacterial resistance to the antituberculous agents has been recently elucidated using the SSCP method, PCR-SSCP (Banerjee et al.

M. M. Madkour and R. Al-Kuhaymi

1994; Morris et al.1995; Gong et al. 2002). It is also possible that PCR can differentiate between lymphadenitis caused by Mycobacterium tuberculosis and that caused by nontuberculous mycobacterial infection. Gong et al. (2002) used one-step PCR and PCR-SSCP for the purposes of diagnosis and detection of rifampicin-resistant strain on FNA sediment material. Sixty-three patients with positive bacteriologic confirmation and/or clinical evidence of tuberculosis and a control group of 55 cases of non-tuberculosis were studied over a 24-month period. The bacilli were detected by PCR in 49 of 63 cases of tuberculosis (77.8%) while by Z-N stain in 25 of 63 (39.7%). Twenty-three cases were positive by PCR and Z-N staining. Twenty-six cases had positive PCR but negative Z-N stain. Two cases had negative PCR but positive Z-N stain. Twelve cases had negative PCR and Z-N stain. The rpo B gene mutation was observed in seven of twenty-two cases of tuberculous lymphadenitis (31.8%). The authors concluded that FNA cytology supplemented by PCR methods and conventional examinations could confirm the diagnosis and predict the presence of multi-drug-resistance bacilli. The comparison between the use of conventional methods ofdiagnosis by FNA and the use ofPCR and its practical application in developing countries has been reported by Goel et al. (2001). The authors reported 142 patients with peripheral lymphadenitis due to various causes. Tuberculosis was diagnosed in 78 (54.9%), based on cytology alone in 71.8% and increased to 83.8% when supplemented by AFB smear stain. The correct diagnosis was achieved in 94.8% of patients when the four conventional methods were combined (FNA cytology, AFB smear, culture and biopsy). The peR was done on 52 cases and was positive in 39, of them 13 were non-tuberculous. Tuberculosis was confirmed by PCR in 37 of39 patients (94.6%). The authors recommended that PCR should only be reserved for the problem cases in developing countries.

28.8 Imaging Findings Most patients with tuberculous cervical lymphadenitis have normal chest radiography. However, an associated abnormal chest radiograph suggestive of pulmonary tuberculosis was present in 42% (Chen et al. 1992). Power Doppler sonography of tuberculous cervical lymphadenitis may show avascularity, displaced hilar vessels and low intranodal vascular resistance, yet remains non specific (Ahuja et al. 2001a, b). Lymph node calcifications may be depicted in less

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tomycin (SM) and isoniazid (INH) is equally effective and had no greater relapse rate than an 18-month regimen (Campbell and Dayson 1979). In February 2003, the joint committee of the American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America published their recommendations on the treatment of pulmonary and extra-pulmonary tuberculosis (AT/ CDC/IDSA 2003). In tuberculous lymphadenitis, a 6month regimen of four drugs, INH, RIF, PZA and EMB, should be given in the initial phase for 2 months and the continuation phase of treatment should consist of INH and RIF for a minimum of 4 months. In the initial 2-month phase of a 6-month regimen, INH, RIF, PZA and EMB should be given daily throughout (regimen 1), daily for 2 weeks followed by two times weekly for 6 weeks (regimen 2), or three times a week (regimen 3). The continuation phase may be given daily, two times weekly by DOT or three times weekly by DOT. 28.9 In the presence of INH resistance, there are fewer Treatment of Mycobacterial Lymphadenitis failures and relapses using this regimen. If drug susceptibility becomes available and the organisms Most patients with mycobacterial lymphadenitis are were found to be susceptible to INH, then EMB can initially treated with anti-tuberculous drugs. The dif- be discontinued in the initial2-month phase of treatferentiation between tuberculous and non-tubercu- ment regimens. lous forms of mycobacterial lymphadenitis cannot be The ATS/CDC/IDSA Committee (2003) indicated ascertained by the histological evidence of caseating that therapeutic lymph node excision is not indicated or necrotizing granulomata with or without positive except in unusual circumstances. Aspiration or incimicroscopy for AFB, and the culture and PCR may be sion and drainage of large fluctuant lymph nodes useful (Pang 1992). may be beneficial (Cheung et al.1988). The guidelines for recommended treatment of In non-tuberculous mycobacterial lymphadenitis, tuberculous lymphadenitis are similar to treatment most authors agree that effective treatment is often regimens used for pulmonary tuberculosis. Regimens achieved by surgical excision of the affected lymph may vary in various epidemiological and economical nodes (Jones and Campbell 1962; MacKellar 1976; circumstances, particularly in high-incidence low- Harris et al. 1982; Joshi et al. 1989; Campbell 1990). In income areas as compared with low-incidence high- Western Australia, Pang (1992) reviewed the records income parts of the world. of 172 patients with culture-positive mycobacterial Recommendations target, in general, countries in lymphadenitis over an 18-year period between January which mycobacterial culture, drug susceptibility test- 1972 and December 1989. Tuberculous lymphadenitis ing, radiographic facilities and second-line drugs are was found in 53 and non-tuberculous mycobactenot widely available as a routine. In endemic areas, rial lymphadenitis was found in 119 patients. All 119 particularly in Asian countries, rising prevalence of patients with non-tuberculous mycobacteriallymphadresistant M. tuberculosis makes it difficult to provide enitis had surgical intervention, including 91 with total appropriate treatment when cultures are not available. excision, 15 with drainage plus total excision, five with The World Health Organization and the International incisional drainage alone and eight patients had second Union Against Tuberculosis and Lung Disease recom- excision for relapse or residual disease. Favorable outmendations of treatment are built around a national come of surgical treatment of non-tuberculous mycocase management strategy, "Directly Observed Ther- bacterial lymphadenitis was confirmed by the authors apy - Short course" (DOTS). These recommendations at 12 months in 86 patients (72.3%). The remaining were based on and supported by the British Medical 33 patients (27.7%) were lost for follow-up after surgery. Flint and colleagues (2000) from New Zealand Research Council studies in 1973,1977,1985,1988. A 6- to 8-month regimen with addition of rifampin reported 57 children with non-tuberculous mycobacte(RIF) or pyrazinamide (PZA) to a base of daily strep- rial lymphadenitis that were treated surgically. Patients

than 10% of patients (Geldmacher et al. 2002; Khan et al. 2000). Hilar mediastinal and paratracheal adenopathy can be depicted by chest X-rays (See imaging of pulmonary tuberculosis chapter). Enhanced CT scan of the mediastinal tuberculous lymphadenitis may show peripheral ring enhancement and hypodensity of the central portion of the lymph nodes (see imaging of pulmonary tuberculosis chapter). Mesenteric, hepatic and peripancreatic tuberculous lymphadenitis may be depicted by enhanced abdominal CT scan. The most common CT features include peripheral ring enhancement and hypodensity of the central part of the lymph nodes. Homogeneous or inhomogeneous enhancement or lack of enhancement oflymph nodes may be seen (Brizi et al.1998; Moon et al.1998; Pombo et al. 1992; 1m et al. 1987).

M. M. Madkour and R. Al-Kuhaymi

452

who had excision achieved a significantly greater healing and lower re-operation rates than those treated with incision and drainage, curettage or aspiration. Spyridis et al. (2001) reported 50 children with mycobacterial cervical lymphadenitis who were examined between 1982 and 1997. Tuberculous adenitis was found in 24 and non-tuberculous mycobacterial adenitis in 26 patients. All patients with non-tuberculous mycobacterial adenitis were managed by total excision of affected lymph nodes. Isolated tuberculous mediastinal or peripheral lymphadenitis in adults is usually treated with antituberculous drugs alone without surgical intervention (Dandapat et al. 1990; Ayed and Behbehani 2001). In children, however, surgical intervention may rarely be indicated if it is accompanied by a severe tracheobronchial compression or when bronchial lymph fistula is detected (Byrd et al. 1976; Freixinet et al. 1995). Reduction of the size of the lymph nodes swelling without complications may occur in 70-90% of patients during and after the completion of treatment (Wong and Jafek 1974; Campbell 1990; Geldmacher et al. 2002). The relapse rate following standard short-course regimen in 427 children with tuberculous lymphadenitis was reported as 2.8% by McMaster et al. (2000). Paradoxical response to treatment with further enlargement or additional swelling of new lymph nodes may occur in 6-30% of patients within the first 2 months of initiating treatment (Campbell 1990; Carter and Mates 1994; Memish et al. 2000; Geldmacher et al. 2002). The pathogenesis of this paradoxical response to treatment is not clearly explained. It is postulated to be due to hypersensitivity response to various antigens of the tubercle bacilli (Afghani and Lieberman 1994; Carter and Mates 1994; Lieberman 1994; Campbell and Dayson 1977; Obeid et al. 1999; Geldmacher et al. 2002). It usually resolves spontaneously without alteration in the course of treatment. In approximately 10% of patients, local complications including ulceration, fistulas or abscess formation may occur after initiating treatment. The treatment of tuberculous lymphadenitis in patients co-infected with HIV is essentially the same as in those without HIY. The ATS/CDC/IDSA Committee (2003) indicated there are two important exceptions to this generalization in patients with HIV: 1. In the continuation phase, once weekly INH-RIF

should not be used 2. Twice weekly INH-RIF should not be used if CD4+ lymphocyte counts less than 100/,.d.

All rifamycins are inducers of metabolic pathways and may result in a decrease in serum concentration of anti-retroviral agents to sub-therapeutic levels. Rifapentine is less of an inducer than RIF and may be used.

References Abba AA, Bamgboye AE, Afzal M et al (2002) Lymphadenopathy in adults. Saudi Med J 23:282-286 Afghani B, Lieberman JM (1994) Paradoxical enlargement or development of intracranial tuberculomas during therapy: case report and review. Clin Infect Dis 19:1092-1099 Aggarwal P, Wali JP, Singh S et al (2001) A clinico-bacteriological study of peripheral tuberculous lymphadenitis. J Assoc Physicians India 49:808-812 Ahuja A, Ying M, Yuen YH et al (2001a) Power Doppler sonography to differentiate tuberculous cervical lymphadenopathy from nasopharyngeal carcinoma. AJNR Am J NeuroradioI22:735-740 Ahuja A, Ying M, Yuen YH et al (2001b) Power Doppler sonography cervical lymphadenopathy. Clin Radiol 56:965-969 AI-Hadrani AM, Aulaqi SM, Al Salami SF et al (2000) Management strategies for peripheral tuberculous lymphadenopathy. Saudi Med J 21:266-269 American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America (2003) Treatment of tuberculosis. Am J Respir Crit Care Med 167: 603-662 Appling D, Miller RH (1981) Mycobacterial cervicallymphadenopathy update. Laryngoscope 91:1259-1266 Arora B, Arora DR (1990) Fine needle aspiration cytology in diagnosis of tuberculous lymphadenitis. Ind J Med Res 91: 189-192 Arora VK, Kumar SV (1999) Pattern of opportunistic pulmonary infections in HIV seropositive subjects: observations from Pondicherry, India. Indian J Chest Dis Allied Sci 41: 135-144 Ayed AK, Behbehani NA (2001) Diagnosis and treatment of isolated tuberculous mediastinal lymphadenopathy in adults. Eur J Surg 167:334-338 Bailey TM, Akhtar M, Ali MA (1985) Fine needle aspiration biopsy in the diagnosis of tuberculosis. Acta Cytol 29: 732-736 Banerjee A, Dubnau E, Quemard A et al (1994) InhA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis. Science 363:227-230 Baran R, Tor M, TahaoJu K et al (1996) Intrathoracic tuberculous lymphadenopathy: clinical and bronchoscopic features in 17 adults without parenchymal lesions. Thorax 51:87-89 Barnes PF, Bloch AB, Davidson PT et al (1991) Tuberculosis in patients with human immunodeficiency virus infection. N Engl J Med 324:1644-1650 Bloch AB, Rieder HL, Kelley GD et al (1987) The epidemiology of tuberculosis in the United States. Clin Chest Med 10:297-313 British Medical Research Council (East African) (1973) Controlled clinical trial of four short-course (6 month) regimens of chemotherapy for treatment of pulmonary tuberculosis. Second report. Lancet 1:1331-1338

Mycobacterial Lymphadenitis British Medical Research Council (East African) (1974) Controlled clinical trial of four short-course (6-month) regimens of chemotherapy for treatment of pulmonary tuberculosis. Third report. Lancet 2:237-240 British Medical Research Council (Hong Kong Chest Service) (1977) Controlled trial of a 6-month and 9-month regimens of daily intermittent streptomycin plus isoniazid plus pyrazinamide for pulmonary tuberculosis in Hong Kong. Am Rev Respir Dis 115:727-735 British Thoracic Society Research Committee (1985) Short course chemotherapy for lymph node tuberculosis: a controlled trial. Br J Dis 290: 1106-11 08 British Thoracic Society Research Committee (1988) Short course chemotherapy for lymph node tuberculosis: final report at 5 years. Br J Dis Chest 82:282-284 Brizi MG, Celi G et al (1998) Diagnostic imaging of abdominal tuberculosis: gastrointestinal tract, peritoneum, lymph nodes. Rays 23:115-125 Butt AA (1997) Nasal tuberculosis in the 20th century. Am J Med Sci 313:332-335 Byrd RB, Griggs GA David G et al (1976) Surgical complications of cervical and mediastinal tuberculous adenitis in an infant. Chest 70:544-546 Campbell IA (1990) The treatment of superficial tuberculous lymphadenitis. Tubercle 71:1-3 Campbell lA, Dyson AJ (1977) Lymph node tuberculosis: a comparison of various methods of treatment. Tubercle 548:171-179 Campbell lA, Dyson AJ (1979) Lymph node tuberculosis: a comparison of treatments 18 months after completion of chemotherapy. Tubercle 60:95-98 Cantwell MF, Snider DE, Cauther GM et al (1994) Epidemiology of tuberculosis in the United States, 1985 through 1992. Am Med Assoc 272:535-539 Carter EJ, Mates S (1994) Sudden enlargement of a deep cervical lymph node during and after treatment for pulmonary tuberculosis. Chest 106: 1896-1898 Chao SS, Loh KS, Tan KK et al (2002) Tuberculous and nontuberculous cervical lymphadenitis: a clinical review. Otolaryngol Head Neck Surg 126:176-179 Chen YM, Lee PY, SU WJ et al (1992) Lymph node tuberculosis: 7 year experience in Veterans General Hospital Taipei, Taiwan. Tuber Lung Dis 73:368-371 Cheung WL, Siu KF, Ng A (1988) Tuberculous cervical abscess: comparing the results of total excision against simple incision and drainage. Br J Surg 75:563-564 Cowie RL, Sharpe JW (1997) Extra-pulmonary tuberculosis: a high frequency in the absence ofHIV infection. Int J Tuberc Lung Dis 1:159-162 Dandapat MC, Mishra BM, Dash SP et al (1990) Peripheral lymph node tuberculosis: a review of 80 cases. Br J Surg 77:911-912 Das DK, Pant IN, Chachra KL (1990) Tuberculous lymphadenitis: Correlation of cellular components and necrosis in lymph node aspirate with AFB positivity and bacillary count. Ind J Pathol MicrobioI33:1-10 Das Gupta A, Ghosh TN, Podder AK et al (1994) Fine needle aspiration of cytology of cervical lymphadenopathy with special reference to tuberculosis. J Ind Med Assoc 92:44-46 Davies PD~ (1985) A possible link between vitamin D deficiency and impaired host defence to Mycobacterium tuberculosis. Tubercle 66:301-306 Deitel M, Bendago M, Krajeden S et al (1989) Modern management of cervical scrofula. Head Neck 1:60-66

453 Dhand S, Fisher M, Fewell JW (1979) Intrathoracic tuberculous lymphadenopathy in adults. JAMA 241:505-507 Dietel M, Bendago M, Kraijden S et al (1989) Modern management of cervical scrofula. Head Neck 11:60-66 Domingo P (1996) Isolated mediastinal tuberculous lymphadenitis. Arch Intern Med 156:1582 Dunn BL, Hodgson DJ (1982) ,Atyical' mycobacteria in milk. J Appl Bacteriol 52:373-376 Ellison E, Lapuerta P, Martra SE (1999) Fine aspiration diagnosis of mycobacterial lymphadenitis: sensitivity and predictive value in the United States. Acta CytoI43:153-157 Fain 0, Lortholary 0, Djouab M, Amoura I et al (1999) Lymph node tuberculosis in the suburbs of Paris: 59 cases in adults not infected by the human immunodeficiency virus. Int J Tuberc Lung Dis 3:162-165 Finfer M et al (1991) Fine needle aspiration biopsy diagnosis of tuberculous lymphadenitis in patients with and without the acquired immune deficiency syndrome. Acta Cytol 35: 325-332 Flint D et al (2000) Cervical lymphadenitis due to non-tuberculous mycobacteria: surgical treatment and review. Int J Pediatr OtorhinolaryngoI53:187-194 Freixinet J, Varela A, Rivero LL et al (1995) Surgical treatment of childhood mediastinal tuberculous lymphadenitis. Ann Thorac Surg 59:644-646 Froude JRL, Kingston M (1982) Extrapulmonary tuberculosis in Saudi Arabia: a review of 162 cases. King Faisal Specialist Hosp Med J 2:85-95 Geldmacher H, Taube C Kroeger C et al (2002) Assessment of lymph node tuberculosis in Northern Germany. Chest 121:1177-1182 Goel MM, Ranjan V, Dhole TN et al (2001) Polymerase chain reaction vs. conventional diagnosis in fine needle aspirates of tuberculous lymph nodes. Acta CytoI45:333-340 Gong G, Lee H, Kang GH et al (2002) Nested PCR for diagnosis of tuberculous lymphadenitis and PCR-SSCP for identification of rifampicin resistance in fine needle aspirates. CytopathoI26:228-231 Grange JM, Collins C, Yates M (1982) Bacteriological survey of tuberculous lymphadenitis in South-east England: 1973-1980. J Epidemiol Community Health 36:157-161 Gupta SK, Chugh TD, Sheikh ZA et al (1993) Cytodiagnosis of tuberculous lymphadenitis: a correlative study with microbiologic examination. Acta CytoI37:329-332 Harris BH, Webb HW, Wilkinson AH Jr et al (1982) Mycobacterial lymphadenitis. J Pediatr Surg 17:589-590 Harrison AC, Jayasundera J (1999) Mycobacterial cervical adenitis in Auckland: diagnosis by the fine needle aspirate. NZ Med J 112:7-9 Hooper AA (1972) Tuberculous peripheral lymphadenitis. Br J Surg 59:353-359 Ibekwe AO, Al Shareef Z, Al Kindy S (1997) Diagnostic problems of tuberculous cervical adenitis (scrofula). Am J OtolaryngoI18:202-205 1m JG, Song KS, Kang KS et al (1987) Mediastinal tuberculous Iymphadneitis: CT manifestations. Radiology 164: 115-119 Jang YJ, Jung SW, Koo TW et al (2001) Sinonasal tuberculosis associated with osteomyelitis of the ethmoid bone and cervicallymphadenopathy. J Laryngol OtoI115:736-739 Jha BC, Dass A, Nagarkar NM et al (2001) Cervical tuberculous lymphadenopathy: changing clinical pattern and concepts in management. Postgrad Med J 77:185-187

454 Johnson IJM, Soames JV, Marshall HF (1995) Nasal tuberculosis - an increasing problem? J Laryngol OtoI109:326-327 Jones PJ, Campbell PE (1962) Tuberculous lymphadenitis in childhood: the significance of anonymous mycobacteria. Br J Surg 50:302-314 Joshi W, Davidson PM, Jones PG et al (1989) Non-tuberculous mycobacterial lymphadenitis in children. Eur J Pediatr 148: 751-754 Julia G, Rodriguez de Castro F, Fernandez JM et al (1990) Transcarinal needle aspiration in the diagnosis of mediastinal adenitis in a patient infected with the immunodeficiency virus. Thorax 45:414-415 Kamboj SS, Goel MM, Tandon P (1994) Correlation study of histopathology and bacteriology in patients of tubercular lymphadenitis. Ind J Chest Dis Allied Sci 36:187-191 Kent DC (1967) Tuberculous lymphadenitis: not a localized disease process. Am J Med Sci 254:866-874 Khan J, Akhtar M, von Sinner WN, Bouchama A et al (1994) CT-guided fine needle aspiration biopsy in the diagnosis of mediastinal tuberculosis. Chest 106:1329-1332 Khan MQ, AI-Qahtani AQ, AI-Momen S et al (2000) Widespread tuberculous calcification. Saudi Med J 21:386-389 Kim SS, Chung SM, Kim IN et al (1996) Application of PCR from the fine needle aspirates for the diagnosis of cervical tuberculous lymphadenitis. J Kor Med Sci 11: 127-132 Krishnaswamy H, Koshi G, Kulkarni KG et al (1972) Tuberculous lymphadenitis in South India - a hospitalpathological and bacteriological study. Tubercle 53:215-220 Kumar N, Tiwari MC, Verma K (1998) AFB staining in cytodiagnosis of tuberculosis without classical features: a comparison of Ziehl Neelsen and f1uoroscent methods. Cytopathology 9:208-214 Lau SK, Wei WI, Hsu C et al (1990) Efficacy of fine needle aspiration cytology in the diagnosis of tuberculous cervical lymphadenopathy. J Laryngol Otoll04:24-27 Lau SK, Wie WI, Kwan S et al (1991) Combines use of fine needle aspiration cytologic examination and tuberculin skin test in the diagnosis of cervical tuberculous lymphadenitis. Arch Otolaryngol Head Neck Surg 117:87-90 Lee KC, Tami TA, Lalwani AK et al (1992) Contemporary management of cervical tuberculosis. Laryngoscope 102:60-64 Liu C, Fields WR, Shaw C (1978) Tuberculous mediastinal lymphadenopathy in adults. Radiology 126:369-371 MacKellar A (1976) Diagnosis and management of atypical mycobacterial lymphadenitis in children. J Pediatr Surg 11:85-89 Manolidis S, Frenkiel S, Yoskowitch A et al (1993) Mycobcterial infections of the head and neck. Otolaryngol Head Neck Surg 109:427-433 McMaster P, Ezeilo N, Vince JD (2000) A retrospective review of paediatric lymph node tuberculosis in Port Moresby, Papua New Guinea. Ann Trop Paediatr 20:223-226 Memish ZA, Mah MW, Mahmood SA et al (2000) Clinico-diagnostic experience with tuberculous lymphadenitis in Saudi Arabia. Clin Microbiol Infect 6:137-141 Mokhtar A, Salman K (1983) Extrapulmonary tuberculosis. Saudi Med J 4:317-322 Moon WK, 1m JG, Yeon KM et al (1998) Mediastinal tuber-

M. M. Madkour and R. AI-Kuhaymi culous lymphadenitis: CT findings of active and inactive disease. AJR 170:715-718 Mori T, Yamauchi Y, Shiozawa K (1996) Lymph node swelling due to bacilli Calmette-Guerin vaccination with multipuncture method. Tuberc Lung Dis 77:269-273 Morris S, Bai GH, Suffys P et al (1995) Molecular mechanism of multiple drug resistance in clinical isolates of Mycobacterium tuberculosis. J Infect Dis 171:954-960 Obeid T, Mousali Y, Wali S et al (1999) Paradoxical enlargement of lymph nodes during therapy of central nervous system tuberculosis. Ann Saudi Med 19:530-532 Onorato 1M, McCray E (1992) Prevalence of human immunodeficiency virus infection among patients attending tuberculosis clinics in the United States. J Infect Dis 165:87-92 Pang SP (1992) Mycobacterial lymphadenitis in Western Australia. Tuberc Lung Dis 73:362-367 Pombo F, Rodriguez E, Mato J (1992) Patterns of contrast enhancement of tuberculous lymph nodes demonstrated by computed tomography. Clin RadioI46:13-17 Prasoon D (2000) Acid-fast bacilli in fine needle aspiration smears from tuberculous lymph nodes. Where to look for them. Acta CytoI44:297-300 Qadri SMH, Akhtar M,Ali MA (1991) Sensitivity of fine needle aspiration biopsy in the detection of mycobacterial infections. Diagn CytopathoI7:142-146 Rieder HL, Snider DE Jr, Cauthen GM (1990) Extrapulmonary tuberculosis in the United States. Am Rev Respir Dis 141: 347-351 Rosenblum LS, Castro KG, Dooley S et al (1994) Effect of HIV infection and tuberculosis on hospitalizations and cost of care for young adults in the United Sates, 1985 to 1990. Ann Intern Med 121:786-792 Shafer RW, Kim DS, Weiss JP et al (1991) Extrapulmonary tuberculosis in patients with human immunodeficiency virus infection. Medicine 70:384-397 Shaha A, Webber C, Marti J (1986) Fine needle aspiration in the diagnosis of cervical lymphadenopathy. Am J Surg 152: 320-423 Shikhani AH, Hadi UM, Mufarrij AA et al (1989) Mycobacterial cervical lymphadenitis. Ear Nose Throat J 68:660-672 Shriner KA, Mathisen GE, Goetz MB (1992) Comparison of mycobacterial lymphadenitis among persons infected with human immunodeficiency virus and seronegative controls. Clin Infect Dis 15:601-605 Spyridis P et al (2001) Mycobacterial cervical lymphadenitis in children: clinical and laboratory factors of importance for differential diagnosis. Scand J Infect Dis 33:362-366 ThabetJH, Ali Farzand, Ibrahim BB (1984) Incidence of tuberculous neck masses in the central zone of Saudi Arabia. J R Coli Surg Edinb 29:226-228 Thompson MM, Underwood MJ, Sayers RD et al (1992) Peripheral tuberculous lymphadenopathy. Br J Surg 79:763-764 Wadman SR, Levine HL, Sebek BA et al (1981) Nasal tuberculosis: a forgotten entity. Laryngoscope 91: 11-16 Wong ML, Jafek BW (1974) Cervical mycobacterial disease. Trans Am Acad Ophthalmol Otolaryngol 78:75-87 Zwischenberger JB, Savage C, Alpard SK et al (2002) Mediastinal transthoracic needle and core lymph node biosy. Chest 121:1165-1170

29 Tuberculosis and Co-infection with the Human Immunodeficiency Virus ALIMUDDIN ZUMLA

and

JOHN

M.

GRANGE

CONTENTS 29.1 29.2 29.3 29.4 29.5 29.5.1 29.5.2 29.5.3 29.6 29.7 29.7.1 29.7.2 29.7.3 29.7.4 29.8 29.8.1 29.9. 29.9.1 29.9.2 29.10 29.11

Historical Background 455 Risk Factors for Tuberculosis 456 Tuberculosis and HIV: Epidemiological Considerations 456 The Distribution of the Burden of HIV-Related Tuberculosis 457 Pathology of Tuberculosis in HIV-Infected Individuals 458 Anergic Response 458 Hyporeactive Response 459 Granulomatous Response 459 Immune Interactions in HIV-Positive Patients with Tuberculosis 459 The Clinical Features of HIV-Related Tuberculosis 460 Pulmonary Tuberculosis in HIV-Positive Adults 461 Extrapulmonary Tuberculosis in HIV-Positive Adults 463 Tuberculosis in HIV-Infected Children 464 The Dilemma of Multiple Aetiology of Childhood Respiratory Diseases 465 Diagnosis of Tuberculosis in HIV-Positive Individuals 466 The Sputum Smear in HIV-Positive Persons 467 Treatment of Tuberculosis 468 Drug Regimens for Treatment of Tuberculosis in HIV-Negative Individuals 468 Treatment of Tuberculosis in HIV-Positive Individuals 468 Anti-Retroviral Therapy for Poor Developing Countries 469 Management Considerations in HIV-Positive Individuals 470

A. ZUMLA, BSc, MBChB, MSc, PhD, FRCP (Lon), FRCP (Edin) Professor of Infectious Diseases and International Health, Director, Centre for Infectious Diseases and International Health, Royal Free & University College Medical School, Windeyer Institute of Medical Sciences, Room G41, 46 Cleveland St, London WIP 6DB, UK J. M. GRANGE, MSc, MD (Lon) Visiting Prof, Centre for Infectious Diseases & International Health, Royal Free and University College Medical School, Windeyer Institute of Medical Sciences, 46 Cleveland St, London WIP 6DB,UK

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

29.11.1 29.11.2 29.11.3 29.11.4 29.11.5 29.11.6 29.11.7 29.11.8 29.11.9 29.12 29.12.1 29.12.2 29.12.3 29.12.4 29.12.5 29.13

Barriers to Effective and Appropriate Therapy 471 Immune Reconstitution Syndrome 471 Increased Drug Side Effects 471 Drug Resistance 472 Recurrence After Treatment 472 Post-Treatment Prophylaxis 472 Prophylactic Therapy 473 Malabsorption 474 Adjunctive Treatments 474 Issues Relating to Control of Tuberculosis in HIV-Endemic Areas 474 Quality of Health Care 474 The WHO DOTS Strategy 475 BCG Vaccination and HIV Serostatus 475 Governmental Responses to the Threat Posed by HIV and Tuberculosis 475 National Tuberculosis Control Programmes 476 Conclusions 476 References 476

29.1 Historical Background Owing to increased poverty in an overpopulated world, a lack of attention to tuberculosis services, and the impact of the Human Immunodeficiency Virus (HIV)/Acquired Immune Deficiency Syndrome (AIDS) pandemic, there are more cases of tuberculosis today than at any previous time in human history. Historically, tuberculosis has been among the most feared of all diseases and has been given names such as the "Great White Plague" and "Captain of all of these Men of Death". Most attempts to affect a cure for tuberculosis in the pre-antibiotic era were either harmful, for example blood-letting, or revolting, such as the mixture of pigeon's faeces and weasel's blood advocated by John of Gaddeston (1280-1361) in his Curatio Scrophulorum. The introduction of effective anti-tuberculosis agents in the middle of the 20th century, commencing withthe discoveryofstreptomycinbySelmanWaksman and his colleagues in 1944, opened the door to the potential conquest of this affliction through devel-

456

opment of other potent anti-tuberculosis drugs. Far from being conquered, however, tuberculosis is currently one of the most prevalent infectious causes of human suffering and death. The incidence and prevalence of this disease continues to rise in developing countries while many developed countries have witnessed a reversal of the downward trend that had occurred since the beginning of the 20th century (Report 2001). Among infectious diseases, tuberculosis remains a leading cause of illness and death, particularly in tropical countries. Due to the relentless spread of tuberculosis and HIV throughout the world, in 1993 the World Health Organization (WHO) took the unprecedented step of declaring tuberculosis and HIV I AIDS global emergencies (World Health Organization 1994).

29.2 Risk Factors for Tuberculosis The principal factors thought to predispose one to tuberculosis are listed in Table 29.1. In the past two decades, HIV infection has emerged as the most important and widespread risk factor for progress from latent tuberculosis infection to active tuberculosis and rapid progression to active diseases after infection or re-infection by Mycobacterium tuberculosis. Infections such as measles, whooping cough and chronic malaria and causes of lung damage, particularly smoking and exposure to silicon and other industrial dusts, are also risk factors. Other predisposing conditions are those that compromise the immune response and include malnutrition, stress, alcoholism, diabetes, renal failure, treatment with immunosuppressive drugs and steroids, liver failure and cancers, especially haematological malignancies. Transmission of infection is further facilitated by overcrowding, poor ventilation and low levels of ultra-violet light-conditions frequently linked to poverty.

29.3 Tuberculosis and HIV: Epidemiological Considerations Infection with HIV is the greatest risk factor for reactivation of tuberculosis among those who are dually infected with Mycobacterium tuberculosis and HIV (Chretien 1990). While a non-immunocompromised

A. Zumla and

J. M. Grange

Table 29.1 Susceptibility factors for developing tuberculosis Age

Race

Immunological

Extremes of age - Less than 5 years of age - Elderly 5-15 years less likely Asians African North American Indians Immunosuppression - HIV/AIDS - Steroids - Cytotoxic drugs - Congenital immunodeficiencies - Protein-energy malnutrition

Chronic medical conditions - Diabetes mellitus - Chronic liver or renal disease - Malignancies - Damaged lungs (e.g. silicosis) Congenital immunodeficiency states Chromosomal associations - HLA-DQ allele - NRAMP 1 gene Stress Endocrine factors BCG or exposure to environmental Previous exposure to mycobacteria mycobacteria may offer some protection Mycobacterial factors Virulence and ?strain differences Dose of organism

person who has overcome primary infection with Mycobacterium tuberculosis has about a 5% chance of developing post-primary tuberculosis later in life, the chance rises to 50% in an HIV-positive person. The annual risk of a person co-infected with the tubercle bacillus and HIV developing tuberculosis is around 8%-over 20 times higher than in an HIVnegative person. The chance of an HIV-positive person developing tuberculosis following either primary infection or reinfection is very high, especially in those with AIDS. In addition, the progression from infection to overt disease can be very rapid, the time scale being "telescoped" from several years to a few months. These factors have led to a number of miniepidemics of tuberculosis in centres caring for AIDS patients. In the year 2001, there were an estimated 35 million HIV-positive persons worldwide. As one third of these were co-infected with tubercle bacilli and therefore had an 8% chance of developing overt tuberculosis annually, an additional million cases of this disease would have occurred in that year as a result of HIV infection. Tuberculosis is a common cause of death in those with AIDS and accounted for 30% of the estimated 3 million AIDS-related deaths in 2000 (Report 2001). The global incidence rates of

457

Tuberculosis and Co-infection with the Human Immunodeficiency Virus

HIV-positive tuberculosis cases as estimated by the WHO are shown in Fig. 29.1. The impact of the HIV epidemic on the incidence of tuberculosis is most evident in sub-Saharan Africa where, for the 10-year period 1990-1999,3.9 million (almost a quarter) of the expected 15 million incident cases of tuberculosis were attributable to HIV infection. It has been forecasted that the number of new cases of tuberculosis per year in this region will double by the end of the decade (Cantwell and Binkin 1997). The strongest association between HIV and tuberculosis has been recorded in sub-Saharan Africa (Cantwell and Binkin 1997). HIV-seropositivity rates among adults and children with tuberculosis range from 20-70%, and there are some countries such as Malawi and Zambia where HIV-seroprevalence rates are consistently above 50%. In Zambia and Cote d'Ivoire, HIV-seroprevalence rates in children aged 1 month to 14 years with tuberculosis are between 10-40%, with the highest overall age-specific HIVseroprevalence being found in children aged 1-4 years (Luo et al. 1994; Lucas et al. 1996a). In Zambia, one in four pregnant women are infected with HIV (Fylkesnes et al. 1997). Furthermore, tuberculosis is now among the top non-obstetric causes of maternal death in that country (Ahmed et al. 1999). Two thirds of Zambian children and adults with tuberculosis are co-infected with HIV (Luo et al. 1994; Chintu and Zumla 1997; Elliott et al. 1990). Tragically, HIV infection is spreading rapidly in the Indian subcontinent, in China and in South East Asia where, owing to the huge population, most of the world's cases of tuberculosis

occur. Molecular studies from the USA have shown that, in almost two thirds of HIV-infected persons, tuberculosis is due to recent infection rather than reactivation of latent infection. Similarly, recent work from sub-Saharan Africa has shown that a significant number of new cases of tuberculosis, and recurrent cases of tuberculosis, also result from recent transmission (Sonnenberg et al. 2001). Meta-analysis of several studies of health care workers who had contact with tuberculosis patients suggest that patients with tuberculosis co-infected with HIV are not more intrinsically more infectious than are HIV-l negative tuberculosis patients (Cruciani et al. 2001).

29.4 The Distribution of the Burden of HIV-Related Tuberculosis The burden of HIV-related tuberculosis is not evenly distributed, as it is determined not only by the overall prevalence of infection by the tubercle bacillus and HIV in the community, but by the social factors that encourage dual infection (Msamanga and Fawzi 1997). In the USA, HIV-related tuberculosis is largely restricted to socio-economically disadvantaged communities in New York City and other large cities (Friedman et al. 1996; Coker 1998). It was the occurrence of mini-epidemics of HIV-associated tuberculosis in New York City in the early 1990s, and the threat to the health of the general population that led to an upsurge of interest and concern for

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,llIIII 11_ (per 1._) Fig. 29.1. Estimated incidence rates of Human Immunodeficiency Viruspositive tuberculosis. (Data for 1999 obtained from the World Health Organization Global Tuberculosis Report 2001)

0<0.1

0

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0.1-0.9 1.0-9.9

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100-249

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A. Zumla and J. M. Grange

458

this condition. In the United Kingdom (UK), HIVrelated tuberculosis is relatively uncommon and is principally restricted to populations who have immigrated from HIV-endemic areas (Rose et al. 2001). Most cases of tuberculosis in the UK occur in the more elderly of the majority white population and in immigrants from countries where HIV infection is, so far, uncommon (Watson et al. 1993; Yates et al. 1993). The situation is, however, changing as HIV infection is spreading to other regions endemic for tuberculosis and from which immigrants come to the UK. Thus tuberculosis clinics are now being encouraged to increase the use of HIV testing (Coker and Miller 1997). From the global perspective, the region most affected by the dual epidemic of tuberculosis and HIV as of 2001 is sub-Saharan Africa (Report 2001)' although Asia and China and Eastern Europe are also being increasingly affected. The more southerly African countries, including Kenya, Tanzania, Zimbabwe, Zambia, Malawi, South Africa and Botswana, are particularly affected, with around one in five adults being infected with HIV (UNAIDS 1998). In these countries, HIV is principally transmitted heterosexually, and women are particularly at risk. In Zambia at least one in four pregnant women are HIV positive (Fylkesnes et al. 1997) and around 50% are also infected with the tubercle bacillus, so that one in eight are therefore co-infected. An example of the societal effect of HIV-related tuberculosis in some African countries is provided by the substantial adverse effect on the health of hospital staff and on children. In one South African hospital, the number of cases of tuberculosis among its staff rose from two in the period 1991-1992 to 20 in 1993-1996, and 12 of the 14 who were tested for HIV infection were positive (Wilkinson and Gilks 1998). An increasing number of cases of tuberculosis in African children are HIV related. In Zambia, the HIV seroprevalence rate among children admitted to hospital with tuberculosis rose from 18% to 67% over an 8-year period up to 1995 while, over the same period, the HIVseroprevalence rate remained at a constant 10% in children admitted for surgical conditions (Luo et al. 1994; Zumla and Chintu 1995).

29.5 Pathology of Tuberculosis in HIV-Infected Individuals An autopsy study from the Ivory Coast, West Africa, showed that 38% of all HIV-positive cadavers and

43-54% of those dying with AIDS-defining pathology had active tuberculosis (Lucas and Nelson 1994). At autopsy, HIV-positive patients with tuberculosis showed fibrous and calcified lesions of tuberculosis adjacent to recent active lesions containing acid-fast bacilli. These new lesions may be due to reactivation of primary complex lesions or may also be due to re-infection. Relapse has been observed with different genotypes of Mycobacterium tuberculosis. The suggested mechanism of reactivation or increase in susceptibility to mycobacterial infections in those infected with HIV is the depletion of CD4+ lymphocytes and macrophages, although tuberculosis has been seen in patients across a range of CD4 counts. Quantitative and qualitative defects in the CD4+ cells lead to impaired granuloma formation (Zumla and James 1999). In patients infected with HIV, the progressive decline in the number of CD4+ cells provides a suitable model for the study of the interaction between the mononuclear cells and formation of epithelioid granulomas. In nonHIV-infected patients with tuberculosis without any obvious evidence of immunodeficiency, granuloma formation and progression of human monocytes through stages of differentiation are well characterised and are typical of cell-mediated immune responses found in other granulomatous disorders. The monocyte differentiates through young macrophages, to mature macrophages, to epithelioid cells and finally to giant cells of the Langhans type. In HIV-infected patients, a range of histological features is seen. Those individuals with well-preserved CD4+ lymphocyte counts often show well-formed epithelioid granuloma formation while poor epithelioid cell formation and "sick" macrophages are seen in patients with more severe forms of immunodeficiency. A wide spectrum of histopathological changes are seen in HIV-infected patients with tuberculosis. However, there are three identifiable histologic stages of cellular immune responses, which may also correlate well with the stage of HIV infection (Zumla et aI.1999).

29.5.1 Anergic Response In the late stages ofAIDS, disseminated anergic tuberculosis is seen at autopsy. While no relative decrease in number of macrophages in the tuberculous lesion is seen, there is decreased intensity of staining with KP-l (CD68). Epithelioid macrophages are scanty,

Tuberculosis and Co-infection with the Human Immunodeficiency Virus

459

Langhans giant cells are absent, and granuloma formation is absent (Fig. 29.2). There are few CD4+ T cells in the lesion. Caseous necrosis is replaced by suppuration, coagulative necrosis and large amounts of apoptotic debris. Large numbers of mycobacteria are present within macrophages and in the necrotic areas (Fig. 29.3).

29.5.2 Hyporeactive Response With progressive immunosuppression and decline of CD4+ T cell counts, loss of Langhans giant cells and subsequently, epithelioid macrophages occur. The proportion of macrophages with abundant cytoplasm is also decreased. Poor intracellular killing of mycobacteria occurs and thus the number of mycobacteria in the lesions also increases. The caseous centres enlarge centrifugally and lesions coalesce. Necrosis is mixed suppurative and caseous.

Fig. 29.2. Histology of tuberculosis lesion in an immunosuppressed patient with low CD4+ lymphocyte counts. Epithelioid macrophages are scanty, Langhans giant cells are absent, and granuloma formation is absent. There are few CD4+ T cells in the lesion. Caseous necrosis is replaced by suppuration, coagulative necrosis and much apoptotic debris

29.5.3 Granulomatous Response These patients have a relatively intact cellular immune response and have a typical granulomatous response (Fig. 29.4). Epithelioid macrophages and Langhans giant cells are abundant and the numbers of mycobacteria in the lesions are low (Nambuya et al. 1988). Clusters of CD4+ T cells around epithelioid macrophages are seen and Langhans giant cells are present. The majority of macrophages have abundant cytoplasm and stain intensely with KP-1 (CD68) macrophage markers.

Fig. 29.3. Histology of tuberculosis lesion in an immunosuppressed patient with very low CD4+ lymphocyte counts. Large numbers of mycobacteria are present within macrophages and in the necrotic areas

29.6

Immune Interactions in HIV-Positive Patients with Tuberculosis

It is recognised that HIV infection increases the risk

of tuberculosis and adversely affects the clinical course of the disease (Bocchino et al. 2000). Conversely, there is evidence that co-infection with Mycobacterium tuberculosis accelerates progression of HIV infection towards AIDS (Whalen et al. 1995). Mycobacterium tuberculosis and HIV are both virulent intracellular pathogens that enter and replicate within macrophages that serve as their reservoirs. It is now accepted that tuberculosis enhances local HIV-1

Fig. 29.4. Histology of tuberculosis lesion in a Human Immunodeficiency Virus-infected patient with well-preserved CD4+ lymphocyte counts. Well-formed granuloma with epithelioid macrophages and Langhans giant cells

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replication in vivo, although the exact mechanisms operating are not known. Cytokines produced during infection with Mycobacterium tuberculosis may result in activation of latently HIV-infected cells with virus expression and induction of virus replication (Zhang et al. 1995). Other studies have demonstrated marked increases in plasma HIV-1 viral load in tuberculosis (Goletti et al. 1996). Increased IL-2, IL-6 and tumour necrosis factor generated by infection with Mycobacterium tuberculosis may be responsible for these increases in HIV viral load (Bellamy et al. 1998). The concept that a Th-l type response without antibody correlates with protection from HIV disease has been clouded by a dispute about whether a progressive shift from Th-l towards Th-2 type response can be shown to accompany AIDS or tuberculosis. In neither early AIDS nor tuberculosis is the Th-l response lost, but there is a superimposed Th-2 component that is clearly inappropriate. HIV-exposed people who resist progressive infection appear to have no detectable antibody, whereas sero-positivity and peripheral blood lymphocytes expressing IL-4 are associated with an inexorable progression towards death. In tuberculosis, the inappropriate Th-2 response leads to formation of IgE antibody, high levels of IgG antibody and peripheral blood lymphocytes that express IL-4 (Schauf et al. 1993). Thus their Th-l response may be maintained, but there is a Th-2 type response superimposed upon it. In fact, in a mouse model, this mixed Th-l and Th-2 responsiveness leads to a cytokine-mediated tissue damage (Clerici and Shearer 1994). Thus the basic immunity required for both diseases is quite similar and a vaccine that promotes a Th-l response will theoretically reduce the burden of both diseases. Mycobacterium tuberculosis has been shown to augment chemokine receptor expression (CCR5) on macrophage membranes and induce apoptosis of a portion of infected macrophages (Sanduzzi et al. 2001).

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conditions suggestive of HIV infection or AIDS have appeared. The nature, presentation and the clinical and radiological features of tuberculosis depend on the degree of immunosuppression. In those with relatively good immunity, CD4+ lymphocyte counts and a low viral load, the manifestations and presenting symptoms of tuberculosis are essentially similar to those in HIV-negative persons. Approximately 70% of cases ofHIV-related tuberculosis are pulmonary and 30% are extrapulmonary. If tuberculosis occurs in the early stages of HIV infection, when immunity is only partly compromised or is intact, the clinical features are indistinguishable from those of post-primary tuberculosis in HIV-negative individuals. Thus tuberculosis is usually localised to the apices of the lungs; there is lung destruction and cavitation (Fig. 29.5) and light microscopy of ZiehlNeelsen stained sputum smears shows abundant acid-fast bacilli. HIV-positive patients with more advanced immunodeficiency present with atypical pulmonary disease, sometimes resembling primary pulmonary tuberculosis and extrapulmonary, including disseminated, forms of the disease. As the immunocompetence decreases, there is an increasing incidence of atypical forms of tuberculosis, and diagnostic difficulties are posed by the rather non-specific presenting features that may be confused with those of other HIV-related infections (Whalen et al. 1995; Chaisson et al. 1987; Festenstein and Grange 1993; Huebner and Castro 1995). The atypical picture is characterised by extensive pulmonary infiltrates with no cavities (Figs. 29.6, 29.7), involvement of the lower lobes of the lung (Fig. 29.8), enlargement of the mediastinal lymph glands (Table 29.2) and sputum smears that show no acid-fast bacilli.

29.7 The Clinical Features of HIV-Related Tuberculosis Pulmonary tuberculosis can occur in patients with a wide spectrum of immunodeficiency and is not entirely dependent on the degree of depletion of CD4+ lymphocytes; thus tuberculosis may develop at any stage of HIV infection (Harries 1998). Though classified as an AIDS-defining condition (Centers for Disease Control 1993), tuberculosis may develop early in the course of HIV infection, often before other

Fig. 29.5. Chest X-ray of an Human Immunodeficiency Virus -infected patient showing apical cavities. Mycobacterium tuberculosis was isolated from the patient's sputum

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Tuberculosis and Co-infection with the Human Immunodeficiency Virus

Fig. 29.6. Chest X-ray shows extensive infiltration of both lung fields in an Human Immunodeficiency Virus-positive patient with tuberculosis

Fig.29.8. Chest X-ray of a Human Immunodeficiency Viruspositive patient with tuberculosis showing a cavitating lesion in the left lower zone Table 29.2. Clinical features of tuberculosis in Human Immunodeficiency Virus-infected patients HIVHIVpositive negative Respiratory symptoms Extrapulmonary disease Sputum smear positivity (AAFB) False-negative tuberculin skin tests Atypical features on chest X-rays Cavitating lung lesions Adverse drug reactions Mortality rate Relapse rate following course of treatment

Fig. 29.7. Extensive shadowing throughout the right lung fields. Mycobacterium tuberculosis was isolated from patient's sputum

29.7.1 Pulmonary Tuberculosis in HIV-Positive Adults

The proportion of patients with smear-negative pulmonary tuberculosis is greater in those who are HIV positive than in those who are HIV negative (Harries 1998) (Table 29.2). The diagnosis of tuberculosis in a HIV-positive patient with a chronic cough, night sweats, weight loss but negative sputum smears for

+++ +++ + ++ +++ + ++ +++ ++

+++ + ++ ± ±

+++ ± ± ±

acid-fast bacilli is a diagnostic challenge for the clinician (Harries and Maher 1996). In studies in HIV-positive African patients with respiratory illness and negative sputum smears, specimens yielding Mycobacterium tuberculosis were obtained by use of bronchoscopy with broncho-alveolar lavage or induction of sputum in about a third of patients (Harries et al. 1997). HIV-infected patients may also have other concomitant infections such as Pneumocystis carinii pneumonia (PCP), bacterial pneumonia due to a wide range of pathogens, Kaposi's sarcoma, nocardiosis and fungal infections. Even where facilities exist for more extensive investigations, such as bronchoscopy with broncho-alveolar lavage and biopsy, sputum culture and

462

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nucleic acid-based methods, the identification of the

Mycobacterium tuberculosis may be difficult. In most developing country health centres, the diagnosis of pulmonary tuberculosis is based on simple techniques only: sputum smear microscopy and, when available, chest radiography. Radiological findings in HIV-related pulmonary tuberculosis in many resemble those of typical pulmonary tuberculosis, but atypical appearances are common, notably as immune function declines. These include vague, spreading opacities suggestive of pneumonia, predominantly lower lobe disease, pleural effusions, air-fluid levels and intrathoracic lymphadenopathy. Studies from HIV-positive tuberculosis patients in the Tropics have confirmed the different pattern of chest X-ray changes that occur (Harries 1998; Harries et al. 1997; TshibwabwaTumba et al. 1997; Batungwanayo et al. 1992; Pozniac et al. 1992; Saks and Posner 1992; Awil et al. 1997) (Table 29.3). These studies have drawn attention to the fact that HIV-related tuberculosis presents with atypical radiological changes that are more dramatic Table 29.3. Chest X-ray patterns in tuberculosis Human Immunodeficiency Virus-positive versus Human Immunodeficiency Virus-negative HIV Authors and (country) Radiographic pattern HIV +ve (0/0) -ve (0/0) Saks and Posner (1992) (South Africa)

Batungwanayo et aI. (1992) (Rwanda)

Pozniak et aI. (1995) (Zimbabwe) Awil et aI. (1997) (Uganda)

Tshibwabwa-Tumba et aI. (1997) (Zaire and Zambia)

Mediastinal and/or hilar adenopathy Pleural effusion Miliary disease Cavitation Atelectasis Mediastinal and/or hilar adenopathy Pleural effusion Upper lobe infiltrate Cavitation Miliary disease Mediastinal and/or hilar adenopathy Pleural effusion Upper lobe infiltrate Cavitation Mediastinal and/or hilar adenopathy Pleural effusion Pneumonic infiltrate Cavitation Miliary disease Mediastinal and/or hilar adenopathy Pleural effusion Miliary disease Cavitation Atelectasis

50

8

38 8 38 31 30

20 0 82 82 0

43 16 39 25 31

9 55 91 9 16

26 43 40 26 23 46 18 7 26 16 10 33

12

13

67 64

6 11

26 57 0 13

7 5 78 24

J. M. Grange

in some cases than in others. Patients with HIV are more likely to exhibit the radiographic features of primary tuberculosis. These manifestations are mediastinal and hilar lymphadenopathy, pleural effusions, middle and lower lung infiltrates and miliary dissemination, with cavitation being uncommon. (The typical radiographic appearances in HIV-negative individuals with post-primary tuberculosis are cavitation, calcification and upper lobe fibrotic changes.) As these HIV-positive patients behave as ,immuno-naive' individuals they therefore develop a "childhood" pattern of tuberculosis. Alarge chest X-ray study of 963 HIV-infected adult Zairian and Zambian adults showed a significantly increased incidence of lymphadenopathy, pleural effusions, parenchymal changes, consolidation and miliary disease, but significantly less cavitary disease and atelectasis (Tshibwabwa-Tumba et al.I997). Similar trends were observed in a comparative radiological study of 61 HIV-positive and 50 HIV-negative South African tuberculosis patients (Saks and Posner 1992). Chest radiographs of the HIV-seropositive group showed a significantly higher percentage of hilar lymphadenopathy (50% vs 8%), pleural effusions (38% vs 20%), and miliary lesions (8% vs 0%) and interstitial changes (11% vs 4%). Cavitation (38% vs 82%) and atelectasis (31% vs 82%) were less common in the HIV-seropositive group than in the seronegative group. Lymphadenopathy on chest Xray in previous studies has been reported in between 25-50% of HIV-infected adults with tuberculosis (Saks and Posner 1992). Classical miliary lesions are seen in a minority of HIV-positive patients with disseminated disease, but in most cases the formation of the characteristic miliary granuloma is suppressed and the X-rays may appear deceptively normal. Further details on the clinical aspects of HIV-related tuberculosis are available from WHO (1996). The available data to date suggest that the atypical changes seen on chest X-rays of many HIV-infected patients with tuberculosis are uniform across countries in sub-Saharan Africa (Table 29.3). However, a wide range of chest X-ray features is seen in both HIV-infected and HIV-non-infected individuals. Approximately one-third of HIV-infected patients show classical chest X-ray findings of tuberculosis. The ability to form cavities or fibrotic changes do not, as was once thought, appear to be related to the CD4 counts. The reasons why some HIV-infected individuals develop atypical radiological changes of tuberculosis while others continue to show classic chest X-ray features of tuberculosis are not clear. These differences have implications for the radiologist,

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especially in developing countries where accurate diagnosis of pulmonary infectious disease is often not possible. The atypical chest X-ray appearances of tuberculosis in a large proportion of HIV-infected adults makes it imperative to keep this disease a prime diagnostic consideration in HIV-infected individuals with pulmonary lesions.

29.7.2 Extrapulmonary Tuberculosis in HIV-Positive Adults Manifestations of extra-pulmonary tuberculosis are frequently seen in HIV-infected persons in sub-Saharan Africa. The most common of these manifestations are: (a) asymmetrical lymphadenopathy (Fig. 29.9), (b) pericarditis, (c) pleurisy (Fig.29.l0), (d) bone and skin lesions and (e) miliary disease (Nambuya et al. 1988; Harries 1998; Harries et al. 1997; Gilks et al. 1990). Patients usually present with non-specific constitutional symptoms (fever, night sweats and weight loss) and local symptoms and signs related to the site of disease. These atypical forms are often the result of a rapid progression of clinical disease following infection and in a high proportion of cases, multi-site and widely disseminated tuberculosis is seen. For reasons that are not clear, involvement of the central nervous and genitourinary systems is, relative to the industrialised countries, uncommon in Africa (Harries et al. 1998). This probably reflects

Fig.29.9. Asymmetrical cervical and superclavicular lymphadenopathy due to Mycobacterium tuberculosis in an Human Immunodeficiency Virus-positive adult

Fig. 29.10. Chest X-ray showing pleural and pericardial effusion in a 44-year-old Human Immunodeficiency Virus-positive patient

patient selection and differences in the availability of diagnostic facilities, while strain differences in the infecting organism is an as yet unproven possibility. More generalised dissemination of disease may result in numerous minute lesions throughout the body. This condition, termed "cryptogenic disseminated tuberculosis", may be very difficult to diagnose during life. Many unsuspected cases are therefore diagnosed at autopsy and pose serious risks to the pathologist. Tuberculin tests may be negative, particularly in the more severely immunosuppressed, although the extent of induration is not closely related to the CD4+ lymphocyte count and is thus an independent marker of immune competence (Diagbouga et al. 1998). Blood cultures are positive in between one third and one half of patients with disseminated HIV-related tuberculosis (Schaefer et al. 1989; di Lonardo et al. 1995). A high proportion of African patients with AIDS develop severe wasting, a condition known locally as "slim disease" (Fig.29.11). Many such patients have chronic diarrhoea, and the condition was thus thought to be due to enteropathy. However, in one study in Africa, almost half the AIDS patients died with "slim disease" and almost half of these were found to have disseminated tuberculosis on autopsy, compared to just over a quarter of those dying without such wasting (Lucas et al. 1994). There was no association between the occurrence of chronic diarrhoea and tuberculosis.

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Fig.29.11. "Slim disease" (wasting due to Human Immunodeficiency Virus disease)

Lymphadenopathy is a frequent manifestation of tuberculosis in HIV-infected individuals and may present in a variety of ways (Bem 1997; Bem et al. 1993). While usually chronic and cryptic, it may also occasionally be acute and resemble an acute pyogenic infection. Diagnosis of lymph node tuberculosis may be made by use of simple techniques such as needle aspiration and staining with Ziehl Neelsen stain; naked eye inspection of biopsied lymph nodes for macroscopic caseation; and direct smears for acid fast bacilli from the cut surface of a lymph node (Bem 1996). HIV-infected individuals with meningitis due to Mycobacterium tuberculosis may be normal or nearnormal on examination of their cerebrospinal fluid, and can easily be confused diagnostically with cryptococcal meningitis (a common presenting condition in HIV infection; Mwaba et al. 2001) making the diagnosis very difficult. Sometimes empirical treatment has to be started on clinical suspicion alone.

29.7.3 Tuberculosis in HIV-Infected Children Accurate figures for burden of tuberculosis in HIVinfected children are not readily obtainable (Donald 2000). This is due to the difficulty of accurately diagnosing childhood tuberculosis, inadequate health information systems in developing countries and the lack of importance accorded to childhood tuberculosis by disease control authorities. Although

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the relationship between HIV/AIDS and tuberculosis in adults is well understood, a clear picture of the relationship between HIV/AIDS and childhood tuberculosis has yet to emerge. One of the principal problems faced in paediatric tuberculosis is the difficulty in making an accurate diagnosis. It is generally recognised that, due to the overlap in symptoms and signs of several common respiratory illnesses, misdiagnosis is common, especially in HIV-infected children where opportunistic infections such as PCP may mimic tuberculosis. The diagnosis of this disease in children is conventionally based on a combination of clinical and laboratory criteria. The chance of seeing acid-fast bacilli in sputum and gastric fluid aspirates is low and such specimens often cannot be readily obtained from children. Even in countries where advanced diagnostic facilities are available, the diagnosis can only be confirmed by culture in about 50% of cases. Several of the signs and symptoms used as clinical criteria for the diagnosis of childhood tuberculosis (such as prolonged cough, weight loss, failure to gain weight) are common features of other pulmonary illnesses that are consequences of HIVinduced immunosuppression. Radiographic changes may be misleading and the distinction between PCP and tuberculosis is often difficult, especially in developing countries where advanced facilities for the diagnosis of PCP are not available. Tuberculin tests may be falsely negative and sometimes uninterpretable in HIV-positive cases. Against this background, it is apparent that some children who do not have tuberculosis will satisfy the clinical criteria for the diagnosis of this disease and will receive a full course of anti-tuberculosis therapy. Conversely, the diagnosis may be missed by the current clinical criteria in others who have tuberculosis but present with atypical signs and symptoms, and these will not receive appropriate treatment. The clinical and laboratory criteria for the diagnosis of paediatric tuberculosis require re-evaluation. The co-existence of tuberculosis with other fatal diseases may confuse the clinical picture. Several studies have shown that tuberculosis and HIV are having an impact on childhood morbidity and mortality (Chintu and Zumla 1997; Chintu et al. 1993, 1995; Donald et al.1995; Donald 2002). Previous beliefs that tuberculosis in children below the age of 2 years did not occur because of duration of exposure (Lucas et al. 1996a,b) is not borne out by a large autopsy study of Zambian children dying of respiratory diseases. The results of autopsy study shows that tuberculosis in children can occur at any age, irrespective of HIV status (Chintu et al. 2002).

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The clinical differences in the presentation of disease between HIV-positive and HIV-negative children

updated and should include specific guidelines on the management of the HIV-positive child.

admissions are for pulmonary diseases. Distinguishing tuberculosis from the other causes is never easy and is usually based on clinical features, tuberculin testing and a history of exposure to a source case. Laboratory investigations are often unhelpful as lesions are usually closed and sputum, even when it can be obtained, is almost always negative for acid-fast bacilli on microscopy. As mentioned above, even when the most advanced diagnostic facilities are available, the diagnosis can only be confirmed by culture in about half the cases (Starke and Taylor-Watts 1989). Positive cultures may be obtained from unusual sites: in a study in South Africa 6 of 14 HIV-infected children with culture-positive tuberculosis had otorrhoea, and ear swabs were the source of the positive cultures in three such cases (Schaaf et al. 1998). As a result of the diagnostic difficulties experienced in HIV-positive children, and the frequent misdiagnosis, it is difficult to assess the magnitude of the problem of HIV-related tuberculosis in children (Chintu et al. 1993, 1995, 2002; Donald et al. 1995; Donald 2002; Lucas et al. 1996b; Starke and TaylorWatts 1989; Schaaf et al. 1998; Starke 1993; Coovadia 1991).An idea of the true risk of tuberculosis in these children may be obtained from autopsy studies. One such study in West Africa suggested a low risk (Lucas et al. 1996a), but autopsies performed on HIV-positive children in Bulawayo, Zimbabwe (Ikeogu et al. 1997), established a diagnosis of tuberculosis in 6 of 122 children (5%), and more recently a large autopsy study of children dying of respiratory illnesses in Zambia has shown that 20% of these children have tuberculosis across a wide range of age groups and HIV status.

services exist. The presence of multiple diseases makes management even more complicated and expensive and may be responsible for estimates that up to three quarters of children with HIV-infection in Africa will die by the age of 5 years (Taha et al. 2000; Pillay et al. 2001). Even when treatment of PCP is optimal, the outcome in children is poor. The only way forward, therefore, is to institute preventive measures (Abrams et al. 2001). The recommended antibiotic, co-trimoxazole, may prevent both PCP and bacterial bronchopneumonia. There are high HIV prevalence and vertical transmission rates in sub-Saharan Africa and the probability of death occurring by 12 months in sub-Saharan Africa ranges from 0.23 to 0.35 and by 5 years is 0.57-0.68. In many developing countries, health care facilities are inadequate and expert care is unavailable. Studies in Malawi, Zimbabwe and South Africa have illustrated the difficulties associated with the early diagnosis, treatment and management of children with respiratory illnesses. Several diagnostic, therapeutic and epidemiologic dilemmas are created by the inadequacy of the current clinical criteria for the specific diagnosis of respiratory infections in children (Vetter et al.1996; Zar et al. 2001). In a setting of poor funding and staffing resources, it is very difficult to determine the precise cause of lung disease in children, owing to the overlap in clinical features of common opportunistic and non-opportunistic lung infections, including tuberculosis. This emphasises the importance of preparing national guidelines for the deployment of available resources and of developing practical diagnostic, therapeutic and prophylactic protocols in resource-poor African countries. The early diagnosis, treatment and prevention of respiratory diseases in children requires a concerted effort on the part of governments and clinicians to develop newer guidelines that will take into account the changing epidemiology of paediatric lung disease in light of the HIV-epidemic. The UNAIDS (2000b) recommendations of co-trimoxazole prophylaxis for adults and children have recently come under Widespread criticism, and several issues need to be addressed before these recommendations are put into practice. Widespread prescription of prophylactic antibiotics to prevent PCP and pyogenic pneumonias has to be carefully weighed against resources available, dangers of emergence of antibiotic resistance and the persistent dilemma of investment of scarce resources in a group of patients whose long term

The accurate diagnosis of respiratory infection in are not as striking as in adults. In Africa, a large proportion of paediatric clinic attendances and hospital children is difficult, even where appropriate health

29.7.4 The Dilemma of Multiple Aetiology of Childhood Respiratory Diseases The great overlap that exists between the clinical presentation of several respiratory infections and the occurrence of multiple pathology in children who succumb to respiratory illnesses indicates that efforts should be focused on tightening the current management guidelines for respiratory infections. Current WHO recommendations on the prevention, early detection and treatment of respiratory infections in children in developing countries need to be

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prognosis under prevailing health services conditions is poor. Furthermore, identification of HIV-positive children is difficult without formal testing. Widespread consultation based on available scientific evidence leading to development of recommendations for the management of respiratory infection in both HIV-positive and HIV-negative children is urgently needed and long overdue. Knowledge of the spectrum of respiratory illnesses is important for the development of prevention, diagnosis and treatment guidelines for all levels of care in HIV-negative and HIV-positive children.

29.8 Diagnosis of Tuberculosis in HIV-Positive Individuals Co-infection with HIV in patients with tuberculosis leads to an increase in the number of cases that are difficult to diagnose because of atypical presentations of pulmonary disease, extrapulmonary disease and increase in the number of sputum-smear negative cases. In many African countries, the time between onset of symptoms and diagnosis of smear-positive pulmonary tuberculosis is about 3-4 months. Even longer delays may be found in patients diagnosed with smear-negative pulmonary tuberculosis, probably because of the lack of radiographic facilities. Delay in the diagnosis and treatment of tuberculosis compromises the chances of a cure in HIV-positive patients by allowing the disease to advance unchecked and by accelerating the decline in immunocompetence. The diagnosis of smear-negative pulmonary tuberculosis and extrapulmonary tuberculosis in resource-poor countries is fraught with difficulty because of a shortage of trained health personnel, poor diagnostic facilities and lack of appropriate and specific diagnostic guidelines. The standard diagnostic tests are used for the diagnosis of tuberculosis in HIV-positive individuals. These include: a. Microscopy b. Culture c. Serology d. Molecular methods e. Chest X-rays f. Tuberculin skin testing Microscopy: Clinical specimens that are examined by light microscopy for acid-fast bacilli after ZiehlNeelsen staining are: (a) sputum, (b) bronchoalveolar lavage, (c) gastric washings, (d) cerebrospinal fluid,

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(e) pleural aspirates, (£) lymph node aspirates, (g) bone marrow and (h) tissue biopsies. Ideally, three sputum specimens collected on successive days should be examined. In children, this may not be possible and gastric aspirates may be useful. Laryngeal swabs are less sensitive than sputum or gastric washings and swabbing is distressful for the child. Differentiation of species is not possible on examination using light microscopy.

Culture: Isolation of Mycobacterium tuberculosis in culture from the clinical specimen provides a definitive diagnosis. Commonly used media are Lowenstein-Jensen (L]) or Kirshner broth containing a mixture of antibiotics to prevent overgrowth of other bacteria and fungi. Other methods such as BACTEC 460 radiometric system and Roche MB check system rely on the growth of bacilli in a Middlebrook broth. The BACTEC system incorporates a Cl4 -labelled substrate and, during metabolism, Cl4 -labelled carbon dioxide is produced and is monitored by the machine. Problems of the disposal of radioactive waste limit the use of this system and more modern automated systems are based on the changing colour of dyes and the unquenching of fluorescent compounds induced, respectively, by the production of CO 2 and the consumption of oxygen. In these systems, mycobacterial growth is detected about 9 days earlier than on LJ slopes. Serological Tests: Despite several descriptions of ELISA tests for tuberculosis, no universally applicable test with acceptable sensitivity and specificity exists. ELISPOT assays have shown promise under controlled situations (Lalavani et al. 200 I) although their usefulness in the field requires study. With the introduction of microarray technology and the identification of newer mycobacterial antigens, there has been renewed interest in development of serological diagnosis. Molecular Methods: Though the gold standard for identification of Mycobacterium tuberculosis is still culture, this is laborious in terms of time and demanding on laboratory space. Newer techniques, predominately molecular, have therefore been developed. The most validated of these have involved the amplification of mycobacterial DNA (or occasionally RNA) by the polymerase chain reaction (PCR) or more recently the ligase chain reaction. These are proving rapid, sensitive and specific in most circumstances; with sensitivities approaching 100% and specificities from 85% in non-pulmonary samples to 95% for sputum

Tuberculosis and Co-infection with the Human Immunodeficiency Virus (Borun et al. 2001; Lindbrathen et al. 1997) and several

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therefore the method used to detect patients who are

systems are now available commercially in kit form. likely to benefit from preventive therapy. The technique also allows the species of mycobacteria to be identified rapidly and accurately (Kox et al. 1997) and the early identification of drug resistance may be achieved by identifying specific resistance-associated genetic loci (Goyal et al.1997). It may also be possible to monitor some therapies with PCR to predict relapse (Sonnenberg et al. 2001). Unfortunately, the sensitivity of these methods is decreased in samples that are negative on microscopy mycobacteria, probably due to inhibiting substances present in the clinical specimens. In addition, problems with contamination and cost are preventing implementation in those areas of the world where tuberculosis is most prominent.

DNA Fingerprinting: Molecular techniques can differentiate between isolates of Mycobacterium tuberculosis. This methodology is becoming useful in differentiating between reactivation and reinfection (Sonnenberg et al. 2001), tracing the source of nosocomial and community outbreaks of the disease, defining the molecular epidemiology of the disease and studying outbreaks of multi-drug resistant tuberculosis. Chest X-Ray: The chest X-ray is sensitive but nonspecific. It is therefore valuable in detecting pulmonary lesions but does not confirm the diagnosis of tuberculosis. As described earlier, a range of chestX-ray changes are seen in HIV-infected individuals with tuberculosis and classical changes due to tuberculosis may not be present.

Tuberculin Skin Testing: Tuberculin skin testing using purified protein derivative is widely performed in industrialised countries as an aid to diagnosing tuberculosis. The test is able to detect infection with tuberculosis, but cannot distinguish latent infection from disease. In most African countries the majority of adults have been infected and the test is thus of little diagnostic value. Furthermore, bacille CalmetteGuerin (BCG) vaccination, which is widely administered in the tropics, results in positive tuberculin skin tests that often persist into adulthood (Waddell et al. 1999). A further limitation of skin testing in areas with high HIV prevalence is that the immune response, which forms the basis of a positive tuberculin skin test, becomes progressively impaired. For these reasons, tuberculin skin testing is of little value as a diagnostic test in adults with suspected tuberculosis in tropical countries, except for young adults presenting with primary disease. It is, however, the only test that can diagnose latent tuberculosis and is

Earlier studies showed that the rate of conversion to tuberculin reactivity was comparable (Nunn et al. 1994; Klausner et al. 1993) or lower (Elliott et al. 1993; Cauthen et al. 1996) among close household contacts of HIV-infected than of HIV-non-infected patients with pulmonary tuberculosis (Wallis and Johnson 2001). Recent tuberculin testing data from a community-based study in the Dominican Republic of 803 household contacts of patients with newlydiagnosed pulmonary tuberculosis revealed a lower rate of transmission from HIV-infected tuberculosis patients than HIV-non-infected patients to their close contacts (61% tuberculin conversion vs. 76%; P=O.OOOI) (Espinal et al. 2000). These data suggest that HIV-infected patients with tuberculosis may be less likely than HIV-non-infected patients to transmit tubercle bacilli to their close contacts. This finding notwithstanding, close contacts of HIV-infected and HIV-non-infected patients with newly diagnosed tuberculosis should be evaluated similarly.

29.8.1 The Sputum Smear in HIV-Positive Persons The sputum smear is still the most frequently used method for diagnosing HIV-associated tuberculosis (Hudson et al. 2000). The sensitivity of sputum smear examination can be improved, and the time taken to examine the slide shortened, by use of fluorochrome staining. Fluorescent microscopes are, however, expensive and not widely available in tropical countries. A simple technique of sputum concentration improves the yield of sputum smear in HIV infection (Bruchfeld et al. 2000). Sputum induction by inhalation of hypertonic saline may yield positive specimens if sputum is otherwise unobtainable or smear negative (Parry et al. 1995). Smears of lymph node needle aspirates have a high yield (Bern et al. 1993; Pithie and Chicksen 1992). If the sputum or lymph node aspirate is smearnegative, an assessment on the basis of clinical features and chest radiograph remains the mainstay of diagnosis, as bronchoscopy is not widely available in the tropics and mycobacterial culture, when available, is slow. WHO has proposed a case definition for smear-negative pulmonary tuberculosis based on three negative sputum smears, radiographic abnormalities consistent with active pulmonary tuberculosis and no response to a course of broadspectrum antibiotics. Most patients fulfilling the case

468 definition in a Malawian study were HIV-seropositive (Hargreaves et al. 2001). The final diagnosis was tuberculosis in 78%, but treatable conditions would have been missed in 14%, indicating the need for further refinement of this approach. Case definitions for extrapulmonary tuberculosis also need to be developed.

29.9. Treatment of Tuberculosis Highly effective anti-tuberculosis chemotherapy has been available for many years, yet there are currently more people with the disease than at any previous period of human history and, unless there are major changes in the global management of the disease, the numbers will certainly increase further. Tuberculosis is among the most cost-effective of all diseases to treat (Murray et al. 1990; Foster et al.1997); a 6-month course of anti-tuberculosis drugs costs approximately only UK£18. Also, by curing one infectious patient, transmission of disease to several others is prevented. Several national and international organisations publish periodically updated comprehensive guidelines for tuberculosis treatment that are valuable for clinicians caring for patients with tuberculosis (Joint Tuberculosis Committee of the British Thoracic Society 1998; Report 1992; Enarson et al. 2000; Centers for Disease Control and Prevention 1998,2000; Burman and Jones 2001). New guidelines and updates are regularly published by the WHO, Centers for Disease Control and other regulatory bodies and these should be referred to by the clinician (Centers for Disease Control and Prevention 1998,2000).

29.9.1 Drug Regimens for Treatment of Tuberculosis in HIV-Negative Individuals

Currently recommended anti-tuberculosis drug regimens were developed from a large series of wellcontrolled trials in large numbers of sputum-positive subjects with pulmonary tuberculosis well before the HIV epidemic. Modern anti-tuberculosis treatment is based on a combination of several drugs that that rapidly sterilise the sputum and prevent the emergence of drug resistance. At present, the minimum recommended duration of treatment based on rifampicincontaining regimens for drug-susceptible tuberculosis is 6 months. Treatment consists of two phases. The

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initial 2-month intensive phase kills rapidly dividing, metabolically active bacilli and is followed by a 4- to 6-month continuation phase, which kills the remaining slowly metabolising organisms. Four drugs (isoniazid, rifampicin, ethambutol and pyrazinamide) are recommended during the initial intensive phase except where local drug resistance rates are known to be low (less than 4%). The combined use of isoniazid, rifampicin and pyrazinamide is critical for the success of 6-month short-course regimens (with the addition of ethambutol or streptomycin if initial resistance to one agent is suspected). Rifampicin and isoniazid should be given during the entire duration of 6month regimens for optimal efficacy. Pyrazinamide is necessary only during the first 2 months of treatment. Ethambutol can be stopped if the patient's bacilli are found to be susceptible to isoniazid and rifampicin. In developing countries, for economic reasons, the initial 2-month phase with quadruple therapy is followed by isoniazid and ethambutol for an additional 6 months. Directly observed short course chemotherapy (DOTS) has been shown to be higWy effective and cost effective in both industrialised and developing nations (China Tuberculosis Control Collaboration 1996; Murray et al. 1991; Wilkinson et al.1996). Thus treatment should be supervised whenever possible.

29.9.2 Treatment ofTuberculosis in HIV-Positive Individuals

The treatment of tuberculosis in HIV-positive individuals follows the same well-established principles used in the treatment of non-HIV-infected individuals (Table 29.4). The choice of chemotherapy regimen may be limited by cost, toxicity or multiple drug resistance. In general, the standard 6-month rifampicin-based short-course chemotherapy regimens described above have been found to be highly effective for the treatment of HIV-infected individuals (Chaisson et al. 1987, 1996; Murray et al. 1999; Jones et al. 1994). The U.S. Centers for Disease Control and WHO currently recommend a minimum of 6 months of treatment for HIV-infected as well as HIV-non-infected individuals. If the clinical or microbiological response is slow, it is recommended that treatment be extended for a total of 9 months or at least 4 months after cultures become negative (Centers for Disease Control and Prevention 1998). Other countries, such as Brazil, have routinely treated HIV-infected patients for 9 months (Brasil Ministerio da Saude 1999).

Tuberculosis and Co-infection with the Human Immunodeficiency Virus Table 29.4. Principles of treatment in Human Immunodeficiency Virus-infected patients with tuberculosis 1. Four drug regimen for initial empirical treatment Isoniazid (INH), rifampicin (RIF) or rifabutin (RFB), pyrazinamide (PZA), and ethambutol (EMB) or streptomycin (SM) Duration of treatment should be for 6 months at least 2. Directly Observed Treatment (DOTS) is preferred for all patients 3. Concurrent treatment of tuberculosis and HIV Rifampicin is a potent inducer of cytochrome CYP4S0 and thus concurrent use of Protease inhibitors (PI's) and nonnucleoside-reverse transcriptase inhibitors (NNRTIs) are contraindicated. Options to consider are: - Antiretroviral regimens which do not include PIs or NNRTIs - Anti-tuberculosis regimens which use streptomycin instead of rifampicin or use of INH, ethambutol and pyrazinamide for 24 months - Rifabutin-based regimens with changes/adjustment to dosages

While most HIV-infected patients with tuberculosis initially respond well to standard 6-month shortcourse chemotherapy, their relapse rates are higher than among HIV-non-infected persons (Perriens et al. 1995; Chaisson et al. 1996; Soriano et al. 1988; Malkin eta 1. 1997; Mallory et al. 2000). HIV infection is associated with progressive immune suppression; in the absence of effective anti-retroviral therapy, other opportunistic infections such as P. carinii pneumonia and cryptococcal meningitis require lifelong suppressive or secondary prophylactic therapy. These issues have raised concerns regarding the optimal duration of the treatment of tuberculosis in HIV-infected patients and the need for an extended treatment of post-treatment prophylaxis. Relapse in HIV-infected patients may be due to recurrence of disease with the original Mycobacterium tuberculosis strain after incomplete eradication of bacilli in an immunocompromised patient or due to exogenous reinfection with another Mycobacterium tuberculosis strain being transmitted in the community (Small et al. 1993; Godfrey-Faussett et al. 1994). As a general principle, in the absence of drug resistance, the standard WHO-recommended shortcourse regimen of four drugs (rifampicin, isoniazid, pyrazinamide and either ethambutol or streptomycin) for 2 months, followed by two drugs (rifampicin and isoniazid) for a further 4 months is recommended (Scientific Statement 1998). Some physicians continue treatment for 9 months to further reduce the risk of relapse (Murray 1998; Centers for Disease Control 1998). Unfortunately, as outlined below, many patients die of other AIDS-related complications during or after completion of anti-tuberculosis therapy. In one study, extending rifampicin-based

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therapy from 6 to 12 months reduced the relapse rate but did not improve survival (Perriens et a1. 1995). In addition, owing to a range of human factors, including perception of the nature of the disease, its treatment and outcome and the stigmatising nature of the diagnosis, HIV-positive patients in some regions are less likely than seronegative patients to complete treatment (Ackah et al. 1995). Thus, it is essential to adopt strategies of DOT in order to ensure completion of therapy (Scientific Statement 1998). This strategy may also help to limit the emergence of drug-resistant tuberculosis but, in several African countries, even the establishment of national tuberculosis programmes employing DOT-based strategies is failing to stem the rising tide of tuberculosis. In Botswana, for example, the incidence of tuberculosis rose by 120% between 1989 and 1996, paralleling that of the prevalence of HIV infection, despite a decade of such control strategies and a low prevalence of drug resistance (Kenyon et al.1999). The response to anti-tuberculosis treatment is best monitored by repeated sputum examination (at least monthly until the sputum culture is negative) by smear and, where facilities exist, culture. About 85% of patients treated with modern short-course regimens containing isoniazid and rifampicin can be expected to convert their sputum culture to negative after 2 months of treatment (Report 1992). Patients in whom treatment is found to be failing on clinically or microbiological grounds should undergo careful reassessment, including consideration of compliance, drug absorption, and drug resistance. If a decision is made to begin additional drugs, at least two drugs must be added to which the patient's isolate may reasonably be expected to be susceptible. The basic rule to follow is never to add a single drug to a failing regimen.

29.10

Anti-Retroviral Therapy for Poor Developing Countries Anti-retroviral therapy is the adjunctive treatment most likely to have a major effect in reducing deaths from tuberculosis in HIV-positive individuals (Harries et al. 2001a). After the 13th World AIDS Conference in July, 2000, there has been a concerted push by industrialised countries to improve access to anti-retroviral drugs for less-developed countries. Despite this push, it will be logistically very difficult to introduce anti-retroviral drugs in resource-poor settings with weak health infrastructures. However, well-functioning control programmes have an established infrastructure with the

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ability to monitor treatment and check on compliance, and they could provide a good entry point for the provision on a wider basis of anti-retroviral drugs in this setting. The use ofhigWy active anti-retroviral therapy (HAART) in HIV-positive patients with tuberculosis is problematic because of major interactions between rifampicin and protease inhibitors (Burman and Jones 2001). However, dual or triple nucleoside analogues or dual nucleoside analogues with a non-nucleoside inhibitor are therapeutic possibilities that will need to be tested first in controlled clinical trials (to determine tolerability and safety) and then in district operational studies (to establish feasibility, equity issues and drug security). There is also the need for modelling and cost exercises to look at long-term cost benefit. When prescribing anti-retrovirals with anti-tuberculosis drugs, it is important to refer to the latest guidelines on the subject (Dean et al. 2002) since these are updated frequently. Two pharmacokinetic issues complicate treatment: (a) the possibility of malabsorption of drugs and (b) the complex drug-drug interactions between anti-retroviral and anti-tuberculosis drugs, as described above. While HIV-infected patients with tuberculosis commonly experience adverse drug interactions, current recommendations are that HAART is commenced early in patients with advanced HIV disease (CD4+ counts<100x106 cells/I) (Dean et al. 2002). In clinically stable patients with CD4+ cells> 1OOxl 06/1, HAART should be deferred until the continuation phase of tuberculosis treatment, i.e. after 2 months of anti-tuberculosis therapy. The current recommendation in this case is to replace rifampicin by rifabutin, a much less powerful inducer of cytochrome enzymes, and to commence or continue with the anti-retroviral drugs (Centers for Disease Control 1998).

29.11 Management Considerations in HIV-Positive Individuals There are several specific issues which arise in the treatment of HIV-infected individuals with tuberculosis. These patients overall tend to have: a. Increased morbidity rates b. Increased mortality rates c. Increased number of drug side effects d. Serious interactions between anti-retroviral drugs and anti-tuberculosis drugs e. The immune reconstitution syndrome f. Increased recurrence rates after completion of treatment

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Increased Morbidity Rates: Clinical response to anti-tuberculosis treatment, clearing of chest X-ray abnormalities and sputum conversion rates occur at the same rates during treatment in both HIV-positive and HIV-negative patients with tuberculosis. The HIV-positive tuberculosis patients do, however, often run a stormy course while on anti-tuberculosis treatment due to other complicating opportunistic infections and tumours. Common presentations of these complicating conditions include recurrent fever, chest infections, recurrent diarrhoea, oral candida, bacteraemia, cryptococcosis and Kaposi's sarcoma. This increased morbidity requires increased prescriptions for antibiotics, antifungal agents, anti-diarrhoeal agents and analgesics, rendering the care more expensive than is the case with HIV-negative patients. There is also evidence that delay in the diagnosis and treatment of tuberculosis may compromise the chances of individual cure in HIV-positive patients. Untreated tuberculosis in HIV-infected persons may accelerate the decline in immunocompetence and the progression to severe immunodeficiency.

Increased Mortality Rates: HIV-positive patients not receiving anti-retroviral therapy have a much higher mortality during and after anti-tuberculosis treatment compared with HIV-negative patients (Luu et al. 1994; Murray et al. 1999; Badri et al. 2001; World Health Organisation 2001; Harries et al. 2001b; Mukadi et al. 2001). This is illustrated by the example of the Central African country Malawi, where HIV infection was present in 72% of adults with smear-positive pulmonary tuberculosis in 1995 (Harries et al.1997). In 1999, WHO reports 22% mortality among new smear positive cases in Malawi with treatment success in 69% (World Health Organisation 2001), which represents good control despite an appallingly high mortality. In sub-Saharan Africa, approximately 30% of HIV-positive smearpositive tuberculosis patients die within 12 months of commencing treatment, and about 25% of those who survive die during the subsequent 12 months. HIV-positive patients with smear-negative pulmonary tuberculosis (possibly because of more severe immunosuppression and diagnostic difficulties) fare even worse (Cantwell and Binkin 1997). The reasons for the high mortality are several and varied. There are the wide social, cultural, and economic issues of poverty, sex, illiteracy and stigma that contribute to the great divide between the rich industrialised nations and the poor less-developed nations of the world. These global inequalities affect factors such as access to care, diagnosis and delivery of care, all of which have an important bearing on illness and death.

Tuberculosis and Co-infection with the Human Immunodeficiency Virus

The introduction of HAART has dramatically reduced mortality rates in HIV-infected patients in the USA and in Europe. Efforts are being made to make HAART available to all HIV-infected patients in developing countries, although the likelihood of this becoming a reality in the foreseeable future is small. Since opportunistic infections are a cause of mortality in HIV-positive persons with tuberculosis, alternative interventions with prophylactic antibiotics may be useful. A placebo-controlled clinical trial of co-trimoxazole prophylaxis in Cote d'lvoire in HIV-positive smear-positive pulmonary tuberculosis patients showed a 50% reduction in mortality in the co-trimoxazole group. The UNAIDS used this data to suggest that all tuberculosis programmes in sub-Saharan Africa consider using co-trimoxazole prophylaxis as an intervention strategy in an attempt to reduce mortality. A study from Senegal, by contrast, found no advantage in using co-trimoxazole prophylaxis and this suggests that use of such prophylaxis may not be universally applicable. The antibiotic susceptibility patterns of local pathogens and also the costs, costbenefits, and consequences of introduction of prophylaxis regimens require careful consideration.

29.11.1 Barriers to Effective and Appropriate Therapy It is not uncommon to find patients registered and being treated for tuberculosis who have an additional disease other than tuberculosis. To treat a patient who has left ventricular failure with anti-tuberculosis drugs is neither helpful to the patient nor to the outcome of tuberculosis treatment. The numbers of patients acquiring tuberculosis has increased by 300-400% in high HIV-prevalent countries in the past decade (Chretien 1990). A large increase in the numbers of patients with tuberculosis without a commensurate increase in resources reduces the quality of patient care. In some African tuberculosis programmes, patients are still admitted to hospital for 1-3 months to receive the initial phase of treatment either because there are difficulties in administering directly observed treatment in the community or because patients are too ill for treatment at home. Overcrowded wards render good nursing and medical care difficult, and there is a substantial risk of other nosocomial infections being transmitted to the patients. HIV-positive patients treated with the older regimens consisting of streptomycin, isoniazid, and thiacetazone during the early stages of the epidemic had higher death rates compared with those given

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rifampicin-containing regimens (Nunn et al. 1991; Elliott and Foster 1996). The latter may offer survival advantages because of the broad-spectrum antibacterial activity of rifampicin in preventing other bacterial infections.

29.11.2 Immune Reconstitution Syndrome The use of anti-retroviral therapy and subsequent improvement in immunological parameters may actually make some patients feel worse, a paradoxical response, due to immune reactivation. Patients may develop ascites, lymphadenopathy, fever, increase in the size of cerebral lesions and pleural effusions. Clinicians treating tuberculosis in HIV-positive patients receiving anti-retroviral therapy need to be aware of this phenomenon. Another problem encountered with the simultaneous administration of anti-retrovirals and anti-tuberculosis chemotherapy is the temporary exacerbation of the symptoms and signs of tuberculosis-the so-called paradoxical reactions (Fishman et al. 2000). These, which have been ascribed to hypersensitivity reactions to antigen released by bacilli killed by the chemotherapy, manifest as fever, enlargement of affected lymph nodes and a worsening of the radiological appearance. They are occasionally encountered in HIV-negative patients but their incidence is higher in HIV-positive patients, particularly those given anti-retroviral drugs, probably as a result of improving immune responsiveness. These reactions are not indicative of treatment failure and usually subside spontaneously. Treatment should not be modified but short courses of steroids may be required for severe paradoxical reactions.

29.11.3 Increased Drug Side Effects Adverse reactions to anti-tuberculosis drugs are more frequent in HIV-positive patients leading to interruption of treatment and occasional fatalities. In HIV-positive patients who were given the old treatment regimens in the mid-1980s, (streptomycin, isoniazid and thiacetazone), adverse cutaneous reactions occurred in 15-20%,and up to 6% of these reactions were severe with Stevens Johnson syndrome or toxic epidermal necrolysis. Cutaneous hypersensitivity reactions appeared to be even more common in HIV-positive children, and severe reactions were

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frequently associated with death (Coovadia 1991). Thiacetazone, which was a useful and cheap antituberculosis drug in the pre-HIV era, was the main cause of adverse cutaneous reactions. For this reason, thiacetazone usage was abolished, in favour of ethambutol. In HIV-positive patients given short course regimens containing rifampicin, isoniazid and pyrazinamide adverse reactions to anti-tuberculosis drugs appear to be infrequent, although side effects of these drugs do occur. In one study in Kenya, thiacetazone toxicity was 18 times more frequent in HIV-positive than in HIVnegative patients and the risk was directly related to the degree of immunosuppression, suggesting an immunological basis (Nunn et al. 1991). Thus, even though they are more expensive, therapeutic regimens containing rifampicin throughout (or rifabutin if anti-retroviral therapy is concomitantly given) should replace regimens containing thiacetazone (Nunn et al. 1991; Elliott and Foster 1996).

29.11.4 Drug Resistance Several outbreaks of multi-drug resistant tuberculosis (MDR-TB) have been reported from industrialised countries amongst patients infected with HIV (Moro et al. 2000). HIV infection itself does not induce MDR-TB, but it fuels the spread of this dangerous condition by increasing susceptibility to infection and accelerating transmission between individuals, especially in closed confined spaces such as prisons. Recent data collated from WHO (PablosMendez et al. 1998) has shown that MDR-TB is highest in India, Eastern Europe, China and South-East Asia, and lowest in sub-Saharan Africa. Nevertheless, given the problems faced by many tuberculosis programmes in sub-Saharan Africa and given the virtual absence of second-line anti-tuberculosis drugs in these countries, MDR-TB is a real and potential threat to tuberculosis control (Pape et al. 1993). The advent of HIV, with large increases in the number of cases of tuberculosis, has threatened to overwhelm National Tuberculosis Control Programmes in subSaharan Africa. As several mini-epidemics of multi-drug resistant HIV-related tuberculosis followed exposure to source cases within hospitals and clinics, welldefined policies for the prevention of transmission of tuberculosis within such institutions, including isolation of known and suspect infectious patients, are essential.

29.11.5 Recurrence After Treatment After completion of treatment, the recurrence rates of tuberculosis (defined as return of clinical features of active tuberculosis, positive sputum smears for acid-fast bacilli or positive sputum cultures for Mycobacterium tuberculosis) are increased in HIV-positive patients. Recurrence rates have been observed at between 18-22 per 100 person-years. The proportion of recurrence of tuberculosis in HIV-infected patients in sub-Saharan Africa due to disease re-activation or re-infection is unknown. This information is important when it comes to determining strategies to prevent tuberculosis recurrence, such as using secondary isoniazid prophylaxis. Patients who relapse with smearpositive pulmonary tuberculosis are treated with the WHO-recommended retreatment regimen (Murrayet al. 1999). Five drugs are given in the intensive phase of this regimen because many such patients have acquired resistance to isoniazid and streptomycin.

29.11.6 Post-Treatment Prophylaxis The value of post-treatment prophylaxis has been investigated in two studies conducted in countries with a high prevalence of tuberculosis. In a large trial in the Democratic Republic of the Congo, 335 HIVinfected adults who completed 6 months of standard short course chemotherapy (2 months of isoniazid, rifampicin, pyrazinamide, and ethambutol followed by 4 months of isoniazid and rifampicin) were randomized to receive an additional 6 months of twice weekly isoniazid and rifampicin or placebo (Perriens et al. 1995). Fewer relapses occurred in the arm receiving extended therapy. There was, however, no effect on survival. In a randomized clinical trial in Haiti, relapse rates in 142 HIV-infected and 91 HIV-non-infected adults treated with 2 months of isoniazid, rifampicin, and pyrazinamide followed by 4 months of isoniazid and rifampicin were determined (Fitzgerald et al. 2000). Patients were randomly assigned to 1 year of posttreatment daily isoniazid or placebo after the initial anti-tuberculosis treatment. Relapse rates were tenfold higher among HIV-infected patients (10% vs 1%). One year of post-treatment isoniazid decreased the relapse rate from 7.8 per 100 person-years of observation (PYO) to 1.4 cases per 100 PYO among the HIVinfected patients but had no effect on relapse in the HIV-non-infected patients. The benefit of post-treatment isoniazid was greatest among patients with symp-

Tuberculosis and Co-infection with the Human Immunodeficiency Virus

tomatic HIV infection at the time of initial diagnosis of tuberculosis. Post-treatment isoniazid had no effect on mortality. This study did not include DNA fingerprinting of relapse isolates to distinguish recurrent disease from exogenous reinfection. Tuberculosis control programmes must balance the costs oflonger durations of treatment and the likelihood of decreased compliance with the potential for decreased relapse rates.

29.11.7 Prophylactic Therapy In view of the very high risk of a co-infected person developing active tuberculosis, and the adverse effect of this disease on the immune status and survival of the patient, there is a very good theoretical case for provision of prophylactic treatment for those at risk. In practice, serious problems have been encountered in diagnosing dual infection, ruling out active tuberculosis and ensuring compliance with therapy without breach of confidence of enhancement of stigma. Studies in Mrica have shown that preventive treatment with isoniazid for 6-12 months provides significant protection against tuberculosis in HIV-infected adults, at least in the short- to medium-term (Whalen et al.1997). Protection seems to be greatest in those with a positive tuberculin skin test, in whom death is also less frequent. Feasibility studies on tuberculosis preventive therapy in sub-Saharan Mrica have given disappointing results, and no country in the region has yet adopted chemoprophylaxis as a strategy for tuberculosis control in HIV-positive individuals. While it may be difficult to implement chemoprophylaxis as a country-wide control strategy, it could be used safely and selectively in certain situations, such as in occupational health services for private businesses and factories, for personnel working in international agencies and missions and amongst high risk groups such as health care workers and prisoners. Thus, isoniazid chemoprophylaxis may be useful in selected groups of people, and it may also be useful to prevent disease recurrence after an episode of tuberculosis has been successfully treated. In the initial studies, a 6- tol2-month course ofisoniazid was found to lower the incidence of tuberculosis in co-infected persons (Fitzgerald et al. 2000; Whalen et al. 1997). Given that HIV-infected patients are at increased risk of developing tuberculosis, the case for giving them prophylactic anti-tuberculosis chemotherapy has been the subject of intense debate (Wllkinson et al. 1998). Prevention of tuberculosis in these individuals is a logical public health aim. Before the HIV epidemic, isoniazid preventive therapy was being recommended for

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contacts of patients with active disease. Concern was, however, expressed about the increased side effects of anti-tuberculosis drugs in HIV-positive individuals and a number of clinical trials have now been undertaken to examine the safety and efficacy of chemoprophylaxis in this group of individuals. Studies of varying design from Haiti, Zambia and Uganda (Fitzgerald et al. 2000; Whalen eta 1. 1997; Wilkinson et al. 1998) have shown that chemoprophylaxis in HIV-infected adults significantly reduced the incidence of tuberculosis. The question of how long the protection lasts and whether such therapy can lead to the emergence of drug-resistant strains of tuberculosis remain, however, to be answered. Importantly, operational issues discussed below need to be addressed. Tuberculosis infection in HIV-infected individuals tends to reactivate after therapy stops. Although prophylaxis leads to a reduction of the risk of tuberculosis by approximately 60% in tuberculin skin test positive adults with HIV infection, identifying HIV-infected individuals is difficult in resourcepoor settings (Wilkinson et al.1998; Bucher et al.1999). The development of voluntary counselling and testing centres is seen as an effective tool to promote safer sex through counselling and to offer those with HIV infection interventions such as preventive therapy for tuberculosis. Early experiences of this approach in Uganda were disappointing, as high drop-out rates were reported (Aisu et al.1995). Improved counselling and the development of rapid on-site HIV testing are yielding better results. It is nevertheless unlikely that enough HIV-infected individuals can be identified and preventive therapy should therefore be seen as benefiting the individual rather than playing a major role in controlling tuberculosis in tropical countries with a high HIV prevalence. The relatively short-term benefit of preventive therapy is a further problem (Quigley et al. 2001; Johnson et al. 2001). Subsequently, shorter combination regimens were also shown to be effective. These include a 3-month course of a rifamycin (rifampicin or rifabutin) plus isoniazid and a 2-month course of a rifamycin plus pyrazinamide (Wilkinson et al. 1998; Halsey et al. 1998) and,in tuberculin-positive HIV-infected patients 3-month regimens (isoniazid+rifampicin+pyrazin amide) provide sustained protection up to 3 years (Johnson et al. 2001). A study in Zambia revealed that the 2-month combination regimens or 6 months of isoniazid, administered twice weekly, reduced the incidence of tuberculosis by about 40% compared with a placebo group, although the overall mortality due to all causes was not reduced (Mwinga et al. 1998). Prevention was more effective in those with relatively limited immunosuppression (positive tuberculin tests, high

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lymphocyte counts and high haemoglobin levels). By 18 months, the incidence of tuberculosis in those who had received prophylaxis was similar to that in the placebo group; indicating the need to consider repeated courses or, perhaps, lifelong prophylactic treatment.

29.11.8 Malabsorption There is some evidence that anti-tuberculosis drugs, particularly rifampicin, may be poorly absorbed in HIV-positive patients (Peloquin et al.1996). Rifampicin is given at a dose of 10 mg/kg irrespective of whether it is administered daily, three times a week, or twice a week (Arthur et al. 2001). If rifampicin is malabsorbed, drug concentrations in tissues and blood may be considerably reduced if given on an intermittent basis. Furthermore, in many tuberculosis programmes in sub-Saharan Africa, the drug is not given strictly on an mg/kg weight basis but rather according to weight bands. Careful clinical studies need to be done in HIVpositive patients to find out whether anti-tuberculosis treatment regimens, given on an intermittent basis, are as effective as those given on a daily basis. These studies should be coupled with research on rifampicin pharmacokinetics to determine whether rifampicin concentrations are adequate in HIV-positive patients receiving intermittent treatment and whether rifampicin concentrations are adequate across the weight distribution within the different weight bands. One of the reasons for the higher death rate in HIV-positive patients with smear-negative pulmonary tuberculosis may be the weaker regimen (often standard treatment) given to such patients. The optimum treatment regimen for smear-negative patients needs to be determined.

29.11.9 Adjunctive Treatments Adjunctive therapy may be needed to reduce early deaths. Several reasons for early deaths in HIV-infected patients with tuberculosis have been delineated-late presentation of patients with severe and extensive tuberculosis; life-threatening HIV-related complications such as severe anaemia and bacteraemia; and the occurrence of a Herxheimer-type reaction due to the rapid killing of tubercle bacilli by anti-tuberculosis drugs (Anglaret et al. 1999). Due to resource implications, the identification of bacteraemia in many African hospitals would be difficult, and ill patients might

require an empirical course of antibiotics to treat commonly occurring infections due to Streptococcus pneumoniae and non-typhoidal Salmonella spp. There appears to be some benefit of corticosteroids in decreasing mortality from tuberculosis pericardial effusion (Wragg and Strang 2000). Although co-trimoxazole prophylaxis for the prevention of opportunistic infections was shown in Cote d'Ivoire to significantly reduce the death rate (Anglaret et al.1999; Wragg and Strang 2000; Wiktor et al.1999), it is unknown whether this effect will be replicated elsewhere in Africa (Maynart et al. 2001). There is a wide variation of prevalence of opportunistic pathogens and patterns of antibiotic susceptibilities of these pathogens and the effectiveness of co-trimoxazole prophylaxis requires validating through other controlled trials. Despite provisional recommendations by UNAIDS (2000b) that co-trimoxazole should be given to all people in Africa living with AIDS (by definition this includes HIV-positive patients with tuberculosis), it would be prudent to gather more evidence about the effectiveness, feasibility, optimum timing and costeffectiveness of this intervention. There are currently three placebo-controlled clinical trials in Central Africa that may well answer some of these questions. Even if co-trimoxazole is effective and its use is feasible, its widespread use by AIDS patients might have serious adverse consequences, such as increased drug resistance This could compromise the treatment of acute respiratory infections in children, in whom co-trimoxazole is first-line therapy, as well as malaria in countries that use sulphadoxine-pyrimethamine as their first-line treatment. Other antibiotics, such as oral quinolones, which have good antibacterial effects against non-typhoidal Salmonella species, may play a role in chemoprophylaxis. Non-antibiotic interventions such as multivitamins and mineral supplements such as zinc and selenium may improve cell-mediated immunity in HIV-positive patients (Mocchegiani and Muzzioli 2000; Baum et al. 2000), and their efficacy should be determined in placebo-controlled trials.

29.12 Issues Relating to Control of Tuberculosis in HIV-Endemic Areas 29.12.1 Quality of Health Care Regular clinical care and treatment for HIV-related complications in patients on anti-tuberculosis treat-

Tuberculosis and Co-infection with the Human Immunodeficiency Virus

ment may be far from adequate in resource-constrained health facilities in sub-Saharan Africa. The adequacy of clinical care needs to be formally documented. If such deficiencies are identified, research into health systems and quality-of-care issues will need to be undertaken, with a particular focus on staff morale and motivation. The capacity and quality of health care provided by the local health service and the health status of the staff (clinical officers, clinicians, nurses, technical personnel) available to care for patients influence the outcome of the treatment of tuberculosis. The health staff in many African countries has the same HIV-seroprevalence rates as the general adult population, and in some urban areas this approaches or exceeds 30%. High absentee rates from work due to illness or attending funerals, and high death rates of the health care staff due to AIDS threaten the capacity of many developing countries to deliver good and effective health care. Tuberculosis programmes are no exception to this serious threat.

29.12.2 The WHO DOTS Strategy The best way of controlling tuberculosis in high HIVprevalent countries in sub-Saharan Africa appears to be the WHO DOTS strategy. This is a six-point strategy incorporating- Government commitment to tuberculosis control - A regular supply of high quality drugs, free at the point of delivery to the patient - Microscopy services for diagnosis - Supervision of therapy - Audit of the efficacy of the control programme - Training of staff Countries need to be assisted in implementing this strategy, which must be adaptable to the challenges posed by the HIV epidemic if credibility is to be maintained, and operational research may be very useful in this setting. A recent study has been conducted in Botswana (Kenyon et al. 1999), a country with a good DOTS programme achieving high cure rates and very low levels of drug resistance. Botswana is, however, a country that has seen escalating HIVinfection rates in the last 5-10 years and this has been associated with escalating tuberculosis case rates. It is clear from this study that DOTS alone may not be sufficient to control tuberculosis in areas with epidemic HIV infection, and additional strategies may be needed for such control if reductions in the incidence of tuberculosis are to be achieved. Tuberculosis pro-

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grammes should integrate more with AIDS control programmes, because it is now apparent that HIV! AIDS control is essential for tuberculosis control.

29.12.3 BeG Vaccination and HIV Serostatus There is a risk that vaccination with BCG, a living attenuated vaccine, will cause infectious complications in HIV-positive persons (Talbot et al. 1997). There is a small increase in the incidence of adverse effects of BCG in the children of HIV-infected women, but most such effects are mild (O'Brien et al. 1995). In one study, complications occurred in 9 of 68 HIV-infected children 3-35 months after neonatal BCG vaccination. Regional lymphadenopathy with or without fistula formation occurred in seven and systemic disease in two children (Besnard et al. 1993). Accordingly, the safety of BCG vaccination in regions with a high incidence of HIV infection requires consideration. WHO (1987) has advised that, while persons known to be HIV positive should never be given BCG, routine immunisation of infants should nevertheless continue in areas with a high incidence of tuberculosis and HIV infection. In the UK it is recommended infants born to mothers known or suspected to be HIV positive that should not receive BCG unless they are subsequently shown to be HIV negative (World Health Organization 1987).

29.12.4 Governmental Responses to the Threat Posed by HIV and Tuberculosis Some countries have introduced information, education and communication campaigns for the general public and front-line health workers about the need for early submission of sputum samples from patients with a chronic cough. There is, however, little evidence that this has had any effect in reducing diagnostic delays. Algorithms are in place for the diagnosis of smear-positive pulmonary tuberculosis based on chest symptoms, lack of response to antibiotics, negative sputum smears, and chest radiography. Moves are afoot to decentralise the initial phase of treatment to peripheral health centres and the community, with the use of family-based members, community-care groups or shopkeepers to administer directly observed therapy. Many patients have difficulties attending health centres for directly observed therapy on a daily basis. Therefore some programmes based on rifampicin-containing regimens have moved

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from daily treatment in the initial phase to intermittent treatment, either three times or twice a week. The WHO DOTS strategy is principally aimed at detecting and treating patients with smear-positive pulmonary tuberculosis patients. The growing burden of smear-negative tuberculosis is now recognised and several programmes now address such patients.

29.12.5 National Tuberculosis Control Programmes The overall objective of tuberculosis control is to reduce mortality, morbidity, and transmission of the disease until it no longer poses a threat to public health. The strategy appears simple in principle but is difficult in practice. Standardised combination chemotherapy is provided to, at least, all sputum smear-positive tuberculosis patients. This treatment cures the disease and prevents future transmission of infection within the community. Targets for tuberculosis control include curing 85% of detected new smear-positive tuberculosis cases and detecting 70% of the existing cases. The achievement of a high cure rate is the highest priority because tuberculosis programmes with high cure rates are thought to attract a large number of existing cases within their catchment areas. Rates of treatment completion are lower in DOTS programmes in high HIV-prevalent countries in sub-Saharan Africa. This is not because the delivery of DOTS is worse, but principally because of high case fatality rates due to HIV coinfection (Sonnenberg et al. 2001).

29.13 Conclusions The emergence of the HIV and tuberculosis pandemics over the last 2 decades have had a devastating effect on tuberculosis world-wide, especially in poor developing countries. In 2001, around 10% of all cases of tuberculosis will be HIV-related, rising to over 20% in Africa. In addition, 30% of the expected 3 million or more AIDS-related deaths in 2001 were due to tuberculosis. It is expected that the problem will likewise become extensive in Asia over the next decade. Many African countries report that their health care facilities are overwhelmed by the additional burden of HIV-related tuberculosis and urgent action is therefore required to stem this epidemic before it becomes totally unmanageable with devastating human and economic consequences that will be felt throughout the world.

A. Zumla and J. M. Grange

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30 Spinal Tuberculosis M. MONIR MADKOUR, M. WASEF AL SEBAI, KHALAF

CONTENTS 30.1 30.2 30.3 30.4 30.5 30.6 30.7 30.8 30.8.1 30.8.2 30.8.3 30.8.4 30.8.5 30.8.6 30.9 30.9.1 30.10. 30.11

Introduction 481 Epidemiology 482 Pathogenesis 482 Clinical Features 483 Cranio-cervical Junction Tuberculosis Spinal Tuberculosis with Neurological Deficits 484 Clinical Features in Children 485 Imaging Features 485 Plain Radiography 485 Conventional Tomography 486 Myelography 486 Scintigraphy 486 CT Scans 486 MRI Imaging 486 Diagnosis 487 Case Illustration 487 Spinal Tuberculosis Versus Spinal Brucellosis 489 Anti-Tuberculous Chemotherapy for Spinal Tuberculosis 490 References 490

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30.1 Introduction Features of spinal tuberculosis has been noted, reported and described by the Ancient Egyptians 5000 years ago. They noted in their paintings and writings its occurrence among ordinary people and among the nobles (Fig. 1.1, Chap. 1 Tuberculosis in Ancient Egypt).

M. M. MADKOUR, MD, DM, FRCP Consultant, Department of Medicine, Riyadh Armed Forces Hospital, P.O. Box 7897, C-119, Riyadh 11159, Saudi Arabia M. W. AL SEBAI Consultant Spinal Surgeon, Riyadh Armed Forces Hospital, P.O. Box 7897, Riyadh 11159, Saudi Arabia K. R. AL MOUTAERY, MD, FRCS (Ed), FACS Head of Neurosurgery, Riyadh Armed Forces Hospital, P.O. Box 7897, Riyadh 11159, Saudi Arabia

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

R. AL MOUTAERY

Hippocrates later described spinal tuberculosis and classified the causes of spinal diseases as: (a) the existence of "tubercles" in the lung, (b) spinal injury, (c) age and extreme fatigue of the spine, (d) painful conditions (Marketos and Skiadas 1999). Hippocrates clearly associated the pathogenesis of spinal tuberculosis to its existence in the lungs as "tubercles:' Galen, "glorious Galen;' "Clarissimus Galenus" or Galen of Pergamon, lived during the 2nd century A.D. At the age of 20 years, he went to Alexandria, Egypt to enrich his medical knowledge. In Egypt he had the chance to examine anatomy closely and learned about human dissections. Alexandria was the most important medical center in the old world and was famous for anatomical studies among many other medical specialties. Galen learned the neuroanatomy of the spine in Alexandria (van Staden 1992). Galen endorsed the Hippocratic division of the disease and the association between spinal and pulmonary tuberculosis. He also noted that vertebral tuberculosis above the diaphragm occurs at a young age with dramatic development and it is difficult to cure. Below the diaphragm, vertebral tuberculosis was often associated with abscess formation on both sides of the lumbar spine, in the psoases and in the groin (Marketos and Skiadas 1999). In 1779, spinal tuberculosis became known as Pott's Caries or disease. Sir Percival Pou, a London surgeon born in 1714, described spinal tuberculosis with subsequent development of Pott's paralysis or paraplegia. Spinal deformities, kyphosis and paraplegia described since ancient times remains the main concern today when dealing with spinal tuberculosis. Spinal surgery developed in Hong Kong in the 1950s in regard to establishing spinal stability and correcting deformity. Other aspects of spinal tuberculosis, such as the epidemiology, pathogenesis, clinical and imaging features as well as the problem of spinal growth in children post-operatively, the late consequences of spinal canal narrowing and neurological deficits will be discussed in this chapter. The following chapter is on spinal surgery, where our imaging features of spinal tuberculosis will be presented together with the surgical management and follow-up.

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30.2 Epidemiology

30.3 Pathogenesis

Skeletal tuberculosis is one of the most common extrapulmonary manifestations of the disease, both in developed and developing countries (Pertuiset et al. 1999).The incidence ofskeletal tuberculosis is rising in recent years with the resurgence of tuberculosis due to the human immunodeficiency virus (HIV) epidemic. In Zambia, Jellis (2002) reported a fourfold increase in the incidence of osteoarticular tuberculosis, 5 years after the start of HIV epidemic in 1980s. This author reported 188 cases of osteoarticular tuberculosis between 1991 and 1995 and found that 17% of children and 60% of adults were HIV positive Oellis 1996). It is estimated that 2 million or more patients worldwide have active spinal tuberculosis (Rajasekaran et al. 1998). Skeletal tuberculosis accounts for 1-5% of all tuberculosis cases and 15% of extrapulmonary tuberculosis and spinal involvement accounts for approximately 50% of all skeletal tuberculosis. In a recent report from Denmark, Houshian and colleagues (2000) studied the epidemiology of bone and joint tuberculosis during the period 1993-1997. They found 95 cases of bone and joint tuberculosis, accounting for 4% of all tuberculosis cases and 15% of extrapulmonary cases and the spine was affected in 50%. These authors noted that immigrant populations were more affected than Danes and the diagnosis was often delayed for several months or years. In New York, the incidence of spinal tuberculosis was reported to be rapidly increasing in recent years (Rezai et al. 1995). The Medical Research Council (MRC) in England and Wales surveyed the number of tuberculosis notifications for 6 months in 1983, and found active tuberculosis in 3002 patients. Respiratory tuberculosis alone was found in 2032 (68%),745 (25%) had non-respiratory disease alone and 225 (7%) had both respiratory and non-respiratory tuberculosis. Bone and joint tuberculosis was reported in 150 patients (5% of all patients and 15% of non-pulmonary tuberculosis). The spine was the most common skeletal site and was found in 60 patients (40%). This survey noted that the age was over 55 years in 50% in the white population; while in the Indian subcontinent migrants the age was less than 35 years in 60% of the cases. In our own series of 2484 patients with tuberculosis seen between 1983 and 2000 inclusive, the spine, bone and joints were affected in 292 patients (11.76%). Spinal tuberculosis with and without joint involvement was encountered in 212 patients (72.6%) (see Table 30.1).

Tuberculous spondylitis occurs as a result of hematogenous spread of M. tuberculosis bacilli to the vertebrae (Tuli 2002; Jellis 1995). M. bovis accounts for 5-10% of tuberculous spondylitis in developing countries (O'Reilly and Daborn 1995). In Latin America, M. bovis accounts for 2% of pulmonary and 8% of extra pulmonary tuberculosis (Cosivi et al. 1998). Non-tuberculous mycobacterial organisms account for 1-4% of tuberculosis cases (Sanders and Horowitz 1995; Shembekar and Babhulkar 2002). Rarely, non-tuberculous mycobacterial organism can also lead to spondylitis, particularly among patients co-infected with HIV. M. Xenopi is most commonly a pulmonary pathogen in immunosuppressed patients or those with underlying lung disease. Only four cases of spine infection with this organism have been reported (Danesh-Clough et al. 2000; Govender et al. 2000; Leibert et al. 1996; Weiner et al. 1998). Hematogenous spread of the bacilli from a distant source, commonly pulmonary, via epiphyseal vessels to the epiphyseal part of the vertebral body adjacent to the superior or inferior end plates (Doub and Badgley 1932; Boachie-Adjei and Squillante 1996; Tuli 2002). Branches of metaphyseal anastomozing arteries pass superiorly and inferiorly, joining the upper and lower anastomozing arteries together and crossing the intervertebral disc to link up with the metaphyseal systems above and below. Therefore, spread of infection through these communicating arteries to vertebrae above and below usually occur. The central part of the vertebral body may be the site of initial localization of infection via nutrient arteries and branches of the spinal arteries. This may be the case when a single vertebral body is initially affected. Subsequently, spread to other vertebrae may occur via subligamentous spread. Rarely, it may start in the posterior element of the vertebra (Weaver and Lifeso 1984). Inflammatory cellular infiltrates with granuloma, necrosis and caseation reactions may occur. Granulomata may enlarge and spread to form an inflammatory tissue mass with abscess formation to involve the entire vertebral body, the disc and adjacent vertebrae. The infection may spread beneath the anterior or posterior longitudinal ligaments to affect other vertebrae. Softening, demineralization and destruction by infection may lead to vertebral body wedging or total collapse (Boachie-Adjei and Squillante 1996). Abscess formation may progress and increase in size as the infection progress (Fig.31.10 a, b, c - Chap. 31).

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The accumulation of this abscess may become tense and under pressure and may extend to areas with least mechanical resistance or may penetrate through a neighboring organ (Bailey et al. 1972). Adhesions, fibrosis and swelling of the surrounding anatomical structures usually follow. Rarely, collapse of the vertebral body may not occur and the infection may be contained in one or two vertebrae where calcification and sequestrum formation may take place {Fig. 31.9 a, b, 31.27c - Chap. 3l}. In the cervical spine, inflammatory swelling and abscess formation may appear behind the perivertebral fascia and form a retropharyngeal mass that may cause dysphasia {Fig. 31.13, 31.23, 31.28 - Chap.31). The abscess content may extend to the sternomastoid muscle and form a neck cold abscess. It may track down to the mediastinum and communicate via fistula to the esophagus, trachea, aorta or pleural cavity (Bailey et al. 1972). Tuberculous spondylitis of the thoracic spine may be accidentally depicted by chest radiography. Abscess formation may appear as a well-defined posterior mediastinal mass {Fig. 31.8 - Chap.3l}. As the disease progresses with vertebral body collapse, inflammatory granulomatous tissue and abscess mass may bulge posteriorly into the spinal canal. Mechanical compression of the cord, compromising its blood supply through pressure or by inducing vasculitis may occur, leading to paraplegia {Fig. 31.2,31.5, 31.6,31.12,31.13,31.15,31.16,31.17,31.20 - Chap.3l} (Hsu et al.1988; Tuli et al.1967; Martin 1971). Posterior abscess formation can be noted clinically as a softtissue fluctuating swelling close to the spine. Rupture of this abscess through the skin with discharging sinus may occur (Fig. 31.11e - Chap. 31). The abscess contents may rarely track down and follow intercostal nerve course pointing to the thoracic wall with cold abscess or discharging sinus formations. Lumbar spine tuberculous abscess commonly penetrates through the sheath of the psoas muscle and gravitates down to the iliac fossa (Boachie-Adjei and Squillante 1996) {Fig. 31.4, 31.6e - Chap.3l}. It may progress further beneath the inguinal ligament to the thigh or to the iliac crest anteriorly or posteriorly with abscess swelling (Tuli et al. 1967). Anti-tuberculous drugs with or without surgical intervention will arrest this destructive inflammatory process. Healing takes places in patients responding to treatment with resulting fusion between adjacent infected vertebrae. Narrowing of the spinal canal and deformities may occur with possible long-term neurological deficits later on (Martin 1970,1971; Rajasekaran and Shanmugasundaram 1987).

30.4 Clinical Features Spinal tuberculosis has no clinical features that are specific to the disease. It may simulate other spinal diseases including brucellosis, pyogenic infections, rheumatic diseases or spinal malignancy {Madkour and Sharif 200l}. High index of suspicion by the treating clinician is essential in order to avoid delay in diagnosis with development of neurological deficits. Proper identification of risk factors, particularly among high-risk groups, is important. The disease is commonly misdiagnosed initially for months or years, both in developing and developed countries. In developing countries, spinal tuberculosis affects younger age groups, including children and infants. In developed countries, spinal tuberculosis is rare and mostly affects the elderly. However, with the recent resurgence of tuberculosis due to the HIV epidemic, spinal tuberculosis is on the rise among the younger age groups. Male predominance is reported by many authors in developing as well as developed countries. The most serious complication of spinal tuberculosis is the development of neurological deficits and disabilities. These may occur in 10-46% of patients with spinal tuberculosis and more commonly among those with dorsal spine region involvement (Griffith 1979; Hodgson and Stock 1960; Moon et al. 1996).

30.5 Cranio-cervical Junction Tuberculosis Clinical features ranges from early, non-specific, insidious symptoms to severe neurological complications, and death may occur due to atlantoaxial instability or cervico medullary compression {Fig. 31.17 a, b, c, d, e, f, g, 31.27 - Chap. 3l} (Kanaan et al. 1999). Night fever, sweating, loss of appetite, weight loss and weakness are commonly present at the onset of the disease {Table 30.l}. Backache may be the sole presenting clinical feature in the absence of constitutional symptoms. The onset of the disease is usually gradual and it may take several months or years for presentation and to establish the diagnosis. The onset may rarely be acute, particularly among those co-infected with HIV (Sigh et al. 1998). Other clinical features of active tuberculosis of lung parenchyma, pleura or lymph nodes may also be present. These may provide clues to the cause and nature of the spinal disease. Active or old pulmonary and pleu-

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Table 30.1. Spinal tuberculosis: clinical and investigative features AI-Othman et al. (2001) n=69 Age (mean) years 52.8 53 Sex (male %) Backache (%) 84 Fever (%) 32 Kyphosis (%) 17 Paresis (%) 28 Pulmonary tuberculosis (%) 7 Positive imaging (%) 80 Paraspinal abscess (%) 80 Positive histology (%) 57 Positive culture (%) 70 Had surgery (%) 46

Our own Rasit Leibert et al. (2001) et al. (1996) series n=53 n=26 n=212 40.2 70 94

45 70 100 57

22 44 18 47 45 44

(317)42

57

(717)100 11

4 7

ral tuberculosis may be found in 5-65% of patients with spinal tuberculosis (Fig. 31.8d - Chap. 31) (AIOthman et al. 2001). Pleural effusion may mask an underlying spinal involvement on plain chest radiography. Accidental discovery of spinal tuberculosis may be found during investigations of symptoms not directly related to the spine. Dysphagia, dyspnea, hoarseness of voice, neck pain and swelling may be the initial presenting feature of retropharyngeal abscess (Fig. 31.28 - Chap. 31) due to cervical spine tuberculosis (Tirri et al. 2000; Pollard and EI-Beheiry 1999; AI-Soub 1996; Ventura et al. 1996). It may also present as a cold abscess in the neck with or without discharging sinus formation. Posterior mediastinal shadow (Fig. 31.8 - Chap. 31) depicted by chest radiography may be an accidental finding in patients with lung parenchymal or pleural tuberculosis (Fig. 31.8 - Chap. 31). Localized back pain at the site of spinal involvement aggravated on active movement is a common feature. Pain may be referred along the spinal nerve and may be misdiagnosed as neuralgia, sciatica (Fig. 31.9 - Chap. 31) or abdominal conditions (Nussbaum et al. 1985; Humphries et al.1986). Localized spinal tenderness is usually elicited by direct percussion of the affected spine. Kyphosis or severe kyphotic deformities are commonly noted on clinical examination. The frequency of clinical symptoms, signs and other investigative features of spinal tuberculosis can be seen in Table 30.1. Cold abscess with or without discharging sinus

may also be found in the chest wall, paraspinal area (Fig. 31.11 e - Chap. 31), abdomen, groin or the thigh (Fig. 191 - Chap. 19).

34.3 47 92 64 33.5 36 26 94 68 69 53 43

30.6 Spinal Tuberculosis with Neurological Deficits Spinal tuberculosis may cause neurological deficits either early due to active disease, which is the most common cause, or rarely as late onset after treatment (Luk and Krisha 1996; Bilsel et al. 2000; Rajeswari et al. 1997). Active spinal tuberculosis may be associated with neurological deficit in 27% and up to 63% of patients (Jain et al. 1999a,b; Srivastav and Sanghavi 2000). It is more commonly reported when craniocervical junction or CI-C2 spine are involved (Fig. 31.17, 31.27, 31.28 - Chap. 31). Bhojray and colleagues (2001) reported 25 patients seen over a 12-year period with craniocervical junction tuberculosis. Conservative treatment of 16 patients and surgery on nine patients achieved good results with no serious complications. Other authors reported similar association of high incidence of neurological deficits and craniocervical junction tuberculosis (Edward et al. 2000; Jain et al.1999; Allali et al. 2000; Vaigya et al.1995; Ventura et al.1996; Parry et al.1999). Neurological deficits are commonly manifested as paraparesis or paraplegia (Fig. 31.2, 31.3, 31.5, 31.6, 31.7, 31.12, 31.13, 31.14 - Chap.31) with variable degrees of severity. Spinal tuberculosis affects adults as well as children with similar features of neurological deficit manifestations (Bilsel et al. 2000; Moon et al. 1996). Spinal tuberculosis of the cervical region may rarely cause monoplegia, hemiplegia or quadriplegia (Dharnrni et aI. 2001; Lrnejjeti et aI. 2000; Vaidya et al.1995; Hsu et al. 1984). Neurological deficits due to active spinal tuberculosis is usually caused by compression of the cord by

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granulomatous tissue mass and abscess or rarely as a result of vasculitis and vascular compression. Subluxation of the atlantoaxial joint leading to compression of the medulla oblongata and upper spinal cord is rarely reported (Allali et al. 2000). Encroachment on the spinal canal by tuberculosis abscess and granulomata was assessed by Jain et al. (1999) in 15 patients with spinal tuberculosis without neurological deficits. These authors indicated that an encroachment of up to 76% of the spinal canal by tuberculous tissue is compatible with undisturbed neural status. Paraparesis or paraplegia may develop many years after treatment with anti-tuberculous chemotherapy. Late onset paraplegia may occur as a result of reactivation of the disease, severe form of unstable kyphotic deformities, bony bridge compression or spinal stenosis above healed tuberculous kyphosis (Luk and Krishna 1996; Rajeswari et al. 1997; Bilsel et al. 2000). Painful radiculopathy of the arm with muscle weakness in the hand with a claw deformity may be the initial presenting feature. Difficulty in the diagnosis may delay the management. Gopalakrishnan and Krishna (2002) reported a patient with cervicothoracic junction spinal tuberculosis with radiculopathy.

30.7 Clinical Features in Children Spinal tuberculosis in children is almost exclusively reported from developing countries, particularly India, Africa, Hong Kong and Korea. In children, the disease is more severe, extensive and involves more vertebrae than in adults. It causes more spinal deformities, kyphosis and neurological deficits (Fig. 31.5, 31.17, 31.19, 31.28 - Chap. 31). The most frequent clinical manifestations of spinal tuberculosis in children include back pain and deformities, weakness of the legs with difficulty in walking, painful torticollis or dysphagia (Rajasekaran et al. 1998; Rajasekaran 2001; Akhadder et al. 1999; Lukhele 1996; Beekarun et al. 1995; Sayi and Mlay 1995). Neurological symptoms and signs of paraparesis or paraplegia are common among children with spinal tuberculosis. It occurs in 25-63% of children with spinal tuberculosis. The diagnosis may be initially difficult but medical treatment alone or in combination with debridement surgery are commonly associated with neurological recovery. Kyphosis and deformities are common in children with spinal

tuberculosis. Its progression may continue after medical and surgical treatment, particularly with anterior approach surgery (Rajasekaran 2001; Schulitz et al. 1997). However, many authors have different views on the best approach, either anterior or posterior, of operative debridement of the spine and the outcome of kyphosis (Upadhyay et al. 1996).

30.8 Imaging Features 30.8.1 Plain Radiography Initial early changes at the metaphyseal area anteriorly, adjacent to superior and inferior end plates, are difficult to depict on plan radiography (Sharif et al. 1989; Weaver and Lifeso 1984) (Fig. 31.1 - Chap. 31). Later, decalcification, lytic lesions may appear and are best seen on lateral view (Harisinghani et al. 2000; McGuinness 2000) (Fig. 31.1a, b - Chap. 31). The anterior boundary of the vertebral body will show diminution of the bone intensity. As the infection progresses, the overlying cortex and the disc destruction occur with loss of the vertebral body height and narrowing of the disc space (Weaver and Lifeso 1984; Harisinghani et al. 2000). Spread of infection through the intermetaphyseal communicating vessels and beneath both longitudinal ligaments, leads to involvement of contiguous or rarely to distant (skip lesions) vertebral involvement (Fig. 31.7, 31.9,31.13,31.20 - Chap. 31). As the anterior part of the vertebral bodies are the common site of infection, wedging with kyphosis is common (Weaver and Lifeso 1984). Rarely when the initial infection affects the central part (equatorial region) of the vertebral body, decalcification (lytic lesions) may be seen on lateral view (Fig. 31.14 Chap. 31). Paravertebral granulomatous tissue mass with abscess formation is usually present at the time of patient's presentation. In the cervical spine, it will appear as a retropharyngeal mass (Fig. 31.17a and 31.23a - Chap. 31). In the thoracic spine, the abscess lies between the spine and the pleural reflections of the lungs and will appear as a mediastinal fusiform soft-tissue opacity (Fig.31.8a, 31.17b - Chap.31). Lung parenchymal shadowing due to active tuberculosis may also be seen on chest radiography. In the abdomen, paraspinal abscesses are more difficult to be seen on plain radiography. The absence of the psoas muscles soft-tissue shadow is a helpful clue to

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its presence and calcification may be noted (Fig. 31.4a - Chap. 31). Posterior element involvement (pedicles, arch, spinous process) is usually secondary to vertebral body infection but rarely may occur in isolation (Fig. 31.11, 31.14 - Chap. 31). Subsequent instability and vertebral displacement may occur (Fig. 31.1 b, 31.13, 31.14 - Chap.31). Lytic lesions or localized decalcification in the posterior element due to tuberculosis may be confused with neoplastic disease.

30.8.2 Conventional Tomography Conventional tomography is still used in some developing countries where computed tomography (CT) and magnetic resonance imaging (MRI) scanning are not available (AI Arabi et al. 1992). Loss of contrast between various tissues is a disadvantage, but eliminating the images of overlying structures is its main advantage. It is a useful imaging modality in assessing occipitocervical junction tuberculosis (Fig. 31.16, 31.17 - Chap. 31).

30.8.3 Myelography Extradural granulomatous mass and abscess may only be depicted by myelography in poor developing countries where CT and MRI facilities are not available (AI Arabi et al. 1992) (Fig. 31.2, 31.12, 31.15 - Chap. 31).

30.8.4 Scintigraphy Scintigraphy is a very useful imaging modality in determining skip spinal involvement or detecting other infected sites that are not symptomatic or suspected. For details, please see the chapter entitled, Scintigraphy

30.8.5 CTScans CT or its more advanced versions will show all the changes that are depicted on plain radiography (Sharif et al.1995a, 1989; Lin-Greenberg and Cholankeril1990; AI Arabi et al.1992; Jain et al.1993; McGuinness 2000). In addition, CT shows the surrounding soft-tissues, paraspinal abscesses and the spinal canal. The extent

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of the vertebral damage, disc destruction and softtissue calcification are better seen by CT scan than by plain radiography. The main disadvantage of CT scan is that only the chosen field is visualized, not the whole area affected. CT guided abscess drainage and tissue biopsy are mandatory and needed during investigation and imaging assessment of spinal tuberculosis. Early vertebral body lesions may appear as focal lowdensity, homogenous areas with regular boundaries and are the characteristic findings on CT scan. As the infection progresses, intraosseous abscesses with bone fragments and pus will be seen in the vertebral body as depicted by CT scan (Fig. 31.1c, 31.2d & e, 31.4, 31.6, 31.10 - Chap. 31). Destruction of the vertebral body and intervertebral disc, development of paravertebral abscess and posterior element involvement can be seen as the disease advances (Fig. 318d & f, 31.13 - Chap. 31). Encroachment of the spinal canal by granulomatous tissue and abscess, extradural compression and displacement ofthe cord can be assessed by CT scan (Fig. 31.13d, 31.15, 31.17, 31.18, 31.27 - Chap.31). In late stage, both osteolytic and sclerotic areas may be present in the vertebral body, particularly after initiating treatment (Fig. 31.15 - Chap. 31). Severe kyphosis and dislocation may be difficult to image axially by CT scan (Fig. 31.22, 31.24, 31.26d - Chap. 31).

30.8.6 MRllmaging The MRI is the diagnostic imaging of choice for spinal tuberculosis. It has the advantage of detecting skip spinal lesions, anterior and posterior ligament involvement and extradural extension of the disease (Sharif et al. 1990, 1995; McGuinness 2000). Decreased signal intensity of the affected vertebrae, loss of disc height and para-vertebral swelling are typically depicted by T 1 weighted images (Fig. 31.5, 31.7,31.9,31.16, 31.17f, 31.27 d & e - Chap. 31). T zweighted images often show increased signal intensity of the vertebrae affected and the surrounding inflammatory soft-tissue around it. Post-gadolinium contrast images will show the rim enhancement of the surrounding tissues, the anterior and posterior ligaments, the dura mater and will also show the degree of cord compression (AI-Mulhim et al. 1995). Para-vertebral abscesses will be depicted as isotonic or low-intensity signals on T 1 weighted images. High signal intensity of the para-vertebral abscesses will be depicted on T z weighted images. Soft-tissue calcifications are difficult to recognize by MRI and better seen on CT scans.

Spinal Tuberculosis

30.9 Diagnosis

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mild diabetes mellitus that was well controlled by diet and glibenclamide 5 mg daily. He had a myelogram and CT scan of the lumbar spine while in Qatar that Spinal tuberculosis may initially be difficult to diag- revealed a soft tissue density in the spinal canal as nose or differentiate from other causes of spinal disor- well as paravertebral region at L4-5 levels. Isotope ders such as infections, malignancies or rheumatic dis- bone scan showed increased uptake at L5. The patient eases. The scarcity of distinctive clinical features may declined surgery and went to private doctors and cause delay in diagnosis with subsequent increased received non-steroidal anti-inflammatory drugs. morbidity. Imaging modalities play an important On arrival at our hospital the patient looked ill, investigative role in providing clues to the diagnosis with fever, severe low back pain that was radiating when used in conjunction with clinical, microbiologi- to the right lower limb, and difficulty in walking. His cal and histopathological findings. Granulomatous temperature was 39.8°C but other vital signs were infections of the spine are common in developing normal. There was no lymphadenopathy, hepatic or countries, particularly those due to tuberculosis and splenic enlargement, and other systems were normal. brucellosis and rarely due to fungal infections or sar- Neurological examination showed loss of lumbar lordosis, paraspinal muscle spasm and tenderness in coidosis (Madkour and Sharif 2001). In developing countries where both tuberculosis the L4-5 region. Straight leg raising was restricted to and brucellosis are endemic, spinal involvement by 30° bilaterally. Knee and ankle tendon reflexes were either or both infections can be difficult to diag- normal, and both plantars were flexor. There were no nose. In our part of the world, when both diseases sensory deficits. are endemic, all patients presenting to our medical The hemogram was normal, apart form a raised facilities with back pain are routinely screened for ESR (35 mm/h). Brucella agglutinins showed Agg: brucellosis (Madkour 1989; Madkour and Sharif 2560, IgG (2ME): 640, Coomb's: negative. Blood cul2001; Madkour et al. 1985, 1987, 1988; Sharif et al. tures were negative. 1989, 1990, 1995). Samples for histopathological and Plain radiographs of the spine showed erosion microbiological examinations obtained by CT guided at the posterior inferior aspect of the body of L5 tissue biopsies and pus aspirations of spinal lesions (Fig. 30.1). Isotope bone scan showed increased and paraspinal abscess are essential for the confir- uptake at L4 and L5 regions. CT scan of the spine mation of the diagnosis. The detection of active lung showed erosion and destructive infective lesion of L5. parenchymal tuberculosis, lymph nodes enlarge- MRI of the lumbar spine showed diffuse loss of signal ment, cold abscess or discharging sinuses provides from the bodies of L4 and L5 on the short TR view. additional sources of samples for histopathological Long TR view showed extensive soft tissue component and microbiological evidences of the diagnosis. in the posterior aspect of L4 and L5 (Fig. 30.1). Soft Other laboratory data, such as the hemogram, sedi- tissue (granulation) in the spinal canal was noted. The mentation rate (ESR), biochemical parameters and disc space was within normal limits. CT scan-guided tuberculin skin test do not provide confirmatory needle biopsies of the vertebral body and soft tissues were carried out. They showed chronic inflammatory evidences of the diagnosis. cell infiltrates but no granulomata. The patient was initially treated with doxycycline 100 mg twice daily and netilmicin 150 mg 8-hourly intravenously with 30.9.1 Case Illustration regular measurements of plasma levels. The patient did not respond to treatment and A 42-year-old man was referred to our hospital in remained febrile. Anterior spinal decompression and January 1988. He had had brucellosis diagnosed bone grafting of the L4-5 region was carried out. At in Qatar in May 1987. Brucella melitensis organ- operation an abscess, originating in the L4-5 region isms were grown from the blood and his brucella and extending down to the iliac fossa, was noted. agglutinins were high. He used to drink goat and About 50 ml of pus was drained from the abscess. camel's milk. He was treated with a combination Extensive granulation tissue was seen in the L4-5 of streptomycin and tetracycline for 2 weeks, and region, pressing anteriorly on the dura. A smear of tetracycline alone for a further 4 weeks. Although the drained pus showed tubercle bacilli. Netilmicin and doxycycline were replaced with he responded initially to this treatment, the patient remained symptomatic with persistent low back pain, rifampicin 600 mg, isoniazid 300 mg and ethambutol fever, chills, sweating and weight loss. The patient had 1.2 g daily. The patient responded well to anti-tuber-

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a

b

e

Fig. 30.1. A 42-year-old man with brucellar and tuberculous spondylitis. Patient's brucella titer on admission was 1:20, 840. B. melitensis was isolated from the blood. a Frontal radiograph showing early formation of a lateral osteophyte in the right side (arrow). b Lateral radiograph. There is a minimal reduction of the disc at L4/L5. Minimal cortical loss is noted in the posterior aspect of the inferior end plate ofL4 (arrow). c Anterior scintigram showing diffuse increased uptake in the bodies of L4 and L5. The disc is still seen as a photopenic area. d Patchy bone destruction in the bodies of L4 and L5, and large extradural mass compromising the spinal canal. e Mid-sagittal cut on magnetic resonance imaging (short TRITE) showing

c

loss of signal in L4 and L5. The disc space does not appear to be reduced but there is a large extradural component that was high signal compared to cerebrospinal fluid (arrows). Acid-fast bacilli were isolated from around 50 ml of fluid drained from a paraspinal abscess at operation

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culous chemotherapy and the temperature settled. The back pain and sciatica improved. Culture of the pus did not grow the tubercle organisms. He is being followed up in the orthopedic as well as brucellosis clinics. This patient had spondylitis probably due both to concomitant brucella and tuberculous infections. While brucellosis was treated, his symptoms persisted. It is only at operation that tubercle bacilli were positively identified by direct smear. Cultures from the pus were negative.

30,10,

Spinal Tuberculosis Versus Spinal Brucellosis Several studies were carried out by our group, at Riyadh Military Hospital, on the clinical and imaging features of spinal brucellosis as well as a

comparison with spinal tuberculosis. Both of these granulomatous diseases of the spine are common in Saudi Arabia. They share many clinical and imaging features and co-infections, although rare, often lead to difficulties in diagnosis (Madkour 1989; Madkour and Sharif 2001; Madkour et al. 1985, 1987, 1988; Sharif et al. 1989,1990,1995). We encountered occasional cases of spinal tuberculosis in children but have never seen it due to brucellosis in this age group. The onset of symptoms of spinal tuberculosis is commonly gradual, but in brucellosis spinal symptoms are usually acute. Tables 30.2-30.4 summarize the clinical and imaging features of 17 patients with spinal brucellosis and 15 patients with spinal tuberculosis that we prospectively evaluated. Pyogenic spinal infections usually have a more acute presentation with symptoms of sepsis and septicemia. No cardiosis and actinomycosis may present with more insidious onset and course (Sharif et al. 1990). Metastatic disease of the spine may be dif-

Table 30.2. Patient population, age and sex distribution, anatomic sites of lesions and invasive procedures performed. Note: numbers in parentheses are percentages Type of infection

Brucellar spondylitis

Sex distribution

Age distribution (years)

Number of affected sides

Site of lesions

Male

Female

Range

Average

12

5

43-70

61

19"

3(16)

7

8

30-66

51

15

0

Cervical

Patients who underwent

Thoracic

Lumbar

3(16)

13(68)

11(73)

4(27)

Surgery

Biopsy 6

(n=17)

Tuberculosis spondylitis

5b

13

(n=15)

"Two patients had double lesions in two different sites b Two patients underwent both percutaneous biopsy and surgical decompression

Table 30.3. Plain radiographic findings. Note: none of the patients had involvement of posterior elements. Numbers in parentheses are percentages Type of infection

Brucellar spondylitis

Number of affected vertebrae

Bone destruction of single vertebra

Bone sclerosis of single vertebra

Disk involvement

Focal

Focal

Disk space Disk gas

Diffuse

Diffuse collapse

38

20

1(2.6)

18"

0

16

5

0

34

4

29(82)

0

11

14

0

lIb

(n=17)

Tuberculous spondylitis

Paravertebral soft tissue spinal mass (per site)

(n=15)

" Anterior osteophytes (parrot's beak) were seen in 14 vertebrae b Abscesses not identified on radiographs included an upper thoracic lesion (T4 to T5) and three lumbar lesions. 'No associated spinal deformity was detected in six patients (three thoracic and three lumbar lesions)

Associated deformity (per site)

2(10.5)

9'

M. M. Madkour et al.

490

Table 30.4. High-resolution findings. Note: numbers in parentheses are numbers of sites Type of infection

Number Bone destruction Bone sclerosis of single vertebra of affected of single vertebra vertebra Focal

Brucellar spondylitis

Diffuse

Paraspinal soft tissue abnormality (per site)

Focal Diffuse Abscess Granulation Loss of tissue muscle fat planes

34(16)

26

8

17

0

0

Tuberculous 32(24) spondylitis

2

32

0

11

14'

6

Bone fragDisk Epidural ments or gas Extension calcifications

11

8

9

0

14

(n=14)a 0

5

(n=14)b a Nine

patients underwent contrast-enhanced computed tomography patients underwent contrast-enhanced computed tomography 'Three patients with thoracic lesions had vertebral abscesses communicating with coexisting pleural collections; one of these abscesses was extending into the erector spinae b All

ficult to differentiate without a tissue biopsy. Other diseases that may mimic spinal tuberculosis include fungal infections, hydatid disease and syphilis.

30.11 Anti-Tuberculous Chemotherapy for Spinal Tuberculosis Chemotherapy for spinal tuberculosis remains the cornerstone of treatment and should be started early, promptly and for adequate period to avoid the occurrence ofneurological complications (Boachie-Adjei and Squillante 1996; Jain 2002; Shembekar and Babhulkar 2002; Tuli 2002). Prompt chemotherapy can reverse neurological deficits and minimize the potential disability resulting from spinal tuberculosis. Neurological deficits in association with active spinal tuberculosis can be reversed and potential disabilities can be minimized successfully with combination of chemotherapy and surgical decompression (Govender et al. 2001a-c; Bailey et al. 1972; Chahal and Jyothi 1990; Garst 1992; Hodgson and Stock 1960; Lifeso et al.1985; Lifeso 1987; Martin 1970; Tuli et al. 1967). A combination of chemotherapy and surgical decompression is associated with successful outcome in most patients with spinal tuberculosis complicated with neurological deficits (Medical Research Council 1978). Surgery for patients without neurological deficits may only be required in about 6%, while among those with neurological deficits, it may be required in up to 60% (Upadhyay et al. 1993). The overall surgical rate of spinal tuberculosis with and without neurological deficit was reported as 49.5% by Lifeso and colleagues from

Riyadh, Saudi Arabia (Lifeso et al. 1985; Lifeso 1987). The chemotherapy success rate for osteoarticular TB is estimated as greater than 90% (Barnes and Barrows 1993; Satoskar et al.1999). The outcome of chemotherapy, however, is guarded by some problems such as the chronicity, development of drug resistance and toxicity, poor patient compliance and the presence of other diseases that compromise patients immunity such as HIV, diabetes mellitus and alcoholism (Shembekar and Babhulkar 2002). The most commonly used regimen of chemotherapy is the initial use of first line drugs (rifampicin and isoniazid with pyrazinamide or streptomycin) for 2 months in a daily dosing. This is followed by a minimum of 4- to 8-month period using two drugs (rifampicin and isoniazid) in a daily dosing. Other regimen using two or three times a week given as directly observed therapy (DOT) can also be used (see chapter on DOT). For patients with drug resistant tuberculosis, please refer to Chap. 46 (multidrug resistant TB). Non-tuberculous mycobacterial infections are usually resistant to first and second line drugs. Amikacin, fluoroquinolone, rifabutin and clarithromycin are effective agents for the treatment of these infections (Barnes and Barrows 1993; Mandell and Petri 1987; Shembekar and Babhulkar 2002).

References Akhaddar A et al (1999) Craniocervical junction tuberculosis in children. Rev Rhum Engl Ed 66:739-742 Al Arabi KM, al Sebai MW et al (1992) Evaluation of radiological investigations in spinal dtuberculosis. Int Orthop 16:165-167 Allali F et al (2000) Atlantoaxial tuberculosis: three cases. Joint Bone Spine 67:481-484

Spinal Tuberculosis Al-Mulhim FA, Ibrahim EM et al (1995) Magnetic resonance imaging of tuberculous spondylitis. Spine 20:2287-2292 AI-Othman A et al (2001) Tuberculous spondylitis: analysis of 69 cases from Saudi Arabia. Spine 26:E565-E570 Al-Soub H (1996) Retropharyngeal abscess associated with tuberculosis of the cervical spine. Tuberc Lung Dis 77: 563-565 Bailey Hi, Gabriel M, Hodgson AR et al (1972) Tuberculosis of the spine in children. Operative findings and results in one hundred consecutive patients treated by removal of the lesion and anterior grafting. J Bone Joint Surg 54A:1633-1657 Barnes PF, Barrows SA (1993) Tuberculosis in the 1990's. Ann Intern Med 119:400-410 Beekarun DD et al (1995) Atypical spinal tuberculosis in children. J Pediatr Orthop 15:148-151 Bhojraj et al (2001) Tuberculosis of the craniocervical junction. J Bone Joint Surg Br 83:222-225 Bilsel N et al (2000) Late onset paraplegia. Spinal Cord 38: 669-674 Boachie-Adjei 0, Squillante RG (1996) Tuberculosis of the spine. Orthop Clin North Am 27:95-103 Chahal AS, Jyothi SP (1990) The radical treatment of tuberculosis of the spine. Int Orthop 4:93-99 Cosivi 0, Grange JM et al (1998) Zoonotic tuberculosis duets Mycobacterium bovis in developing countries. Emerg Infect Dis 4:59-70 Danesh-Clough T et al (2000) Mycobacterium xenopi infection of the spine: a case report and literature review. Spine 25: 626-628 Dhammi IK, Singh S, Jain AK (2001) Hemiplegic/monoplegic presentation of cervical spine (C l-C2) tuberculosis. Eur Spine J 10:540-544 Doub HP, Badgley CE (1932) The roentgen signs of tuberculosis of the vertebral body. Am J RoentegenoI27:827-837 Edwards RJ et al (2000) Management of tuberculomas of the craniocervical junction. Br J Neurosurg 14:600 Garst RJ (1992) Tuberculosis ofthe spine: a review of236 operated cases in an underdeveloped region from 1954 to 1964. J Spinal Disord 5:286-300 Gopalakrishnan D, Krishna KN (2002) Cervico-thoracic junction spinal tuberculosis presenting as radiculopathy. Neurol India 50:93-94 Govender S et al (2000) Spinal tuberculosis in HIV positive and negative patients: immunological response and clinical outcome. Int Orthop 24:163-166 Govender S et al (2001a) Anterior spinal decompression in HIV positive patients with tuberculosis. A prospective study. J Bone Joint Surg Br 83:864-867 Govender S et al (2001b) Long-term follow-up assessment of vascularized rib pedicle graft for tuberculosis Kyphosis. J Pediatr Orthop 21:281-284 Govender S et al (2001c) Tuberculosis of the cervicodorsal junction. J Pediat Orthop 21:285-287 Griffths DLL (1979) The treatment of spinal tuberculosis. In: McKibbin B (ed) Recent advances in orthopaedics. Churchill Livingstone, Edinburgh, pp 1-17 Harisinghani MG et al (2000) Tuberculosis from head to toe. Radiographics 20:449-470 Hodgson AR, Stock FE (1960) Anterior fusion for the treatment of tuberculosis of the spine: the operative findings and results of treatment in the first one hundred cases. J Bone Joint Surg 41A:295-310 Houshian S et al (2000) Bone and joint tuberculosis in Denmark: increase due to immigration. Acta Orthop Scand 7:312-315

491 Hsu LCS, Cheng CL et al (1984) Tuberculosis of the lower cervical spine (C2 to C7). J Bone Joint Surg 66B:I-5 Hsu LCS, Cheng CL et al (1988) Potts paraplegia of late onset. J Bone Joint Surg 70B:534-538 Humphries MJ et al (1986) Spinal tuberculosis presenting with abdominal symptoms - a report of two cases. Tubercle 67: 303-307 Jain AK (2002) Treatment of tuberculosis of the spine with neurologic complications. Clin Orthop Relat Res 398:75-84 Jain AK,Aggarwal A, Mehrotra G (1999a) Correlation of canal encroachment with neurological deficit in tuberculosis of the spine. Int Orthop 23:85-86 Jain AK, Kumar S, Tuli SM (1999b) Tuberculosis of the spine (CI-D4). Spinal Cord 37:362-369 Jain R, Sawhney S, Berry M (1993) Computer tomography of vertebral tuberculosis: patterns of bone destruction. Clin RadioI47:196-199 Jellis JE (1995) Bacterial infections: bone and joint tubeculosis. Bailliere's Clin Rheumatol 9:151-159 Jellis JE (1996) Orthopaedic infection associated with HIV disease. Surgery 12:175-177 Jellis JE (2002) Human immunodeficiency virus and osteoarticular tuberculosis. Clin Orthop Relat Res 398:27-31 Kanaan IV et al (1999) Craniocervical junction tuberculosis: a rare but dangerous disease. Surg Neurol 51:21-25 Leibert E et al (1996) Spinal tuberculosis in patients with human immunodeficiency virus infection: clinical presentation, therapy and outcome. Tuberc Lung Dis 77:329-334 Lifeso RM (1987) Atlantoaxial instability in adults. J Bone Joint Surg 69B:183-187 Lifeso RM, Weaver P, Harder EH (1985) Tuberculous spondylitis in adults. J Bone Joint Surg 67A:1405-1413 Lin-Greenberg A, Cholankeril J (1990) Vertebral arch destruction in tuberculosis. J Comput Assist Tomogr 14:300-302 Lmejjati M et al (2000) Tumor-like tuberculosis of the sacrum. Joint Bone Spine 67:468-470 Luk KD, Krishna M (1996) Spinal stenosis above a healed tuberculous Kyphosis. A case report. Spine 21:1098-1101 Lukhele M (1996) Tuberculosis of the cervical spine. S Afr Med J; 86:663-556 Madkour et al (1987) Radiological features of Brucella spondylitis. American Roentgen Ray Society, 87th annual meeting, paper no 1,154,155 Madkour MM (1989) Occupational related infectious arthritis. In: Balint GP, Buchanan WW (eds) Baillihes clinical rheumatology: occupational rheumatic diseases, vol 3. Saunders, London, pp 157-192 Madkour M, Sharif H (2001) Bone and joint imaging. In: Madkour M (ed) Madkour's brucellosis, 2nd edn. Springer, Berlin Heidelberg New York, pp 90-132 Madkour M et al (1985) Brucellosis in Saudi Arabia. Saudi Med J 6:324-332 Madkour M et al (1988) Osteoarticular brucellosis: results of bone Scintigraphy in 140 patients. AJR 150:1101-1105 Mandell GL, Petri WA Jr (1987) Drugs used in the chemotherapy of tuberculosis, M avium complex disease and leprosy. In: Hardmen JG, Gilman AG, Limbird LE (eds) Goodman and Gillman's: The pharmocological basis of therapeutics, 9th edn. McGraw-Hill, New York, pp 1155-1174 Marketos SG, Skiadas PK (1999) Galen: a pioneer of spine research. Spine 24:2358-2362 Martin NS (1970) Tuberculosis of the spine: J Bone Joint Surg 52B:613-628

492 Martin NS (1971) Paraplegia. A report on 120 cases. J Bone Joint Surg 53B:596-608 McGuinness F (2000) Tuberculous spondylitis. In: McGuinness F (ed) Clinical imaging of non-pulmonary tuberculosis. Springer, Berlin Heidelberg New York, pp 43-80 Medical Research Council (1978) Working part on tuberculosis of the spine: a controlled trial of anterior spinal fusion and debridement in the surgical management of tuberculosis of the spine in patients on standard chemotherapy: a study in two centers in South Africa. Tubercle 59:79-105 Moon MS, HA KY, Sun DH et al (1996) Pott's paraplegia. Clin Orthop 323:122-128 Nussbaum ES et al (1985) Spinal tuberculosis: a diagnostic and management challenge. J Neurosurg 83:243-247 O'Reilly LM, Daborn CJ (1995) The epidemiology of Mycobacterium bovis infections in animals and man. Tubercle Lung Dis 16:1-46 Okuyama Y et al (1996) Tuberculous spondylitis (Pott's disease) with bilateral pleural effusion. Intern Med 35: 883-885 Parry 0, Bhebhe E, Levy LF (1999) Non-traumatic paraplegia in a Zimbabwean population - a retrospective survey. Cent Afr J Med 45:114-119 Pertuiset E et al (1999) Spinal tuberculosis in adults. A study of 103 cases in a developed country 1980-1994. Medicine (Baltimore) 78:309-320 Pollard BA, El-Beheiry H (1999) Pott's disease with unstable cervical spine, retropharyngeal cold abscess and progressive airway obstruction. Can JAnaesth 46:772-775 Rajasekaran S (2001) The natural history of post-tuberculous Kyphosis in children. Radiological signs which predict late increase in deformity. J Bone Joint Surg Br 83:954-962 Rajasekaran S, Shanmugasundaram TK (1987) Prediction of the gibbus deformity in tuberculosis of the spine. J Bone Joint Surg 69A:503-509 Rajasekaran S et al (1998) Tuberculous lesions of the lumbosacral region. A IS-year follow-up of patients treated by ambulant chemotherapy. Spine 23:1163-1167 Rajeswari R et al (1997) Late onset paraplegia - a sequelae to Pott's disease. A report on imaging, prevention and management. Int J Tuberc Lung Dis 1:468-473 Rasit AJ et al (2001) The pattern of spinal tuberculosis in Sarawak General Hospital. Med J Malaysia 56:143-140 Rezai AR et al (1995) Modern management of spinal tuberculosis. Neurosurgery 36:87-97 Sanders WE Jr, Horowitz EA (1995) Other mycobacterium species. In: Mandell GL, Benett JE,Dolin R (eds) Principles and practice of infectious disease, 4th edn. Wiley, New York, pp 2264-2272

M. M. Madkour et al. Satoskar RS,Bhandarkar SD,Ainapure SS (1999) Chemotherapy of tuberculosis. Pharmacology and pharmacotherapeutics, 16th edn. Popular Prakhashan, Mumbai, India, pp 713-729 Sayi EN, Mlay SM (1995) Tuberculosis of the spine in children at Muhimbili Medical Center - Dar es Salaam. East Afr Med J 72:46-48 Schulitz KP et al (1997) Growth changes of solidly fused Kyphotic bloc after surgery for tuberculosis. Comparison offour procedures. Spine 22:1150-1155 Sharif HS et al (1989) Brucellar and tuberculous spondylitis: Comparative-imaging features. Radiology 171:419-425 Sharif HS et al (1990) Granulomatous spinal infection: MR imaging, Radiology 177:101-107 Sharif HS et al (1995a) Role of MRI and CT imaging in the management of tuberculous spondylitis. Radiol Clin North Am 33:787-804 Sharif HS et al (1995b) Role of MRI in the management of spinal infections. AJR Am J RoentgenoI158:1333-1345 Shembekar A, Babhulkar S (2002) Chemotherapy of osteoarticular tuberculosis. Clin Orthop Relat Res 398:20-26 Singh Bet al (1998) Isolated cervical tuberculosis in patients with HIV infection. Otolaryngol Head Neck Surg 118:766-770 Srivastava S, Sanghavi NG (2000) Non-traumatic paraparesis: Aetiological, clinical and radiological profile. J Assoc Physic India 48:988-990 Tirri R et al (2000) Pott's disease of the lower cervical spine in a diabetic patient. Monaldi Arch Chest Dis 55:205-207 Tuli SM (2002) General principles of osteoarticular tuberculosis. Clin Orthop Relat Res 398:11-19 Tuli SM, Srivastava TP, Varma BP, Sinha GP (1967) Tuberculosis of the spine. Acta Orthop Scand 38:445-458 Upadhyay SS, Sell P, Saji MJ et al (1993) Seventeen year prospective study of surgical management of spinal tuberculosis in children. Spine 18:1704-1711 Upadhyay SS et al (1996) The effect of age on the change in deformity after anterior debridement surgery for tuberculosis of the spine. Spine 21:2356-2362 Vaidya MK, Shah GV, Bharucha KE (1995) Pregnancy and its outcome in quadriplegia due to Pott's spine. Int J Gynaecol Obstet 49:319-321 Van Staden H (1992) The discovery of the body: human dissection and its cultural contexts in ancient Greece. Yale J Bioi Med 65:223-241 Ventura G et al (1996) Pott's Disease of the cervico-occipital junction in an AIDS patient. Tuberc Lung Dis 77:188-190 Weaver P, Lifeso R (1984) The radiological diagnosis of tuberculosis of the adult spine. Skeletal RadioI12:178-186 Weiner BK et al (1998) Mycobacterium avium intracellulare: vertebral osteomyelitis. JSpinal Disord 11 :89-91

31 Surgical Management of Spinal Tuberculosis M. WASEF

AL

SEBAI, M. MONIR MADKOUR,

CONTENTS 31.1 31.2

History of Tuberculosis Spinal Surgery 493 Pathogenesis, Clinical and Laboratory Features 494 Imaging Features 494 Plain Radiography 494 Conventional Tomography 514 Myelography 514 CT Features 514 MRI Features 514 Scintigraphy 518 Treatment ofTB Spine 518 Antibiotics With or Without Surgery (MRC Trials) 518 Operative Treatment 519 Indications for Surgical Intervention 519 Approaches and Surgical Techniques 522 Needle Biopsy (Under Fluoroscopic or CT Guidance) 522 Drainage of Abscesses 522 Debridement of Tuberculous Lesion 522 Spinal Fusion 523 Instrumentation 523 Decompressive Techniques and Treatment of Paraplegia 524 Surgical Treatment of Kyphosis 524 Cervical TB 530 Summary 530 References 532

K. R. AL

MOUTAERY

31.1 History of Tuberculosis Spinal Surgery

Surgical intervention in the treatment of spinal tuberculosis (TB) antedated the discovery of the antibiotics. Although some of these innovative surgical procedures were successful, the outcome was poor due to the fact that surgery was not supplemented with the yet undiscovered anti-microbial agents. Surgical treatment of TB spondylitis was first described by Sir Percival Pott in 1779 who performed autopsies on patients with TB spondylitis, which was later named after him, i.e.,"Pott's disease" (Pott 1936). 31.6 Laminectomy was the most popular surgical 31.7 intervention for the management of TB spondylitis 31.8 till Seddon in 1934-1935 abandoned it as it caused 31.8.1 further spinal instability. 31.8.2 Posterior spinal fusion was first described by two 31.8.3 separate authors in 1911 (Albee 1911; Hibbs 1911). 31.8.4 The idea of posterior spinal fusion was abstracted 31.8.5 31.9 from the fact that the natural sequence of events of TB joint healing was associated with ankylosis. 31.10 These two authors described their procedure using 31.11 this observation and aimed at speeding recovery. 31.12 However, such a surgical technique did not arrest the progression of kyphosis or alter the outcome of paraplegia. Posterior decompression through costotransversectomy was successful in surgical management of paraplegia (Menard 1894). However, most of these patients developed secondary infections. Anterior spinal surgical technique was described by Ito et al. in 1934 as a "New radical operation for Pott's disease:' This approach certainly provided a wider field of exposure, which allowed better M. W. AL SEBAl, FRCS, FACS debridement and fusion. Consultant Spinal Surgeon, Riyadh Armed Forces Hospital, After the discovery and availability of antibiotHonorary Assistant Professor, King Saud University, P.O. Box ics in 1945, antibiotics and anterior spinal surgical 7897, Riyadh 11159, Saudi Arabia M. M. MADKOUR, MD, DM, FRCP technique in combination made a major impact on Consultant, Department of Medicine, Riyadh Armed Forces the prognostic outcome of TB spine. Subsequently, Hospital, P.O. Box 7897, C-119, Riyadh 11159, Saudi Arabia several trials on treating TB spine using anti-TB antiK. R. AL MOUTAERY, MD, FRCS (Ed), FACS biotics with or without surgery have been reported in Head of Neurosurgery, Riyadh Armed Forces Hospital, the world literature. P.O. Box 7897, Riyadh 11159, Saudi Arabia

31.3 31.3.1 31.3.2 31.3.3 31.3.4 31.3.5 31.3.6 31.4 31.5

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

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One of these major trials was carried out in 1956 by Hodgson and Stock in Hong Kong. These authors adopted the anterior spinal approach with radical excision and strut graft fusion to prevent both kyphosis as well as late-onset paraplegia. They were successful in their trial and managed to reduce post-operation hospitalization period remarkably. Similar large-scale prospective trials on treatment of TB spondylitis were sponsored by the British Medical Research Council (BMRC) working party. Several reports from BMRC were published between 1973 and 1999 (BMRC 1973a,b, 1974, 1974, 1976, 1978a,b, 1982, 1985, 1986, 1989, 1998, 1999). Some of these reports will be discussed later in the text of this chapter.

31.2 Pathogenesis, Clinical and Laboratory Features See spondylitis and neuro-TB chapter.

31.3 Imaging Features I. II. III. IV. V. VI.

Plain radiography Conventional tomography Myelography Computed tomography (CT) Magnetic resonance imaging (MRI) Scintigraphy

31.3.1 Plain Radiography

Early vertebral body metaphyseal TB osteomyelitis may initially appear as normal, using plain radiography. Later, as tuberculoma lesions expand and enlarge, the vertebral body becomes decalcified and edematous can be depicted by plain radiography, computed tomography (CT) and magnetic resonance imaging (MRI). Decalcification of the lower or upper anterior margin of the vertebral body may appear as diminution of the intensity of the "White-stripe" boundary (Fig.31.1). These early changes can be demonstrated better on lateral view than anteriorposterior images. As the infection progresses it

spreads to the cortex and the intervertebral disc, leading to its destruction. As the vertebral body softened, bulging of the disc occurs - "Intervertebral herniation of disc". This will lead to decrease in vertebral-body height and slight narrowing (in contrast to pyogenic infection) of the disc space. Spread of infection via the intermetaphyseal communicating vessels may lead to infection of vertebral bodies above and/or below the original focus of infection (Fig. 31.2). As the anterior part of the vertebral bodies is primarily affected, associated with intervertebral disc sequestration and herniation, kyphosis and wedging of the vertebral bodies follow (Fig. 31.2). Unequal involvement of vertebral bodies and muscle spasm secondary to unilateral psoas abscess may produce scoliosis in few cases. (Figs. 31.3-31.5). A distant skip lesion high up in the thoracic or cervical spine may occur in about 4% of patients (Figs. 31.6, 31.7). Sharif and colleagues (1993) from our hospital reported skip lesions at different levels. Paravertebral abscess may be present at the time of presentation of the patient. In the thorax, the abscess masses can be readily seen on plain radiography of the mediastinum. They appear as more dense and fusiform in shape in contrast to the lucent lung tissue (Figs. 31.2, 31.8). Paraspinal TB abscesses are difficult to visualize if they occur at the dorso-lumbar junction. In the lumbar region, paraspinal abscesses can be detected when they obliterate the retroperitoneal tissue planes or if they contain calcification (Fig. 31.9). Rarely, sclerotic lesions of the vertebral bodies, as part of healing, may occur in patients with active disease process (Fig. 31.10). Posterior-element infection with bone destruction may involve one or both of the vertebral pedicles, the whole of the neural arch or the spinous process (Fig. 31.11). Neural arch tuberculous infection associated with paraspinal abscess was noted in seven of our patients (Fig. 31.11). Tuberculous infection may occur in single vertebral body and may lead to vertebral collapse with plain radiography appearances similar to those of metastatic carcinoma (Figs.31.12, 31.13). Such presentations were noted in five adult patients in our series (a feature that is less common in adults than children). Subluxation secondary to spinal TB was reported in the cervical spine, particularly the upper cervical spine; similar findings were seen in a few patients with thoracolumbar involvement (Figs. 31.1,31.14). Advanced cases with affection of long segment of the spine are currently rarely seen (Fig. 31.15).

Surgical Management of Spinal Tuberculosis

495

a

b

c

d Fig. 31.1. Early tuberculous spondylitis in a 17-year-old male who presented with back pain. a Lateral x-ray shows early lesion at lower inferior border of L[ (arrow). b There is destruction of the lower part of L[ and the upper part of Lz. L1 body is posteriorly displaced with facet joint subluxation 6 weeks later (arrow). c Computed tomography reveals minimal degrees of bone destruction, small soft-tissue shadow and bifacetal subluxation (arrows). d Lateral x-ray film taken 14 months after a two-stage operation shows sound fusion and maintained reduction of subluxation

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M. W. Al Sebai et al.

Fig. 31.2. This is a 26-year-old female who presented with back pain and incomplete paraplegia. a, b Anteroposterior and lateral radiographs show classical Pott's disease of the lower half of T9 and the upper part of TIO. Note: the paravertebral soft-tissue shadow on AP view (arrowheads) and the degree of kyphosis on the lateral view (40°). c Myelography shows a total spinal blockage of the dye at TIO (arrow). d, e Post contrast computed tomography scan shows osteolytic lesion of T9, 10 and 11. Note: the cord compression by the epidural abscess (arrowheads) with dye appearance at T9 and TIO levels

497

Surgical Management of Spinal Tuberculosis

a

b

c Fig. 31.3. This is a 28-year-old male who presented with back pain and progressive paraplegia. a Plain radiography demonstrating bilateral paravertebral abscess (arrowheads) and scoliosis of 19° because of unequal involvement of vertebrae. b Lateral view shows severe destruction of TI2, partial affection of lower part of TIl, loss of the disc space in between TIl and TI2 (arrow) and localized kyphosis of 29°, c, d Anteroposterior and lateral radiography after two-stage operation shows correction of deformity on both planes

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a

c

Fig. 31.4. This is a 26-year-old female who presented with back pain, loin pain and abdominal swelling. a Anteroposterior radiography shows minimal destruction of L2 and L3 bodies and scoliosis mainly because of muscle spasm. Note absence of psoas shadow on the same side (arrow). b Computed tomography shows huge unilateral abscess (arrowhead). c Post-operative x-ray shows correction of deformity

b

b[>

a Fig.31.5. This is a 13-year-old girl who presented with back pain, deformity and progressive paraplegia. She was referred as a case of congenital kyphoscoliosis with neurological complication. a, b Plain radiographic examination demonstrates kyphoscoliosis with L" looks like a hemivertebra (black arrowhead). Note that the pedicle and posterior elements are not seen on one side (white arrowhead) with obliteration of the disc space between T12 and L,.

499

Surgical Management of Spinal Tuberculosis

c

d

e

g

f

h c, d, e Magnetic resonance imaging (MRI) study indicates diminished signal in the body of L[ on n (arrow), and increased signal intensity on T2 (arrowhead). On post-gadolinium n, MRI, there is enhancement of the remaining destroyed body, there is extensive anterior spinal abscess (arrow) and cord compression by epidural abscess (arrowhead). fAxial scan demonstrates affection of posterior and anterior columns of L[ (arrowheads). g, h Post-operative x-ray films following two-stage operation shows correction of deformity and fusion

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M. W. Al Sebai et al.

a

c Fig. 31.6. This is a 25-year-old lady who presented with abdominal pain and fever. Investigations revealed incomplete intestinal obstruction and destructive lesion in the lower thoracic spine causing lower extremities weakness. Lumbar spine was noticed to be minimally affected. She was operated on by two-stage operation for the lower thoracic lesion 2 weeks after start of antituberculous treatment. Patient continued to have constitutional symptoms and lymphopenia. Lumbar spine lesion continued to deteriorate and necessitated radical debridement after extension of the fixation and fusion of the lumbar spine. a Lateral plain radiograph shows severe destruction of TIO with localized kyphosis (arrowhead) as well as early lesion at L3 (arrowhead) with intact disc spaces between L2> 3 and L3> 4' b Non-contrast computed tomography (CT) demonstrating

l>

Surgical Management of Spinal Tuberculosis

501

severe destruction of TID, 11 including costovertebral junction and the pedicle on left side (arrowhead). There is a big anterior and posterior abscess. c Non-contrast CT of the lumbar spine shows marginal anterior osteolytic lesion (arrowhead) with anterior abscess. d Lateral view x-ray, 4 months following two-stage operation of the thoracic spine and correction of its deformity. Note the complete collapse of L3 with localized kyphosis (arrowhead). e Non-contrast CT demonstrates fragmentary lesion of L3 (arrowhead) with bilateral psoas abscess. Note the left-sided lesion at Ls (open arrow). f Post-operative plain radiograph, 18 months following extension of fixation and fusion to the lumbar spine and radical debridement and fusion between L2 and L4

502

M. W Al Sebai et al.

d Fig. 31.7. This is a 60-year-old lady who presented with back pain, girdle pain and paraparesis with signs of upper motor neuron disease. a Lateral radiograph demonstrates collapse of T6 with obliteration of the disc space between T5 and T6 vertebrae (arrow). b,c T1 and T2 weighted, sagittal scans demonstrate destruction of T6 with intraosseous abscess at T5. Note: the unusual high intensity signals in the bodies of T5 and T6 on T1 scali (thick arrow). There is also diffused lesion behind the cord with increased signal intensity on both T1 and T2 imaging indicating fat (lipomatosis) (thin arrow). d, e T1 and T2 weighted, axial

t>

Surgical Management of Spinal Tuberculosis

503

e

scans demonstrate the cord is compressed between the anterior destructive lesion (arrow) and the posterior lipomatosis (arrowhead). f Lateral view of the lumbosacral spine in the same patient, shows destructive lesion at L4, 5 and the sacrum (arrow). g Sagittal T1 weighted magnetic resonance imaging. Tuberculous spondylitis of L4,5 and the sacrum with diffuse anterior abscess (arrow). h Lateral plain radiograph of the thoracic spine following radical debridement and fusion between T4 and T6

M. W. Al Sebai et al.

504

a

b

L-

~

~

...

c

d

[>

Surgical Management of Spinal Tuberculosis

505

g

Fig. 31.8. This is a 21-year-old male admitted by the thoracic surgeon because of tuberculous mediastinal abscess. Evaluation of the spine preoperatively did not show major spinal affection. While the patient was walking 5 days following chest drainage, he fell down paraplegic. a Plain chest radiography shows huge mediastinal mass (arrows). b, c Plain radiographs of the thoracic spine show haziness of vertebral bodies with reduction of the disc spaces (open arrows) with no gross collapse or instability. d Computed tomography reveals the huge mediastinal shadow (A) surrounding the spine without destruction. Note: also bilateral pleural effusion (arrows). e Five days following drainage anterior-posterior radiograph shows translation of vertebrae at the level of T6, 7 (arrowhead). Myelography shows total blockage at the T8 level. f Post-contrast computed tomography demonstrates translation of vertebrae with shearing at the pedicles (arrowhead) and cord transection. g. Anterior-posterior radiography, 4 years following surgery shows fusion at translation site

506

M. W. AI Sebai et al.

a

c

b

Fig. 31.9. This is a 60-year-old male, presented with severe low back pain, left sciatica and inability to walk. a, b Plain anterior posterior and lateral radiographs show severe destruction of L4 , less severe destruction of L3, localized kyphosis and surrounding calcification. Note: the destruction of facet joints at L3, L4 level (arrow). c, d Tl and T2 weighted studies reveal loss of the Lr L4 disc, (thin arrow) with extensive destruction of L4 vertebrae (thick arrow). e, f Post-gadolinium sagittal and axial scans demonstrate total destruction of L4 body, enhancing L3 and Ls (arrowhead) and low-intensity signals represents caseating material (arrow). Note: also on axial cut, the nerve root is surrounded by granulation tissue (curved arrow) and severe thecal compression (arrowhead). g Post-operative lateral radiograph shows anterior fusion and posterior fixation. Note: the correction of kyphosis

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c Fig. 31.10. a, b Plain radiograph in a 45-year-old lady shows L2-L 3 disc space narrowing, unilateral and anterior osteophytes (arrowheads) with destruction of L3 upper and plate. Serological tests for Brucellosis were negative. c Post-contrast computed tomography demonstrates anterior-marginal bone destruction (arrowhead in the upper cut) and multi-loculated abscess with surrounding enhancement (arrowhead in the lower cut). d Lateral plain radiograph shows anterior debridement and fusion 3 months post-operative

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Fig.31.11. a Lateral radiograph of a 40-year-old lady who presented with back pain, shows no obvious abnormality. b Anterior-posterior radiograph reveals destruction of the lower half of the spinous process of L4 (arrows). c Non-contrast computed tomography shows destruction of the spinous process (arrow) with surrounding paraspinal and subcutaneous abscess (A). d Lateral radiograph 2 years after debridement shows no further changes

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Fig. 31.12. This is a 60-year-old lady who presented with back pain and complete paraplegia diagnosed as a metastatic disease of the spine a Plain radiographic examination demonstrates vertebra plana at T5 (arrow). b The conventional myelogram demonstrates the vertebral-body lesion (arrow) with compression of the spinal canal contents (open arrow). c Post-contrast computed tomography shows fragmentation lesion with small soft-tissue shadow (arrow). Note: also cord compression (arrowhead) d Lateral radiograph after combined operation of posterior decompression, fusion and fixation followed by anterior radical debridement and fusion

Fig. 31.13. This is a 30-year-old male who presented with neck pain, back pain and inability to walk because of weakness of the lower limbs and painful left hip joint. a, b Plain radiograph shows destructive lesion C6, C7 and T1 and kyphotic deformity with huge retropharyngeal abscess (long arrow). There is subluxation C6, C7 on lateral radiograph (thick arrow) and cervicothoracic scoliosis because of unilateral destruction of C7 as shown on anterior-posterior radiograph (arrow). c, d plain radiographs of the thoracic spine shows another lesion affecting mainly T8 (vertebra plana) (arrow). e Computed tomographs of the cervicothoracic region revealed affection of C7 mainly, including the right pedicle and transverse process (arrowhead). fThoracic computed tomographs show destruction of the anterior and posterior elements ofT8 (arrow) with cord compression by an epidural abscess (arrowhead). g Computed tomographs of the left hip show soft-tissue shadow (arrow) and decreased bone density (open arrow). h Lateral radiograph of the cervical spine following combined operation shows correction of deformity. i Thoracic spine lateral radiography after combined operation demonstrates correction of deformity, posterior fixation and anterior fusion

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d Fig.31.14. This is a 45-year-old lady who presented with back pain, inability to walk and incomplete paraplegia. a Lateral radiograph shows a lesion involving two vertebra. The disc space is obliterated and the upper vertebra is dipped into the lower one. b Diagram shows the bifacetal dislocation Tll-Tl2. c Non-contrast computed tomography shows TIl body inside lower part of TI2 in the upper scan and bare facet sign in the lower scan because of dislocation (arrows). d Sagittal reformat of the computed tomography show the facet dislocation posteriorly (arrow). e Radiography 10 months after combined operation shows fusion and reduction of dislocation

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d Fig. 31.15. a Radiography of a 40-year-old lady with chronic back pain and deformity of six years duration. Severe destruction of the lumbar spine with kyphosis and shortness of the trunk. b Anterior-posterior radiograph demonstrates the disorganization of the facet joints and calcification. c The conventional myelogram demonstrates the thecal indentation. d Post-contrast computed tomography show the destruction of the vertebrae TI2 and all lumbar vertebrae. e Lateral radiography following debridement and fibular graft fusion between TIl and the sacrum

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31.3.2 Conventional Tomography Conventional tomography remains as an important imaging modality particularly in countries where TB is common in poor underdeveloped parts of the world with lack of CT and MRI facilities. It also has the advantage of the absence of overshadowing of overlying structures. However, the loss of densities between various tissues limits its value (Fig. 31.16). It is of considerable value in the occipito-cervical junction as it shows the extent of bone destruction and subluxation between the first and second cervical vertebrae (Fig. 31.17). Conventional tomography is also useful in depicting TB infection at the cervico-thoracic junction and the dorsal spine (Figs. 31.16,31.17).

31.3.3 Myelography Water-soluble contrast myelography is still used in poor underdeveloped countries with endemic TB. However, it has been superseded by CT, CT-myelography or MRI in rich industrialized countries. Its value is limited to certain groups of patients with posterior subligamentous abscesses or extradural tuberculous granulomatous masses protruding in the spinal canal that are not depicted by plain radiography or conventional tomography. An extradural space-occupying lesion change appears as displacement of the contrast column or even total spinal blockage (Fig. 31.2).

31.3.4 CT Features Axial CT scanning is ideal for showing the extent of bone involvement in TB but is less efficient in soft tissue mass lesions, particularly extradural granulomatous encroaching on the spinal canal. Another disadvantage of CT is the difficulty in the detection of skip distant spinal lesions that may occur and are not included in the site of imaging. Some recent advances in the development of soft and hardware may help in soft tissue involvement but are not as cost effective. Early changes characteristically appear as rarefaction, homogenous focal low-density lesions with regular boundaries. Clarification appears as the disease advances with subsequent abscess formation (Fig. 31.9).

Destruction of the cortical bone and intervertebral disc occur as the disease advances and these can be clearly depicted by axial and sagittal CT (Fig. 31.2). Loss of clarity in the fat planes surrounding the vertebra is an early feature that indicates paravertebral extension of the infection. In advanced tuberculous vertebral osteomyelitis, loss of normal bone architecture, extensive fragmentation, kyphosis, multiloculated paravertebral abscesses and subligamentous spread of infection are characteristic findings (Fig. 31.10). Spinal canal encroachment by extradural inflammatory tissue granulomas and abscess formation may enhance with contrast media if pus is present (Fig. 31.4). The four distinctive patterns of vertebral body destruction have been described by Jain et al. in 1993 as fragmentary, osteolytic, subperiosteal and localized sclerotic. The fragmentary type is the most common and is described by most authors and noted in 47% of patients (Fig. 31.18). CT-guided needle biopsy and aspiration is an important tool for diagnosing TB of the spine. CT with intrathecal injection of a small volume of low concentration metrizamide has been used to evaluate extradural encroachment of the spinal cord (Bront et al. 1983; McGraham and Dublin 1985). However, it is an invasive procedure and carries the risk of further spread of infection (AI Arabi et al.1992).

31.3.5 MRI Features MRI imaging modality is the investigation of choice for spinal infection. It has good tissue differentiation, bone marrow visualization, as well as excellent depiction of the spinal canal, its content and the paravertebral soft tissue. It does not expose the patient to ionizing radiation. However, it has a poor definition of bone and calcified tissue than CT modality. At the time of presentation, MRI may show vertebral end-plate destruction, loss of disc space height and paraspinal abscess. However, early changes of tuberculous spondylitis may only appear in a single vertebral body, which may simulate neoplastic disease. A Tl-weighted image may show an area of a homogeneous low signal of intensity at the infected area (commonly the anterior inferior part of the vertebral end-plate). The T2-weighted images may show an increased signal in the infected area of the vertebral body. Occasionally, posterior areas of the vertebral body may show similar changes. As the disease advances, a vertebral abscess may appear as a

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Fig. 31.16. a Conventional tomography in a young man presented with progressive paraplegia. There is destruction of the upper thoracic vertebrae with kyphosis. b, c Pre and post-gadolinium II scans of II to TS tuberculous spondylitis. There is obliteration of the disc spaces and big anterior collection (arrow). Note: the extensive epidural abscess pressing the cord. (Small arrow in Tl and arrowhead in enhanced Tl). d T2 weighted imaging show high signal intensity in the bodies, in the disc spaces and the abscesses. Note: prevertebral abscess (arrow) and epidural abscess (arrowhead). e Conventional tomography done 6 weeks after debridement and fusion shows correction of kyphosis

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Fig. 31.17. This is an 8-year-old girl who presented with painful torticollis, inability to support her head and paraparesis. a Lateral radiograph shows invagination of the odontoid process (arrowhead) and retropharyngeal collection, (arrow), and subluxation Cl>~' b Anterior-posterior radiograph demonstrates upper mediastinal shadow (arrow) and decreased intervertebral disc spaces at the cervicothoracic region. c Non-contrast computed tomographs of the craniocervicaljunction reveal destructive lesion of the occipital condyles, CI and C2 (thin arrows). There is distortion of the anatomy of the region with invagination of the odontoid process (thick arrows). d Non-contrast computed tomographs of the cervicothoracic junction reveal destruction of the vertebrae with fragmentation and cord compression (arrow). e Conventional tomography was useful in this case to show the severe kyphosis in the upper thoracic spine and subluxation ofTl-T2. (curved arrow). Note: also invagination of odontoid process (arrow). fA sagittal Tl and T2 scans show anterior medulla compression by the tip of odontoid process (arrowhead) and prevertebral abscess with increased signal intensity in both Tl and T2 because of proteinaceous material. There is destruction of the upper thoracic vertebrae with severe cord compression (arrow). g Post-operative radiography show reduction of craniocervical as well as CI, C2 subluxation. This was treated by traction and brace. The thoracic spine demonstrates the correction of kyphosis following combined operation

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Fig. 31.18. This is a 39-year-old lady who was transferred from another hospital 3 months following laminectomy. She had back pain and inability to walk because of neurological deterioration following laminectomy. a, b Plain radiographs show destructive lesion affecting T9, 10 and 11 with extensive destruction of TlO (arrow) and kyphosis. There is absence of posterior elements of TlO and II because oflaminectomy (arrowheads). c Post-contrast computed tomographs show extensive destruction of TlO with fragmentation (small arrow) and cord compression (arrow) in spite oflaminectomy (arrowhead). d Post-operative lateral radiograph shows correction of deformity and fusion following two-stage operation

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low-intensity signal with rim enhancement by gadolinium contrast (Fig. 31.9). Early changes of the disc in Tl-images, do not show signal changes or may show blurring of the disc-space margins. In T2-irnages, high-signal intensity in the disc is uncommon, unlike early disc involvement in pyogenic infection. Subligamentous spread, anterior or posterior, is depicted better on Sagittal Tl-imaging (Fig. 31.5) as isointense with other structures. In Tl-images, high intensity signal beneath the anterior longitudinal ligament may appear with margins enhancement by gadolinium. Multiloculated large paravertebral abscesses may show isointensity or low intensity signals on Tlweighted images. T2-weighted images will show a high signal as well as the size and extent of the abscesses.

31.3.6 Scintigraphy Please refer to Chap. 30.

31.4 Treatment of T8 Spine The goals of treatment are to eradicate the infection and to treat neurological deficit and spinal deformity. The best method of treatment should produce rapid fusion, prevent late recurrence after clinical healing and prevent the development of progressive and severe deformity. The traditional treatment of Pott's disease prior to the discovery of effective chemotherapy was prolonged immobilization, utilizing prolonged bed rest and/or body casts (Dobson 1951). Although many of the patients did remarkably well, mortality was in the range of 20% and 20-30% of the patients suffered recurrence of infection (Dobson 1951). The clinical availability of streptomycin in 1944, para-amino salicylic acid in 1950 and isoniazid in 1951 ushered in a new area in the management of Pott's disease. In 1962, Konstam and Blesovsky reported the management results of 207 patients with Pott's disease who were treated with chemotherapy and allowed to walk without bracing (Konstam and Konstam 1958). Only 27 patients underwent operations for abscess drainage and 86% made complete recoveries. One hundred patients had to be withdrawn from the study because of

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poor drug compliance and only 35 patients were monitored for longer than 2 years. This was the first study to show that chemotherapy without long-term immobilization would be used to treat Pott's disease successfully.

31.5 Antibiotics With or Without Surgery (MRC Trials> The multinational prospective study on the efficiency of conservative chemotherapy and surgical treatment coordinated by the Medical Research Council (MRC) has just completed a final IS-year follow up report. They conducted a series of randomized clinical trials of the following treatment modalities: (1) chemotherapy with immobilization via either strict bed rest or body cast, (2) outpatient chemotherapy with mobilization, (3) chemotherapy and debridement of obviously infected bone without fusion, (4) radical operation of anterior resection and debridement with autologous bone-strut grafting (Medical Research Council Working Party 1973a, b, 1974a, b, 1976, 1978a, b, 1982, 1985, 1986, 1989). The first two modalities of non-operative treatment regimens resulted in a favorable outcome (return to normal activity without pain or neurological deficit) in 85% and 86%, respectively, with radiographic evidence of fusion in 36% and 67%, respectively. Operative debridement resulted in no better outcome, although patients who were debrided tended to have an earlier resolution of abscesses. Overall, the patients treated without radical debridement experienced an increase in kyphosis of II°,30% had an increase in kyphosis of II° to 30° and 10% had an increase of up to 50°. Although it appears from these studies that conservative treatment is as effective as surgical intervention for earlier and milder diseases, there are still reservations on the effect of such treatment for more severe diseases (Luk 1999). The optimal duration of anti-tuberculous chemotherapy required for complete recovery is still debated. The duration currently recommended by most experts is 12 months (Moon 1997; Pertuiset 1999). Shorter durations of 6-9 months have been advocated in adults. These trials failed to resolve this issue because of methodological inadequacies regarding sample size and statistical analysis (Pertuiset 1999).

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31.6

Operative Treatment Active surgical intervention of the diseased area in the care of Pott's disease was begun even before the introduction of specific anti-tuberculous chemotherapy, even though most of the authors considered chemotherapy as the mainstay treatment for TB. Still, lesions could be safely treated without surgery to be defined (Boachie-Adjei and Squillante 1996).

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3. Unresponsiveness to medical therapy as manifested by development or progression of neurological deficits, spinal deformity, intractable pain and progression of disease 4. Non-compliance with medications 5. Non-diagnostic biopsy

Tuli described a middle-path regimen of selective operative treatment (Tuli 1975). He considered surgery for cases with neurological deficits that failed to improve during the initial trial of chemotherapy. All other patients received chemotherapy with surgery reserved for posterior lesions, persistent active infection, instability, doubtful diagnosis or recurrence 31.7 of neurological deficit. Lifeso, from Saudi Arabia, Indications for Surgical Intervention modified surgical indications (Lifeso et a1.1985). The Hodgson and Stock proposed that the operation, in authors indicated the need for immediate anterior combination with chemotherapy, be done as early as decompression and fusion for complete paralysis, possible after the diagnosis for the following reasons profound neurological deficits due to cervical or (Hodgson and Stock 1956): upper thoracic lesion and gross destruction of the 1. Diseased material may be obtained for a definitive cervical spine or any severe kyphosis associated with active disease. They recommended that patients diagnosis 2. The patient's general condition improves dra- who have slight or no neurological deficit and slight matically immediately after the evacuation of the kyphosis can be safely treated with medical therapy alone, and close observation should then be the rule. abscess In our own series we separated the cases into three 3. In the thoracic spine, especially in children, early decompression of the abscess is necessary, as the groups: (1) Early cases with no or minimal bony affecabscess tends to extend up and down the spine tion are treated conservatively. Drugs to be continued for 12 months, with four drugs in the first 2 months rapidly 4. Bone sequestra, sequestrated intervertebral discs, and two drugs for the remaining 10 months. (2) Cases caseous material and avascular bone may be with bony destruction and involvement of disc spaces removed and placement of an anterior strut graft are treated surgically by anterior radical debridement and fusion, except in cases with posterior arch affecunder compression will lead to early fusion 5. Late recurrence is uncommon after radical exci- tion, which needs posterior surgery. (3) Cases with sions of the diseased focus and solid fusion have affection of three or more vertebrae, affection of posterior and anterior columns and progressive deformity been achieved 6. Increasing deformity may be prevented while the patient is on medical treatment and bed rest. These three categories are considered as radiological 7. Paraplegia may be prevented 8. In the presence of established paraplegia, anterior signs of instability of the spine. For these cases, both decompression and bone grafting lead to rapid anterior radical debridement and fusion and posterior fixation and fusion are needed (Figs. 31.19,31.20) (Al recovery 9. The anterior approach gives accurate diagnosis Sebai et al. 2001). In our patients this has resulted in and exposure for dealing with penetration of an improvement in the correction of the deformity as well as encouraging neurological recovery and alloworgans, especially of the lung ing early mobilization. Rezai et al. considered the criteria for surgical management, in combination with chemotherapy, of PoU's disease as (Rezai et al. 1995): 1. Neurological deficit including acute neurological deterioration 2. Spinal instability with more than 50% vertebral body collapse or destruction and spinal deformity of more than 5°

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Fig.31.19. a Lateral radiography of 3-year-old girl who presented with chronic back pain and incomplete paraplegia, shows destruction of the vertebrae no to L2• There is kyphosis of 86°. b Post-operative lateral radiograph following radical debridement and anterior fusion between no and L3. It shows correction of kyphosis to 55°. c Post-operative lateral radiograph following second-stage of posterior fusion and instrumentation reveals further correction of kyphosis to 26°. (With permission from International Orthopaedics 25,2001)

l> Fig. 31.20. This is a 56-year-old lady who complained of back pain and chest wall pain. Chest radiograph and lateral view of the thoracic spine revealed no gross abnormality. She had increasing pain 4 months later with inability to walk because of incomplete paraplegia. a, b Lateral plain radiographs at this stage showed compression of T7 and lytic lesions affecting L[ and L2 with preservation of disc spaces (arrows). c Bone scan revealed multiple foci of increased uptake interpreted as most likely metastatic disease of the spine. d Post-intravenous contrast computed tomographs show destructive lesion of T7 extending to the pedicle and costovertebral junction with severe cord compression, which is pushed to the right side (arrowheads). Note absence of soft-tissue shadow around the vertebrae (arrow). e Computed tomographs of the lumbar spine show destruction of L} and L2 with fragmentation (arrowhead) and surrounding enhancing soft-tissue shadow (curved arrow). f Post-gadolinium T1 images show destruction of T7 and L1 vertebrae. (arrows) Note enhancing epidural lesion compressing the cord at T7 and to a lesser degree at L}. g, h Lateral radiographs of the thoracic and lumbar spine, 3 weeks following start of anti-tuberculous treatment and bed rest. There is progressive collapse of the vertebrae and obliteration of the disc space between L1 and L2 • (arrows). i, j Lateral and anterior-posterior radiographs following combined operation showing fusion and fixation

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31.8.2 Drainage of Abscesses

31.8.1 Needle Biopsy (Under Fluoroscopic or CT Guidance)

Aspiration or surgical drainage was carried out for patients with a large cold abscess because it was thought that evacuation of the abscess improves the patient's general condition and rapid progression of the abscess along the spine was prevented. This has been shown to be ineffective and surgical drainage of a cold abscess alone is no longer recommended (Moon et al. 1987, 1996). However, in certain cases with huge psoas abscesses, with or without minimal spinal affection, presenting with abdominal mass causing discomfort to the patient, the patient may get quick relief after drainage (Fig. 31.21).

Approaches and Surgical Techniques

This technique is usually used for the thoracic and lumbar spine disease. The approach depends on the anatomic region and part of the vertebra involved. Spinal needle is used for aspiration to get cytological diagnosis while Tru-cut biopsy could be used for histopathological diagnosis. Definite cytological diagnosis was obtained in up to 88.5% of cases (Kang et al. 1999). Biopsy of the cervical spine poses special problems because of the proximity to many vital organs. With CT, the exact relationship of the skeletal lesion to the adjacent structures can be established, allowing a safe route to be selected (Kattapuram and Rosenthal 1987). Gupta et al. reported the use of ultrasound guidance for needle biopsy of lytic lesions of the cervical spine in four cases without complications (Gupta et al. 1993).

31.8.3 Debridement of Tuberculous Lesion To eradicate the tuberculous lesion, anterior debridement was done first by Ito et al. in 1934. Kondo and Yamada wrote the end results of focal debridement

Fig.31.21. Non-contrast computed tomographs of a 26-year-old male who presented with back pain, abdominal pain and systemic manifestations. There are huge bilateral multiloculated abscesses (A) extending from the upper abdomen down to the pelvis

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in spinal TB and its indications in 1937 (Kondo and Yamada 1937). Hodgson and Stock popularized the anterior spinal surgery and described the anterior radical surgery (Hong Kong operation) (Hodgson and Stock 1956). Focal debridement can effectively remove the diseased tissue and can evacuate the abscess; however, it does not prevent the progression of kyphosis, especially if compared with the radical operation in both adults and children (Upadhyay et al. 1993, 1994). Simple debridement gives no long-term advantage over ambulant chemotherapy alone and, therefore, is no longer accepted as a preferred method of treatment (Medical Research Council Working Party 1982,1985). In the Hong Kong operation, the spine is approached anteriorly so that the affected area may be dealt with more directly. The sequestrated bone and caseous material must be debrided back to bleeding bone above and below and back to the posterior longitudinal ligament. The decompression should go back to the dura in cases of neurological deficit when spinal decompression is necessary. The angular deformity is corrected by insertion of a strut graft. A slightly oversized graft is put under compression by springing open the kyphosis during insertion. The choice of graft material is based on considerations of graft incorporation and structural support. The strut graft should be strong yet osteogenic in nature, tri-cortical or bi-cortical iliac crest grafts are ideal, but frequently the area to be grafted is too large for the iliac grafts to be sufficient. Longer struts can be obtained from the fibula or ribs. These should be supplemented with iliac bone because the fibula is strong but mostly cortical bone (non-osteogenic). Bradford and Daher described the use of vascularized rib grafts for stabilization of kyphosis (Bradford and Daher 1986). Good results were also obtained by the use of allograft in 47 children by Govender and Parbhoo (1999).

and fusion can, however, be associated with fall-off in the post-operative kyphos, frequently because of slipping of the graft, graft fracture, protrusion, absorption or non-union and, in part, because of the continued growth in the posterior elements in the growing child (Bailey et al. 1972). In severe cases, the combined approach of anterior and posterior spinal fusion gives the best results. Comparison of four procedures of fusion revealed that the combined fusion and anterior debridement guaranteed an equal growth of the anterior and posterior heights in children (Schulitz et al. 1997). Long-term follow-up for children who had anterior and posterior fusion without instrumentation for extensive disease and kyphosis, revealed solid fusion and improvement of the kyphotic deformity (Altman et al.I996). However, the use of posterior instrumentation in the face of active disease helps in providing early fusion, prevention and correction of kyphosis as well as earlyambulation (Boachie-Adjei and Squillante 1996; Moon et al.1995, 1996).

31.8.5 Instrumentation

The role of posterior instrumentation and fusion in the treatment of spinal TB has only recently been reported (Korkusuz et al.1997; Moon et al.1995, 1996; Rezai et al.1995). In infectious diseases, instrumentation introduces a foreign body that acts as a focus, the infection is notoriously resistant to antibiotic therapy and usually requires removal of the instrument (Gristina and Costerton 1985; Gristina et al. 1985). However, both clinical and microbiological results suggest that posterior instrumentation is not associated with persistence or recurrence of spinal tuberculous infection and is useful to provide immediate stability and protect against the development of a kyphotic deformity (Oga et al. 1993). In adults with deformity and paraplegia, Moon et al. found the combined two-stage operation to be most successful (Moon et al. 1995, 1996). In their cases, anterior surgery was preceded 31.8.4 by posterior instrumental stabilization surgery. Spinal Fusion Additional posterior spinal fixation after anterior Posterior spinal fusion was used to hasten recovery decompression and fusion was reported by others since 1911 (Albee 1911; Hibbs 1911). This procedure (Abramovitz et al. 1986; Graziano and Sidhu 1993; did not prevent progressive kyphosis or development Jeanneret and Magerl 1994). Despite the general of paraplegia. Debridement followed by anterior acceptance of the Hong Kong operation for the fusion offers the advantage of debridement and a treatment of spinal TB, Guven and co-workers have result in the diminution of the kyphotic deformity used posterior instrumentation and fusion without (Hodgson and Stock 1956, 1960; Medical Research anterior debridement in ten neurologically intact Council Working Party 1974). Anterior debridement patients. They achieved clinical and radiological

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evidence of fusion in all cases (Guven et al. 1994). Chemotherapy was instituted 2 weeks pre-operatively and continued for a mean period of 11 months. Lee et al. also used transpedicular instrumentation as an adjunct in the treatment of thoracolumbar and lumber spine with early stage bone destruction (Lee et al. 1999). Combined posterior decompression and internal fixation was reported by Rath et al., avoiding the risks of anterior approaches for the elderly and debilitated patient (Rath et al. 1996). Jeanneret and Magerl used percutaneous debridement and external spinal fixation as an alternative procedure to conservative or more invasive operative treatment modalities in the following conditions: (a) painful lesion of the spine with minimal bone loss, not amenable to efficient orthotic stabilization, (b) when emergency decompression of the spine is mandatory and anterior decompression is not possible emergently, (c) osteomyelitis of the spine at L51S1, and (d) in the presence of infective wounds, making internal posterior stabilization unsuitable (Jeanneret and Magerl 1994). They had good results, as far as healing of infection, neurological outcome and kyphotic deformitywith shorter period of bed rest. A small number of recent reports deal with anterior spinal cord decompression, block bone grafting and anterior internal fixation in cases of vertebral osteomyelitis (Kostuik 1983; Redfern et al.1988; Yilmaz et al.1999). Yilmaz et al. reported 22 patients who had TB of the spine with moderate to severe localized kyphosis and 16 patients who had more than two involved levels; all had stabilization with anterior instrumentation (Yilmaz et a1.1999). They obtained an average correction of kyphosis of 64% and there was no recurreJ;lce of the disease. However, anterior instrumentation should not be used to correct kyphotic deformity when the posterior column is affected.

31.9 Decompressive Techniques and Treatment of Paraplegia The first case of tuberculous spondylitis treated successfully by laminectomy was in 1882. In the early part of the 20th century it has become a common procedure for patients with Pott's paraplegia. Seddon condemned the procedure because it removes the integrity of the posterior arch and may lead to instability and further neurological damage (Figs. 31.18, 31.22) (Seddon 1934/1935). Laminectomy is considered contraindicated in the usual form of TB (Fel-

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lander 1975; Hodgson et al. 1964; Kemp et al. 1974). The only indication for laminectomy in the treatment of spinal TB is atypical disease involving the neural arch (Fellander 1975; Kemp et al. 1974; Rahman et al. 1987; Rand and Smith 1989). Decompression in the thoracic spine may be performed through a transthoracic approach, through a costotransversectomy or by an extrapleural approach. Transthoracic approach is more successful than costotransversectomy (Kirkaldy-Willis and Thomas 1965). The extrapleural approach has the theoretic benefit of avoiding the tuberculous empyema. However, no studies have demonstrated any actual advantage of an extrapleural approach over a standard thoracotomy. Decompression in the lumbar spine may be done by retroperitoneal approach. A left-sided approach is preferred because the arterial structures are easier to deal with than the venous counterpart. In approaching the lumbosacral junction, the common and external iliac vessels are mobilized. Cervical spine infection has a high incidence of cord compression, more than 40%. Hsu and Leong reported excellent results from using the Hong Kong procedure via anterior approach in conjunction with medical treatment (Hsu and Leong 1984).

31.10 Surgical Treatment of Kyphosis Kyphosis is one of the two major complications of spinal TB. It has been common in patients treated with chemotherapy alone (Moon et al. 1995). Almost 3% of cases of TB of the spine develop a severe kyphotic deformity. The patients at risk are those who develop the disease under the age of 10 years, and who had involvement of three or more vertebral bodies (Tuli 1995). A severe kyphosis is more than a cosmetic disfigurement because nearly all such patients develop cardiopulmonary dysfunction, painful impingement between the ribs and pelvis and compression of the spinal cord with paraplegia at an average of 10 years after the onset of the disease (Smith et al. 1996; Tuli 1995). Severe kyphosis is not only difficult to treat, but also dangerous, with a high complication rate. There are two clinical types of kyphosis, mobile and rigid (Moon et al.1995). Mobile kyphosis could be treated by traction, posterior fusion, anterior radical surgery or two-stage operation (Moon 1997). Skull traction was found effective in correction of non-rigid kyphosis in cervical spine (Fig.31.23) (Moon et al. 1987, 1996). A two-stage

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Fig.31.22. This is a 50-year-old lady, referred from another hospital because of persistent back pain and inability to walk 6 months following laminectomy and distraction rod fixation for lumbar tuberculous spondylitis. a Lateral radiograph show extensive destruction of L4 , lumbar kyphosis and dislodged rods. b, c Functional flexion and extension radiographs reveal gross instability. d Non-contrast computed tomographs demonstrate destruction of the body of L4 (arrow). They show evidence of previous laminectomy (arrowheads) and dislodgement of the rods (small arrowheads). e, f Plain radiographs, 2 years following staged operation show fusion and correction of deformity

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Fig.31.23. a Lateral radiograph of a young man that shows destructive lesion of C6-7 with obliteration of the disc in between and kyphotic deformity. Note subluxation of the facet joints C6-7 (long arrow) and large prevertebral soft-tissue shadow (short arrows). b Lateral radiography following skull traction demonstrates reduction of subluxation (arrows) and correction of deformity. c Post-operative plain radiography shows fusion and correction of deformity

c

operation could be done either with the posterior stage done first or as the second stage. Anteri6lr radical debridement followed by posterior resection and instrumentation was recommended by Yau et al. (1974) (Fig. 31.19). Combined two-stage operation, where posterior instrumentation is done first, achieves good correction of kyphosis, provided the deformity is not fixed and severe has been reported by others (Fig. 31.24) (Moon 1991; Moon et al. 1995,

1996). The rigid deformity could be corrected by posterior closing wedge osteotomy, two-stage operation or multi-stage operation (Fig.31.25) (Guven et al. 1994; Wu et al. 1996). Because of technical demands and higher risk of neurological injury, correction of a severe kyphosis without neurological deficit should not be done for cosmetic reasons alone. In a paralytic case, partial correction can be attempted together with decompressive surgery (Fig. 31.26).

Surgical Management of Spinal Tuberculosis

a

c

527

b

Fig.31.24. This is a 25-year-old lady who has had kyphosis since early childhood following a chronic illness. She presented with recent onset back pain and weakness of lower limbs. a Lateral plain radiography shows kyphosis of 75° between T8 and L4 and destruction of the vertebrae T9 to L3• Note the lordosis of thoracic spine above the kyphos (arrow). b Anterior-posterior view demonstrates the crowding of ribs, loss of disc spaces between no and L4 and increased density of the bone. c Non-contrast computed tomography demonstrates areas of destruction (arrowheads) because of reactivation of tuberculous spondylitis. d Lateral radiography following combined operation shows correction of kyphosis to 30° and fusion with fibular graft between T8 and L4

528

M. W. Al Sebai et al.

a

c

Fig. 31.25. This young lady presented with back pain and deformity. She had kyphosis and cauda equina syndrome since childhood. a Lateral radiography shows kyphosis of 72° between TIO and L2 • There are fused, deformed Til, 12 and L[ vertebrae at the apex (arrow). b Anterior-posterior plain radiograph demonstrates previous laminectomy between TI2 and L2 and old myodil with evidence of arachnoiditis (arrow). c Lateral radiography 2 years following staged operation shows fusion and correction of deformity to 22°

529

Surgical Management of Spinal Tuberculosis

a

c

d

Fig. 31.26. This is a 35-year-old male who started to have back pain and progressive paraplegia. He had kyphosis since early childhood. a, b Lateral and anterior-posterior plain radiographs show kyphosis 92° between T8 and Lz and fusion of T9 to L1 with no soft-tissue shadow (arrow). c The conventional myelogram demonstrates stretching of the cord over the kyphos without blockage of the dye (arrow). d Postcontrast computed tomographs at the apex of the kyphos revealed indentation of the thecal sac (arrowheads). Note absence of signs of reactivation or surrounding soft-tissue shadow. e, £lateral and anterior-posterior plain radiographs, 3 years following two-stage operation. Note: fusion both anteriorly and posterolaterally as well as partial correction of kyphosis

f

530

31.11

Cervical T8 TB of the cervical spine is uncommon. Its incidence, according to the few reports in the literature, varies from 3% to 5% (Dobson 1951; Hsu and Leong 1984; Martin 1970). Because of its low incidence, it has not been included in the MRC trials (Medical Research Council Working Party 1973a, b, 1974, 1976, 1978a, b, 1982,1985,1986,1989). Lifeso recognized three stages of CI-2 tubercular infection and recommended surgical treatment for all of them (Lifeso 1987). We treated four cases with upper cervical spine TB; two of them had fractured odontoid process following car accidents. We assume that the infection precipitated the fracture (Fig. 31.27). The other two cases had subluxation with destruction of the vertebrae. Three of these four cases needed posterior fixation and fusion. The fourth case was treated by traction and chemotherapy, while surgery was directed to the cervico-thoracic lesion in the same patient, which was responsible for the neurological deficit (Fig.31.17). Spinal instability following TB of the spine has been described. Three patients with varying degrees of subluxation following cervical TB were reported from Malaysia (Arumagasamy et al. 1977). Although subluxation of cervical spine TB has been rarely reported, bifacetal dislocation has not been described before 1991. We reported cervical spine

M. W. Al Sebai et al.

bifacetal dislocation for the first time in a IS-year-old girl with cervical tuberculous spondylitis (Fig. 31.28). (AI Arabi and Al Sebai 1991). TB of the cervico-thoracic spine junction can be challenging both in visualization on plain radiography as well as in surgical approach. In our own series, we noted diagnostic delay resulting in neurological deficit in 16 of our patients. The surgical approach of C7 TB was better performed from the lower neck in our series (Fig. 31.13). In T1 spinal TB, our approach was periscapular one (Fig. 31.16). However, Horner Syndrome developed post-operatively in one patient who had periscapular approach, which gradually recovered over the subsequent 6 months.

31.12 Summary In recent years, since the discovery of antibiotics, treatment of spinal TB has been revolutionized. Several trials aimed at finding the best methods of treatment have been discussed. We also highlighted the use of antibiotics alone or in conjunction with surgical intervention in the management. Continuous debate among authors on the indications of surgery has been discussed. In our own experiences, we have noted the occurrence of unusual sites of spinal

a

Fig.31.27. a Lateral radiograph of the cervical spine in a 62-year-old man following a car accident shows fracture odontoid process with posterior displacement. Note increased prevertebral shadow (arrow). b Following traction, lateral radiograph demonstrates reduction of displacement and the retropharyngeal soft-tissue shadow (arrow). c Non-contrast computer tomographs demonstrate partial destruction of the occipital condyles and anterior arch of C1(thin arrow). Note fragments of bone that have been extruded into an anterior abscess (thick arrow). d, e T1 magnetic resonance imagine (MRI) indicates diminished signal of odontoid process and Cl while T2 MRI shows increased signal intensity with retropharyngeal abscess (arrowheads). f The post-gadolinium scan outlines the retropharyngeal, tuberculous abscess (arrow). Note degenerative lesion at C5-6. g Lateral radiography following aspiration of prevertebral abscess and posterior fixation of Cl-2

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a Fig. 31.28. a Lateral radiography of the cervical spine in a 15-year-old girl shows bifacetal dislocation C3-4 (arrow). There is extensive anterior, retropharyngeal tuberculous abscess displacing the airway forward (small arrows). b Post-operative lateral radiograph taken 4 months following two-stage operation demonstrates reduction of dislocation, fusion and fixation

involvement among our patients, such as posterior element, occipito-cervical and cervico-thoracic junctions. We also highlighted the diagnostic and surgical difficulties that we encountered during the management of these unusual cases. Surgical treatment of paraplegia and kyphosis were also discussed.

References Abramovitz IN, Batson RA, Yablon JS (1986) Vertebral osteomyelitis: the surgical management of neurologic complications. Spine 11:418-420 AI Arabi KM, Al Sebai MW (1991) Bifacetal dislocation following tuberculosis of the cervical spine. Tubercle 72: 294-298 AI Arabi KM, AI Sebai MW, AI Chakaki M (1992) Evaluation of radiological investigations in spinal tuberculosis. Int Orthop 16:165-167 Albee FH (1911) Transplantation of a portion of the tibia into the spine for Pott's disease: a preliminary report. JAMA 57: 885-886 AI Sebai MW et al (2001) Operative treatment of progressive deformity in spinal tuberculosis. Int Orthop 25:322-325 Altman GT, Altman DT, Frankovitch KF (1996) Anterior and posterior fusion for children with tuberculosis of the spine. Clin Orthop Relat Res 325:225-231 Arumagasamy N, Pyn CC, Keng KK (1977) Tuberculous abscesses of the cervical spine with quadriparesis. Surg Neurol 8:35-40 Bailey HL et al (1972) Tuberculosis of the spine in children. J Bone Joint Surg 54A:1633-1657 Boachie-Adjei 0, Squillante RG (1996) Tuberculosis of the spine. Orthop Clin North Am 27:95-103

Bradford DS, Daher XH (1986) Vascularized rib grafts for stabilization of Kyphosis. J Bone Joint Surg 68B:357-361 Bront ZM, Burke VD, Jeffrey RB (1983) CT in the evaluation of spine infection. Spine 8:358-364 Dobson J (1951) Tuberculosis of the spine. Analysis of the results of conservative treatment and of the factors influencing the prognosis. J Bone Joint Surg 33B:517-531 Fellander M (1975) Paraplegia in spondylitis: results of operative treatment. Paraplegia 13:75-88 Govender S, Parbhoo AH (1999) Support of the anterior column with allografts in tuberculosis of the spine. J Bone Joint Surg 81:106-109 Graziano GP, Sidhu KS (1993) Salvage reconstruction in acute and late sequelae from pyogenic thoracolumbar infection. J Spinal Discord 6:199-207 Gristina AG, Costerton JW (1985) Bacterial adherence and the glycocalyx and their role in musculoskeletal infection. Orthop Clin North Am 15:517-535 Gristina AG et al (1985) Bacterial adherence and the pathogenesis of osteomyelitis. Science 228:99-103 Gupta RK et al (1993) Ultrasound-guided needle biopsy oflytic lesions of the cervical spine. J Clin Ultrasound 21:194-197 Guven 0 et al (1994a) A single stage posterior approach and rigid fixation for preventing Kyphosis in the treatment of spinal tuberculosis. Spine 19:1039-1043 Guven 0, Yalcin S, Karahan M (1994b) Eggshell procedure in correction of neglected cases of Pott's Kyphosis. Proceedings of the 5th biannual conference of European Spinal Deformities Society. Birmingham, England. Springer, Berlin Heidelberg New York, pp 84-85 Hibbs RA (1911) An operation for progressive spinal deformities. NY State Med J 93:1013-1016 Hodgson AR, Stock FE (1956) Anterior spinal fusion: a preliminary communication on the radical treatment of Pott's disease and Pott's paraplegia. Br J Surg 44:266-275 Hodgson AR, Stock FE (1960) Anterior spinal fusion for the treatment of tuberculosis of the spine. J Bone Joint Surg 42A:295

Surgical Management of Spinal Tuberculosis Hodgson AR et al (1964) A clinical study of 100 consecutive cases of Pott's paraplegia. Clin Orthop 36: 128-150 Hsu LCS, Leong JCY (1984) Tuberculosis of the lower cervical spine (C2 t C7). J Bone Joint Surg 66B:I-5 Ito H, Tsuchiya J, Asami G (1934) A new radical operation for Pott's disease: report of then cases. J Bone Joint Surg 16: 499-515 Jain R, Sawhney S, Berry M (1993) Computed tomography of vertebral tuberculosis: patterns of bone destruction. Clin RadioI47:196-199 Jeanneret B, Magerl F (1994) Treatment of osteomyelitis of the spine using percutaneous suction/irrigation and percutaneous external spinal fixation. J Spinal Disord 7:185-205 Kang Met al (1999) CT guided fine needle aspiration biopsy of spinal lesions. Acta RadioI40:474-478 Kattapuram SV, Rosenthal DI (1987) Percutaneous biopsy of the cervical spine using CT guideance. AJR 149:539-541 Kemp HBS, Jackson JW, Shaw NC (1974) Laminectomy in paraplegia due to infective spondylitis. Br J Surg 61:66-72 Kirkaldy-Willis WH, Thomas TG (1965) Anterior approaches in the diagnosis and treatment of infections of the vertebral bodies. J Bone Joint Surg 47A:87-110 Kondo E, Yamada K (1937) End results of focal debridement in bone and joint tuberculosis and its indications. J Bone Joint Surg 39A:27 Konstam PG, Blesovsky A (1962) The ambulant treatment of spinal tuberculosis. Br J Surg 50:26-38 Konstam PG, Konstam ST (1958) Spinal tuberculosis in southern Nigeria: with special reference to ambulant treatment of thoraco-lumbar disease. J Bone Joint Surg 40B:26-32 Korkusuz F, Islam C, Korkusuz Z (1997) Prevention of postoperative late Kyphosis in Pott's disease by anterior decompression and intervertebral grafting. World J Surg 21:524-528 Kostuik JP (1983) Anterior spinal cord decompression of lesions of the thoracic and lumbar spine, techniques, new methods of internal fixation. Spine 8:512-531 Lee TC et al (1999) Transpedicular instrumentation as an adjunct in the treatment of thoracolumbar and lumbar spine tuberculosis with early stage bone destruction. J Neurosurg 91 [SuppI2]:163-169 Lifeso R (1987) Atlanto-axial tuberculosis in adults. J Bone Joint Surg 69(B):183-187 Lifeso RM, Weaver P, Harder EH (1985) Tuberculosis spondylitis in adults. J Bone Joint Surg 67A:1405-1413 Luk KD (1999) Tuberculosis of the spine in the new millennium. Eur Spine J 8:338-345 Martin NS (1970) Tuberculosis of the spine. A study of the results of treatment during the last twenty-five years. J Bone Joint Surg 52B:613-628 McGraham JP, Dublin AB (1985) Evaluation of spinal infection by plain radiographs, computed tomography, intrathecal metrizamide and CT guided biopsy. Diagn Imag Clin Med 54:11-20 Medical Research Council Working Party on Tuberculosis of the Spine, First Report (1973a) A controlled trial of ambulant out-patient treatment and in-patient rest in bed in the management of tuberculosis of the spine in young Korean patients on standard chemotherapy. A study in Masan, Korea. J Bone Joint Surg 55B:678-697 Medical Research Council Working Party on Tuberculosis of the Spine, Second Report (1 973b) A controlled trial of plaster of Paris jackets in the management of ambulant

533 outpatient treatment of tuberculosis of the spine in children on standard chemotherapy: a study in Pusan, Korea. Tubercle 54:261-282 Medical Research Council Working Party on Tuberculosis of the Spine, Third Report (1974a) A controlled trial of debridement and ambulatory treatment in the management of tuberculosis of the spine in patients on standard chemotherapy: a study in Bulawayo, Rhodesia. J Trop Med Hyg 77:72-92 Medical Research Council Working Party on Tuberculosis of the Spine, Fourth Report (1974b) A controlled trial of anterior spinal fusion and debridement in the surgical management of tuberculosis of the spine in patients on standard chemotherapy: a study in Hong Kong. Br J Surg 61:853-866 Medical Research Council Working Party on Tuberculosis of the Spine, Fifth Report (1976) A five-year assessment of controlled trials in in-patient and out-patient treatment and plaster of Paris jackets for tuberculosis of the spine in children on standard chemotherapy. Studies in Masan and Pusan, Korea. J Bone Joint Surg 58B:399-411 Medical Research Council Working Party on Tuberculosis of the Spine, Sixth Report (1978a) Five year assessments of controlled trials of ambulatory treatment, debridement and anterior spinal fusion in the management of tuberculosis of the spine: studies in Vulawayo (Rhodesia) and in Hong Kong. J Bone Surg 60B:163-177 Medical Research Council Working Party on Tuberculosis of the Spine, Seventh Report (1978b) A controlled trial of anterior spinal fusion and debridement in the surgical management of tuberculosis of the spine in patients on standard chemotherapy: a study in two centers in South Africa. Tubercle 59:79-105 Medical Research Council Working Party on Tuberculosis of the Spine, Eighth Report (1982) A 10 year assessment of a controlled trial comparing debridement and anterior spinal fusion in the management of tuberculosis of the spine in patients on standard chemotherapy in Hong Kong. J Bone Joint Surg 64B:393-398 Medical Research Council Working Party on Tuberculosis of the Spine, Ninth Report (1985) A 10 year assessment of controlled trials of inpatient and outpatient treatment and of plaster of Paris jackets for tuberculosis of the spine in children on standard chemotherapy: studies in Masan and Pusan, Korea. J Bone Joint Surg 6B:I03-110 Medical Research Council Working Party on Tuberculosis of the Spine, Tenth Report (1986) A controlled trial of six month and nine month regimens of chemotherapy in patients undergoing radical surgery for tuberculosis of the spine in Hong Kong. Tubercle 67:243-259 Medical Research Council Working Party on Tuberculosis of the Spine, Eleventh Report (1989) A comparison of 6 or 9 month course regime of chemotherapy in patients receiving ambulatory treatment or undergoing radical surgery for tuberculosis of the spine. Indian J Tuberc [Suppl] 36:1-21 Medical Research Council Working Party on Tuberculosis of the Spine. Thirteenth report (1998) A IS-year assessment of controlled trials of the management of tuberculosis of the spine in Korea and Hong Kong. J Bone Joint Surg 80B: 456-462 Medical Research Council Working Party on Tuberculosis of the Spine. Fourteenth Report (1999) Five-year assessment of controlled trials of short-course chemotherapy regimens of 6, 9 or 18 months duration for spinal tuberculosis

534 in patients ambulatory from the start or undergoing radical surgery. Int Orthop 23:73-81 Menard V (1894) Causes de paraplegie dans Ie mal de Pott. Son traitment Chirurgical Par l'ouverture directe de goyer tuberculeuse des vertebras. Rev Orthop 5:47-54 Moon MS (1991) Combined posterior instrumentation and anterior interbody fusion for active tuberculosis Kyphosis of the thoraxolumbar spine. Curr Orthop 5: 177-179 Moon MS (1997) Tuberculosis of the spine. Controversies and a new challenge. Spine 22:1791-1797 Moon MS et al (1987) Conservative treatment of tuberculosis of the thoracic and lumbar spine in adults and children. Int Orthop 11:315-322 Moon MS et al (1995) Posterior instrumentation and anterior interbody fusion for tuberculosis Kyphosis of dorsal and lumbar spines. Spine 20:1910-1916 Moon MS et al (1996) Pott's paraplegia - 67 cases. Clin Orthop Relat Res 323:122-128 Oga M et al (1993) Evaluation of the risk of instrumentation as a foreign body in spinal tuberculosis. Clinical and biologic study. Spine 18:1890-1894 Pertuiset E (1999) Medical therapy of bone and joint tuberculosis in 1998. Rev Rhumat 66:152-157 Pott P (1936) Remarks on that kind of palsy of the lower limb, which is frequently found to accompany a curvature of the Spine, and is supposed to be caused by it. Williams and Wilkins, Baltimore MD, pp 271-323 (Medical classics, vol I) Rahman N, Al Arabi KM, Khan FA (1987) Atypical forms of spinal tuberculosis. Acta Neuro Chir 88:26-33 Rand C, Smith MA (1989) Anterior spinal tuberculosis: paraplegia following laminectomy. Ann R Coli Surg Engl 71:105-109 Rath SA et al (1996) Neurosurgical management of thoracic and lumbar vertebral osteomyelitis and discitis in adults: a review of 43 consecutive surgically treated patients. Neurosurgery 38:926-933

M. W. Al Sebai et al. Redfern RM et al (1988) Stabilization of the infected spine. J Neurol Neurosurg Psychiatry 51:803-897 Rezai AR et al (1995) Modern management of spinal tuberculosis. Neurosurgery 36:87-97 Schulitz KP et al (1997) Growth changes of solidly fused Kyphotic block after surgery for tuberculosis. Comparison of four procedures. Spine 22:1150-1155 Seddon HJ (1934/1935) Pott's Paraplegia: prognosis and treatment. Br J Surg 22:769-799 Sharif HS et al (1993) Role of CT and MR imaging in the management of tuberculous spondylitis. Radiol Clin North Am 33:787-804 Smith IE et al (1996) Kyphosis secondary to tuberculosis osteomyelitis as a cause of ventilatory failure. Chest 110: 1105-1110 Tuli SM (1975) Results of treatment of spinal tuberculosis by "Middle-path" Regime. J Bone Joint Surg 57B:13-23 Tuli SM (1995) Severe Kyphotic deformity in tuberculosis of the spine. Int Orthop 19:327-331 Upadhyay SS et al (1993) 17-year prospective study of surgical management of spinal tuberculosis in children. Hong Kong operation compared with debridement surgery for short and long term outcome of deformity. Spine 18: 1704-1711 Upadhyay SS et al (1994) Surgical management of spinal tuberculosis in adults. Hong Kong operation compared with debridement surgery for short and long term outcome of deformity. Clin Orthop Relat Res 302:173-182 Wu SS et al (1996) Management of rigid post-traumatic Kyphosis. Spine 21:2260-2267 Yau AMC et al (1974) Tuberculous Kyphosis: correction with spinal osteotomy, halopelvic distraction, and anterior and posterior fusion. J Bone Joint Surg 56A:1419-1434 Yilmaz C et al (1999) Anterior instrumentation for the treatment of spinal tuberculosis. J Bone Joint Surg 81A: 1261-1267

32 Tuberculosis of the Central Nervous System M. ZUHEIR

AL-KAWI

by Hippocrates (460-377 B.C.). Aristotle (384-322 B.C.) observed that persons associated with a person affected 32.1 History 535 by"phthisis" may contract the disease, thereby alluding 32.2 Epidemiology 536 to the possibility of its contagious nature. 32.3 Microbiology 536 Avicenna (Ibn Sina, 980-1037) described the 32.4 Pathogenesis 536 cerebral involvement by hot or cold swelling (inflam32.5 Pathology 537 32.6 Clinical 538 mation). The latter is thought to represent chronic 32.6.1 Tuberculoma 538 meningitis (most likely tuberculous) that frequently 32.6.2 Tuberculous Spondylitis 538 led to death as he noted. 32.6.3 Tuberculous Meningitis 539 With the industrial revolution in Europe, a mas32.7 Complications 539 32.7.1 Hydrocephalus 539 sive population shift toward inner cities resulted 32.7.2 Vascular Complications 540 in crowding and created conditions that favored 32.7.3 Hyponatremia 540 the spread of infection. Consequently, TB became a 32.7.4 Cranial Neuropathies 540 major cause of death between the late 17th and early 32.7.5 Seizures 541 20th centuries. Schoenlein (1793-1864) coined the 32.7.6 Tuberculous Encephalopathy 541 32.7.7 Adhesive Arachnoiditis 541 term tuberculosis to highlight the gross pathological 32.7.8 Myelopathy 541 appearance of small lumps caused by granulomata 32.8 Diagnosis 541 and the word "phthisis" fell into disfavor. Laennec 32.9 Management 543 (1781-1826), who was credited with the invention of 32.10 Prognosis 543 the stethoscope, described in detail the auscultative References 544 findings in pulmonary TB. Following on the research done by Villemin (1827-1892) to show that TB was transmissible, Koch 32.1 (1843-1910) described the necessary postulates for the History proof of a contagious nature of any illness. The conditions he described were widely accepted as classical Tuberculosis (TB) has affected humans since antiq- teachings and were as follows: finding the pathogen uity. References to what is believed to be tuberculous in every lesion in the body, being able to culture the infection were made in some writings from ancient pathogen outside the patient's body and reproducing Egypt and Babylon. Typical spine deformity of Pott's the disease by inoculation into animals. By applying the disease appear in numerous drawings of hunchbacks aforementioned postulates to TB he was able to estabon the walls of ancient Egyptian tombs. By morbid lish the infectious nature of the Bacillus tuberculosis. anatomy, spinal TB can be traced back to about The glory of his discovery, however, was tarnished by 2000 B.C., as was shown by psoas abscess found in the tuberculin blunder. He touted a prepared glycerin extract of the bacillus as a secret cure for TB. In fact, the a mummy. Microscopically, Zimmerman demonstrated the extract injected in large quantities to patients with TB tuberculous bacillus in a mummy of a child (Cave 1939; did cause many deaths. By the turn of the last century, Zimmerman 1979). Symptoms of TB were recognized Osler noted that in 1911, "in a population of one million, seventeen hundred persons died from TB" (Osler 1921). At the Pasteur Institute, Calmette and Guerin M. z. AL-KAWI, MD, FACP Senior Consultant Neurologist & Deputy Chairman, Depart- (1921) produced a live vaccine prepared by successive ment of Neurosciences, King Faisal Specialist Hospital and subculturing of a strain of mycobacterium bovis. This Research Center, P.O. Box 3354, Riyadh 11211, Saudi Arabia was what came to be known later as BeG vaccine.

CONTENTS

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

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Until the middle of the last century, treatment remained generally supportive-aimed at boosting the innate defenses of the body to overcome the infection. It was not until 1943that specific treatment against the causative organism was started. Chemotherapy began in earnest with the advent of streptomycin followed by PAS in 1946 and then isoniazid (INH) in 1951; the latter heralded the era of modern effective anti-tuberculous chemotherapy.

32.2 Epidemiology It is estimated that one billion people are infected with M. tuberculosis worldwide. Active TB claims nearly 8 million new victims each year (Barnes and Barrows 1993) Among them, 15% will develop extrapulmonary infection and 6% of that is meningeal (Kochi 1991). Therefore, we can estimate that there are approximately 70,000 new victims of TB meningitis per annum. Most initial infections with M. tuberculosis remain clinically silent. The lifetime risk of developing a clinical case of TB after an initial silent infection has been estimated at 10%. TB of the central nervous system (CNS) is the most serious form of extrapulmonary TB, and about 10% of immuno-competent patients who develop clinical TB manifest CNS involvement (Udani et al. 1971). TB of the CNS has a higher incidence in children with no particular gender preponderance. Prior to the acquired immune deficiency syndrome (AIDS) epidemic, good steps were made in the prevention and treatment of TB and its CNS complications. In a review of a large number of autopsies done in Germany from 1955 to 1969, there was a statistically significant decrease in frequency of TB meningitis to about 1/7 when compared with the data from 1924 to 1938. This difference was attributed to the BCG vaccination and to the effective anti-tuberculous medications (Weigel 1976). In spite of the advances made in the fight against infectious diseases, the overall prevalence of TB is again on the increase worldwide. The AIDS epidemic created circumstances favoring the spread of TB both in the developing and developed countries alike. Extrapulmonary TB is considered an AIDS-defining condition. The likelihood of contracting clinical TB is much higher in the AIDS population (Selwyn et al' 1992). The proportion of AIDS patients who develop TB is estimated at 5-9% (Sanchez-Portocarrero et al. 1999). The importance of this observation

is highlighted by the fact that TB in a human immunodeficiency virus (HIV)-infected patient may present as an overwhelming systemic disease (Gachot et al. 1990). CNS TB may be the initial presentation of AIDS and has a high mortality among such affected individuals. Tuberculous meningitis is the most frequent meningeal infection in the HIV patients living in areas with high prevalence of TB (Berenguer et al. 1992). Infection with HIV may increase the risk of developing TB meningitis five-fold from 2% of patients to 10% (Tagliati et al.I994). Another growing at-risk population is the medically compromised patients with systemic diseases or organ failure who are kept alive with modern management techniques.

32.3 Microbiology The predominant organism in human infections is M. tuberculosis. The organism M. tuberculosis is considered a gram-positive bacterium, though it is difficult to stain by the standard method. Its growth is very slow in culture, which clinically correlates with the slow infection it causes in vivo. Similarly, a long treatment course with anti-tuberculous medications is necessary to eradicate infection and to insure nonresurgence. The genome of M. tuberculosis has been sequenced and it includes approximately 4000 genes in a circular chromosome consisting of over 4 million base pairs (Cole et al. 1998).

32.4 Pathogenesis The microorganism reaches the CNS in the course of dissemination following a primary infection. Entry into the host is most frequently airborne. The fung tissue is infected first along with a regional lymph node. Several factors determine the clinical picture and outcome of CNS TB. These include age, nutritional status, load and virulence of infecting organism, immune deficiency and prior immunization with BCG. The density of bacilli in a unit volume of inspired air is dependent on severity of disease in the infecting person and the effectiveness of air circulation in the environment. The longer the exposure to contaminated air, the more likely the infection is to take place. Acid-fast bacilli do not produce toxins, therefore, they cause no initial tissue reaction or

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inflammation if the host has not been sensitized to tuberculoproteins (non-immune host). Primary hematogenous dissemination usually occurs in childhood and is clinically silent. Proliferation of M. tuberculosis favors foci with high blood flow and oxygenation. Vertebral column and lung apices are common sites. Positive tuberculin test signals establishment of cell-mediated immunity that commonly appears within 2 months. Granulomas may lead to healing-albeit incomplete-of the infected foci or lead to tissue destruction. Persons with impaired cellmediated immunity due to HIV infection or other diseases are more likely to become infected with M. tuberculosis after exposure than persons with normal immunity. Intact cell-mediated immunity decreases the chances of dissemination. Lymphocytopenia of (CD4+) T-lymphocytes was reported in TB patients who were seronegative for HIV (Kony et al. 2000) Cell mediated immunity plays an important role in both the host defense against TB and the tissue destruction that characteristically occurs with the infection. Tuberculoproteins activate T-lymphocytes, which produce cytokines that, in turn, activate macrophages. Macrophages not only perform a bactericidal role, but precipitate tissue destruction as well (Crowle et al. 1983). The production of the free radical nitric oxide is central in this process as it is a vasodilator, inflammatory mediator and cytotoxic (Anggard 1994). Tumor necrosis factor alpha (TNF a) appears to playa significant role in the host defense against TB and in the production of systemic symptoms such as weight loss and fever (Takashima et al. 1990). Recent experience with infliximab, a TNF-a-neutralizing agent developed for the treatment of rheumatoid arthritis and Crohn's disease, caused dissemination of latent tuberculous infection. This highlighted the role ofTNF-a in the host defense against tuberculous infection (Keane et al. 2001). The meninges are infected by organisms carried in the bloodstream. Primary hematogenous dissemination occurs early after primary infection, while rupture of a subpial or subependymal granuloma (Rich focus) may occur any time later in life. Recently the serum and cerebrospinal fluid (CSF) levels of vascular endothelial growth factor were found to be higher in tuberculous meningitis and they decreased in parallel with the clinical improvement (Matsuyama et al. 2001). The complexity of factors and varied methodologies are responsible, in part, for the variability of features of CNS infection reported from different centers. In a series from Riyadh; meningitis consti-

tuted 28% of cases, mass lesions 36% and neurological sequelae of spinal TB 36% (Bahemuka et al.1988), while in a pediatric population from London; meningitis constituted 60%, tuberculomas in 13% and mixed meningitis/tuberculoma in 26%. Vaccination with BCG was shown to protect against tuberculous meningitis (Awasthi and Moin 1999) and to modify the outcome whereby death and severe sequelae are avoided (Farinha et al. 2000).

32.5 Pathology Tuberculomas are granulomatous masses of variable sizes. They develop as the body's immune system attempts to contain a focus of M. tuberculosis. Macrophages induced by T-lymphocytes engulf the bacilli and form giant cells. Caseous material may appear at the center and typically contains a few bacilli. Gliosis and lymphocytic infiltration surround such foci. A variable amount of edema can be demonstrated by imaging studies. Tuberculomas are most frequently seen intraparenchymal but flat granulomas may grow on the meninges and have been called tuberculomas en-plaque (Fig. 32.1a). Tuberculous abscess of the brain is uncommon. It represents failure of the immune mechanism described above and consequently contains a high count of bacilli. It is suspected on imaging studies when an intensely enhancing thin wall surrounds a content that displays imaging characteristics of liquefaction. In tuberculous meningitis, the infection develops at a relatively rapid pace inside the subarachnoid spaces as opposed to the slower rate of progression in other organs. The basilar inflammation produces thick gelatinous exudates, which entrap the cranial nerves as they pass through the cisterns. The third, fourth, sixth and eighth cranial nerves are involved most frequently. Similarly, inflammation may induce tuberculous endarteritis. Penetrating branches of the anterior, middle, and posterior cerebral arteries are most commonly involved. Those include anterior choroidal, medial and lateral lenticulo-striate, thalamogeniculate and thalamoperforating arteries. Major arteries can also be thrombosed, causing massive infarctions. Granulomas surrounding blood vessels at the base of the brain may give a characteristic appearance on contrast enhanced computed tomography (CT) or magnetic resonance imaging (MRI) that is grape-cluster like.

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Pathological features were noted to be different in the HIV patients with tuberculous meningitis since they show reduced and atypical inflammatory response and extensive vasculopathy. The radiological correlate of this finding was the relatively less meningeal enhancement and the absence of communicating hydrocephalus on CT scan (Katrak et al. 2000).

32.6

Clinical The CNS may be directly compromised by inflammation, mass lesion or infarction or it may be affected by compression from collapsing supportive structures (i.e., spine). In the first instance, the patient may develop meningitis, parenchymal mass lesion (tuberculoma or abscess) or a combination thereof. In the latter instance, spinal cord compression may occur as a consequence of vertebral destructive infection and epidural cold abscess (Pott's disease of the spine). In order of severity, the combination of meningeal-parenchymal type ranks the highest, followed by meningitis. The majority of patients present in a sick state within a few weeks of infection. Cerebral or medullary tuberculomas and spinal TB are rather chronic smoldering infections with significant late complications.

32.6.1 Tuberculoma Tuberculomas are slow-growing inflammatory mass lesions which may be associated with variable perifocal edema. Lesions are mostly intraparenchymal. Any part of the CNS may be involved but it is more common in the cerebral hemispheres, a distribution that is probably proportional to the parenchymal volume. Tuberculoma may rarely be encountered in the spinal cord (intramedullary). Spinal cord tuberculoma may be the only significant manifestation of TB. Spinal or radicular pain and progressive weakness are the usual presenting symptoms. Correct diagnosis is possible in the presence of TB elsewhere. Intramedullary neoplasm is usually suspected before the correct diagnosis is reached (Kocen and Parsons 1970). Imaging studies show a fusiform swelling of the cord along with a central area of iso- or slight hyperintensity on T1WI, surrounded by edema that is typically hyper-intense on T2WI.

Intrasellar tuberculomas are rare and constituted less than 2% of all intrasellar masses in some series. They have female predominance and swelling of the pituitary stalk is a useful sign (Sharma et al. 2000).

32.6.2 Tuberculous Spondylitis Vertebrae are the most commonly involved part of the skeletal system. Approximately half of tuberculous infections of the skeletal system are localized to the spine. During the initial hematogenous dissemination of M. tuberculosis, small foci of infection settle in the skeletal system to be reactivated at a later stage. The infection may as well spread from an adjacent infected lymph node. Any part of the vertebral column may be affected, but over half of the patients develop involvement of the thoracic spine, especially the lower part (Alothman et al. 2001). Back pain usually precedes neurological manifestations. Tuberculous spondylitis frequently presents as progressive paraplegia. Early disease recognition may be hampered by late presentation in the endemic area or by unfamiliarity with the early symptoms in developed parts of the world. This discrepancy is responsible in part for the variability in the reported frequency of neurological complications in tuberculous spondylitis. By the time the patient presents for medical help a few vertebrae have already been damaged. The vertebral body adjacent to the disk space forms the initial lesion. Infection of the intervertebral disk soon follows. Typically, two or more adjacent vertebrae are destroyed with formation of granulomas or cold abscess in the surrounding paraspinal soft tissues. The dura is a strong barrier to the spread of infection into the CNS or development of meningitis. The cord is compressed by the epidural abscess. Pain is an early symptom caused by local inflammation. Root irritation gives a radicular distribution of pain around the trunk. Spinal pain may be dull and localized over the involved vertebrae. It is protracted with fluctuations in severity. Movement induces painful spasms, and to prevent them patients may avoid movements and become stiff. Neurological manifestations range from flaccid paraparesis in cases of cauda equina compression to spastic quadriplegia in cervical lesions. Pyramidal tract signs usually precede sensory and sphincter involvement. Rarely a sinus tract may drain to the skin. The paraspinal abscess may be noted clinically in the cervical or retropharyngeal region or can be demonstrated on spinal radiograph. Systemic symp-

Tuberculosis of the Central Nervous System

toms are similar to tuberculous infection in other parts of the body. These include low-grade fever, anorexia, weight loss, anemia, lassitude and night sweats. The long duration of symptoms, the development of typical gibbus, thoracic spine involvement and elevated erythrocyte sedimentation rate are suggestive of Pott's disease as opposed to spinal epidural infection or neoplastic conditions (Alothman et al. 2001; Buranapanitkit et al. 2001). The diagnosis is suggested by imaging, including plain radiographs of the spine, CT and MRI. The diagnosis is confirmed by obtaining a tissue sample by fine needle aspiration. The treatment is essentially medical. Surgical intervention can be avoided in many cases (Alothman et al. 2001). We noted good results with proper antituberculous treatment even in the face of neurological involvement. In the presence of significant spondylitis and compression, spinal decompression may be required. Removal of pus or granulation tissue through a laminectomy is sufficient when spondylitis is mild (Curling et al.1990). Epidural tuberculous infection is not unique to spinal TB. Disseminated infection may, on rare occasions, affect cranial epidural space and result in cerebral symptoms.

Illustrative case: a 24-year-old lady presented with focal seizures on the left side with secondary generalization. She had a past history of fever and night sweats. Chest films were suggestive of miliary appearance. CT of the head showed an enhancing lesion in the right frontal epidural space (Fig. 32.1a). The material recovered from the lesion after trephine procedure was caseous with a lot of acid-fast bacilli consistent with tuberculous abscess. The patient was treated with triple anti-tuberculous medications. She completed a 6-month course of therapy and remained seizure free after anti-epileptic drugs were discontinued.

32.6.3 Tuberculous Meningitis Fever, headache, lethargy and altered mentation are the most frequent presenting symptoms. Anorexia, night sweats and stiff neck may occur earlier. It is not uncommon for symptoms to be present for an average of 6 weeks before the person seeks medical attention. Approximately 50% of patients have meningeal signs early, while focal signs are seen in up to 20% (Berenguer et al. 1992). Past history of

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pulmonary TB is not an absolute necessity since less than 50% of adults with tuberculous meningitis give such a history. The spread of infection to the subarachnoid spaces results in diffuse meningitis that may rapidly become complicated by vasculitis, cranial nerve palsies, encephalitis or myelitis. Cranial neuropathies may appear at any time during the course of infection but are usually late. Optic, oculomotor and acoustic are most common. Some types of movement disorder may appear during tuberculous meningitis. Tremor is the most common, while chorea is mainly seen in young children. It is believed that deep infarcts are responsible for such manifestations (Alarcon et al. 2000).

32.7 Complications 32.7.1 Hydrocephalus Hydrocephalus is a common complication of tuberculous meningitis. It may occur early or late in the course of illness. Worsening headache and deteriorating level of consciousness are the main symptoms. Adhesive ependymitis may sequester a part of the ventricular system (usually temporal) and cause a localized hydrocephalus with mass effect that can lead to herniation. Imaging studies are necessary for any sudden change in the condition of the patient and hydrocephalus can be easily recognized. Diversion of CSF flow is necessary and usually done by ventriculoperitoneal shunting.

Illustrative case: a 37-year-old man presented with headache, vomiting and low-grade fever for 2 weeks. His examination showed lethargy and nuchal rigidity. Brain CT showed enhancement at the basal cisterns but no mass lesions or hydrocephalus. Lumbar puncture yielded a slightly xanthochromic fluid with protein of 1200 mg/l, sugar 1.8 mmolll and 329 WBC/ mm 3• Few acid-fast bacilli were seen on smear. He improved after treatment with rifampin, isoniazid, pyridoxine and pyrazinamide. He was discharged home after 2 weeks and was compliant with treatment. He returned to the emergency room 4 weeks after discharge, complaining of severe headache and vomiting. He was afebrile but pupils showed right pupil measuring 5 mm and left pupil 3 mm. Fundoscopic exam showed papilledema. On CT examina-

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M. Z. Al-Kawi

b

a Fig. 32.1a, b. a Tuberculoma en-plaque in the frontal region. T1 WI with enhancement, sagittal section b CT showing right temporal horn hydrocephalus. Sequestration of the temporal horn occured in the course of TB meningitis

tion there was a large hypodense mass lesion in the right temporal lobe with density compatible with CSF with transependymal edema in the temporal white matter (Fig. 32.1b). A ventriculoperitoneal shunt was placed in the right temporal horn and fluid under high pressure was released. The patient improved following surgery and completed 9 months of anti-tuberculous treatment.

32.7.2 Vascular Complications Arteries that supply the brain emerge in the basal cisterns. The same area that bears the brunt of inflammation in tuberculous meningitis. The walls of vessels immersed in the thick gelatinous exudate are affected by inflammation and arteritis may lead to vascular occlusion or thrombosis. Less commonly, but more seriously, intraparenchymal hemorrhage may occur.

may be lowered by hyponatremia and occurrence of seizures may be enhanced by low serum sodium. Extremely low levels. especially when the concentration decreases rapidly, may lead to encephalopathy. Attention to electrolyte balance is imperative during treatment.

32.7.4 Cranial Neuropathies

Optic: Obstruction of CSF pathways occurring in tuberculous meningitis may result in increased intracranial pressure and papilledema. Ultimately, damage to the optic nerve occurs by ischemia. Direct involvement of the optic nerve or the chiasm may be due to arachnoiditis and chronic granulomatous inflammation (Bruetsch 1948). Oculomotor Palsies: similarly, oculomotor nerve may be involved by microvascular thrombosis or by raised intracranial pressure. Ocular movements and pupillary reaction may be impaired. Ocular signs may develop independently of the level of consciousness.

32.7.3 Hyponatremia

Deafness: Sensorineural hearing loss is a common

Hyponatremia is common in tuberculous meningitis. It is attributed to inappropriate anti-diuretic hormone secretion (Singh et al. 1994). Seizure threshold

complication of meningitis in general and tuberculous meningitis in particular. The use of ototoxic drugs may contribute to this morbidity. It is unlikely to find evidence of labyrinthitis ossificans on CT of

Tuberculosis of the Central Nervous System

temporal bones in people suffering of hearing loss as a sequel of tuberculous meningitis.

32.7.5 Seizures Seizures are common presenting symptoms in cerebral tuberculomas. They occur later in tuberculous meningitis and may be associated with a worse prognosis. Rarely it may be the presenting manifestation of an extraparenchymal lesion such as an epidural TB abscess (Fig. 32.1a). They need to be treated by a suitable anti-epileptic drug, keeping in mind the interaction with anti-tuberculous chemotherapy and the side effects on liver functions.

32.7.6 Tuberculous Encephalopathy This complication was considered an allergic type-IV hypersensitivity occurring in the CNS as a reaction to tuberculous infection. It presents with an encephalopathic picture of drowsiness rapidly progressing to coma and death within weeks. There is mild CSF inflammatory changes and diffuse brain edema. Pathologically there is demyelination and perivascular inflammation (Dastur and Udani 1966). It is of interest that pulmonary TB without direct CNS infection was reported to be associated with neuromyelitis optica syndrome. This was believed to represent another remote immune-mediated complication as well (Silber et al. 1990).

32.7.7 Adhesive Arachnoiditis The thick inflammatory exudate at the base of the brain and around the cord may cause adhesions that compromise blood circulation to adjacent structures, resulting in loculation or block of CSF flow or causing entrapment of nerve roots. Symptoms of cranial nerve dysfunction, myelopathy or radiculopathy may occur.

32.7.8 Myelopathy Ischemia due to arteritis in the cord vasculature is probably the major cause of myelopathy. The result-

541

ing disability is therefore frequently permanent. The development of intramedullary granuloma is less common and may have a better outcome with treatment. Extramedullary mass effect in spinal tuberculous meningitis (Fig 3.1) or a loculated CSF pocket may cause pressure leading to myelopathy.

32.8 Diagnosis As with many other diagnoses, a proper degree of clinical suspicion is necessary. This can be easily achieved in areas of the world with high prevalence of TE. In the developed countries, however, a similar high index of suspicion should be adopted when the patient belongs to a population group susceptible to HIV or already seropositive for HIV. Other indicators for tuberculous infection include history of TB in a family member or contact with a person known to have open pulmonary TE. A positive Mantoux intradermal skin tuberculin test may be helpful but has inadequate sensitivity and specificity. It may be positive in a high proportion of adult population in endemic regions. However, severe infection may be associated with skin anergy and negative test in the presence of disseminated tuberculous infection. The diagnosis is usually based on four sources of evidence: the clinical manifestations, cerebrospinal fluid examination in combination with CT scan of the head, and evidence of TB elsewhere in the patient's systems. Evidence for TB elsewhere is helpful but its absence does not rule out the diagnosis. It should be looked for on chest film. The chance of finding a lesion on a routine chest radiograph has been reported with wide variability in the literature. Hilar lymphadenopathy, primary complex or miliary TB may be strongly suggestive but the latter may be missed if not particularly sought. Chest CT is more sensitive and should be performed in suspected cases. Considering the pathogenesis of CNS TB, the same hematogenous spread of infection should deliver the organism in the vascular choroid layer of the eye. The presence of choroid tubercle, however, is infrequently reported. This may reflect the difficulty in examining the peripheral regions of the fundus in a sick patient. When present, a choroidal tubercle is characteristic and appears as a small slightly raised rounded pale yellowish lesion with indistinct margins. Imaging of tuberculous meningitis usually shows significant enhancement in the basal cisterns. CT or MRI scan usually reveals basilar enhancement

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assumed to correlate with the intensity of the inflammation and the thickness of the exudates (Fig. 2.1). The parenchyma shows evidence of deep cerebral infarctions commonly in the distribution of the thalamoperforating and lenticulostriate arteries (Fig. 2.3). Stenosis or occlusion of the intracranial portion of the internal carotid artery and proximal segments of its branches, the anterior cerebral and middle arteries, may be identified on cerebral angiogram (Fig. 2.6). It is not unusual to find ischemic areas in addition to parenchymal inflammatory lesions (tuberculomas). Examination of CSF obtained by lumbar puncture is the definitive test for diagnosis of tuberculous meningitis. When the risk of herniation during lumbar puncture is a concern in patients with increased intracranial pressure, puncture may be performed with a small gauge needle to retrieve a small amount of CSF for essential diagnostic tests after the patient is prepared by the administration of intravenous mannitol 20% (0.25-0.5 g/kg) over 30 min. The findings of increased opening pressure, lymphocytic pleocytosis (usually in the range of 10-500 cells/mm\ high protein content and low glucose levels are typical but not universal. Early in the course of infection, there might be polymorphonuclear predominance. CSF glucose is usually low in tuberculous meningitis. Mean glucose values range from 22-38 mg per 100 ml, but 12-15% of patients may have normal glucose. Glucose should always be examined simultaneously in the blood and CSF. Failure to check the blood level may be a source of error when diabetes masks hypoglycorrhachia or iatrogenic hyperglycemia occurs in patients receiving dextrose intravenously. Glucose in the CSF falls below 40% of that in the serum. The low glucose may not be only because of consumption by organisms or white blood cells as had been considered in the past, but the inflammatory reaction may cause a disturbance in the CSF glucose transport system. Protein levels are extremely variable and may be influenced by the intensity of inflammatory reaction, but more importantly by the presence of block due to adhesive arachnoiditis. When protein levels exceed 1 gm/l00 ml, xanthochromia appears and the fluid may form a pellicle on the top or may clot altogether. Identifying acid-fast bacilli in the smear is an irrefutable evidence of tuberculous meningitis. Examining the pellicle stained for acid-fast bacilli may prove to be a richer diagnostic source than the fluid itself. Alternatively, the last tube of lumbar puncture specimen is the best tube to recover acid-fast bacilli on a smear. Positive smears in adults range from 10% to

M. Z. Al-Kawi

40% of cases of tuberculous meningitis. The sensitivity of the smear can be augmented by centrifugation of a larger specimen volume and by intensive examination. It was shown to be directly related to the diligence of the technologist performing the test and to the time spent on the microscope. Culture of M. tuberculosis from a CSF specimen is the gold standard for the diagnosis of tuberculous meningitis. The proportion of positive examinations, however, is not high. Growth of acid-fast bacilli in cultures of CSF requires 4-6 weeks and is positive in approximately 75% of cases of tuberculous meningitis. Its value is therefore confirmatory. Similarly, IgG antibody against M. tuberculosis in spinal fluid has been looked for by enzyme-linked immunosorbent assay (Kalish et al. 1983) but it is currently less often used. The time it takes for intrathecal synthesis of antibody renders the test insensitive in the early stages when the diagnosis is most needed. Recent advances in polymerase chain reaction (PCR) technology methods have shown a faster diagnostic yield. It has a reported sensitivity of 50%, and a 10% falsepositive rate (Lin et al. 1995). However, PCR confirmation of tuberculous meningitis faces difficulties because of inconsistent standards (Macher and Goosby 1995). Currently, the use of PCR to diagnose tuberculous meningitis from CSF specimen cannot be a routine practice because of its unreliability in detecting and confirming correctly the presence of M. tuberculosis. Diagnosis in patients with HIV infection is often delayed. Factors suggestive of tuberculous meningitis include endemicity of TB in the community, the presence of pulmonary TB, and hypoglycorrhachia (Theuer et al. 1990). Tuberculomas manifest as enhancing mass lesions, the usual triad of lesions which show no vascular blush if cerebral angiography is performed and are associated with signs that are less than would normally be expected for the size and location of the lesion. Biopsy is frequently necessary but a surgical procedure on the CNS can be avoided (see management of tuberculoma below). Since CNS TB is usually secondary to tuberculous infection elsewhere, search for an accessible tissue for biopsy and culture (Le., cervical or mediastinal lymph node) should be considered. Stereotactic brain biopsy is often the only certain method for diagnosing mass lesions in HIVinfected patients. Spinal TB recognition on imaging studies is discussed in the chapter on imaging in this book. Fine needle aspiration biopsy is a quick and reliable way for obtaining pathological specimen for microscopic

543

Tuberculosis of the Central Nervous System

examination and bacteriological confirmation of spinal TB. It can be done under radiological guidance (CT or fluoroscopy) with little morbidity and a high diagnostic yield, thereby avoiding more invasive diagnostic procedures. Material obtained is also helpful for culture and sensitivity. This allows immediate initiation of appropriate treatment, and decreases hospitalization time (Francis et al. 1999).

32.9 Management The treatment of CNS TB is more problematic than treatment of pulmonary TB. To be effective, the drugs have to cross the blood-brain or the blood-CSF barriers in adequate concentrations. Treatment of tuberculous meningitis should be initiated with a regimen of at least three drugs. Selection of drugs takes into account their ability to achieve an effective concentration across the blood-brain or the blood-CSF barriers. Compliance needs to be assured and that may necessitate supervised intake in some instances. First line drugs include isoniazid, pyrazinamide and rifampin. Ethambutol or streptomycin may be added in the first 2 months, especially if drug resistance to M. tuberculosis is suggested by knowledge about local incidence or prior treatment (Raviglione and O'Brien 1997). In a study of 150 CSF cultures from Egypt, 10% were resistant to isoniazid, 7% to ethambutol and 3% to rifampin while none showed multi-drug resistance (Girgis et al. 1998). Duration of treatment may extend from 9 months to 2 years depending on the patient's response. Blood tests may show a mild to moderate rise in liver enzymes during the early phase of therapy. This should not by itself constitute an indication for interruption of treatment, unless a serious liver dysfunction is suggested by a significant persistent rise in the enzymes or the development of jaundice. Peripheral neuropathy may develop in patients treated with INH for TB, particularly when pyridoxine is not supplemented. Second-line drugs include: ciprofioxacin, amikacin, kanamycin, cycloserine, rifabutin and clofazimine. The use of corticosteroids is controversial but is believed to improve outcomes in patients with tuberculous meningitis who are HIV negative (Kent et al. 1993). Indications for the use of glucocorticoids have included severe disease, increased intracranial pressure, mass effect from associated tuberculomas,

deterioration following the institution of antituberculous therapy, and spinal block. The rationale for use of corticosteroids is to attempt to reduce the inflammatory response through its potential effects on cytokines, chemokines, and matrix metalloproteinases, and on inhibiting cell recruitment and the synthesis of prostaglandins and leukotriene (Coyle 1999; Dooley et al. 1997). When tuberculoma is suspected and the patient's condition allows a watchful waiting, then a therapeutic trial may spare the patient an invasive diagnostic intervention (i.e., CNS biopsy). Our approach is to start the patient on triple or quadruple anti-tuberculous first line medications and to avoid the use of corticosteroids during the trial period. Corticosteroids may confuse the results of a therapeutic trial by its nonspecific anti-inflammatory effects or by its ability to make lymphoma deposits vanish. After 3 weeks of triple therapy, imaging should be repeated. If the mass lesion increases a biopsy is indicated. If the lesion decreases or remains the same the trial should be continued for an additional 3 weeks. The average time for early visible decrease in the size of a tuberculoma responding to the therapeutic trial is 6-8 weeks. Follow-up imaging in 6 weeks helps in deciding to have a biopsy if no improvement is noted. Treatment is continued if improvement is noted. If the diagnosis is secured early, corticosteroids may be used to ameliorate edema and reduce intracranial pressure. In rare occasions, paradoxical enlargement of lesions occurs during the first weeks of therapy. Corticosteroids may be used to suppress such a "paradoxical response" although their effectiveness is not proven. Initial therapy for most patients with HIV and TB in the CNS should consist of a four-drug regimen because of the possibility of drug-resistant TB. Rifampin-based or rifabutin-based drugs should be administered. Compliance is necessary in the treatment of TB in any host, but more so in patients with HIV infection. Special attention should be paid to interactions between anti-tuberculous medications and anti-retroviral drugs.

32.10 Prognosis Prognosis in tuberculous meningitis correlates with the duration of illness before hospitalization, clinical stage on admission and the presence or absence of hydrocephalus.

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The British Medical Research Council suggested classifying the severity of meningitis into three stages: in stage I are patients who are fully conscious, rational, and do not have focal neurological signs. Stage II patients are confused or have focal neurological signs such as hemiparesis or cranial nerve palsy. Stage III patients are stuporous or comatose. This classification may have some management and prognostic implications. The higher the stage, the worse the prognosis. In a study from India, multivariate analysis identified focal weakness, low score on Glasgow coma scale and abnormalities in somatosensory evoked potential as predictors of poor outcome (Misra et al. 2000). Pediatric patients may have significant sequelae especially if younger than 20 months or show evidence of infarction or hydrocephalus on imaging (Wallace et al. 1991). In patients infected with mv, illness lasting more than 2 weeks before admission and a CD4+ count of less than 200 per cubic millimeter predict poor prognosis (Berenguer et al. 1992). Depressed levels of consciousness and hemiplegia were associated with poor prognosis (Katrak et al. 2000). The presence of tuberculoma does not necessarily preclude a good long-term prognosis in properly treated HIVinfected patients (Malaskyand Reichman 1992). Tuberculous spondylitis has a better prognosis and effective treatment for a compliant patient can lead to resolution of a significant part of neurological manifestations.

References Alarcon F, Duenas G, Cevallos N et al (2000) Movement disorders in 30 patients with tuberculous meningitis. Mov Disord 15:561-569 Alothman A, Memish ZA, Awada A et al (2001) Tuberculous spondylitis: analysis of 69 cases from Saudi Arabia Spine 26:565-570 Anggard E (1994) Nitric oxide, mediator, murderer and medicine. Lancet 343:1199-1206 Awasthi S, Moin S (1999) Effectiveness of BCG vaccination against tuberculous meningitis. Indian Pediatr 36:455-460 Bahemuka M, Babiker MA, Wright SG et al (1988) The pattern of infection of the nervous system in Riyadh: a review of 121 cases. Q J Med 68:517-524 Barnes PF, Barrows SA (1993) Tuberculosis in the 1990 s. Ann Intern Med 119:400-410 Berenguer J, Moreno S, Laguna F et al (1992) Tuberculous meningitis in patients infected with the human immunodeficiency virus. N Engl J Med 326:668 Bruetsch WL (1948) Etiology of optochiasmal arachnoiditis. Arch Neurol Psychiatry 59:215

M. Z. Al-Kawi Buranapanitkit B, Lim A, Kiriratnikom T (2001) Clinical manifestation of tuberculous and pyogenic spine infection. J Med Assoc Thai 11:1522-1526 Cave AJE (1939) The evidence for the incidence of tuberculosis in ancient Egypt. Br J Tuberc 30: 142 Cole ST, Brosch R, Parkhill J et al (1998) Deciphering the biology of Mycobacterium Tuberculosis from the complete genome sequence. Nature 393:537 Coyle PK (1999) Glucocorticoids in central nervous system bacterial infections. Arch Neurol 56:796-801 Crowle AJ, Douvas GS, May MH (1983) The cellular and molecular nature of human tuberculoimmunity. Bull Int Union Tuberc 58:72-80 Curling aD, Gower DJ, McWhorter JM (1990) Changing concepts in spinal epidural abscess: a report of 29 cases. Neurosurgery 27:185 Dastur DK, Udani PM (1966) Pathology and pathogenesis of tuberculous encephalopathy. Acta Neuropathol (Bed) 6: 311-326 Dooley DP, Carpenter JL, Rademachen S (1997) Adjunctive corticosteroid therapy for tuberculosis: a critical reappraisal of the literature. Clin Infect Dis 25:872-887 Farinha NJ, Razali KA, Holzel H, Morgan G, Novelli VM (2000) Tuberculosis of the central nervous system in children: a 20-year survey. J Infect 41 :61-68 Francis 1M, Das DK, Luthra UK et al (1999) Value of radiologically guided fine needle aspiration cytology (FNAC) in the diagnosis of spinal tuberculosis: a study of 29 cases. Cytopathology 10:390-401 Gachot B, Wolff M, Clair B et al (1990) Severe tuberculosis in patients with human immunodeficiency virus infection. Intensive Care Med 16:491-493 Girgis NI, Farid SZ, Mansour MM et al (1998) Tuberculous meningitis, Abbassia Fever Hospital ... 1976-1996. Am J Trop Hyg 58:28-34 Kalish SB, Radin RC, Levitz D et al (1983) The enzyme linked immunosorbent assay method for IgG antibody to purified protein derivative in cerebrospinal fluid of patirnts with tuberculous meningitis. Ann Intern Med 99:630-663 Katrak SM, Shembalkar PK, Bijwe SR et al (2000) The clinical, radiological and pathological profile of tuberculous meningitis in patients with and without human immunodeficiency virus infection. J Neurol Sci 181:118-126 Keane T, Gershon S, Wise RP et al (2001) Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 345:1098-1104 Kent SJ, Crowe SM, Yung A et al (1993) Tuberculous meningitis: a 30-year review. Clin Infect Dis 17:987 Kocen RS, Parsons M (1970) Neurological complications of tuberculosis: some unusual manifestations. Q J Med 39:17 Kony SJ, Hane AA, Larouze B (2000) Tuberculosis-associated severe CD4+ T-lymphocytopenia in HIV-seronegative patients from Dakar. J Infect 41: 167-171 Lin JJ, Harn HJ, Hsu YD, Tsao WL et al (1995) Rapid diagnosis of tuberculous meningitis by polymerase chain reaction assay of cerebrospinal fluid. J NeuroI242:147-152 Macher A, Goosby E (1995) PCR and the misdiagnosis of active tuberculosis. N Engl J Med 332:128-129 Malasky C, Reichman LB (1992) Long-term follow-up of tuberculoma of the brain in an AIDS patient. Chest 101:278-279 Matsuyama W, Hashiguchi T, Umehara F et al (2001) Expression of vascular endothelial growth factor in tuberculous meningitis. J Neurol Sci 186:75-79

Tuberculosis of the Central Nervous System Misra UK, Kalita J, Roy AK et al (2000) Role of clinical, radiological, and neurophysiological changes in predicting the outcome of tuberculous meningitis: a multivariate analysis. J Neurol Neurosurg Psychiatry 68:300-303 Osler W (1921) The evolution of modern medicine. Yale University Press, New Haven, CT Raviglione MC, O'Brien RJ (1997) Tuberculosis. In: Fauci AS et al (eds) Harrison's principles of internal medicine, 14th edn. McGraw-Hill, New York, pp 1004-1014 Sanchez-Portocarrero J, Perez-Cecilia E, Romero-Vivas J (1999). Infection of the central nervous system by Mycobacterium tuberculosis in patients infected with human immunodeficiency virus (the new neurotuberculosis). Infection 27:313 Selwyn PA, Sckell BM,Alcabes P et al (1992) High risk of active tuberculosis in HIV-infected drug users with cuaneous anergy. JAMA 268:504 Sharma MC, Arora R, Mahapatra AK et al (2000) Intrasellar tuberculoma - an enigmatic pituitary infection: a series of 18 cases. Clin Neurol Neurosurg 102:72-77 Silber MH, Willcox PA, Bowen RM (1990) Neuromyelitis optica (Devic's syndrome) and pulmonary tuberculosis. Neurology 40:934-938 Singh BS, Patwari AK, Deb M (1994) Serum sodium and

545 osmolal changes in tuberculous meningitis. Indian Pediatr 31:1345-1350 Tagliati M, Godbold J, Hassett J et al (1994) Neuromuscular disorders in HIV infection: cross-sectional cohort analysis of 250 patients. Neurology 44:A367 Takashima T, Ueta C, Tsuyuguchi I et al (1990) Production of tumor necrosis factor alpha by monocytes from patients with pulmonary tuberculosis. Infect Immun 58:3286-3292 Theuer CP, Hopewell PC, Elias D et al (1990) Human immunodeficiency virus infection in tuberculosis patients. J Infect Dis 162:8 Udani PM, Parekh UC, Dastur DK (1971) Neurological and related syndromes in CNS tuberculosis. Clinical features and pathogenesis. J Neurol Sci 14:341 Wallace RC, Burton EM, Barrett FF et al (1991) Intracranial tuberculosis in children: CT appearance and clinical outcome. Pediatr RadioI21:241-246 Weigel B (1976) Changes of the tuberculosis of the central nervous system since the introduction of prophylactic BCG vaccination and tuberculostatic therapy. Zentralbl Allg PathoI120:21-33 Zimmerman MR (1979) Pulmonary and osseous tuberculosis . in an Egyptian mummy. Bull NY Acad Med 55:604-608

33 Imaging of Brain and Spinal Cord Tuberculosis FRANCIS MCGUINESS

CONTENTS Brain and Spinal Cord Tuberculosis 547 Histopathology of Intracranial Tuberculosis 548 Tuberculous Meningitis (TBM) 548 Imaging Characteristics of TBM 550 Tuberculomas of TBM 554 Parenchymal Cerebral Tuberculosis 555 Parenchymal Tuberculomas 555 Imaging Characteristics of Tuberculomas 557 Paradoxical Response of Tuberculomas to Treatment 560 Late Stage Appearances of Tuberculomas 560 33.7.1 Tuberculous Brain Abscesses 561 33.8 Atypical Tuberculous Masses 561 33.9 Miliary Cerebral Tuberculomas 562 33.10 Tuberculosis of the Calvarium 33.11 with CNS Lesions 563 33.12 Tuberculous Otitis Media and Tuberculosis of the Temporal Bone 564 33.12.1 Imaging 565 33.13 Differential Diagnosis of TBM and Parenchymal Tuberculosis 565 33.14 Tuberculous Radiculomyelopathy and Myelitic Tuberculomas 570 Imaging Methods in Spinal 33.15 Neurotuberculosis 571 33.15.1 Plain Radiography 571 33.15.2 Water-Soluble Contrast Myelography (WSCM) 572 33.15.3 CT Combined with Water-Soluble Myelography 572 33.15.4 Magnetic Resonance Imaging 573 33.16 Differential Diagnosis 575 33.16.1 Spinal Arachnoiditis 575 33.16.2 Infective Leptomeningitis 576 33.16.3 Spinal Meningitis in Neoplastic Conditions 576 33.16.3.1 Meningeal Carcinomatosis 576 33.16.4 Fungal Diseases 579 33.16.5 Spirochetal Disease 580 33.16.6 Other Granulomatous Diseases 581 33.16.7 Parasitic Diseases 582 33.16.7.1 Schistosoma 582 33.16.8 Neurocysticercosis 582 33.16.8 Demyelinating Disease 582 33.16.8.1 Multiple Sclerosis 582 References 583

33.1 33.2 33.3 33.4 33.5 33.6 33.6.1 33.6.2 33.7

F. MCGUINESS Apt. 169, AI Haurin El Grande, 2912 Malaga, Spain

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

33.1 Brain and Spinal Cord Tuberculosis Events during the past decade have dramatically changed the nature and magnitude of the problem of tuberculosis. Much of what many physicians learned in training about this disease is no longer true. In many respects tuberculosis has become a new entity. (Snider and Roper 1992) While taking into account the coinfection of AIDS and tuberculosis, the authors, Drs Snider and Roper, were also stressing the major global increase in tuberculosis infection that occurred in the 1980s. This epidemic led to the World Health Organisation (WHO) declaring a worldwide emergency in April 1993 and describing the spread of tuberculosis as a neglected health crisis. In its most recent report in 2000, WHO estimates that 1.9 billion persons are infected with the tubercle bacillus and have the potential to develop postprimary tuberculosis (TB). That is one third of the world's population (Pio and Chaulet 1998). Central nervous system tuberculosis can affect any of the elements of the neural tissues as well as their investing meninges. Jinkins estimates that between 2% and 5% of patients with active tuberculosis elsewhere in the body and up to 10% of those with the AIDS coinfection develop central nervous system lesions (Jinkins 1991; Kanamalla et al. 2000). The infection shows a predilection for the younger age groups, many patients being under the age of 5 years and the majority below the age of 30 (McGuinness 2000; Jamieson 1995; Schoeman et al. 1988; Cremin and Jamieson 1996). However, in the West there is an increase in the incidence of the disease in those over 60 years of age. The structure and reproductive properties of Mycobacterium tuberculosis are such that tuberculous infections develop insidiously. Mycobacterium tuberculosis var. hominis is the common causal agent of infection, although Mycobacterium tuberculosis var. bovis also causes a number of extrapulmonary infections.

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Both bacilli have a protective layer of phospholipids, phosphoglycolipids, and waxes, and are not detected by Gram stain. Ziehl-Neelsen stain and fluorescent staining methods reveal the organism, but in only a few cases is the bacillus found in the initial examination of cerebrospinal fluid (CSF). The slow reproductive time of 48 hours makes the organism difficult to culture, and means that clinical presentation and biochemical assessment are paramount to making the initial diagnosis of tuberculous meningitis (TBM), tuberculous meningomyelitis (TBSM), and tuberculoma (Jinkins 1991; Kanamalla et al. 2000; McGuinness 2000; Jamieson 1995; Cremin and Jamieson 1996; Shah 2000).

33.2 Histopathology of Intracranial Tuberculosis The manifestations of intracranial tuberculosis are diverse and are reflected in the imaging. In interpreting the images, an understanding of the underlying histopathology of the disease is helpful. Detailed descriptions of these changes are to be found in the literature (McGuinness 2000; Shah 2000; Dastur et al. 1995; Dastur 1972; Kirkpatrick 1991; Reid and Fallon 1992). A brief account of the major pathologic changes in central nervous system tuberculosis follows. Central nervous system tuberculosis is almost invariably the result of hematogenous spread of infection from a focus elsewhere in the body. In the majority of cases, the primary source of the disease is a focus of pulmonary or pulmonary-lymphatic tuberculosis. In infants and children, a primary pulmonary focus leading to local lymph node involvement or the development of progressive postprimary tuberculosis is the common cause of spread of the infection to the nervous system (McGuinness 2000; Jamieson 1995; Cremin and Jamieson 1996; Shah 2000). In older patients (from adolescence onwards), reactivation of pulmonary disease, or miliary tuberculosis is a common cause of hematogenous dissemination to the central nervous system. Dissemination from tuberculous foci in the gastrointestinal or genitourinary systems, or from foci in bones and joints, the paranasal sinuses, or the middle ear are less common occurrences (Kanamalla et al. 2000; McGuinness 2000; Jamieson 1995; Cremin and Jamieson 1996; Shah 2000; Dastur et al.1995). Breakthrough of the infection from osteogenic tuberculous foci in the spine or the cranial vault is

less frequent, due to the protective nature of the dura mater. The dura mater, comprising two layers - the outer layer fused to the periosteum and the inner layer bound to it closely - forms a formidable barrier to the spread of infection across its boundary (McGuinness 2000; Shah 2000). Although the initial response of the body to tuberculous infection is a nonspecific inflammatory one, a cell-mediated immune response develops within 2 to 3 weeks. Further foci of tuberculous infection elicit the development of granulomata. Granulomatous tuberculous foci comprise central clumps of epitheliod cells and macrophages containing intracellular tubercle bacilli. The core is surrounded by fibroblasts and mononuclear inflammatory cells and often contains Langerhans giant cells (Kanamalla et al. 2000; McGuinness 2000; Cremin and Jamieson 1996; Shah 2000; Dastur et al.1995). These foci were described by Rich in 1933 and bear his name (Rich and McCordock 1933; Rich 1944). There are two theories concerning the development of tuberculous lesions in the leptomeninges, the cerebrum, and myelum. The common theory is that Rich foci, resulting from hematologic spread, develop in the leptomeninges and rupture into the subarachnoid space. The cerebrospinal fluid has minimal protection against infection and the space and leptomeninges become widely infected (Kanamalla et al. 2000; McGuinness 2000; Dastur et al. 1995; Dastur 1972). A second theory is that the hematogenous spread to the capillary and venule walls in the leptomeninges and similar vessels penetrating the cerebrum and myelum, causes inflammatory breakdown of the vessel walls and of the blood-brain barrier. This allows spread of the infection both superficially over the leptomeningeal surface and deeper into the brain or spinal cord substance. This seems the likely cause of the development of the meningocerebritis characteristic of tuberculous meningitis, and the associated tuberculomas show a preference for development at the cortico-white matter interface, where the peripheral blood vessels are at their narrowest (Kanamalla et al. 2000; McGuinness 2000; Cremin and Jamieson 1996; Shah 2000; Dastur et al. 1995; Dastur 1972).

33.3 Tuberculous Meningitis (T8M) TBM develops when a microscopic granuloma, a Rich focus, situated beneath the pia mater, in the cerebral

Imaging of Brain and Spinal Cord Tuberculosis

cortex, or in the wall of a cerebral venule, ruptures into the subarachnoid space. Untreated, TBM is a fatal disease and unless diagnosed and treated early leads to calamitous neurologic defects. TBM is still a common disease. This is especially so in the 24 high-burden countries named in the WHO report on worldwide tuberculosis (Pio and Chaulet 1998), but it also remains a problem in the economically rich states of the world. Wallace quotes approximately 4,000 cases of TBM per year, reported to the Centers for Disease Control of the United States (Wallace et al. 1991; Ogawa et al. 1987). Both Wallace and Hooijboer (Hooijboer et al. 1996) emphasize that although commonly occurring in immigrant groups in the United States and Europe, meningitis surprises the physician by expressing itself among native-born children as well. TBM is an insidious disease and a high clinical awareness is essential to its diagnosis. Most published series emphasize the fact that the common presentation to the physician is after the initial stages, when the illness is well established (Jinkins 1991; McGuinness 2000; Jamieson 1995; Schoeman et al. 1988; Cremin and Jamieson 1996; Wallace et al. 1991; Hooijboer et al. 1996; Kioumehr et al. 1994; De Castro et al 1995; Jinkins et al.1995; Cremin 1995; Leiguarda et al.1988; Waeker and Connor 1990). The presentation is characterized by malaise, lassitude, low grade fever and an intermittent headache. Unlike the acute pyogenic and viral meningitides, high fever, papilloedema, and focal cerebral symptoms are unusual in the early stages. In this phase of the infection the clinical findings are similar to the other chronic meningitides caused by fungus, parasites, meningeal carcinomatosis, Lyme disease, and neurosarcoidosis (McGuinness 2000; Shah 2000). The severity of the disease is classified according to the Medical Research Council of the United Kingdom staging system of 1948. Stage I disease is characterized by nonspecific symptoms in a conscious patient, including headache, vomiting, irritability, or lethargy with no paresis and a good general condition. Stage II disease shows drowsiness, photophobia, meningeal irritation, and focal neurologic signs with possible seizures. Stage III disease presents with profound changes in the sensorium, major neurologic signs, and coma (McGuinness 2000; Wallace et al. 1991; Waeker and Connor 1990; Medical Research Council 1948; Lincoln et al. 1960). CT scanning is advised before lumbar puncture. Examination of the cerebrospinal fluid after the first few days, demonstrates a lymphocytic pleocytosis, increased protein level, and diminished glucose.

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Bacteriologic or histologic support for the diagnosis is sought by the purified protein derivative skin test (PPD), which is particularly helpful in children producing a high percentage of positives. Examination of sputum, gastric washings, and CSF by direct smear and culture should be carried out in all suspected cases. CSF examination with acid-fast stains is, in most reported series, positive in only a small proportion of cases, usually less than 10% (McGuinness 2000; Jamieson 1995; Cremin and Jamieson 1996; Wallace et al. 1991; Hooijboer et al. 1996; Kioumehr et al. 1994; De Castro et al1995; Jinkins et al. 1995; Leiguarda et al. 1988). Waeker (Waeker and Connor 1990) reports only one of 30 children having a positive smear, and 37% with positive CSF cultures. Shah (Shah 2000) suggests a higher proportion of 90% of cases being CSF-positive to acid-fast staining methods. Search for the bacillus should also be made in the urine and in cultures taken from any ear infection (McGuinness 2000; Wallace et al. 1991; Naranbhal et al. 1989). Histologic support or positive bacteriologic cultures may derive from samples taken from other regions, remote from the nervous system. Chest radiography is only positive for visible evidence of tuberculosis in 40-50% of cases, and a negative chest radiograph in no way precludes the diagnosis of TBM (McGuinness 2000; Jamieson 1995; Cremin and Jamieson 1996; Hooijboer et al. 1996; De Castro et al 1995; Jinkins et al. 1995; Leiguarda et al.1988; Waeker and Connor 1990; Ozates et al. 2000). Control examinations of family members are of great importance and often reveal active tuberculosis in parents or siblings (McGuinness 2000; Ogawa et al.I987). The most effective radiologic investigation in cases of TBM is a contrast-enhanced CT scan (CECT), and where this investigation is available it should be carried out immediately on presentation of the patient. After the initial compromise of the leptomeninges by Rich foci, cell-mediated immunity leads to the development of a glutinous exudate. In the initial stages the exudate is largely confined to the basal subarachnoid areas, but rapidly involves the basal cisterns, particularly the interpeduncular and suprasellar spaces (McGuinness 2000; Dastur et al. 1995; Dastur 1972; Kirkpatrick 1991; Reid and Fallon 1992). Spread of the exudate along the periarterial spaces of the major arteries and their branches follows, with encasement of the common carotid, anterior, middle, and posterior cerebral arteries. This facilitates spread of the exudate to the ambient system, prepontine cistern, and the supratentorial subarachnoid space, including Sylvius' fissure. The exudate is an inflammatory response to

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the presence of both intra-and extracellular bacilli. The cell-mediated response from activated T cells leads to an outpouring of lymphocytes, plasma cells, and macrophages, which reorganize into countless microscopic tubercles. In the later stages of the disease, these tuberculous granulomas are surrounded by fibroblasts, and caseous necrosis occurs in the central core (Jinkins 1991; McGuinness 2000; Jamieson 1995; Schoeman et al. 1988; Cremin and Jamieson 1996; Shah 2000; Dastur et al. 1995; Dastur 1972; Wallace et al. 1991; De Castro et a11995; Jinkins et al. 1995).

33.4 Imaging Characteristics of T8M The common triad of imaging changes in TBM on contrast-enhanced CT and gadolinium-enhanced MRI are basal meningeal enhancement, hydrocephalus and parenchymal supratentorial infarctions. These changes are the direct result of the underlying histopathologic processes. Enhancement is due to the breakdown of the blood-brain barrier in the leptomeninges and the intense basal inflammatory exudate, hydrocephalus due to the blockage of the normal CSF pathways, and infarctions are the result of spasm or closure of basal cerebral vessels. Basal contrast enhancement in the early stages is confined to the leptomeninges, although in chronic cases the pachymenix may be extensively affected. The enhancement follows the pathway of the basal vessels and the perivascular or Virchow-Robin spaces. As the inflammatory response to the infection develops, exudates are seen in the basal leptomeninges and basal cisterns, especially in the ambient, sylvian, pontine, and suprasellar areas. Widespread enhancement of exudates is the common pattern, although rarely focal enhancement has been reported involving Sylvius' fissure (Shah 2000; Klingensmith and Datu 1978) and the left parietal leptomeninges (Elkeslassy et al. 1997). Linked with the other two elements of the triad this enhancement is highly suggestive of TBM but is by no means pathognomonic. Other conditions - bacillary or viral meningitis, fungal meningitis, other granulomatous diseases, inflammatory response to the rupture of a paracytic or dermoid cyst, and meningeal metastatic disease - may demonstrate basal meningeal enhancement, but usually of a less intense nature and a narrower distribution (Jinkins 1991; McGuinness 2000; Kioumehr et al. 1995).

F. McGuiness

Noncontrast CT studies (NCCT) are of little value in the detection of meningeal disease. The beam hardening artefacts due to the overlying cranium and the bones of the posterior fossa make it difficult to image the meninges. In the few cases where calcification develops at an early stage in TBM, NCCT has an advantage. The presence of basal exudates is suspected when the subarachnoid space is obliterated by isoattenuating tissue. With CECT these can be readily demonstrated. The usual pattern is of long continuous segments of enhanced leptomeninges, often with associated pial enhancement of the perivascular intergyral spaces. In advanced cases, evidence of cerebritis may be seen, signaled by areas of hypoattenuation in the underlying cerebral cortex. The most apparent leptomeningeal pathologic change is evidenced by the predilection of post-contrast enhancement for the basal cisterns, particularly the suprasellar region, the prepontine region, and ambient system (Kanamalla et al. 2000; McGuinness 2000; Jamieson 1995; Cremin and Jamieson 1996; Shah 2000; Dastur et al. 1995; Dastur 1972; Wallace et al. 1991; Kioumehr et al.1994; De Castro et a11995; Jinkins et al.1995; Waeker and Connor 1990; Ozates et al. 2000; Kioumehr et al.1995). (Fig. 33.1a, b) Magnetic resonance imaging (MRI),is the gold standard for the imaging of the brain and leptomeninges. As in the case of CT imaging, precontrast studies are often of little value in acquiring information on meningeal infectious disease (Kanamalla et al. 2000; Shah 2000; Kioumehr et al. 1995; Meltzer et al. 1996). Post intravenous gadolinium enhanced images possess an inherent high contrast resolution and improved tissue differentiation. These qualities linked with multiplanar imaging make it the imaging modality of choice in intracranial infectious disease. It is unfortunate that MRI examination is not universally available in most of the areas of the world with a high burden of tuberculosis. In some of these areas a heightened clinical awareness and often limited laboratory facilities are the only aids available to the physician. Recent MRI applications suggest that fluid attenuation inversion recovery (FLAIR) acquisitions are helpful in cases where meningeal disease is suspected (Kanamalla et al. 2000; Singer et al.1998). Gadolinium-enhanced Tl-weighted MRI images readily reveal the extent of leptomeningeal enhancement in TBM and the distribution of the lesions. They will also bring to light the concomitant changes of subcortical cerebritis, hydrocephalus, brain infarctions, ependymitis, and associated tuberculomas (Kanamalla et al. 2000; McGuinness 2000; Shah 2000; Jinkins et al.1995; Gupta et al.1994). The second com-

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a

b Fig. 33.1 a Axial Tl-weighted, postgadolinium scan, demonstrating intense enhancement of the basal meninges in a case of tuberculous meningitis. The white arrow points to border-zone disease adjacent to the fourth ventricle. b A similar scan at a lower level. There is enhancement of the surface of the brain stem and of exudates in the surrounding cisterns (arrow). On both scans there is enhancement of the meninges over the convexities, and a number of small parenchymal granulomas. There is hydrocephalus

ponent of the imaging triad, hydrocephalus, is almost sary, although in TBM many stage I and stage II cases universally present at the time of patient presentation. will require ventricular drainage early in the course of It commonly develops in tandem with the glutinous treatment. (Fig. 33.2a, b). Early development of hydrocephalus in TBM basal exudates which cause disruption of CSF circulation and reabsorption. The hydrocephalus is charac- is emphasized by most authors (Jinkins 1991; teristically of high pressure, and the periventricular Kanamalla et al. 2000; McGuinness 2000; Jamieson white matter is suffused to a greater or lesser extent 1995; Schoeman et al. 1988; Cremin and Jamieson with hydrostatic edema. Until recently the reabsorp- 1996; Kioumehr et al. 1994; De Castro et al 1995; tion of CSF was thought to occur solely by the activity Jinkins et al.1995; Ozates et al. 2000; Gupta et al.1994; of the arachnoid granulations overlying the cerebral Bonafe et al. 1985; Dastur et al. 1970; Artopulous et convexities. Hydrocephalus in TBM was thought to be al. 1984; Chang et al. 1990). Wallace (Wallace et al. secondary to obstruction of the flow of CSF around 1991) and Waecker (Waeker and Connor 1990) also the midbrain and in the basal subarachnoid space note its early development and find it a more reliable by leptomeningeal exudates, which also blocked the diagnostic pointer in TBM than the presence of basal arachnoid granulations. Recent work by Greitz et al., exudates. Of Wallace's nine cases, ventriculomegaly however, suggests a new concept of CSF absorption was present in seven, while it was present in all of (Greitz et al. 1997). Using flow-sensitive MRI and Waecker's 30 cases. In Ozates' study of 289 TBM radionuclear cisternography, they propose that the patients (Ozates et al. 2000), 204 developed hydromain site of absorption of CSF is through the walls of cephalus in the course of the disease, and it was prescerebral arterioles, capillaries, and venules. In TBM, ent in 163 patients on presentation. In general, the compromise of these vessels, by spasm and arteritis, severity of hydrocephalus corresponds to the severresulting from encasement by exudate in the sub- ity of the infection, it is more pronounced in children arachnoid space, would be an important factor in the than in adults, and serial CT studies show that it often early development of communicating hydrocephalus. worsens during the first few weeks despite adequate Rarely, in TBM the hydrocephalus is of the obstructing chemotherapy. type, resulting from the obstruction of the aqueduct of Arteritis, vessel encasement by exudate, spasm, and Sylvius or the foramina of Luschka and of Magendie by vessel occlusion lead to compromise of the arterial flow subarachnoid granulomas or glutinous subarachnoid in the vessels of the circle of Willis and their branches. exudates. It is important to recognize this complica- So leading to the third feature of the clinical triad, ceretion, as in these cases early shunt placement is neces- bral infarction. Cerebral cortical, white matter, and tha-

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a Fig. 33.2a, b. Sagittal T1 and proton-density scans. There is a grape-like cluster of tuberculous granulomas obstructing the outlet of the fourth ventricle, resulting in hydrocephalus (arrow)

lamic infarction is a major cause of permanent brain damage, occurring despite adequate antituberculous chemotherapy, and may be taken as a good indicator of an eventual poor clinical outcome. Angiographic and postmortem studies have demonstrated occlusions ranging from closure ofthe suprasellar segment of the carotid artery to thrombosis of its major branches, leading to large territorial infarctions (McGuinness 2000; Dastur et al. 1995; Dastur 1972; Leiguarda et al. 1988; Gupta et al. 1994). The typical angiographic changes of irregularities in caliber ofvessels branching from the circle ofWillis, occlusion of the medium-size arteries at the base of the brain, and early venous drainage were described by Lehrer (Lehrer H 1966), and when combined with a hydrocephalic pattern of vessel distribution, were called by him, the angiographic triad of TBM. However, the smaller perforating branches are more commonly affected than the larger arteries, and occlusion of the medial-striate and thalamo-striate perforating arteries, leads to a characteristic picture of infarction in the thalamus and caudate nucleus. As in many of the manifestations of TBM, infarction is more common in patients under 5 years of age (Kanamalla et al. 2000; McGuinness 2000; Jamieson 1995; De Castro et al 1995; Leiguarda et al. 1988). This underscores the notion that the branches of the arteries of the circle of Willis become involved in the' inflammatory process as they pass through the basal exudates. In the case of children, the small caliber of the vessels makes them more vulnerable and susceptible to thrombotic occlusion than the larger caliber vessels of adults. Postmortem studies have shown

that venules as well as arteries are involved in this pathologic process. Large vessel infarction does however occur, even in adults, and may be demonstrated by digital subtraction angiography (DSA) (Fig. 33.3) or magnetic resonance arteriography (MRA). Large vessel infarction in the territories of the anterior or middle cerebral arteries leads to extensive cerebral cortical infarction. These areas subsequently develop encephalomalacia and segmental areas of overlying cortical atrophy. At a later stage, areas of calcification, best seen on CT examination, have been described in these areas (McGuinness 2000; Ogawa et al. 1987; De Castro et al1995; Jinkins et al. 1995). Although there are no reported cases of clinical deterioration after DSA, the examination is today deemed unnecessary in cases of TBM (McGuinness 2000; Rochas-Echeverri et al. 1996). Impending infarction is suggested by a shaggy appearance of the perivascular exudates on CFCT, and the results of infarction are clearly demonstrated on both CT and MRI examinations (Ogawa et al. 1987). Gupta has demonstrated the presence of large and small vessel arteritis by MRA studies, a noninvasive method of examination (Gupta et al.1994). At post mortem, the incidence of infarction is around 40% (Dastur et al. 1995; Dastur 1972; Dastur et al. 1970). Published studies of investigation by CT examination suggest a discovery rate of around 2838%. MRI studies are more sensitive, having a discovery rate of around 50% and demonstrate that many of these lesions are hemorrhagic, which may lead to cavitation (McGuinness 2000; Jamieson 1995; Schoeman et al. 1988; Cremin and Jamieson 1996; Shah 2000; Wal-

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lace et al.1991; Jinkins et al.1995; Leiguarda et al.1988; Gupta et al.1994; Rochas-Echeverri et al.1996). Schoeman (Rochas-Echeverri et al.1996),described a group of 27 children investigated with MRI, with much higher rates of infarction, 20 of whom presented with stage II or III disease, had midbrain or basal ganglia lesions. Ten presented with brain stem, parahippocampal gyri, or hypothalamic changes. By contrast, Ozates in a review of 289 TBM cases - 214 children and 75 adults - examined by CT, reports a lower overall incidence of infarctions of 13%. Infarctions are seen on CT scans as areas of hypoattenuation. On Tl-weighted gadolinium-enhanced MRI (Tl Gd) the areas of infarc-

a

a

tion stand out as hypodense lesions (Fig. 33.4a, b). On T2 MRI, acquisitions infarctions show a high signal and are difficult to differentiate from areas both of leptomeningitis and border-zone disease. Border-zone changes are a form of cerebritis that develops beneath the inflamed leptomeninges, and these are frequently seen in the superficial cerebral cortex, the cerebral peduncles abutting onto the interpeduncular fossa, and the midbrain and pons adjacent to areas of cisternal enhancement. They are usually present in advanced disease and indicate a poor prognosis (McGuinness 2000; Jamieson 1995; Cremin and Jamieson 1996). (See Fig. 33.5a, b.)

Fig. 33.3a,b. Avertebral artery angiogram with much wall irregularity in the basilar artery and the posterior fossa branches, resulting from tuberculous arteritis (arrows)

b Fig. 33.4a, b. Extensive, bilateral, thalamic infarction and hydrocephalus on coronal MRI (arrows). Images courtesy of Dr J. Lotz, Riyadh Military Hospital, Saudi Arabia

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Infarctions are commonly supratentorial, and brain stem infarction only occurs in 2-3% of cases, mostly in infants and children. The clinical syndromes resulting from TBM cerebral and brain stem infarctions encompass a wide variety of patterns, ranging from focal or generalized seizures, mentation and gaze disturbances, monoplegias, hemiplegias, and nuclear cranial nerve lesions. Although rare, the arteritis of TBM can lead to aneurysm formation with fatal consequences, and a small number of such cases have been described (McGuinness 2000; Jinkins et al. 1995; Leiguarda et al. 1988; Gupta et al. 1994; Cross et al. 1995). One such case, reported by Cross et al., responded to endovascular occlusion treatment of the aneurysm, after presenting with life-threatening epistaxis (Cross et al.1995).

a

33.5 Tuberculomas of T8M The wide distribution of microscopic granulomas in the subarachnoid space, leads to the development of tuberculomas. These tend to be small in size and are generally seen related to the supratentorialleptomeninges. Parenchymal tuberculomas complicating TBM tend to be found at the cortico-white matter border, although deeper masses may be found. In adults, most are supratentorial, while in children, tuberculomas of the cerebellum and brain stem are commoner. Initially solid, tuberculomas mature to develop central caseating necrosis. Often developing in clusters they display the radiologic properties of granulomas. When solid they are isodense or hypodense to brain tissue on CT and MRI scans carried out without contrast medium. Postcontrast studies demonstrate homogeneous enhancement in solid lesions and an intense ring enhancement in tuberculomas undergoing central caseating necrosis. An area of edema is often present and in TBM the lesions are usually no greater than 0.5 cm in diameter (Fig. 33.6). Basal inflammatory exudate affects the cranial nerves as well as the vessels that course through it. Cranial nerve deficits are a common complication of stage II and III TBM. The optic nerve or chiasma is open to compression due to suprasellar leptomeningitis. The long, basal, intracranial courses of the third, fourth, and sixth nerves expose them to exudate damage. The fifth and seventh nerves are sometimes affected

b Fig.33.5a, b. Sagittal and axial, T2-weighted images demonstrate extensive basal exudate and border-zone disease. This encroaches on the anterior margin of the right cerebellar hemisphere (arrows)

Fig.33.6. MRI of an enhancing, grape-like cluster of tuberculomas (arrow). Note also the ependymitis in the temporal horn of the right lateral ventricle (arrow head). This was in a terminal case of tuberculous meningitis

Imaging of Brain and Spinal Cord Tuberculosis

as they leave the midbrain. Gupta has demonstrated enhancement of the inflamed nerve sheaths on T1 Gd MRI (McGuinness 2000; Jinkins et al. 1995; Gupta et al. 1994) (Fig. 33.7a, b). Permanent damage results as healing converts the basal exudates into dense, fibrotic material, with the pattern of deficit varying from patient to patient (McGuinness 2000; Jinkins et al. 1995; Gupta et al.1994; Artopulous et al.I984). Long-standing TBM may in some instances lead to infection of the dura mater leading to thickening and pachymeningitis. Common sites include the floor of

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the middle cranial fossa, the dura overlying the cerebral convexities, and the tentorium. Calcification may be present. Contrast studies reveal intense homogeneous enhancement of the affected areas (Shah 2000; Ng et al.1996; Praharaj et al.I997). Isolated areas of calcification of the dura mater and cases showing punctate gyral calcification are reported (Kanamalla et al. 2000; McGuinness 2000; Shah 2000; Wallace et al. 1991; De Castro et aI1995). Calcification may be an early feature or may occur years later, after successful treatment of the infection.

33.6 Parenchymal Cerebral Tuberculosis Parenchymal cerebral tubercular disease occurs sporadically, and as a complication of TBM. It may be subdivided into 1. Parenchymal tuberculomas 2. Tuberculous abscess 3. Tuberculomas en Plaque 4. Miliary tuberculomas

33.6.1 Parenchymal Tuberculomas a

b Fig. 33.7. a Postgadolinium T1 image demonstrating enhancement of a left-sided tuberculous infection of the middle ear (arrow). There is infection of the temporal lobe (arrow head). b A coronal image confirms the middle ear infection (arrow) and the associated temporal-lobe tuberculoma. Central areas oflow signal caseation are seen (arrow head), as is a surrounding zone of edema (curved arrows)

In cases ofTBM,the incidence ofcerebral tuberculoma varies. Atlas suggests a low incidence of 10% (Atlas 1991), but Jinkins found higher rates in Saudi Arabia: in a study of 80 patients with intracranial tuberculosis, 11 % had compound meningeal/parenchymal lesions and 89% had parenchymal tuberculomas. Of all mass lesions in his practice, Jinkins found that 10-15% were tuberculomas (Jinkins 1991). In developing countries, sporadic parenchymal tuberculomas make up a large proportion of intracranial space-occupying lesions. In patients in India, Gupta suggests that between 10% and 40% of all intracranial mass lesions are tuberculomas (Gupta et al. 1988; Gupta et al. 1990). Salgado points out an increasing incidence of tuberculomas in developed countries (Salgado et al.I989). Cremin and Jamieson (Schoeman et al. 1988; Cremin and Jamieson 1996) recorded parenchymal tuberculoma formation in 10% of their cases in children. Sporadic cerebral tuberculous masses had a different clinical presentation from lesions in TBM, which were multiple in 15-20% ofTBM patients. Tuberculomas may be single or multiple, and when multiple, may demonstrate differing degrees of devel-

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opment at the same time. Most tuberculomas occur at the cortico-white matter junction, suggesting an origin by hematologic spread (Fig. 33.8a, b). A small number develop by direct spread from Rich lesions in the pia mater, in which case the overlying meninges enhance on CECT or T1 Gd MRI. The origin, in a few cases, is by spread from a venous sinus (McGuinness 2000). In the less common forms of tuberculomas of the basal ganglia, brain stem, and cerebellum, differentiation from primary or secondary neoplasms is a problem, especially in adults (Fig. 33.9). Beneath the tentorium, both single and multiple lesions are described, but account for only between 1% and 5% of tuberculomas (Jinkins 1991; Kanamalla et al. 2000;

Fig. 33.9. Sagittal postcontrast MRI demonstrates an isolated tuberculoma of the brain stem. It is impossible on this image to differentiate the appearance from that of a primary brain stem tumor

a

b Fig. 33.8a, b. Postcontrast computer scans of a young patient. As well as hydrocephalus, the scans demonstrate multiple enhancing, subcortical tuberculomas in the frontal and parietal regions, and at a higher level beneath the convexity

McGuinness 2000; Schoeman et al. 1988; Cremin and Jamieson 1996; De Castro et al 1995; Jinkins et al. 1995; Gupta et al. 1988; Salgado et al. 1989; Shen et al. 1990; Draouat et al. 1987; Vengsarkar et al. 1986; Van Dyke 1988; ,Jinkins et al.1987; Al Deeb et al.1992; Gupta et al.1991; Rajshekhar and Chandy 1997). All age groups are affected. In developing countries, tuberculomas show a predilection for children, but any age group may be affected (Jinkins 1991; Kanamalla et al. 2000; McGuinness 2000; Atlas 1991; Gupta et al. 1988; Salgado et al. 1989; Vengsarkar et al. 1986; Van Dyke 1988; Jinkins et al. 1987; Abugali et al. 1994). In developed countries, the elderly, as well as patients with a susceptibility, or those suffering from diabetics, alcoholicism, drug-abuse, or AIDS, are likely to be affected, but exceptions occur and even infants may develop tuberculomas (Vallejo et al. 1994). The onset of symptoms is insidious and gradual elevation of intracranial pressure, focal epilepsy, and focal neurologic deficits are the common presenting signs. Fever may be present. Clinically, differentiation from tumor, fungus, or paracytic disease is difficult, and this is also a problem radiologically. Many radiologists have expressed the opinion that the radiologic diagnosis of tuberculoma is always tentative. Recent developments in MRI, have defined groups of appearances in which the probability of the diagnosis of parenchymal tuberculoma is extremely high, especially in areas where tuberculosis is endemic. CT and MRI studies carried out without contrast agents are

Imaging of Brain and Spinal Cord Tuberculosis

Fig. 33.10. Precontrast CT demonstrates an isodense right frontal, subcortical, tuberculous mass (arrow). There is a surrounding zone of edema and a pressure effect on the lateral ventricle (arrow head)

likely to overlook both isodense parenchymal tuberculomas and TBM (Fig. 33.10). In cases of suspected tuberculoma, a careful search for an active focus of infection in other systems should be made. For this, sputum testing, gastric washings, CSF study, and chest radiography (including lateral views in children (Cremin and Jamieson 1996), should be carried out. Abdominal ultrasound or CT will demonstrate peritoneal tuberculosis if present, and in women, pelvic disease can be the source. Urine bacteriology is also necessary. However in some patients, if biopsy of the tumor is thought inadvisable, the response to antituberculous therapy will be the only way to make the diagnosis (Jinkins 1991; McGuinness 2000; Schoeman et al. 1988; Cremin and Jamieson 1996; Gupta et al. 1988; Gupta et al. 1990; Gupta et al. 1991).

33.6.2 Imaging Characteristics ofTuberculomas

In the early phase, tuberculomas are solid granulomas and are slightly hypodense or isodense to normal brain tissue on NECT. After contrast these solid lesions, which are characteristically round, or occasionally oval or lobulated, enhance homogeneously on CECT. When first discovered, tuberculomas are usually about 2 cm in diameter and may be single or multiple. There is accompanying low density white matter edema, which may be intense

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in these early lesions. The resulting mass effect may displace the ventricular system and give rise to hydrocephalus if foramina are compromised. This is more likely if the lesion lies in the mesencephalon or in the brain stem. Supratentorial sites are commoner. As central caseation and encapsulation develops, the pattern of enhancement on CECT becomes heterogenous centrally and the outer capsule enhances as a ring. A cerebral edema surrounding these caseating lesions is usually less intense than is the case in the solid granulomas. On angiography and dynamic CT, they are centrally avascular. Tuberculomas discovered at this stage are often up to 5 cm in diameter but in endemic regions have been demonstrated up to 8 cm in size, and these may show a laminated pattern, resulting from alternating phases of granuloma formation and caseation (Gupta et al. 1988, Gupta et al. 1990). At the next stage, central necrosis of the tuberculoma develops. The fluid or semifluid center of the mass does not enhance on CECT (Fig. 33.11a-c). Characteristically, a dense ring of enhancing tissue surrounds a hypodense core. This ring comprises glial tissue and the compressed collagen capsule of the tuberculoma. Jinkins suggests that from the very start, new fragile blood vessels develop in this zone, and the passage of contrast through leaky walls allows the blood-brain barrier to be breached and the granuloma to enhance, either totally, or at a later stage peripherally (Jinkins et al.1987). Enhancement is a rough index of activity of the lesion, and in the early stages of the disease may increase in intensity, however with inception of treatment it eventually wanes. Involution of the mass during treatment is a slow process that may take months or years, although some tuberculomas exhibit a reduction in size in as few as 4-6 weeks after commencement of treatment. Other cases may take months or even years to resolve. Any increase in size during treatment raises the question of drug resistance, misdiagnosis, or paradoxical enlargement. Some small lesions may resolve without therapy (Vengsarkar et al. 1986), but in countries where cysticercosis is also endemic, the true diagnosis in these cases is often in doubt (Gupta et al.1990). In children, Cremin and Jaimeson describe grapelike clusters of tuberculomas that may be associated with solid lesions elsewhere (Schoeman et al. 1988; Cremin and Jamieson 1996). In ring enhancing lesions the thickness of the ring may vary around the circumference. Usually it is continuous but when broken is difficult to differ-

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Fig. 33.11. a Precontrast CT reveals an isodense, right occipital mass (arrows). b After contrast injection, there is strong ring enhancement around a caseating or necrotic center (arrow head). c Postcontrast CT demonstrates ring enhancement of solid tuberculomas in the right posterior cerebral white matter (arrows)

entiate from metastatic disease (De Castro et al. 1995, Vengsarkar et al. 1986). Multiple lesions often show different stages of development and difference in size. Large, single lesions are difficult to differentiate from neoplasms and lymphoma, especially when situated deep in the midbrain, the brain stem, or cerebellum. DSA demonstrating avascularity is considered as helpful in these cases (Jinkins et al.1987). The MRI appearances of tuberculomas are described in the literature, but with wide variations in appearance. Many of these descriptions were made before the availability of contrast studies. Later studies are more consistent. That of Jinkins et al. is the standard classification (Jinkins et al. 1995). 1. The noncaseating granuloma is Tl hypointense to brain tissue and T2 hyperintense, enhancing homogeneously with postgadolinium contrast study. (Fig. 33.12a-d) 2. A solid caseating granuloma is hypointense to isointense on Tl images and isointense to hypointense on T2, with a hypointense rim, depending on the degree of capsule development. With contrast examination a strong rim enhancement is seen. Both these types of lesion are surrounded by a zone of edema, which is hypointense on Tl and hyperintense on T2, remaining unchanged in appearance on postgadolinium examination. (Fig. 33.13) 3. When central necrosis or liquefaction occurs, the central signal is Tl hypointense. On T2, the necrotic material gives a fairly homogeneous hyperintense signal, and the surrounding capsule appears hypointense. Tl-weighted postgadolinium MRI study reveals intense ring enhancement of the lesion.

In those cases of long-standing laminated lesions as yet no postcontrast studies have been published, so the enhancing characteristics are not yet known. These lesions show alternating bands of iso- and hypointense tissues on Ti, and of hypo- and hyperintense tissue on T2 (Gupta et al. 1990). The reason for shortening of the T2 signal in some tuberculomas is not clear, but may be the result of the presence of paramagnetic free radicals in enclosed macrophages, distributed inhomogeneously throughout the lesion (Gupta et al. 1991). There is a general agreement that the imaging appearances of intracranial tuberculomas are nonspecific and that the ability of tuberculous lesions to mimic other diseases of pyogenic, fungal, neoplastic, and paracytic origin leads to a wide range both of appearances and of differential diagnoses (Jinkins 1991; Kanamalla et al. 2000; McGuinness 2000; Schoeman et al.1988; Cremin and Jamieson 1996; De Castro et al 1995; Jinkins et al. 1995; Gupta et al. 1988; Jinkins et al. 1987; Al Deeb et al.1992; Bhargava and Tandon 1980). Wechman suggested that one particular CT pattern was specific to tuberculoma and was supported by van Dyke (Wechman 1979; van Dyke 1988). The pattern which they named the "target sign" comprises a round or oval lesion, isodense or slightly hyperdense on NECT, containing a small central nidus of calcification. With examination by CECT, a peripheral enhancing ring was seen as well as the central calcific lesion (Fig. 33.14a, b). But neither author had access to MRI study. Van Dyke noted the appearance in 10 of 30 patients with tuberculomas, all of whom were black South Africans. The appearance has only rarely been described in other parts

Imaging of Brain and Spinal Cord Tuberculosis

559 Fig. 33.12. a Axial, postgadolinium MRI. A group of right-sided thalamic tuberculomas. These are solid and the right lateral ventricle is effaced (arrow). Note also the extensive enhancement of the thickened meninges over the left convexity, in this young patient with tuberculous meningitis. b Coronal, postgadolinium MRI. There is an irregular, ovoid tuberculoma in the right side of the brain stem (arrows). c A sagittal, postgadolinium study of a patient with three tuberculomas. All enhance but show some central relative hypodensity. The lesions are seen in the parasagittal, cerebellar, and brain-stem locations (arrows). d An axial, postgadolinium MRI scan reveals a single enhancing tuberculoma high in the brain stem

Fig. 33.13. An axial nonenhanced, T2-weighted MRI of an occipital tuberculoma of mixed signals (arrow). There is extensive surrounding edema (arrow heads)

Fig. 33.14a, b. A case of tuberculoma. a A lesion with density slightly higher than the surrounding brain tissue. Note the central calcification, as well as the mass effect and the dilatation of the posterior horn of the lateral ventricle. b After injection of contrast medium, showing intense enhancement of the rim of the lesion, and the typical appearance of the "target sign"

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of the world, namely North Africa, India, and Saudi Arabia (Draouat et al. 1987; Vengsarkar et al. 1986; Abduljabbar 1991). Recent studies by Bargallo et al. in Spain, augmented by MRI, have shown the sign present in cases of AIDS, complicated by intracranial toxoplasmosis in one case and lymphoma in another. In a third case it was seen in an elderly woman with a pyogenic brain abscess (Bargallo et al. 1996). In van Dykes' cases, the sign may be due to a specific response of a local population to tuberculosis. Other factors must also be considered. The presence of central calcification suggests a long-term lesion, so delay in presentation at a hospital may be one factor. However, peripheral enhancement indicates an active lesion. The target sign is therefore a suggestive but nonspecific indicator of a tuberculoma.

33.7 Paradoxical Response of Tuberculomas to Treatment Since first described by Lees, McLeod, and Marshall in 1980 (64), a number of cases have been cited where tuberculomas have developed or increased in size during apparently adequate antituberculosis therapy of nonresistant tuberculous organisms. None of these patients were of Caucasian origin, but included Indians, Chinese, Vietnamese, and one North American black (Teoh et al. 1987). The reasons for this paradoxical phenomenon have not yet been discovered. Some patients have associated tuberculous lymph node disease, and the lymph nodes also increase in size. This last feature is well recognized during antituberculous therapy, a possible explanation being a local hypersensitivity and inflammatory response, resulting from the release of tuberculoprotein from dead or dying mycobacteria (Campbell and Dyson 1971). However, while infected lymph nodes contain large numbers of mycobacteria, this is not the case in parenchymal cerebral lesions, where the numbers of mycobacteria are small. The relapse time from the apparently successful treatment of the tuberculoma and the onset of new focal signs,convulsions, or raised intracranial pressure, due to paradoxical expansion, varies between 1 month and 18 months. Patients have come from a wide range of age groups, from infants to the elderly (Teoh et aI. 1987). The phenomenon occurs both in parenchymal tuberculoma and in tuberculoma-complicating TBM and may throw the diagnosis into doubt. In some

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cases, biopsy of the lesion may be necessary to obtain histologic confirmation of the diagnosis. Brain biopsy or surgery are not without danger in tuberculosis and ideally should be reserved for those cases where intervention is required due to the effects of raised intracranial pressure or where malignancy, fungal, or paracytic disease cannot otherwise be eliminated from the diagnosis (Vengsarkar et al. 1986; Bouchama et al.1991).

33.7.1 Late Stage Appearances ofTuberculomas The behavior of parenchymal tuberculomas during antituberculous therapy is related to the size of the lesion at the time of initial diagnosis. Small, single or multiple lesions of less than 1 em in diameter usually disappear completely during therapy, often within the first few months and almost invariably within 1 year. This is the norm in children (Schoeman et al. 1988; Cremin and Jamieson 1996). This is the case if the lesion is a solid granuloma, without central caseation or calcification. Larger nonsolid or calcifying lesions above 2 em in diameter usually take between 2 and 3 years to resolve, especially if the lesion is both large and lobulated, as in those described by Bhargava (Bhargava and Tandon 1980). Jinkins (Jinkins et al. 1987) in his study of 80 patients with parenchymal tuberculomas, described 57 patients with isolated granulomatous lesions and followed them up with CECT until therapy could be safely stopped. He took failure to enhance on CT study as an indication of healing. Many of these cases required between 18 months and 2 years therapy before resolution. Fourteen of 57 eventually showed a normal CT. Eight showed a residual, nonenhancing, calcified lesion, and 12 displayed calcification with associated overlying cerebral atrophy. Seventeen patients showed focal cerebral atrophy alone. One patient continued to demonstrate an enhancing lesion after 2 years of chemotherapy. Five patients were lost to followup. This is a higher percentage of calcified lesions than in some other studies. Wilkinson (Bouchama et al. 1991) and Reed (Wilkinson et al. 1971) in two separate series stated that 38% of TBM patients showed late stage calcification, but that only 1% and 6% of parenchymal tuberculoma developed this phenomenon in their respective studies. This is in agreement with van Dyke, only one of whose 30 cases developed significant late stage calcification (Fig. 33.15a, b) (van Dyke 1988).

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Imaging of Brain and Spinal Cord Tuberculosis

b

a

Fig. 33.15a, b. Pre- and postcontrast computer scans after craniotomy. a There is extensive cortical and white matter calcification and some cortical atrophy (arrows). b Postcontrast scanning shows a number of areas of enhancement within the lesion (arrows). These areas represent continued activity in this tuberculoma some months after commencement of antituberculous chemotherapy

33.8 Tuberculous Brain Abscesses Although uncommon, true tuberculous abscesses develop from parenchymal tuberculous granulomas or the spread of tuberculous foci in the meninges to the brain substance in patients with TBM. Cremin and Jaimeson have pointed out that two distinct types of necrosis occur in tuberculomas. Microscopically, those possessing a structure of fibrovascular elements, as demonstrated with reticulin stains, undergo gummatous necrosis, where the inflammatory granulatomatous tissue undergoes necrosis. Cremin points out that this type of central necrosis gives an MRI signal on T2 studies that is isodense to brain tissue and surrounded by a dense zone of edema. Tuberculomas of this type do not develop into abscesses (Schoeman et al. 1988,Cremin and Jamieson 1996). Those tuberculomas that do convert into abscesses show a different structure on microscopy as they have no reticulin elements, being composed entirely of cellular elements. The necrosis of these epithelioid cells, macrophages, and polymorphonucleocytes passes through a phase of inspissation or caseation to liquefaction and the development of a true abscess (Cremin and Jamieson 1996). These are usually isolated lesions, occasionally occurring simultaneously with other solid tuberculomas. Radiographically they are indistinguishable

from pyogenic abscesses. They show similar MRI characteristics, being oval or round in shape with a thin, strongly enhancing wall that, on T1 Gd MRI examination, is in marked contrast to the hypodense liquid center (Fig. 33.16a-c). A point of clinical importance is that, while solid or caseating tuberculomas contain few bacteria, the tuberculous abscess contains the mycobacterium in large numbers. If such an abscess ruptures into the ventricular system or the subarachnoid space, a devastating ventriculitis or meningitis ensues. Drainage of these lesions is therefore a dangerous procedure. Seeding of daughter lesions along the needle track has been described by De Castro (De Castro et al 1995) who points out that in the West, abscesses are more likely to develop in the elderly, or in the immunosuppressed.

33.9 Atypical Tuberculous Masses Tuberculoma 'en plaque' lesions occur more commonly as a complication of TBM than as isolated tuberculomas. En plaque lesions may also occur when a tuberculoma abuts onto the meningeal surface of the brain and a proliferation of granulomatous tissue extends into the adjacent meninx. When

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a

b

Fig. 33.16. a A group of right-frontal tuberculous abscesses in the subcortical white matter, causing midline shift. Postgadolinium imaging demonstrates an intense enhancement of the abscess wall (arrow), while the liquid contents remain of low signal (arrow head). b Two deep, midline tuberculous abscesses in the region of the tentorium (arrows). There is a smaller collection posteriorly (arrow head). c Two right, frontal tuberculous abscesses, one of which has been sucessfully drained (arrow). The second shows the characteristic appearance of an enhancing thin wall surrounding hypodense fluid. (arrow head). There is hydrocephalus. This was in a late stage case of tuberculous meningitis

present as isolated lesions, the clinical presentation is similar to any other space-occupying lesion (Gee et al. 1992). A common site of such lesions is the tentorial edge, where the resemblence to meningioma causes difficulty in diagnosis (Fig. 33.17a). The lack of vascularity on DSA is a helpful pointer. Other primary and secondary tumors may be differentiated in the same way, but stereotactic biopsy will be necessary in some cases (Bouchama et al.1991; Rajshekhar and Chandy 1997). When tuberculous meningeal mass lesions are confluent with the cerebral cortex, there is extensive gyral enhancement on both CECT (Fig. 33.17b, c) and TlGd images, the underlying cortex and white matter show edema beneath the lesion. This edema will be hypodense on NECT and Tl MRI, and hyperintense on T2, showing no enhancement on Tl Gd acquisitions. Other atypical tuberculomas are exceedingly rare. Graveli (Graveli et al. 1998) describes a lesion

of the cavernous sinus, with the characteristics of a meningioma. Shah et al. treated a patient with a tuberculoma of the sphenoid sinus showing bone destruction of the superior section of the clivus and a soft tissue mass, and a second patient who presented with a tuberculoma in the brain as a mass in the tectal plate (Shah et al.1993; Shah et al.1994).

33.10 Miliary Cerebral Tuberculomas Miliary tuberculosis is a multiorgan infection which develops when the host defenses prove inadequate in controlling the generalized spread of the disease. It is characterized by Widespread 2-3-mm granulomas, typically seen throughout the lung fields, and histologically present in other organs. However, on presentation only 50% of cases have an abnormal

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Imaging of Brain and Spinal Cord Tuberculosis

b

a

c Fig. 33.17. a An enhancing en plaque tuberculoma at the tentorial edge (arrow). Difficult to differentiate from a meningioma. b, c Pre- and postcontrast CT scans demonstrate a hyperdense lesion in the frontoparietal region. After intravenous contrast injection, there is extensive enhancement of the adjacent meninges. This is associated with ring enhancement of a I-cm tuberculoma with a central, hypodense nidus (arrows). Images courtesy of Dr Ng Chang Gung, Memorial Hospital, Kwei Shan, Tao Yuan, Taiwan

chest radiograph. At autopsy between 47% and 55% of cases are described with cerebral involvement (Slavin et ai. 1980). In children, 68% of those with tuberculous meningitis are reported to show concomitant miliary lesions in the brain (Jinkins 1991; Gee et ai. 1992). Gupta pointed out that cerebral miliary tuberculosis may be more common than previously realized, and found typical lesions in seven patients with pulmonary miliary tuberculosis, who had no symptoms or signs of central nervous system disease (Gupta et ai. 1997). Small solid granulomatous lesions are isodense on NEeT and isointense on T1 images. On T2, these small lesions give a high signal. Larger caseating lesions are revealed as low signal on T2. After contrast injection, small lesions enhance solidly whilst caseating lesions show ring enhancement. Gupta pointed out that the majority of lesions occur at the gray/white matter interface. This suggests embolic hematologic spread, and arrest at the site of narrowing of cortical arterioles. A similar mechanism influences the distribution of cerebral metastases (Atlas 1991).

33.11 Tuberculosis of the Calvarium with CNS Lesions Tuberculosis of the calvarium is a rare condition but in a small proportion of reported cases the inner table is penetrated to give rise to a tuberculous epidural abscess. This in turn has led to focal tuberculosis in the underlying cerebrum. There are three distinct types of lesion. The most common is a single osteolytic lesion in the skull vault. This is usually a well-defined, punched-out defect with smooth but occasionally irregular margins. A thin border of sclerotic bone has been described (McGuinness 2000; Dastur 1972). The inner table is first involved, and the inner defect is often more extensive that the outer (Le Roux et ai.1990). The central fragment of bone is often sequestrated, a button sequestrum, and there is painless overlying soft tissue swelling, while in some cases a cutaneous sinus may develop. The bone defect may cross the suture line. A less frequent appearance is of a more diffuse lesion with ill-defined margins. In both types of lesion there may be a surrounding zone of osteoporosis. Some authors have noted that

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previous trauma had occurred at the site of the lesion (Le Roux et al.1990). The second type of presentation is common in India and Africa. Multiple bone defects are seen, and these may be associated with cystic bone lesions elsewhere in the long bones of the skeleton or with dactylitis (McGuinness 2000; Cremin and Jamieson 1996; De Castro et al1995; Le Roux et al.1990; Wessels et al.1998). In the third presentation, known as "Pott's puffy tumor:' the scalp swelling is the major component and the underlying button sequestrum and calvarial osteomyelitis are only revealed on skull radiography or CT (Fig. 33.l8a,b) (McGuinness 2000; Le Roux et al. 1990).

a

b Fig. 33.18. a Pott's puffy tumor. CT study of a soft tissue lesion in the right frontal region demonstrates an extensive swelling, isodense to brain tissue. There is thinning of the bone of the underlying calvarium. b Postgadolinium MRI. This defines the subcutaneous abscess as a low signal collection, surrounded by a ring of enhancing tissue. The tuberculous osteitis of the frontal bone and an underlying epidural inflammatory lesion are demonstrated

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In cases where underlying infection occurs within the skull or cerebrum, a wide range of clinical patterns have been described (Le Roux et al. 1990). The common complication is seizure, but diabetes insipidus, vision disturbance, 3rd and 6th nerve palsies, mild hemiparesis, and proptosis have been described (McGuinness 2000; Cremin and Jamieson 1996; De Castro et al 1995; Le Roux et al. 1990; Patankar et al. 2000; Gupta et al.1989).

33.12 Tuberculous Otitis Media and Tuberculosis of the Temporal Bone In the pre-chemotherapy era, tuberculous otitis media was common. In 1915, Turner commented that 50% of cases of otitis media in infants were tuberculous, the figure falling to 2% in adolescents. In the post-1950s period, it has become rare in the West, and although sporadic cases occur in Caucasians, most cases are found in immigrant communities (McGuinness 2000; De Castro et al 1995; Buchanan and Rainer 1988; Cavallin and Muren 2000). In South Africa, the condition is common among the socially deprived, and in Natal is an important cause of facial palsy in children. In Singh's 43 patients, 17 developed lower motor neurone 7th nerve palsy (Singh 1991). In young African patients, 50% have pulmonary tuberculosis, and otitis media may be part of a more widespread central nervous system disease, while hematogenous spread may have occurred from foci in the liver, kidney, or spine. Often the infection in the ear is bilateral. In the West, isolated unilateral otitis is more common. Target groups with immune problems may be infected. One of Lee and Drysdale's cases had been treated with steroids for rheumatoid arthritis (Lee and Drysdale 1993). Although rare in the West, if not treated, it remains a chronic, disagreeable condition that leads to deafness in the affected ear. Complications, such as mastoiditis with sinus formation, bony sequestration, and intracranial infection can arise. Profuse otorrhea continues for many years. The condition is usually painless. On clinical examination, the drum is seen to be perforated or partially destroyed. Visually the drum and mucosa are pale, as are granulations when present. The middle ear fills with caseous material, which has the appearance of cottage cheese. Biopsy of the granulations reveals caseating granulomas, and immediate screening sometimes reveals AAFB.

Imaging of Brain and Spinal Cord Tuberculosis

It is essential to send material for culture as almost invariably a misleading secondary pyogenic infection will have occurred (McGuinness 2000; Buchanan and Rainer 1988).

33.12.1 Imaging Plain radiographs show clouding of the mastoid cells or osteoporosis and bone destruction in the middle ear. These nonspecific changes are confirmed by conventional tomography. Axial imaging where available is much superior. Standard middle ear protocols reveal bone destruction and soft tissue masses. And destruction of the ossicles may be documented (Hoshino et al. 1994). On MRI studies postcontrast TlGd images demonstrate the extent of the inflammatory change. Granulation tissue enhances and caseating tissue remains isodense, or hypodense intracranial extension of the disease is shown (Fig. 33.7a, b). The common intracranial complications are tuberculomata, often of the temporal lobe, meningitis, and neural deficits in nearby cranial nerves (VI, VII, VIII, XI, and XII). Grewal et al. describe a tuberculoma of the mastoid bone (Grewal et al. 1995). Differentiation from other chronic conditions depends on culture and biopsy. Of infections, chronic otomastoid cholesteatoma and fungal granulomatous diseases may show similar appearances. Wegener's granulomatosis, Langerhans cell histiocytosis, rhabdomyosarcoma, and recurrent bacterial infections may all produce similar appearances (Mumtaz et al.).

33.13 Differential Diagnosis of TBM and Parenchymal Tuberculosis It is clear from the radiologic literature that there are no specific CT or MRI findings in either TBM or parenchymal cerebral tuberculosis, and that the diagnosis rests on a combination of clinical assessment, imaging appearance, and response to therapy. A wide range of pathologic processes, including malignancy, pyogenic and fungal infections, paracytic infestations, and a range of other disconnected conditions, ranging from trauma to vascular malformation and aneurysm, can mimic either TBM or parenchymal tuberculosis (Jinkins 1991; Kanamalla et al. 2000; McGuinness 2000; Cremin and Jamieson 1996; Shah 2000; Wallace et al. 1991; De Castro et al 1995; Jinkins et al. 1995;

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Rochas-Echeverri et al. 1996; Cross et al. 1995; Atlas 1991; Bargallo et al. 1996; Ng et al. 1996; Rajshekhar and Chandy 1997; Graveli et al.1998; Shah et al.1993; Le Roux et al. 1990). Basal meningitis with infarctions is commonly seen in Haemophilus injluenzae infection. Infarctions are also common in aspergillosis and mucormycosis, where direct spread from the paranasal sinuses is usual. In these cases, infarctions follow extension of the condition though vessel walls, and are seen in the cortex and subcortex, but major vessel infarctions also occur. In disseminated cerebral coccidioidomycosis (DCC), intense basal meningeal enhancement involving the sylvian systems is seen, and is often more intense than that of TBM. However, cases where basal enhancement is absent, even in the presence of hydrocephalus, occur in both conditions (McGuinness 2000; Schoeman et al. 1988; Dublin and Phillips 1980). In DCC, the basal ganglia and white matter lesions are more diffuse than in TBM, and focal granulomas and basal ganglia infarctions are rare. Ventriculitis is also an early finding in DCC, and a late stage development in TBM (McGuinness 2000; Dublin and Phillips 1980). Geographically the distribution areas of DCC, histoplasmosis, blastomycosis, and TB overlap, giving rise to problems of differentiation (Ogawa et al.1987). In cryptococcus neoformans infection, basal meningeal enhancement, arteritis, and basal ganglia infarctions are seen. But in cryptococcal infection the organism can usually be isolated from the CSF and recognized using rapid laboratory techniques. In spirochetal disease, basal meningitis can develop together with parenchymal granulomatous gummas. In syphilitic infection these are often attached to the meninges, and associated cerebral atrophy and basal fibrous nonenhancing pachymeningitis is another diagnostic clue, as well as laboratory findings. Tickborne Lyme disease is another spirochetal infection that may affect the cerebrum. Granulomas in the basal ganglia can be present, but unlike those of tuberculosis are diffuse, and more solid lesions lack ring enhancement. Contrast enhancement of the CSF, on Gd MRI, has been described in both syphilis and Lyme disease, as well as in cryptococcal infection (Good and Jager 2000, Sakamoto et al. 1997). Abscess formation in bacterial, mycobacterial, and fungal disease cannot be differentiated radiologically. Bacteriologic or histologic examination, as well as the response to medical treatment, is the only means of differentiating among them. Single or multiple malignant tumors may mimic tuberculomas. The ring enhancement of tumors is

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often of varying thickness, and the ring is sometimes incomplete. The surrounding zone of edema tends to be less intense than in tuberculoma. With DSA, tuberculomas are avascular (Jinkins 1991; McGuinness 2000; Rochas-Echeverri et al.1996; Gupta et al.1991). Leptomeningitis carcinomatosis shows a patchy enhancement of the basal meninges (McGuinness 2000; Kioumehr et al. 1995). Primary lymphomas tend to be periventricular in position, and may cross the midline, passing through the corpus callosum, unlike supratentorial tuberculomas. Lymphomas have limited mass effect, are structurally diffuse, and show little or no edema and no ring enhancement (McGuinness 2000). Secondary lymphomas commonly affect the meninges, in contrast to the usual subcortical position of multiple tuberculomas. Single en plaque tuberculomas can cause some confusion, but enhance intensely, and have to be differentiated from meningiomas. They are avascular structures on DSA and MRA. Cysticercosis (CC) and TB have similar geographical distributions. CC lesions are distributed throughout the body and the diagnosis is often made from the biopsy of subcutaneous lesions. In cerebral CC, the various radiologic appearances of developing and degenerating cysts are described in the literature (Rajshekar et al.1993; Jena et al. 1988). The mural node of the living cyst can be defined by MRI, but may be difficult to define on CT studies. After death of the parasite, an intense local reaction and ring enhancement on T1 Gd studies are seen, with a central low signal area. Punctate calcification is often present on CT, while on MRI the various stages of development and death of the cyst are seen more clearly. At all stages, however differentiation is difficult and a trial of drugs may be necessary to make the diagnosis (Rajshekar et al. 1993; Jena et al. 1988; Rajshekhar and Chandy 1996). Rajshekhar points out that in a series of 16 patients examined by both CECT and T1 Gd MRI revealing a solitary CC granuloma, no additional information was acquired from the MRI studies. Cost plays an important role in the management of the generally underprivileged patients presenting with CC disease. He sees thin-slice contrast-enhanced CT as the examination of choice (Fig. 33.19a-d) (Rajshekhar and Chandy 1996). Toxoplasmosis produces intracerebral pathology that may be confused with tuberculoma. Toxoplasmosis is the most common infestation in AIDS, where tuberculosis may coexist. Cystic solid or ring enhancing lesions are described, often with a central enhancing nodule (McGuinness 2000; Atlas 1991). The distribution of the lesions in the subcortex

F. McGuiness

and deep white matter is similar in both conditions. However, in toxoplasmosis, subependymal lesions are common, the ring enhancement is usually thicker and more irregular than in tuberculoma and hemorrhage into the lesion often occurs. Gupta has described hemorrhage in some tuberculomas analyzed by MRI and proton spectroscopy, but such lesions are uncommon (Gupta et al. 1991). Antitoxoplasmic therapy often reduces the size of the lesions in between 2 to 3 weeks, another way of differentiating them from tuberculomas. Neurosarcoidosis occurs in 5% of sarcoidosis cases and is usually a subacute condition, clinically unlikely to be confused with TBM. However the meningeal enhancement of sarcoidosis produces some similarities to TMB. Subfrontal meningeal enhancement in a patient who is not acutely ill is a common manifestation, and the suprasellar cisterns, parasellar spaces, and hypothalamic parenchyma are commonly involved, which can result in diabetes insipidus. Neurosarcoid changes are usually diffuse and show gyral and subcortical enhancement, and extension along the perivascular spaces. They are therefore likely to be confused with tuberculous border-zone disease. Parenchymal granulomas also occur. They can be of wide distribution above and below the tentorium. They are usually solid enhancing lesions and show little surrounding edema (Fig. 33.20). Hydrocephalus only occurs when periventricular infiltrating lesions cause CSF obstruction. MRI examination is particularly useful in demonstrating the spread of pathologic granulomatous tissue along the vessels in the Virchow-Robin spaces (Urback et al. 1997). When present, destructive lesions of the calvarium are another differential finding. Sarcoid lesions of the skull vault offer a point of biopsy, as do sarcoid lesions in other parts of the body. Other granulomatous disorders are unlikely to be confused with tuberculosis. Intracranial neurobrucellosis is a rare disorder even in areas where brucellosis is endemic. The incidence varies from 4% to 10% in reported series of cases of brucellosis (97). Meningitis tends to be chronic and intermittent rather than acute, although fever, neck stiffness, lethargy, and impaired consciousness are described. As the perineurium, as well as the vessel walls, are affected cranial nerve lesions are common. Madkour notes that sensorineural hearing loss may be the presenting sign, but the 6th, 7th, 2nd, and 5th cranial nerves are also commonly affected. Meningeal enhancement if present is mild and hydrocephalus uncommon. However, deep white matter granulomas have been seen (Fig. 33.21a, b). CT scans may be normal except

Imaging of Brain and Spinal Cord Tuberculosis

567

b

a

---:z.;.o,-d Fig. 33.19a-d. Coronal and sagittal contrast-enhanced MRI. a· Coronal and b sagittal, contrast-enhanced MRI in two patients with solitary cysticercus granulomas. Showing a poorly circumscribed area of enhancement, lying beyond the apparent limits of the granuloma itself, in both cases

c

when mild hydrocephalus is present. MRI studies are of help, because evidence of enhancement of cranial nerves is more likely in brucellosis than in TBM (Fig. 33.22a-d) and intracerebral lesions when present are clearly imaged (Madkour 2001, Shakir 1986). Other intracranial mass lesions that may be similar in appearance to tuberculoma include those of tumefactive multiple sclerosis (TMS). In this condition, large, contrast-enhancing, white matter lesions, surrounded by vasogenic edema are found. They are usually low signal on Tl and high signal on T2, with minimal ring enhancement on TlGd acquisitions. The surrounding edema may be very extensive, and

the clinical presentation will usually differentiate TMS from single tuberculoma. The neurologic deficit is generally more widespread, and there can be a history of previous acute spinal myelitis (Fig. 33.23a,b) (Miller et al. 1989). Granulomatous masses in Candida meningitis, a common complication of AIDS, leukemia, and lymphoma, are generally extra-axial and fail to enhance on Tl Gd images. Cryptic angiomatous malformations presenting as mass lesions, develop a layered appearance as a result of local episodes of bleeding into the angioma. The presence of methhemoglobin accounts for the MRI appearance. In the rare cases of layered tuber-

568

F. McGuiness

Fig. 33.20. Coronal Tl-weighted postgadolinium images. Multiple, enhancing, solid granulomatous lesions are seen in the cerebrum and brain stem (arrows). The appearances are indistinguishable from multiple tuberculomas. The patient was a proven case of multisystem sarcoidosis

a

b Fig. 33.21. a Postcontrast CT revealing periventricular enhancement (arrow) and edema (arrow heads). This was a case of cerebral brucellosis. b Diffuse, high signal, thalamic lesions in cerebral brucellosis

569

Imaging of Brain and Spinal Cord Tuberculosis

a

b

c

d Fig. 33.22a-d. A case of brucella polyneuritis in a child. a Contrast-enhanced Tl-weighted image. Swelling and contrast enhancement of the prechiasmic portion of the right optic nerve (arrow) b Swelling of the left fifth cranial nerve and marked contrast enhancement of the fifth cranial nerves and gasserian ganglion in Meckel's cave (arrows). c Marked contrast enhancement of both seventh and eighth cranial nerves (arrows). d Coronal Tl-weighted image shows a well-defined, low signal, cystic mass with peripheral contrast enhancement, anteromedial to the left seventh and eighth cranial nerves (arrow)

b

a

Fig. 33.23. a Sagittal, postgadolinium MRI demonstrates two cerebellar tuberculomas (arrows). b A case of multiple sclerosis (MS). There are similar lesions in the cerebrum but in MS they are slightly less well defined (arrows); there is a poorly defined lesion in the cerebellum (arrow head)

570

culoma, MRI spectroscopy demonstrates that tuberculomas have low levels of iron and other metallic elements (Gupta et al. 1991). Intracranial aneurysm may be differentiated from tuberculoma by MRI or DSA examinations. Where CT is the only available modality, small aneurysms of the circle of Willis have caused diagnostic problems (Gucuyener et al. 1993). Aneurysm is an uncommon complication of tuberculous arteritis, but does occur and can lead to intracranial hemorrhage, epistaxis, or bleeding from the aural canal (Leiguarda et al. 1988, Cross et al. 1995). MRI will differentiate between tuberculomas and aneurysms.

F. McGuiness

The study of spinal cord tuberculosis has made great strides since the advent of contrast-enhanced computer tomography (CECT) and magnetic resonance (MRI) studies. Before that conventional myelography was limited, both in its scope, and by the nature of the disease process (Chang et al. 1989). Excessive glutinous exudates associated with spinal meningitis impede the normal circulation of CSF, making lumbar puncture and the introduction of contrast agents difficult, and in the later stages almost impossible. Postmortem studies show that the exudates are very extensive, often filling the subarachnoid space completely, and compressing the cord and other spinal contents, with resulting cord edema and ischemia. Cord and nerve root swelling, as well as the development of granulomatous tissue, rapidly produces spinal block (Dastur et al.1995). In the late stages gliotic, collagen, and fibrotic pathologic tissue forms, causing irreversible changes in the theca and myelum. If tuberculous meningitis (TBM) and tuberculous spinal meningitis (TBSM) are present together, the deficits in the peripheral nervous system may be obscured by the low level of consciousness of the patient. Acute onset of back pain, paraesthesia, muscular weakness and, sphincter dysfunction are common features of TBSM. However, an insidious progressive pattern also occurs, mimicking intraspinal tumor, polyradiculopathy, or spinal demyelination. This type

cord cavitation result in permanent neurologic deficits (McGuinness 2000). In all cases, it is essential to investigate both the brain and the spinal lesion, as concomitant intracranial and intraspinal lesions are common (McGuinness 2000; Tandon 1978; Gupta et al.1997; Shen et al.1993). In a small number of cases, CT or MRI at the level of a spinal block will reveal tuberculous osteomyelitis of a vertebral body or, rarely, an isolated tuberculous epidural granuloma (McGuinness 2000). Wadia and Dastur divided tuberculous radiculomyelopathy into two groups: 1. Primary, arising from a focus of tuberculosis outside the central nervous system (CNS). 2. Secondary, arising from intracranial TBM or from spinal tuberculous osteomyelitis. In a series of 70 cases, they found the primary type to be more common (Wadia 1973; Wadia and Dastur 1969). The secondary type of TBSM is either the result of downward spread ofTBM infection, through the cerebrospinal fluid, or of the spreading outward and upward from a focus of spinal osteomyelitis, commonly in the lumbar or low thoracic regions. More recently, Dastur has confirmed that 50% of cases are of the primary type and over 30% follow the pattern of spreading down from intracranial TBM (Dastur et al. 1995). This is supported by the findings of Gupta. Of 20 consecutive cases of intraspinal tuberculosis, 75% were of the primary type and 25% secondary to TBM. None of the cases had vertebral tuberculous osteomyelitis (Gupta et al.1994). Geographical and racial differences may affect the mechanisms of spread, as Chang et aI., in a study of 13 cases, reported 85% associated with TBM, one case resulting from tuberculous spinal osteomyelitis, and only one primary case of an extramedullary tuberculoma arising low in the thoracic spine (Chang et al. 1989).As in TBM, the pressure effect of exudate in the confines of the spinal canal, combined with arteritis, gives rise to small vessel occlusion, with resulting ischemic myelitis. Local hematologic spread results in single or scattered intra-axial tuberculomas. The development of granulomatous tissue in the exudates produces thickening and deformity of the nerve root theca which at a later stage is converted to fibrous tissue. All elements of the theca and axial nervous system can be involved in the infection. Both leptomeningeal TB and tuberculous radiculomyelopathy are descriptive terms in current use,

has also been described as developing many years

but as not all of the intraspinal elements need to be

after apparently resolved intracranial TBM (Chang et al. 1989). In treated TBSM, inactive fibrotic and glial tissue remain in the spinal canal, and combined with

simultaneously affected, the term spinal neurotuberculosis, used by Dastur is also applicable (Dastur et al. 1995) (Figs. 33.24, 33.25).

33.14 Tuberculous Radiculomyelopathy and Myelitic Tuberculomas

Imaging of Brain and Spinal Cord Tuberculosis

Fig.33.24. Sagittal Tl-weighted postgadolinium scan of the thoracic spine. Markedly thickened spinal meninges and thick enhancing exudates compress the thoracic spinal cord and displace it anteriorly (arrows). A case of spinal tuberculous meningitis

Fig. 33.25. A single tuberculous lesion expanding the cord at the Th4 level. Ring enhancement with a central, lower signal due to a tuberculoma

As in TBM, the spread of the infection along the arachnoid-pia mater complex is rapid. Granulomas develop on the leptomeningeal and cord surface, leading to leptomeningeal thickening, and in the areas of cord involvement, to fusiform expansion of

571

the cord. Pitting and excavation of the cord surface often develops, involving the superficial neural tracts in the area. Varying patterns of neurologic deficit are present, because myelitis as well as nerve root pathology underlies the sensory and motor fall-out. The myelitic lesions are usually confined to short lengths of the cord, with intervening normal segments, and some cases show a true transverse myelitis. Cord edema involving considerable lengths of the myelum is another pattern. Fusiform swelling of the cord and eventually cavitation are described (Chang et al.1989; McGuinness 2000; Gupta et al.1994; Kumar et al. 1993). Spinal block occurs commonly, and although it may result from the development of granulomatous tissue at any level in the spinal canal, its usual site is at the level of the conus medullaris. As impediments to CSF flow develop, spinal puncture becomes increasingly difficult and a dry tap may result. The CSF becomes thick, at low pressure, and xanthochromic, due to a high protein content. Injecting of intrathecal contrast agents is increasingly difficult as granulomatous tissue advances and the flow of contrast is impeded. In the absence of MRI facilities, cervical myelography is sometimes necessary, but the same problems of impeded flow can be encountered in this area also. The clinical presentation of TBSM is similar to a large number of conditions, ranging from cord tumors to demyelinating disorders, and polyneuropathies. Tuberculous myeloradiculopathy should always be included in the differential diagnosis of spinal lesions, although rare, isolated TBSM does occur from tuberculous spondylitis or epidural granuloma, as well as that arising from TBM. Tuberculous disease in other body systems outside the nervous system occurs in between 50% and 80% of cases of TBSM (McGuinness 2000; Gupta et al. 1994), so the absence of tuberculosis elsewhere in no way excludes the possibility of tuberculous radiculomyelopathy.

33.15 Imaging Methods in Spinal Neurotuberculosis 33.15.1 Plain Radiography Plain radiography is of little direct help, except in cases where TBSM is associated with tuberculous spondylitis. However, as a method of exclusion of other causes of spinal cord or nerve root pathology,

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it can be rewarding. If arachnoiditis is due to the remnants of oily contrast medium the cause is demonstrated, as is the case in some patients with vertebral neoplasm, metastasis, myeloma, or lymphoma.

33.15.2 Water-Soluble Contrast Myelography (WSCM) CT and MRI are not available in the majority of hospitals worldwide, and this is particularly the case in many of the 24 countries with a high burden of tuberculosis (WHO. Global tuberculosis control. 2000). By use of a basic radiography unit, myelography of the spinal axial nervous system may be acheived, even without a tilting table (McGuinnes 2000). Using myelography, it is possible in the majority of cases to define the lesion and the extent of the extramedullary disease. The disadvantage is that the pia-arachnoid and nerve root systems are well seen, but only the surface of the myelum can be studied. Variations of volume of the myelum are defined, but the presence of myelitis, intramedullary granulation lesions, and ischemic foci are not demonstrated. Also, it cannot be ascertained whether the lesions of the subarachnoid space and nerve roots are actively inflamed or represent scar tissue. As is the case in TBM, the changes seen in TBSM are nonspecific. Bacterial and fungal inflammatory diseases are mimicked, as are parasitic disease, tumor, arteriovenous malformation, sarcoidosis, polyradiculopathies, and demyelating disease. An attempt should be made to examine the full length of the cord, because in TBSM, multiple lesions are common, with areas of normal cord and theca intervening. In cases of TBSM, a normal myelogram is uncommon (Gupta et al. 1994). The usual patterns of the disease are as follows: 1. Irregular filling of the subarachnoid space, due to the presence of granulomatous exudates, granulomas, and thickening of the dentate ligaments. 2. Thickening of the nerve roots of the cauda equina and the paired nerve roots, particularly in the lower thoracic and lumbar regions. 3. Partial or total extramedullary blockage at the level of the conus medullaris or in the lower tho~ racic region. Blockage at higher levels, Th5, ThlC7, and C5, do occur, but are less common. 4. Long, vertical~ band-like filling defects, perhaps the result of thickening of the anterior midline septum. 5. Variations in the dimensions of the myelum, due to myelitis and cord edema. Most intramedullary tuberculomas in meningitis are too small to cause visible cord expansion.

F. McGuiness

6. Large mass lesions due to arachnoid or pial granulomas, simulating extramedullary tumours. These, in practice, are usually found posterior to the cord and in the lower thoracic area. 7. Epidural spinal abscess, due to extension of tuberculous vertebral osteomyelitis or, rarely, isolated epidural abscess without vertebral involvement. 8. Multiple filling defects in the contrast column, either fine and Widespread or larger and coarser, due to granulomatous lesions. Thecal granulomatous tissue also gives rise to surface irregularities and variations in the dimensions of the thecal sac (Chang et al. 1989; McGuinness 2000; Gupta et al. 1994; Kumar et al. 1993). On lumbar puncture in both TBM and TBSM in the early stages, a polymorph-leucocytic response may be found, suggesting a bacterial cause. Once the immune system has been triggered, then the picture changes to the characteristic findings of CSF pleomorphism, raised protein, and low sugar levels. In contrast to the appearances of spinal extramedullary tumor, the margins of granulomatous tissue are usually irregular and lack the smooth outline of most tumors. Thickening of the elements of the cauda equina is unlikely to be confused with the more serpentine appearance of vascular malformations of the spinal canal. Other granulomatous masses due to syphilitic gummas, or neurosarcoid are confusing, as well as those occurring in paracytic disease, such as schistosomiasis. Similar appearances of coarse filling defects may be the result of leptomeningeal carcinomatosis or due to the lymphomas, but the clinical findings outside the nervous system will usually point to the correct diagnosis in these cases (McGuinness 2000).

33.15.3 CT Combined with Water-Soluble Myelography CT examination in spinal inflammatory disease has the disadvantage that many images may be necessary to pinpoint multilevel pathology. Sagittal reconstructions are not of sufficient quality to define small lesions within the myelum, and there is relatively poor tissue differentiation between CSF, exudates, and the myelum (McGuinnes 2000). Gross volume changes of the myelum are recognized, and Chang et al. describe a pear-shaped cross section of the cord, in the lower thoracic region as being a common finding in cases of TBSM (Chang et al. 1989). Improved images are obtained by combining CT with contrast

Imaging of Brain and Spinal Cord Tuberculosis

myelography, although the disadvantage remains that if multiple level lesions are present, they may lie outside the area programed for examination. Small intramedullary TB lesions are isodense or hypodense on CT, and contrast examination adds little information in such cases. However, extra-axial granulomas may enhance, and if present epidural or paravertebral abscess will be recognized by postcontrast studies.

33.15.4 Magnetic Resonance Imaging In differentiating between the various tissues in the spinal canal, and in its multiplanar image acquisition, MRI is excellent in defining the pathology of spinal neurotuberculosis. This is especially so in the area of the cauda equina and the lumbar nerve roots (McGuinness 2000; Gupta et al. 1994; Kumar et al. 1993; Ross 1987; Gero et al. 1991), although some authors consider that water-soluble contrast CT has advantages (Chang et a11998). However, there is no doubt that in delineation of lesions within the cord, gadolinium-enhanced Tl-weighted MRI studies are superior to WSCM and to CT myelography. Active tuberculous lesions appear isodense or slightly hypodense on Tl images and either solid and hyperintense, or hyperintense with central area of low signal, on T2 imaging. After gadolinium-contrast injection, there is intense enhancement of tuberculomas, granulomatous tissue, and thecal inflammatory lesions. On Tl Gd studies in the areas affected by the disease, there is loss of differentiation between the spinal cord, the CSF, and the spinal meninges. These types oflesions are present either segmentally or throughout the length of the spinal canal. There are also variations in the caliber of the myelum, with thickening due to cord edema, or narrowing following cord compression. Areas of edema show a high signal on T2 images, but do not enhance after contrast injection. Tuberculomas of the cord are commonly of increased signal or isodense on T2. They are differentiated from areas of edema by enhancement after gadolinium on Tl acquisitions. There is no particular pattern of distribution of tuberculomas or extramedullary granulomas, except that those lesions causing spinal block are usually found in the lower thoracic or upper lumbar regions. The MRI findings are not specific to the disease, and are to be seen in other infections, fungal diseases, neoplasm, and paracytic infestations. Isolated epidural granulomatous masses are described by Gupta in the absence of both TBSM and tuberculous spondylitis (Gupta et al. 1994). In MRI

573

studies of the cervical spine, areas of the brain stem and medulla oblongata are invariably included in the disease (Shen et al. 1993). Isodense tuberculomas, if present will only be revealed on postcontrast studies. In all cases of suspected spinal tuberculosis, both the spine and the brain should be studied (McGuinness 2000; Gupta et al. 1997; Shen et al. 1993). Tuberculous radiculopathy of the cauda equina is not well demonstrated by noncontrast MRI. This is in contrast to nonspecific lumbar arachnoiditis, where MRI has been a useful tool (Ross 1987). In suspected lumbar radiculopathy, Tl Gd studies are usually only carried out in the sagittal plane. There is a case for including a coronal, postgadolinium study in the protocol to improve the definition of the cauda equina, the emerging nerve roots, and the associated pathologic changes (McGuinness 2000). WSCM is still a valuable method for imaging the changes of both active tuberculous radiculopathy and chronic adhesive tuberculous radiculopathy. However, a normal WSCM does not exclude spinal tuberculosis. Gupta describes five cases with normal conventional myelography, where subsequent Tl Gd studies revealed lesions in the myelum (Gupta et al. 1994). Despite its limitations in failing to image changes in the myelum, the superior definition of long stretches of nerve roots makes WSCM an important method of investigation, and one that is available to all radiologists (McGuinness 2000). Tl Gd MRI is important in the differentiation of active tuberculous granulomatous tissue from chronic fibrotic posttuberculous scarring, and in separating edema in the myelum from tuberculoma. Both fibrotic tissue and edema fail to enhance on TlGd examination (Chang et al. 1989; McGuinness 2000; Gupta et al. 1994). Although uncommon in the acute stage, syrinx formation and cavitation of cord lesions is described (Chang et al. 1989; McGuinness 2000; Sanchez Pernaute et al. 1996). Cavitation is more likely to develop in thoracic cord lesions than in other areas (Fig. 33.26a-c). Loculation of CSF, resulting from local obliteration of the subarachnoid space, is a common finding in both acute and suba<:ute presentations. Parenchymal lesions, depending on the stage of development, appear isodertse or slightly hypodense on unenhanced Tl images, and may not be visualised. T2 images usually show homogeneous low-signal appearances, but mixed-signal lesions are also described (Wadia and Dastur 1969; lena et al. 1991). In two cases of tuberculoma reported by lena, noncontrast T2 images revealed low-signal lesions (Fig. 33.27a, b). In Tl studies of intramedullary tuberculoma, both solid enhancing and ring

F. McGuiness

574

b

a

c

Fig. 33.26. a A noncontrast study demonstrates expansion of the cord by an isodense lesion, with an associated area of syringomyelia beneath it (arrows). b,c Sagittal and axial postcontrast scans show the ring enhancement of a tuberculoma (arrows). Images courtesy of Dr Pernaud, University Hospital, Maques de Valldecilla, Santander, Spain

a Fig. 33.27a, b. An intramedullary, tuberculous lesion extending over three cervical segments (arrows), with a mixed signal on Tl and a high signal on T2. Biopsy should be avoided in such cases

575

Imaging of Brain and Spinal Cord Tuberculosis

enhancing lesions are seen. The MRI changes may be summarized as follows: Intramedullary 1. Cord edema or infarction 2. Cord tuberculoma 3. Cord cavitation Meningeal 1. Fluid loculation 2. Obliteration of the subarachnoid space 3. Meningeal enhancement (Fig. 33.28) 4. Adherent and thickened nerve roots 5. Meningeal tuberculomas 6. Intradural extramedullary granulomatous mass lesions (Fig. 33.29)

Fig. 33.28. Sagittal Tl, postgadolinium scanning reveals local enhancement of the meninges and cauda equina (arrows) in a case of spinal tuberculous meningitis

33.16

Differential Diagnosis 33.16.1

Spinal Arachnoiditis Nerve root thickening and deformity confined to the lumbar region is characteristic of nonspecific spinal arachnoiditis (NSA). Once a common sequela to the use of oily contrast media in myelography, it is now more likely to follow spinal surgery or spinal anesthesia. The thickened nerve roots are displaced posteriorly and may be adherent to the dura, leading to the appearance of an ~mpty dural sac, although central clumping is also described. Adherance leads to some degree of spinal block, and contrast introduced above the level of the lesion on WSCM produces a "dripping candle" appearance, as contrast flows down through the thickened nerve roots (Ross 1987). In TBSM, all elements of the spinal canal contents are commonly involved in the infection, so that the dura, spinal cord surface, and nerve roots all show inflammatory changes, and usually at a number of levels. In the acute phase, the infection enhances on TlGd MRI. In the long standing fibrotic lesions, the tissues are nonenhancing as is the case in NSA. Enhancement of nerve roots occurs when the blood-nerve root barrier breaks down and is reported in subarachnoid hemorrhage, trauma, ischemia, inflammatory radiculopathy, and demyelation as well as axonal degeneration (Jinkins 1993). In tuberculosis, the younger age groups are commonly affected, while in NSA, cases tend to be between the ages of 30 to 50 years. Hypertrophic interstitial polyneuritis, a rare condition of the lumbar nerve roots in the young, is differentiated by the slow progress and lack of inflammatory change (McGuinness 2000; Kumar et al.1993; Donovan Post et al.1990).

.. Fig. 33.29. Axial, midthoracic, postgadolinium scan. There are two large paravertebral abscesses with ring enhancement (arrows). The cord is displaced anteriorly by an epidural collection (arrow head). There is tuberculous spondylitis in the vertebral body and transverse process (curved arrow)

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Fig.33.30. Sagittal scans of the thoracic spine demonstrate irregular, low signal thickening of the meninges at a number of levels (arrows). Bacteriologic study of the CSF confirmed enterococcal meningitis

33.16.2 Infective Leptomeningitis Isolated spinal meningitis is unusual, and the majority ofspinal cases are secondary to spread from intracranial meningeal infection. The most common agents are viral or pyogenic (Fig. 33.30). The clinical presentation of the meningitides, with fever, neck, back and radicular pain, often linked with changes in mentation, sensory loss and muscle weakness, leads to examination of the CSF. In the acute stage of TBSM, there is a polymorphonuclear cell reaction, with a slightly raised protein, suggestive of pyogenic infection. The characteristic pleomorphism and high protein levels of TBSM, develop only after the triggering of the cell-mediated immune response. This underlines the need for repeated CSF examinations. Unfortunately the results of immediate bacteriologic examinations are usually negative, although rapid culture methods are helpful, in centers where they are available (McGuinness 2000; Wadia 1973). In those cases with coexistent or recent TBM, the onset ofspinal symptoms is virtually diagnostic of TBSM, and conventional or CT myelography will demonstrate a supportive (but nonspecific) picture (Chang et al. 1989; McGuinness 2000). TBSM is a disease of the young (WHO. Global tuberculosis control 2000; Gupta et al. 1994; Gero et al. 1991). In nongranulomatous infections, the mean age is higher (Donovan Post et al. 1990). However, the upsurge in tuberculous infection in older age groups must also be considered. MRI changes of dural thickening, linear enhancement of the cord surface, and nodular enhancement

F. McGuiness

of the nerve roots of the cervical, thoracic, and lumbar regions are common to pyogenic meningitis, disseminated coccidioidomycosis and syphilis (Gero et al. 1991; Sharif 1992; Phillips et al. 1990). These diagnoses are rapidly confirmed by bacteriologic, immunologic, or biochemical examination of the CSF and serum. Linear enhancement confined to the nerve roots is described in aseptic meningitis and in immunemediated meningitis (Gero et al. 1991; Phillips et al. 1990). AIDS patients with secondary central nervous system cytomegalo-virus infections develop a polyradiculomyelitis. This demonstrates a strong enhancement of the conus and cauda equina nerve roots. These roots are thickened, but there is no irregularity or nerve root clumping. The CSF protein level is raised, there is a polymorphonuclear cell reaction, and serum CVM antibody titres are raised (Hansman Whiteman et al.1994). In some cases of spinal bacterial meningitis there is no demonstrable abnormality on T1 Gd MRI examination (Donovan Post et al.1990). In TBSM, the imaging appearances are invariably advanced at the time of presentation of the patient (Gero et al.I991). In spinal infections, the clinical assessment of the patient is paramount, while the imaging documents the extent of the disease. (McGuinness 2000).

33.16.3 Spinal Meningitis in Neoplastic Conditions 33.16.3.1 Meningeal Carcinomatosis

TBSM and meningeal carcinomatosis share many imaging features on WSCM, CT, and MRI (Chang et al. 1989; McGuinness 2000; WHO. Global tuberculosis control 2000; Phillips et al. 1990; Krol et al. 1988). The neoplasms commonly metastasizing to the spinal leptomeninges are primary carcinomas of the breast and lung as well as lymphomas and melanomas. In most instances the primary focus will already have manifested itself in other body systems (Fig. 33.31). Multiple cytologic examination of the CSF is necessary, as sensitivity is low. Although, in the case of lymphoma, CSF lymphocytosis can be unusually high (McAllister and O'leary 1987; Williams et al. 1990). Also mass lesions associated with lymphoma are often epidural and a paravertebral element is sometimes present (McGuinness 2000) (Fig. 33.32). Bone marrow changes seen on MRI are also helpful

Imaging of Brain and Spinal Cord Tuberculosis

Fig.33.31. Sagittal scan of the thoracic spine reveals multiple, low signal lesions (arrows). These were foci of meningeal carcinomatosis

Fig. 33.32. Postgadolinium scan of the thoracic spine with posterior meningeal enhancement in the upper area and patchy enhancement in the lower area (arrows). A case of spinal meningeal lymphoma with meningeal infiltration

577

in differentiating metastases from TBSM (Krol et al. 1988; McAllister and O'Leary 1987). Meningeal and nerve root thickening, bunching, nodular lesions, as well as surface changes in the conus medullaris, are common to both conditions. In intracranial tumors, spread to the spinal meninges by "dropping down" will give rise to local areas of similar imaging patterns, but less widespread than in TBSM (Chang et al. 1989; McGuinness 2000; Phillips et al. 1990; Hansman Whiteman et al. 1994; Blews et al.1990). In intramedullary tumors the same clinical pattern is seen as in tuberculoma of the myelum. Tuberculomas are usually less than 5 mm in diameter, usually do not expand the cord, in which case they are not seen on WSCM. MRI defines tuberculomas, which are commonly associated with TBM or TBSM (McGuinnes 2000; Gupta et al.1997; Shen et al. 1993; Wadia and Dastur 1969; Gupta et al. 1994). Isolated (Jinkins 1993; Sanchez Pernaute et al. 1996; Jena et al. 1991; Donovan Post et al. 1990; Rhoton et al. 1988 (Figs. 33.33-33.35) and multiple lesions are described (McGuinness 2000; Gupta et al. 1997; Shen et al.1993; Wadia and Dastur 1969; Gupta et al.1994) (Fig. 33.36). The common primary tumors of the myelum, astrocytome, ependymomas and hemangioblastomas generally show different MRI characteristics, and are more likely to expand the cord, to contain cystic ele-

Fig. 33.33. Sagittal postgadolinium scan of the brain demonstrating a cord tuberculoma at the cervico-medullary junction. Ring enhancement with a hypodense center and expansion of the cord

578

F. McGuiness Fig. 33.34. A high signal tuberculoma, low in the thoracic cord. There is a central necrotic nidus (arrow)

Fig. 33.35. An axial, Tl postgadolinium scan of the neck, with fat supression, demonstrates a small intensely enhancing solid tuberculoma of the cervical cord (arrow)

Fig. 33.36. Multiple supra- and infratentorial tuberculomas demonstrate ring enhancement (arrows). There is a single tuberculoma of the thoracic cord

Imaging of Brain and Spinal Cord Tuberculosis

ments, to be less well defined and to lack intense ring enhancement (Jinkins 1991). Ependymomas enhance patchily, due to the presence of cystic components (Sanchez Pernaute et al. 1996; Slasky et al. 1987). Multiple small secondary deposits in the myelum present a diagnostic problem, but at this stage of the disease manifestations elsewhere .and the presence of bone secondaries defined by radiographs, isotope, or MRI examination are usual (Fig. 33.37). Myelomatous meningitis has similar appearances to TBSM, carcinomatosis, and some granulomatous conditions. The characteristic vertebral changes and laboratory findings differentiate the condition from TBSM (Quint et al.1995).

579

may be acute or chronic. Extensive thickening of the leptomeninges in the basal cisterns and over considerable contiguous areas of the cervical theca are seen. In disseminated coccidioidmycosis (DCC) cervical meningeal thickening of such a degree as to cause flattening of the cervical cord is sometimes present (McGuinness 2000). The cervical spine lesions are the result of extension from intracranial meningitis, which shows features similar to TBM and TBSM, including parenchymal lesions. The two conditions are differentiated by culture of the organisms from the CSF, by complement fixation antibody titre studies, and, if necessary meningeal biopsy at the time of shunting for high pressure hydrocephalus. Blood vessels are invaded in fungal diseases and infarctions occur. Wrobel describes two cases of anterior spinal artery occlusion in DCC with cervical meningeal enhancement in TlGd MRI studies (Wrobel et al. 1992). Histoplasmosis also disseminates in the CNS, and although rare, the changes in the leptomeninges and myelum are similar to those of TBSM (Desai et al. 1991).

Fig.33.37. Sagittal thoracolumbar scan, demonstrating multiple, high signal bone marrow metastases (arrows). There is also irregular thickening of the meninges, due to further metastatic deposits, in this case of carcinoma of the nasopharynx

Biopsy of TB lesions of the myelum should be avoided and a trial of antituberculosis therapy is preferable, because the histology of tuberculosis may be unclear in a frozen section (McGuinness 2000).

33.16.4 Fungal Diseases

Fig. 33.38. Mixed signal in extensive mycetoma of the posterior cervical soft tissues (arrows). The fungus has extended Disseminated fungal infections produce images simi- into the spinal canal, both anteriorly and posteriorly, resulting lar in appearance to TB (Fig. 33.38). These diseases in cord compression (arrow heads)

F. McGuiness

580

In patients with AIDS, opportunistic infections population (McGuinness 2000,Villoria et al. 1992; of the central nervous system reflect the diseases Whiteman 1997). endemic in the geographical area. TBM and TBSM tend to be early complications and affect between 2% and 18% of patients. The higher levels of infection, 33.16.5 reported in Spain, appear related to the underlying Spirochetal Disease trigger of the disease being drug abuse as opposed to other causes (Villoria et al. 1992). Toxoplasmo- Tick-borne Lyme disease, due to Borrelia burgdorsis and cryptococcal infections usually appear Jeri, is widespread in Europe and in North America. at a later stage of the disease, when the immune When the CNS is involved, lymphocytic pleomorresponse has reached a lower level. Although the phism and raised CSF protein are seen. The onset is changes are widespread in the CNS, the inflamma- milder and slower than in TBM or TBSM, but both tory response is diminished. The enhancement of radiculopathy and myelopathy occur. Although the lesions seen on both CECT and T1 Gd MRI is less MRI appearances are not usually so dramatic as in than in patients with a normal immune response. TB, enhancement of both the leptomeninges and the This is also the case in the appearances of AIDS- CSF has been described (Fig. 33.39a-c). More often related CNS tuberculosis, when compared with the enhancement is confined to the pial surface of the imaging appearances of similar cases in the general cord (Demaerel et al. 1994).

b

a Fig. 33.39. a Sagittal contrast-enhanced Tlweighted (500/30) spin echo image of the cervical spine, shortly following injection. There is mild contrast enhancement of the CSF in the pontine and chiasmic cisterns, which gives a slightly higher signal than that in the fourth ventricle. Note clear differentiation between the avidly enhancing meninges and the less intense CSF, in this case of confirmed neuroborreliosis. b, c Coronal images obtained 30 min after the spinal images, showing markedly enhanced CSF in the basal cisterns and around the spinal cord. Note the normal signal of the CSF in the ventricles

c

Imaging of Brain and Spinal Cord Tuberculosis

581

Fig. 33.40. Extensive meningeal thickening and enhancement posteriorly (arrows). The result of syphilitic pachymeningitis

In neurosyphilis, spinal gummas are exceedingly rare, but have similar imaging characteristics to tuberculomas. The more common expression of syphilis is hypertrophic leptomeningitis, or pachymeningitis, a chronic condition affecting the cervical segments. Enhancement is seen on TlGd MRI (Fig. 33.40). Enhancement in the myelum, corresponding to posterior column pathology, has also been described, in cases of tertiary syphilis (Gero et al. 1991; Tashiro et al. 1987). Testing serum and CSF for levels of venereal disease research laboratory (VDRL) antigen are part of the protocol in all cases of CNS disease (McGuinness 2000).

Expansion of the myelum on WSCM is documented (Hitchon et al. 1984,Huang and Haq 1987; Kelly et al. 1988). MRI has confirmed granulomas, and these lesions may extend over a number of spinal segments, and enhance on Tl Gd MRI studies (Nesbit et al. 1989; Williams et al. 1990). CSF findings are of lymphocytic pleomorphism and raised protein, but the CSF sugar level is normal (McGuinness 2000). If sarcoid of the myelum is suspected, MRI imaging of the brain will often reveal characteristic granulomas of chiasmal, hypophyseal, and paraventricular distribution (Greco and Steiner 1987; Nesbit et al. 1989; Williams et al. 1990; Hayes et al. 1987). CSF enhancement in intracranial sarcoid has recently been described (Good and Jager 2000). 33.16.6 Isotope imaging with Ga 67 reveals sarcoid Other Granulomatous Diseases lesions in other organs, and hilar lymph nodes are often enlarged on chest radiographs, or on Neurosarcoidosis is a noncaseating granulomatous mediastinal CT. Biopsy of the conjunctiva, liver, or condition with systemic manifestations. Patho- lymph nodes, or a transbronchial biopsy, enables a logic change in the CNS is commonly intracranial histologic diagnosis in a high proportion of cases and spinal neurosarcoidosis is a rare complication (McGuinness 200). Neurobrucellosis is commonly (Hitchon et al. 1984; Huang and Haq 1987; Kelly et intracranial, and meningitis, cerebritis, and cranial al. 1988; Greco and Steiner 1987). As it is essentially neuropathies occur. Although rarely involving the curable with steroid therapy, it is important to distin- spinal elements of the CNS, brucella radiculopaguish parenchymal sarcoid from tuberculomata and thies are described. Swelling of the nerve roots spinal tumors. Sarcoid granulomas expand the cord involved is present, and they enhance on postconand infiltrate the meninges. If surgical intervention trast MRI studies. High titres of serum agglutinatis necessary with biopsy of the meninges, culture ing antibodies are present, as well as a history of specimens for TB should be routine and cord biopsy exposure to infected animals or their products (Tali avoided (Hitchon et al. 1984). et al. 1996).

582

33.16.7 Parasitic Diseases 33.16.7.1 Schistosoma

Schistosoma mansoni (SM), S. haemotobium (SH), and the Eastern form, S. japonicum (SJ), all cause granulomatous lesions in the CNS (Scrimgeour and Gajdusek 1985). Sporadic cases are being frequently reported in nonendemic areas, as both immigration and accessibility by air travel increases. SM or SH ovae are deposited in the brain, myelum, or meninges. SH ovae are presumed to pass through the vertebral plexus of veins, and in cases of hepatosplenic schistosomiasis, SM passes through pulmonary arteriovenous shunts to the brain. SJ is more likely to infest the brain than the spinal cord (Murphy et aI. 1998; Silbergleit and Silbergleit 1992; Dupuis et aI.1990). Young males are the most commonly affected, and although rare, the condition should be considered in any case of myelitis, where the patient has recently traveled in an endemic area. The clinical presentation is similar to local tuberculous myelitis, with low back pain, lower limb paraesthesia, and loss of sphincter function as the usual symptoms. The disease is normally confined to the thoracic cord or conus medullaris regions. Myelography and MRI demonstrate local expansion of the cord, and with T1 Gd imaging, both pial and intramedullary enhancement are described (McGuinness 2000; Murphy et aI. 1998; Silbergleit and Silbergleit 1992; Dupuis et al. 1990). Lymphocytic pleomorphism and raised CSF protein levels are found, but there is also an eosinophilia. Serum and CSF antibodies against schistosomiasis are present.

F. McGuiness

defects. Intramedullary cysts are usually found in the lower thoracic region, and the MRI characteristics are of a multiseptate lesion similar in appearance to a cystic neoplasm with enhancing margins. As cavitation of the cord may be associated with tuberculomas (McGuinness 2000; Sanchez Pernaute et al. 1996; Slasky et al. 1987), they must be included in the differential diagnosis. Laboratory testing for cysticercosis-specific antibody is positive in a high proportion of instances (Gupta et aI. 1994; Lotz et aI. 1988; Castillo et aI. 1998).

33.16.8 Demyelinating Disease 33.16.8.1 Multiple Sclerosis

In all cases of suspected spinal myelitis or space occupation, CT or MRI of the brain should be carried out, as silent intracranial lesions may be present (Fig. 33.41). Spinal lesions in multiple sclerosis (MS) are often preceded by an episode of acute myelitis, followed by recovery. Later signs of intracranial or spinal MS recur. Dissemination in time is an important feature of MS lesions (Hansman Whiteman et aI. 1994; Miller et aI. 1989; Posner et aI. 1983). The clinical presentation is of great importance in MS, as the

33.16.8 Neurocysticercosis Cysticercosis in the spine is rare. Lotz et aI., in a combined study of pathology and imaging pointed out that in the cranium the disease is more commonly found in the subarachnoid spaces than in the parenchyma (Lotz et al. 1988). Racemose cysts in the basal cistern complex of the posterior fossa sometimes extend into the cervical region as extramedullary lesions. Intramedullary lesions are very rare, but must be differentiated from tuberculomas. WSCM and CT will show expansion of the cord over a number of segments, or in the case of subarachnoid lesions, extensive filling

Fig.33.41. Enhancing lesions in the cord and brain stem (arrows). A case of multiple sclerosis

Imaging of Brain and Spinal Cord Tuberculosis

enhancing spinal lesions are difficult to differentiate, using imaging methods, from tubrculomas, granulomas, or tumors of the cord (McGuinness 2000).

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Imaging of Brain and Spinal Cord Tuberculosis tal tuberculosis localised to the ear. Arch Dis Child 64: 738-740 Nesbit GM, Miller GM, Baker HL et al (1989) Spinal cord sarcoidosis:a new finding at MR imaging with Gd-DTPA enhancement. Radiology 173:839-843 Ng SH, Tang LM, Lui TN (1996) Tuberculoma en plaque. Neuroradiology 38:453-455 Ng SH, Tang LM, Lui TN et al (1996) Tuberculoma en Plaque. Neuroradiology 38:453-455 Ogawa SK, Smith MA, Brennessel DJ, Lowy FD (1987) Tuberculous meningitis in an urban medical center. Medicine 66:317 Ozates M, Kemaloglu S, Gurkan F et al (2000) CT of the brain in tuberculous meningitis: a review 289 patients. Acta Radiol 41 :2000-13-17 Patankar T, Varma R, Krishnan A et al (2000) Radiographic findings in tuberculosis of the calvarium. Neuroradiology 42:518-521 Phillips ME, Ryals TJ, Kambhu SA, Yuh WTC (1990) Neoplastic vs inflammatory meningeal enhancement with Gd-DTPA. J Comp Ass Tomogr 14:536-541 Pio A, Chaulet P (1998) WHO, Tuberculosis handbook. WHO/ TB/98.259 Posner CM, Paty DW, Scheinberg L et al (1983) New diagnostic criteria for MS: guidelines for research protocols. AnnNeurol13:227-231 Praharaj SS, Sharma MC, Prasad K et al (1997) Unilateral meningeal thickening: a rare presentation of tuberculous meningitis. Clin Neurol Neurosurg 99:60-62 Quint DJ, Levy R, Krauss JC (1995) MR of myelomatous meningitis. AJNR 16:1316-1317 Rajshekar V, Haran RP, Prakash GS, Chandy MJ (1993) Differentiating solitary small cysticercus granulomas and tuberculomas in patients with epilepsy. J Neurosurgery 78:402-407 Rajshekhar V, Chandy MJ (1997) Tuberculomas presenting as isolated brain stem masses. Brit J Neurosurg II (2): 127-133 Rajshekhar V, Chandy M (1996) Comparative study of CT and MRI in patients with seizures and a solitary cysticercus granuloma. Neuroradiology 38:542-546 Reed MH, Ferguson CA (1978) The radiology of intracranial tuberculosis in children. Can Assoc Radiol J 29:113 Reid H, Fallon RJ (1992) Bacterial infections. In: Adams JH, Duchen WL (eds) Greenfields neuropathology. Edward Arnold, London, pp 302-334 Rhoton EL, Ballinger WE, Quisling R, Sypert GW (1988) Intramedullary spinal tuberculoma. Neurosurgery 22:733-736 Rich AR, McCordock HA (1933) The pathogenesis of tuberculous meningitis. Bull Johns Hopkins Hosp 52:5 Rich AR (1944) The pathogenesis of tuberculousis. Charles C Thomas, Springfield Rochas-Echeverri LA, Soto-Hernandez JL, Garza S et al (1996) Predictive value of digital subtraction angiography in patients with TBM. Neuroradiology 38:20-24 Ross JS, Masaryk TJ, Modic MT, Delamater R et al (1987) MR imaging oflumbar arachnoiditis. AJR 149:1025-1032 Sakamoto S, Kitagaki H, Ishii K et al (1997) Gadolinium enhancement of the cerebrospinal fluid in a patient with meningeal fibrosis and cryptococcal infection. Neuroradiology 39:504-505 Salgado P, Del Brutto OH, Talamas 0, et al (1989) Intracranial tuberculoma: MR imaging. Neuroradiology 31:299-302

585 Sanchez Pernaute R, Berciano J, Robollo M, Pascual J (1996) Intramedullary tuberculoma of the spinal cord with syringomyelia. Neuroradiology 38:S105-S106 Schoeman J, Hewlett R, Donald P (1988) MR of childhood tuberculous meningitis. Neuroradiology 30:473-477 Scrimgeour EM, Gajdusek DC (1985) Involvement of the CNS in schistosoma mansoni and S. Haematobium infection. Brain 108:1023-1038 Shah GV, Desai SB, Malde HM, Naik G (1993) Tuberculosis of the sphenoid sinus: CT findings. AJR 161:681-682 Shah GV, Sowan AM, Doctor MR, Shah PS (1994) MR findings in a patient with a tuberculoma of the teetal plate. AJR 162:469-470 Shah GV (2000) Central nervous system tuberculosis: imaging manifestations. Neuroimaging Clin N Am 10-2:355-374 Shakir RA (1986) Neurobrucellosis. Postgrad Med J 62: 1077-1079 Sharif H (1992) Role of MR imaging in the management of spinal infections. AJR 158:1333-1345 Shen WC, Cheng TY, Lee SK (1990) Disseminated tuberculomas of the spinal cord and brain demonstrated by MRI with gadolinium-DTPA. Neuroradiology 35:213-215 Shen WC, Cheng TY, Lee SK (1993) Disseminated tuberculomas of the spinal cord and brain demonstrated by MRI with gadolinium-TPA. Neuroradiology 35:213-15 Silbergleit R, Silbergleit R (1992) Schistosomal granuloma of the spinal cord: evaluation with MR imaging and intraoperative sonography. AJR 158: 1351-1353 Singer MB, Atlas SW, Drayer BP (1998) Subarachnoid space disease: diagnosis with fluid-attenuated inversion-recovery MR imaging and comparison with gadolinium enhance spin-echo MR imaging - blind reader study. Radiology 208:417-22 Singh B (1991) Role of surgery in tuberculous mastoiditis. J LaryngoIOtoI105:907-915 Slasky BS, Bydder GM, Niendorf HP, Young JR (1987) MR imaging with gadolinium DTPA in the differentiation of tumour, syrinx and cyst of the spinal cord. J Comp Ass Tomogr 11:845-850 Slavin RE, Walsh TJ, Pollack AD (1980) Late generalised tuberculosis:a pathological analysis of 100 cases in the pre-antibiotic and antibiotic eras. Medicine 59:352-366 Snider DE, Roper WL (1992) The new tuberculosis. N Engl J Med 362:703-705 Tali ET, Keskin T, Oznur et al (1996) MRI of Brucella polyneuritis in a child. Neuroradiology 38:S190-S192 Tandon PN (1978) Tuberculous meningitis (cranial and spinal). In: Vinken PJ, Bruyn GW (eds) Infections of the nervous system. Handbook of clinical neurology, vol 33. Elsevier, Amsterdam pp 195-162 Tashiro K, Moriwaka F, Sudo K et al (1987) Syphilitic myelitis with its MRI verification and succesful treatment. Jpn J Psych NeuroI41:269-271 Teoh R, Humphries MJ, O'Mahony G (1987) Symptomatic intracranial tuberculoma developing during the treatment of tuberculosis: a report of 10 patients with a review of the literature. QJM New Series 63 241:449-460 Urback H, KristofR, Zentner Jet al (1997) Sarcoidosis presenting as an inta-or extra-axial cranial mass: report of two cases. Neuroradiology 39:516-519 Vallejo JG, Ong LT, Starke JR (1994) Clinical features, diagnosis and treatment of tuberculosis in infants. Pediatrics 94:1-7 Van Dyke A (1988) CT of intracranial tuberculosis, with

586 special reference to the "target sign." Neuroradiology 30: 329-336 van Dyke A (1988) CT of intracranial tuberculosis, with specific reference to the "target sign:' Neuroradiology 30:329-336 Vengsarkar US, Pisipaty RP, Parekh B, Panchal VG, Shetty MN (1986) Intracranial tuberculoma and the CT scan. J Neurosurg 64:568-574 Villoria MF, de la Torre J, Fortea F, Munoz L et al (1992) Intracranial tuberculosis in AIDS: CT and MRI findings. Neuroradiology 13:11-14 Wadia NH, Dastur DK (1969) Spinal meningitides with radiculomyelopathy. Part 1: clinical and radiological features. J Neurol Sci 8:239-260 Wadia NH (1973) Radiculomyelopathy associated with spinal meningitides (arachnoiditis) with special reference to the tuberculous variety. In: Spillane JD (ed) Tropical neurology. Oxford University Press, London, pp 63-72 Waeker NJ Jr, Connor JD (1990) Central nervous systemtuberculosis in children: a review of 30 cases Wallace RC, Burton EM, Barrett FF et al (1991) Intracranial tuberculosis in children: CT appearances and clinical outcome. Pediatr RadioI21:241-246

F. McGuiness Wechman JM (1979) CT of intacranial tuberculomas. Clin RadioI30:567-573 Wessels G, Hesseling PB, Beyers N (1998) Skeletal tuberculosis: dactylitis and involvement of the skull. Pediatr Radiol 28: 234-236 Whiteman MLH (1997) Neuroimaging of central nervous system tuberculosis in HIV-infected patients. Neuroimag Clin N Am WHO. Global tuberculosis control. WHO report 2000. Geneva, Switzerland, WHO/CDS/TB/200.275 Wilkinson HA, Ferris AJ, Muggid AL (1971) Central nervous system tuberculosis:a persistent disease. J Neurosurg 34: 15-22 Williams DW, Elster AD, Kramer SI (1990) Neurosarcoidosis: gadolinium enhanced imaging. J Comp Assist Tomogr 14: 704-707 Williams MP, Olliff JFC, Rowley MR (1990) CT and MR in parameningeal leukaemic masses. J Comp Ass Tomogr 14:736-742 Wrobel CJ, Meyer S, Johnson RH, Hesselink JR (1992) MR fidings in acute and chronic coccidioidomycosis meningitis. AJNR 13:1241-1245

34 Extraspinal Musculoskeletal Tuberculosis M. MONIR MADKOUR, AIDA

J. KUDWAH, MOHAMMED ABD EL BAGI

CONTENTS 34.1 34.1.1 34.1.2 34.1.3 34.1.4

Introduction 587 Epidemiology 588 Pathogenesis 588 Clinical Features 588 Diagnosis of Extraspinal Bone and Joint Tuberculosis 590 34.1.5 Tuberculosis of the Hip Joint 590 34.1.6 Imaging Features of Tuberculosis of the Hip 591 34.1.7 Treatment 591 34.1.8 Tuberculosis of the Knee 591 34.1.8.1 Case Illustration 591 34.1.9 Imaging Features of Knee Tuberculosis 592 34.1.10 Tuberculosis of the Foot and Ankle 592 34.1.11 Imaging Features of Foot and Ankle Tuberculosis 593 34.2 Sacroiliac Joint Tuberculosis 593 34.3 Tuberculosis of the Joints of the Upper Extremity 594 34.3.1 Treatment of Upper Limb Joint Tuberculosis 595 34.3.2 Sternoclavicular Joint Tuberculosis 596 34.3.3 Poncet's Disease 596 34.3.4 Extraspinal Tuberculous Osteomyelitis 597 34.3.5 Tuberculous Osteomyelitis of the Chest Wall 597 34.3.6 Tuberculous Tenosynovitis, Bursitis, and Myositis 599 34.3.7 Epidemiology 599 34.3.8 Pathogenesis 599 34.3.9 Clinical Features and Diagnosis 599 34.4 Multifocal Osteoarticular Tuberculosis 600 References 601

M. M. MAOKOUR, MD, DM, FRCP Consultant, Department of Medicine, Riyadh Armed Forces Hospital, P.O. Box 7897, C-119, Riyadh 11159, Saudi Arabia M. ABO EL BAGI, MB BCh, DMRD, FSRRCSI Department of Radiology, Riyadh Armed Forces Hospital, P.O. Box 7897, Riyadh 11159, Saudi Arabia A. J. AL-KuoWAH, MD, DD, FRCP (Ed) Consultant Dermatologist, Department of Dermatology, Riyadh Armed Forces Hospital, P.O. Box 7897, C-117, Riyadh 11159, Saudi Arabia

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

34.1

Introduction Tuberculous arthritis and osteomyelitis may present with indolent and often nonspecific clinical features that constitute a challenge to the treating clinician (CDC 1997; Cremin 1971; Jacobs et al. 1991; Rieder et aI. 1990; Silva 1980). Such obstacles often lead to a delay in diagnosis of a disease which is curable, with subsequent joint destruction and disabilities. The duration of symptoms before diagnosis may be up to 20 years as noted (Soler et al. 2001). Difficulties in early diagnosis are more noticeable in developing countries, for example in Saudi Arabia and other countries (Ellis et al. 1993; Negusse 1993), particularly in children with more severe joint destruction and loss of function (Singh et al. 1992). This may be compounded with partial, inadequate antituberculous treatment prior to presentation, which may reduce the effectiveness of clinicoradiological and microbiological diagnostic tests. In coinfection of HIV and tuberculosis, where both conditions are of insidious onset and where reactive arthritis or septic arthritis are also common in HIV patients, the diagnosis of tuberculous arthritis and osteomyelitis becomes difficult (Chretien 1990; Elliott 1990; Govinder et al. 2000; Jellis 1996; Leibert et al. 1996; Ragni et al.1995; Soler et aI. 2001; Veerken and Bermejo 1992; Wright et al.1996; Jellis 2002). Atypical mycobacterial infection of the musculoskeletal system is increasingly reported. The most frequent are Mycobacterium intracellulare, M. fortuitum, M. kansasii, M. avium, and others (Ip and Chow 1992; Williams and Riordan 1973; Cortez and Pankey 1973; Chow et al. 1983,1987). See chapter on nontuberculous mycobacteria. The most common cause of extraspinal osteoarticular tuberculosis is Mycobacterium tuberculosis and to a lesser extent other related organisms such as M. africanum and M. bovis found in poor, developing countries with high levels of raw milk consumption (Watts and Lifeso 1996; Kosin and Bishop 1991).

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34.1.1 Epidemiology Osteoarticular tuberculosis accounts for 1% to 5% of all tuberculosis cases and for about 15% of extrapulmonary disease (Weir and Thorton 1985). The spine is involved in approximately 50%, joints in 30%, extraspinal osteomyelitis in 19%, and tenosynovitis and bursitis in 1% (Jaovisidha et al.1996; Martini et al.1986a,b,c; Singh et al. 1992; Watts and Lifeso 1996). Tuberculous arthritis most commonly affects the weight-bearing joints, particularly the hips and knees in equal frequencies, and less frequently the ankles and feet. In the upper extremities the wrist joint is the most frequently affected, followed by the elbow and shoulder (Skoll and Hudson 1999). The frequency of individual joint involvement varied in different series, particularly from developing countries where children and young adults are more commonly affected. Singh and colleagues (1992) reported a series of 104 children with osteoarticular tuberculosis seen over a two-year period. The ages ranged between 9 months and 18 years with male predominance. The hip joints were affected in 14.9%, the knees in 10.3%, and extraspinal osteomyelitis occurred in 18.2%. The spine was affected in 43%. Shah and colleagues (1992) reported 80 patients with osteoarticular tuberculosis seen during hospitalization over a 3-year period. About 60% of patients were below the age of 40 years with female predominance (57.5%). The spine was affected in only 21.2%, the joints in 48.6%, and extraspinal tuberculous osteomyelitis occurred in 30%. Associated pulmonary or renal tuberculosis was found in 36.25%. The knee joints were affected in 15%, the hips in 11.2%, the ankles in 6.2%, the elbows in 10%, the wrists in 3.7% and the sacroiliac in 2.5%. In Addis Ababa, Negusse (1993) reported 42 children with osteoarticular tuberculosis attended the Ethio-Swedish Children's Hospital over a period of 3 years. The hip joints were more affected than the spine, in 22 patients and 15 patients, respectively. Associated active pulmonary tuberculosis was found in four patients.

34.1.2 Pathogenesis Tuberculous arthritis may occur as a progression of primary infection, particularly in children in developing countries (Resnick 1988). Localization of infection into the joint is commonly caused by hematog-

enous spread of the bacilli from a primary focus such as the lung. However, in more than 50% of patients with tuberculous arthritis, no evidence appears in imaging focused on the lung. Another possible mode of transmission of infection is via lymphatic spread. Joint involvement may also occur due to spread of infection from epiphyseal bone eroding into the joint space. And, another possible mode of transmission of infection to the joint is direct inoculation (Davidson and Horowitz 1979; Abdelwahat et al. 1998). Granulomatous inflammatory tissue reaction takes place in the joint synovium with granulation tissue, caseation, necrosis, and joint effusion. Fibrin in the synovial fluid may precipitate in the form of so-called rice bodes, similar to those seen in rheumatoid arthritis (Al-Qattan et al. 1994). A pannus of granulation tissue may slowly progress and cause erosion and damage to the articular cartilage and adjacent cancellous bone. Slow cartilage and bone destruction in tuberculous arthritis is due to the inability of M. tuberculosis bacilli to produce proteolytic enzymes that are found in pyogenic arthritis caused by Staphylococci and Streptococci. However, as the disease progresses, complete joint destruction may occur, similar to that caused by pyogenic infections. In untreated joints, ankylosis and sinus formation may result (Fig. 34.1).

34.1.3 Clinical Features Tuberculous monoarthritis is the most common presenting feature, but oligoarticular or polyarticular involvement, on rare occasions, may occur (Valdazo et al. 1990). The onset is usually insidious with mild pain and swelling of the soft tissue surrounding the affected joint. These features may be easily mistaken as post-traumatic (Hunfeld et al. 1998). As the disease progresses, limitation of joint movement, cold abscesses with draining fistulas, and destruction with deformity of the joint may occur (Singh et al. 1992; Dhillon et al. 2001a,b; Babhulkar et al. 2002). Clinical features of tuberculous arthritis are commonly mild and nonspecific, and many mimic other arthritic diseases. Subsequently, the diagnosis is commonly delayed (Kim et al. 1999). Constitutional symptoms, such as fever, loss of appetite, and weight loss may be lacking in patients with tuberculous arthritis. Joint pain may be absent despite the presence of swelling (Ruggieri et al. 1997; Hoffman et al. 2002). In a series of 52 children with tuberculosis of the knee, Hoffman and colleagues reported swelling in all patients, pain in 65%, and draining sinuses in 10%.

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a d

b

c

e Fig. 34.1a. Tuberculous discharging sinus below the left medial aspect of the left knee. Note the discharge pus over the left leg. b Note the swelling of the left knee, wasting of the thigh and leg muscles, and shortening of the left leg. c Tuberculous arthritis of the left knee. Frontal radiography demonstrates advanced destructive changes. There are marked osseous erosions mostly peripheral in location (open arrows), periarticular osteoporosis, and diminished joint space (Phemister triad). Complete obliteration with ankylosis of the joint space medially has ensued. Note normal appearance of the right knee. d Tc 99m bone isotope demonstrates high tracer uptake in the left knee. e Lateral radiograph of lower lumbar spine demonstrates evidence of healed brucella spondylitis. Note marginal osteophytes (arrow heads), erosion of the anterior aspect of the superior end plate of L4 vertebral body (open arrow) and preservation of the disc spaces (d)

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An acute septic arthritis-like feature (warm,reddened, and swollen joint) was noted in eight patients (15%). Tuberculous arthritis may occur in patients with systemic lupus erythematosus and mixed connective tissue disease where systemic steroid are used for treatment of these conditions (Stecher et al. 1992). In such cases, delay in diagnosis is likely to be common. The disease may simulate oligoarticular-onset juvenile rheumatoid arthritis ORA). Al-Matar and colleagues (2001) reported two Canadian children who were initially diagnosed as JRA-a 25-year-old Caucasian girl and a 6-year-old boy who had emigrated with his family from Somalia. Treatment with systemic and intraarticular steroids were given with no response. A considerable delay of the diagnosis for 18 months was emphasized by the authors. They related such a long delay to the rarity of the disease in Canada and the similarity of the clinical and investigative findings to those of JRA.

34.1.4 Diagnosis of Extraspinal Bone and Joint Tuberculosis Tuberculous arthritis is often nonarticular and rarely affects more than one joint. Monoarthritis should always be initially regarded as infectious till proven otherwise. Tuberculous monoarthritis can be diagnosed if the attending clinician maintains a high level of vigilance and examines a detailed history and physical examinations for possible clues of tuberculosis that may be found in other body organs or systems. Among patients with monoarthritis, the most common causes are infections, crystals, trauma, spondyloarthropathy, and rheumatoid arthritis. The differential diagnosis of tuberculous arthritis should include pyogenic arthritis caused by bacteria or fungi. In developing countries such as Saudi Arabia, brucellosis may be common and may simulate tuberculous arthritis, although the onset is more acute (Madkour 2001). Sarcoidosis may be polyarticular, but is rarely present as monoarthritis, which is intermittent and persistent. Tuberculin skin test (PPD) may be positive in more than 90% of patients with osteoarticular tuberculosis (Berney et al. 1972; Halsey et al. 1982; Kerri and Martini 1985; Lee et al. 1995). The hemogram shows normal white cell count and mildly elevated ESR (Wang et al. 2000). Arthrocentesis and synovial tissue biopsies are the most important diagnostic investigations in patients with osteoarticular tuberculosis (Versefeld and Solomon 1982; Wollinsky 1994; Yao and Sartoris 1995; Suh et al. 1996; Sant and

Bajaj 1991). The synovial fluid may appear as clear or turbid with a raised white blood cell count ranging from 2,500 to 100,OOO/mm3 with 60% neutrophils. Synovial fluid protein is usually raised and glucose may be low in approximately 50% of patients, which are nonspecific. Synovial fluid smear positivity may range from 0% to 83% (Berney et al. 1972; Lee et al. 1995). Fluid culture may be positive in up to 50% of patients (Ellis et al. 1993; Wang et al. 2000; Berney et al. 1972). Synovial tissue biopsy may yield the bacilli in 47% t090% of cases (Albers et al. 1984; Bush and Schneider 1984; Berney et al. 1972; Halsey et al. 1982; Lee et al. 1995). Histopathology of synovial tissue biopsy may be positive in up to 90% of cases, and when combined with microbiology, definitive diagnosis can be achieved in 95% (Gorbach et al. 1992). Gen-Probe methods using PCR or its new versions, Amplified Mycobacterium Tuberculosis Direct Test (AMTDT), are more sensitive than PCR with sensitivity of 94.7% to 96% and specificity close to 100% (Gamboa et al. 1998; Wobeser 1996). Imaging features of osteoarticular tuberculosis are discussed in detail in the chapter "Imaging of Bone and Joint Tuberculosis:'

34.1.5 Tuberculosis of the Hip Joint The hip joint is one of the most common extraspinal sites to be affected by tuberculosis. It is essential that clinicians differentiate it from septic arthritis, as both diseases are common in children and young adults. Serious disabilities may occur if a diagnosis is not made early. Mild hip pain with limping is the most common early presenting clinical feature with or without constitutional symptoms. Patients may present late in the course of the illness with cold abscesses, discharging sinuses, and hip deformities. Hip pain tends to be worse at night and may lead to sleep disturbances. In advanced stages, walking may become difficult particularly with the occurrence of pathological dislocation of the hip joint. Hip pain and limitation of movements are readily elicited with active or passive movements during physical examination. The affected limb may be shorter than the opposite one, with flexion, adduction, and internal rotation. Muscle wasting around the hip joint may be noted. Clinical and imaging features of tuberculosis of the hip have been classified (see the chapter "Imaging of Bone and Joint Tuberculosis") by several authors to identify guidelines for diagnosis, assessing the extent of joint damage, managing, and checking

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for indications for total hip replacement (Shanmugasundaram 1983; Babhulkar and Pande 2000).

34.1.6 Imaging Features ofTuberculosis of the Hip We have devoted a separate chapter to imaging of bone and joint tuberculosis from our own series; please refer to the chapter "Imaging of Bone and Joint Tuberculosis." For tuberculosis of the hip joint, see also Figs. 16,24,25, and 26 in that chapter.

34.1.7 Treatment The management of hip tuberculosis is a multidisciplinary task that involves clinicians, microbiologists, histopathologists, occupational therapists, and physiotherapists. Chemotherapy with duration of treatment ranging from 18 to 24 months, for long-term therapy, to short-term therapy of 6 months has been extensively reported (American Thoracic Society 1986; Dutt et al. 1986; Hannanchi et al. 1988; Tenth Report of the Medical Research Council 1986; Dutt and Stead 1989; Cohn et al. 1990; Combs et al. 1990). Isoniazid and rifampicin with or without ethambutol, streptomycin, and pyrazinamide are used in all regimens. In early phases of the disease, chemotherapy is given with the application of bilateral traction to ensure hip rest and supervised mobilization without weight-bearing for 4 to 6 weeks. Lack of any favorable response to this conservative approach to treatment is an indication for surgery to prevent hip destruction. Synovectomy and joint debridement may be useful but may not prevent painful fibrous ankylosis. In advanced hip joint damage with restriction of mobility and function, total hip replacement may be necessary too (Kim et al. 2001; Yoon et al. 2001; Babhulkar et al. 2002). Long-term follow-up after total hip replacement for hip tuberculosis for up to 28 years was reported by Kim and colleagues (2001). These authors reported the follow-up for up to 28 years of 60 patients with total hip replacement for hip joint tuberculosis. Six patients had relapses of hip tuberculosis and the prosthesis was removed from three patients. The reasons for the relapses were either inadequate drug dosage or duration, or poor compliance of the patient. The authors also reported a 54year-old woman with left acetabular destruction and calcifications. Tuberculosis was not diagnosed preop-

eratively. Tissue biopsies were sent for histopathology and showed granulomas but these results were not conveyed to the treating clinician. The patient was discharged without chemotherapy. She returned 1 year later with persisting discharging sinus. The diagnosis was confirmed only by performing a PCR. The final clinical outcome can be predicted by the imaging features of hip tuberculosis at the time of presentation. Normal and Perthes' type with preserved joint space tend to have a good prognosis. Hips with atrophic, traveling acetabulum, protrusio acetabuli, and mortar and pestle types will have poor results (Babhulkar et al. 2002).

34.1.8 Tuberculosis of the Knee Tuberculosis of the knee usually presents as chronic monoarthritis with insidious onset of pain, swelling, and limping, with or without the presence of constitutional symptoms. There may be a history of trauma to the knee. The duration of symptoms may be up to 2 years before presentation. In about 15% of patients the duration of symptoms may be 1week with features of septic arthritis including fever, with swollen, warm, and tender knee (Hoffman et al. 2002). The knee may be held in flexion, and active or passive movement during physical examination is associated with severe pain. In advanced stages, knee deformity with flexion, posterior and lateral dislocation, and wasting of surrounding muscles may be noted on examination. Discharging sinuses (Fig. 34.1a,b) may be noted in about 26% of cases (Kerri and Martini 1985; Friedman and Vishwa 1970). Because of its gradual onset in most patients or even during acute presentation the, diagnosis of tuberculous arthritis of the knee is commonly delayed between 4 to 40 months (Halsey et al. 1982; Newton et al. 1982; Kerri and Martini 1985; Lee et al. 1995; Dhillon et al. 1998). Evidence of pulmonary tuberculosis in patients with knee tuberculosis maybe present in 10% to 47% ofpatients (Friedman and Vishwa 1970; Chow and Yau 1980). 34.1.8.1

Case Illustration A 45-year-old male shepherd living in a rural area in the central province of Saudi Arabia presented with pain and swelling of the left knee, limping, and discharging sinus. The pain had started 12 years earlier, and he related it to a minor trauma to the knee. He noticed the intermittently discharging sinus over the left leg for about 7-9 months before presentation to our hospital.

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He denied any history of tuberculosis or constitutional symptoms. He had a past history ofbrucellosis with low back pain, fever, sweating, and chills 16 years ago, which had been treated in a peripheral clinic and responded well. He keeps sheep, goats, and camels in the back yard of his house and regularly consumes raw milk. The patient attended several hospitals for his left knee and refused biopsies, arthroscopies, or knee replacement. The patient looked well and had no other systemic findings. The left knee was swollen with flexion deformity of 15 degrees (Fig. 34.1a, b). There was a discharging sinus below the medial aspect of the left knee. The muscles of the thigh and leg were wasted. The left leg was 3 cm shorter than the right. Examination of the spine showed no deformities or localized tenderness. Plain radiography of the knees showed gross destruction of the left knee (Fig. 34.1c, d). Bone scintigraphy showed increased uptake in the left knee (Fig. 34.1e). The hemogram was normal and the ESR was 48 mmlhr. His biochemical parameters were normal. Brucella agglutinins were not raised; repeated at one-month intervals, these remained at a low titer of 1:80. Blood culture for brucella was negative. Culture of sinus discharge yielded Mycobacterium tuberculosis after 4 weeks. Lumbar spine radiography showed a healed old destructive lesion at the anterior superior end plate with osteophyte formation. The intervertebral disc space was preserved, and there was no vertebral body collapse, osteoporosis, or deformities (Fig. 34.1e). The patient was treated with antituberculous chemotherapy for 1 year complemented with physiotherapy and a high-heeled shoe. He refused total knee replacement. The patient responded well to treatment and the sinus healed and the ESR returned back normal. The most likely cause of his old healed spinal lesion at the fourth lumbar vertebra is brucellosis. (The fourth lumbar vertebra is the most common site of spinal brucella spondylitis. Infection commonly starts at the anterior superior end plate, and collapse of the vertebral body, unlike tuberculosis, is rare.) The intervertebral disc space was preserved and there were no deformities.

34.1.9 Imaging Features of Knee Tuberculosis Full detailed imaging features of tuberculosis of the knee using different modalities at various stages of the disease can be seen in our chapter on "Imaging of Bone and Joint Tuberculosis"; and also see Figs.4, 11,12, 14, 15,17,20,21,23, and 28 for knee tuberculosis. Kerri and Martini (l985) described radiological classification of 52 patients with tuberculosis of the

M. M. Madkour et al.

knee into four stages. Stage 1, with osteopenia and soft tissue swelling. Stage 2, with erosions but normal joint space. Stage 3, with narrow joint space. Stage 4, with gross anatomic distortions. These classifications do serve as predictive of the outcome of chemotherapy alone or combined with surgery (Lee et al. 1995). Stage 1 and 2 had good outcomes, while in stage 3 and 4 with cartilage destruction had unfavorable outcomes. Wilkinson (l969) graded the response to treatment using the range of knee flexion and imaging features as parameters. Results are considered excellent with full range of movement and normal XR; good, with flexion of more than 90 degrees and normal XR; fair, with flexion between 35 and 90 degrees and narrowing ofjoint space; poor, with worse flexion or ankylosis and joint space narrowing. Treatment of stage 1 and 2 knee tuberculosis using chemotherapy alone provided good results (Gupta 1982; Kerri and Martini 1985; Hoffman et al. 2002). Some authors have used chemotherapy and surgical synovectomy and debridement, but others found synovectomy patients had more symptoms and stiffer knee postoperatively (Wilkinson 1969; Katayama et al. 1962; Gupta 1982). Early mobilization without the need for splinting postoperatively with stage 1 and 2 was found to be as effective as with splinting (Gupta 1982; Hoffmann et al. 2002). In stage 3 and 4 disease, however, flexion deformity of the knee should be prevented by placing it in splint. For adult patients with persistent pain or significant knee joint destruction, arthrodesis or arthroplasty may be necessary (Eskola et al.1988; Kim 1988).

34.1.10 Tuberculosis of the Foot and Ankle Foot and ankle tuberculosis involve sites rarely involved in patients with osteoarticular diseases. Large series are reported from developing countries and only a few reports of 1 to 3 cases from developed countries. Dhillon and colleagues (2001, 2002) from India reviewed the world literature and postulated that onefifth of the world population of tuberculosis patients are in India. They also found that the reported incidence of foot and ankle involvement varied from 3% to 12%. Among the 224 patients with foot and ankle tuberculosis, these authors reported that articular involvement was more frequent than tarsal or small bone osteomyelitis. Tuli (l997) from India reviewed 1,074 patients with skeletal tuberculosis seen over a 32-year period and found 154 patients with foot and ankle disease (l4.3%). A more recent report by Dhillon and colleagues from India (Dhillon and Nagi 2002) described their own experience of 74 patients with

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tuberculosis of the foot and ankle over an ll.5-year period. There have been only a few case reports from developed counties in recent years. Dalldorf and colleagues (1994) from New York reported a 34-year-old alcoholic man with rightfoot pain and swelling without any constitutional symptoms. Delay in diagnosis was experienced by these authors similar to many others. Eventually the diagnosis was confirmed microbiologically from open tissue and fluid materials. Nicklas et al. (1996) from Ohio, USA, reported a 38-year-old female with painless swelling of the second toe of the right foot. Other systemic physical examinations were normal. At operation, bone and soft tissue biopsies revealed granulomatous inflammation and positive culture of the bacilli after 6 weeks. Malhan et al. (2001) from Yorkshire, UK, reported a 28-year-old man with a 2month history of pain and swelling of the right ankle without constitutional symptoms. Open biopsy for histopathology showed granuloma with negative tissue culture. The diagnosis was confirmed by PCR. Ruggieri and colleagues (1997) reported three Italian children aged 14 months to 6 years with tuberculosis of the ankle. These authors experienced difficulties and delay in diagnosis. Ong and colleagues (1998) from Singapore reported a 25-year-old woman with left-foot pain without swelling. Six months later during routine periodic health screening for foreign domestic helpers, she had swelling and persistent pain in the foot. Foot and chest radiography showed osteoporosis at the small joints and paravertebral abscess with collapse of vertebral bodies of T7-T8 consistent with Pott's disease. The clinical features of foot and ankle tuberculosis at the time of presentation are nonspecific and may vary widely. Patients may present with painless swelling of the ankle, foot, or toe without constitutional symptoms. Pain may be the only presenting feature, without swelling. Acute onset with pain, swelling, redness, hotness, limping, and diminished motion may be the presenting features. Constitutional symptoms may be present in 45% of patients. The ankle may be held in extension and muscular atrophy of the lower limb may be noted. Sinuses may be noted in 23% of patients at presentation. The duration of symptoms may range from weeks to 4-5 years (Ruggieri et al. 1997; Dhillon and Nagi 2002).

34.1.11 Imaging Features of Foot and Ankle Tuberculosis Tuberculous lesions may be either osseous, articular, or a combination of both as depicted by imaging modali-

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ties. Imaging features are clearly described from our own series, in the chapter "Imaging of Bone and Joint Tuberculosis (please see Figs. 2, 3, 5, 31, 32, 36, and 37). Chemotherapy alone is adequate for the treatment offoot and ankle tuberculosis. Clinical symptoms may disappear after 2-5 months, while imaging improvements with consolidated cortex and disappearance of periostitis may be achieved after 6 months. Surgical intervention may occasionally be required for open biopsy, debridement, or arthrodesis.

34.2 Sacroiliac Joint Tuberculosis Tuberculosis of the sacroiliac joint is rare and because the joint is deeply located with a limited range of movement, signs of this disease are easily overlooked (Soholt 1951). The main presenting symptom is buttock pain on the affected side. Pain may be poorly localized in the buttock and may be mistaken for lumbar spine, hip, lower abdominal, or pelvic diseases (Soholt 1951; Feldmann et al. 1981; Goldberg and Kovarsky 1983). The onset of pain is usually insidious over weeks or months. It may be associated with limping and may cause sleep disturbances. The pain may radiate to the lower limb with a positive straight leg raising test (Pouchot et al. 1988). Buttock abscess may rarely be present at the time of presentation as we noted in three of our patients (see Fig. 35.1, Fig. 35.22 and Fig. 34.2). Wasting of the quadriceps muscle may be present. Discharging buttock sinuses may be noted at the time of presentation (Fig. 34.2). Sacroiliac joint examination will reveal tenderness on pressure and conventional stress tests will induce pain at the affected side. Sacroiliac joint tuberculosis is usually unilateral. Rarely, it may be associated with evidences of osteoarticular tuberculosis in another location such as the pubic symphysis (Fig. 35.22). Constitutional symptoms may be lacking. Chemotherapy alone for 12-18 months is usually sufficient. Symptoms improve gradually and commonly subside after 4-6 months of treatment (Pouchot et al. 1988). Bed rest and immobilization in a cast may rarely be required. Surgery for drainage of buttock abscess, and rarely for arthrodesis, may be indicated if symptoms persist after 9 months of treatment (Pouchot et al. 1988).

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M. M. Madkour et al. Table 34.1. Osteoarticular tuberculosis of the wrist, hand and elbow literature review) Authors (year) Brashear et al (1975) Martini et al (1980) Arafiles et al (1981) Benkeddache (1982) Albers et al (1994) Bush et al (1984) Martini et al (1986)

Fig. 34.2. Tuberculous sinus in the right buttock (white arrow) in a 42-year-old patient with right sacroiliac joint tuberculosis.

34.3 Tuberculosis of the Joints of the Upper Extremity Tuberculosis of the wrist and hand, elbow and shoulder occurs in approximately 10% of all cases of bone and joint tuberculosis, and the wrist and hand are the most frequently affected (Martini et al. 1986; Hunfeld et al. 1998; Skoll and Hudson 1999). We reviewed the literature that was available to us (see Table 34.1) to determine the frequency of involvement of the hand and wrist, elbow and other sites in the upper limb. We found 363 reported cases of tuberculosis of the upper extremities-in the wrist and hand in 206 (57%), the elbow in 130 (36%), and other sites in 27 (7%). Tuberculosis of the wrist and hand may present with pain and swelling. It is usually monoarticular and the onset is insidious with progressive loss of motion (Chen et al. 1997; Skoll and Hudson 1999). Discharging sinuses and symptoms of carpal tunnel syndrome may be the presenting feature late in the disease (Al-Qattan et al. 1994; Chen et al. 1997; Cedidi et al. 1998; Skoll and Hudson 1999). Constitutional symptoms may be lacking in less than 50% of patients. Secondary bacterial infections after an injury to the hand may present with acute pyogenic arthritis and mask the presence of tuberculous infection (Al-Qattan et al.1994). Soft tissue swelling, tenderness, and limitation of both flexion and extension motion of the wrist may be detected on physical examination. As the disease progresses,bone and ligaments subluxation and deformities may be noticed. Soft tissue swelling may form abscesses and discharging sinuses at the time of presentation.

Sites

No of cases

Wrist 10 Elbow 29 Elbow 11 Hand & Wrist 27 Wrist 101 Hand & Wrist 11 Elbow 42 Wrist 10 Other sites 22 of upper limb Parkinson et al (1990) Elbow 5 Al-Qattan et al (1994) Wrist 3 Vohra et al (1995) Elbow 10 Visuthikosol et al Hand & Wrist 23 (1996) Chen et al (1997) Elbow 23 Cedidi et al (1997) Hand & Wrist 1 Wrist Skoll et al (1999) 7 Elbow 4 Other site 1 Hand & Wrist 11 Wang et al (2000) Elbow 2 Other sites 3 Wrist Farnell et al (2001) 1

Chemotherapy

± surgery Surgery Surgery Surgery Surgery

Surgery Surgery Surgery Surgery Surgery Surgery Surgery Surgery

Surgery

Surgery includes: open biopsy, synovectomy & debridement, drainage of cysts or abscesses, excision of sinuses, release of carpal tunnel, carpectomy or arthrodesis

Fig. 34.3. Tuberculosis osteomyelitis and arthritis of the wrist. Plain radiograph demonstrates evidence of marginal osseous erosions with soft tissue swelling (white arrows). Focal osteolytic lesion in the distal radius due to tuberculous osteomyelitis (black arrow heads). There is also periarticular osteoporosis

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The clinical features of elbow joint tuberculosis are similarly insidious and monoarticular, and symptoms may last for months or years before presentation. As the disease progresses loss of motion and functional disability may occur. Acute onset of symptoms with local features of pyogenic arthritis and constitutional symptoms may be the presenting features. Patients with elbow joint tuberculosis are more likely to have enlarged supratrochlear lymph nodes, which may caseate, and form an abscess or draining sinus (Patel 2001). The soft tissue swelling and edema around the elbow can easily be felt at the back of the elbow on both sides of the olecranon and triceps tendon. The shoulder joint lesion usually starts at the glenoid {Fig. 35.35) or at the humeral head. Granulation tissue formation, fibrosis, and osseous destruction lead to pain, stiffness, and limitation of the range of motion. The onset of the disease is similarly insidious with nonspecific symptoms that may last for months or years before presentation. Symptoms and signs may be similar to other rheumatic diseases. As the disease advances, muscle spasm and wasting, particularly of the deltoid and supraspinatus, may occur. The imaging features of tuberculosis of upper limb joints are nonspecific. These features have been classified by many authors into four stages describing the changes from early disease to late and to the advanced, destructive inflammatory process. Features may range from normal appearances, soft tissue swelling, osteoporosis, bone erosions, focal cysts, joint space reduction, to advanced joint destruction. These classifications are helpful as a guideline in predicting the response to chemotherapy and physiotherapy alone or the possible need for surgical intervention as well (Martini 1988). Stage I: No bony lesions; localized osteoporosis Stage II: One or more erosions (or cavities) in the bone; discrete diminution of the joint space. Stage III: Involvement and destruction of the whole joint without gross anatomic distortion. Stage IV: Gross anatomic distortion.

ultrasonography, CT, and MRI. They show soft tissue swelling with joint effusion, olecranon tip changes, cubital fossa cystic mass, and evidence of early lower humerus osseous involvement. In the shoulder joint, plain radiography may look normal and axial CT will depict the soft tissue swelling and erosion particularly in the subglenoid bone (Fig. 35.35).

34.3.1 Treatment of Upper Limb Joint Tuberculosis

Chemotherapy alone for 12-18 months, supplemented with joint rest and physiotherapy, are sufficient to cure early disease in most patients without the need of additional surgical intervention. (Rossmann and Mac Gregor 1995; Houston et al.1994; Bass et a11994) A volar wrist splint and regular occupational therapy and physiotherapy are important supplementary therapies. The range of motion of the wrist will improve with physiotherapy in early stages of the disease. Surgical synovectomy, debridement, drainage of abscesses, excision of sinuses, release of carpal tunnel syndrome, carpectomy, or" even arthrodesis for advanced disease may be required (AI-Qattan et al. 1994; Skoll and Hudson 1999; Cedidi et al. 1998). The prognosis of wrist joint tuberculosis is usually good. However, residual motion loss and functional disabilities, as well as relapse of sinuses, may occur. Treatment of elbow joint tuberculosis follows the same principle. Immobilization of the elbow in a plaster of Paris back-slab with elbow at 90 degrees for as long as 4 weeks, followed by active mobilization and regular physiotherapy for up to 6 months. Surgery to the elbow joint may be required for open drainage of any abscess, synovectomy, and debridement (Skoll and Hudson 1999; Chen et al.1997). Complications of surgery were reported by many authors. Chen and colleagues (1997) reported their experiences of 23 patients with elbow joint tuberculosis treated with chemotherapy and surgery, Fifteen had uneventful healing, four had injury and palsy of the posterior interosseous nerve, three had persistent Plain radiography is helpful in most patients but sinuses after excision, and two had developed sinuses CT and MRI will depict the extent of lesions much after synovectomy and arthrodesis. The range of better than plain radiography (see "Imaging of Bone movement was better in early stages of the disease and Joint Tuberculosis"). Plain radiography of the (stage I and II) than in later stages. The management wrist and hand (Fig. 34.3 plain radiograph of the outcome of elbow joint tuberculosis tends to be less wrist with tuberculosis) clearly depicts soft tissue predictable and generally poorer than that of wrist swelling, osteoporosis, bone erosions, and cysts. joint tuberculosis (Martini et al. 1980). Various imaging modalities of the elbow joints can Tuberculosis of the shoulder joint usually responds be seen in Figs. 35.33 and 35.34: plain radiographs, favorably to chemotherapy when it is initiated in the

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early stages of the disease. The shoulder should be immobilized in position-of-function in plaster of spica or removable polythene brace for 3 months. The optimum position is 80 degrees abduction, 30 degrees forward flexion, and 30 degrees of internal rotation. Fibrous ankylosis usually takes place but daily activity can be performed using the scapulothoracic movement for compensation. Persistent joint pain may be helped by excision arthroplasty with debridement of the affected synovium and bony parts. However, surgical arthrodesis of the gleno-humeral joint may be necessary if other measures fail to control the persisting pain.

34.3.2 Sternoclavicular Joint Tuberculosis Tuberculosis of the sternoclavicular joint is rare and frequently misdiagnosed for pyogenic infection, other rheumatic diseases,metastasis,or brucellosis (Madkour 2001). The infection usually starts at the medial end of the clavicle (Fig. 35.30 and Fig. 36.7a-l). The disease is usually unilateral but may rarely be bilateral (Dhillon et al. 2001; Sipsas et al. 2001). The onset of symptoms is usually insidious with pain and swelling of the joint for 6 to 32 months. Mild to moderate restriction of the motion of the shoulder may occur because of pain. Constitutional symptoms may be present at the time of presentation in approximately 50% of patients (Dhillon et al. 2001). Painless swelling of the joint or discharging sinus may be the presenting feature. Plain radiography may not be helpful in depicting changes. Computed tomography or MRI with contrast is ideal for showing soft tissue swelling and erosion of the clavicular head. An incidental retroclavicular lymph node, paratracheal lymph adenopathy, subcutaneous presternal abscess, destruction of D3 vertebral body with paravertebral soft tissue component may also be depicted, as we noted in one of our patients (Fig. 35.29a, b, and Fig. 35.30). Chemotherapy alone without surgery is sufficient for the treatment of sternoclavicular joint tuberculosis. However, Dhillon and colleagues in 2001 reported nine patients with tuberculosis of the sternoclavicular joint and two required surgical debridement after 2-3 months of chemotherapy without response. The symphysis pubis is a rare site of tuberculous arthritis and may be accompanied by tuberculosis of the sacroiliac joint as noted in one of the two patients who presented to us with symphysis pubis tuberculosis (Fig.35.1 and Fig. 35.27). The first patient was a 50-year-old woman who presented to us with a I-year history of progressive low back and pelvic pain; she had

no constitutional symptoms. She noticed progressive difficulty walking due to the pain and was using nonsteroidal anti-inflammatory drugs to relieve that pain. Frontal radiography of the pelvis depicted widening, erosion, and perarticular sclerosis of the right sacroiliac joint. The symphysis pubis joint was widened with marginal erosions and perarticular sclerosis. ACT-guided biopsy sample was taken. Granulomatous lesions were seen on histopathological examination and the patient was treated with chemotherapy. She had no evidence of other bony focal disease as noted by isotope scintigraphy. The second patient was a 37-year-old man who presented with a 7-month history of suprapubic pain with swelling, fever, weight loss, and difficulty in walking because of the pain. Axial CT with contrast showed bilateral pubic bone erosions with subcutaneous abscess formation. Close needle CT-guided drainage, aspiration, and collection of biopsy sample were performed on the abscess and the bone. Granuloma formations were seen on histopathological examination and cultures were negative. The patient was given chemotherapy and responded well to treatment (Fig. 35.27). Patients with tuberculosis of the symphysis pubis may present with hypogastric mass at the onset of the disease. Manzaneque et al. (1992) reported a 79-year-old woman with primary Sjogren's syndrome and immune thrombocytopenia who was treated with systemic steroid for 7 months. She represented with a 2 week history ofhypogastric swelling. Computed tomography showed cystic mass attached to the pelvic wall with destruction of the right and left pubis. CT-guided aspiration of the cyst yielded tubercle bacilli. In another report, Balsarkar and Joshi (2001) described a 28-year-old man who presented with a 6-week history of swelling in the hypogastric area. Radiography showed bony erosion of the symphysis pubis. Aspiration of the mass yielded the bacilli. Chemotherapy alone for 14-18 months or with drainage of abscess if present is sufficient treatment of tuberculosis of the symphysis pubis.

34.3.3 Poncet's Disease Named after Antonin Poncet, a Lyons surgeon born in 1849, who described an inflammatory condition of the joints or periarticular structures resulting from the presence of a tuberculosis focus elsewhere in the body and named it tuberculous rheumatism. The disease was described earlier by Charcot in 1864 and by Lanereaux in 1871. It is a form of reactive arthritis, which may be either polyarticular, oligoarticular, or monoarticular in distribution. The disease is pre-

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dominantly nonmigratory and morning stiffness is usually absent. The pathogenesis of this disease is still not clearly understood, as localization of tuberculous infection of these joints is not found. Allergy or hypersensitivity to tubercle protein was the favorite hypothesis adopted by many authors (Wilkinson and Roy 1984). Chaudhuri et al. (1995) suggested that Poncet's disease and erythema nodosum could be a different expression of the immunopathogenic response to the bacilli. The disease may be either primary, as the first manifestation of tuberculosis, or secondary if it occurs during the course of active disease (Chaudhuri et al. 1995). Patients may present with arthralgia, and acute, subacute, or chronic arthritis. Constitutional symptoms, erythema nodosum, conjunctivitis, lymphadenopathy, and active pulmonary tuberculosis may be associated findings (Chaudhuri et al. 1995). The disease responds well to chemotherapy alone, with complete remission with no residual joint deformities.

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in 4, radius in 3, and ulna in 2 patients. The author described four basic imaging patterns of long bone lesions as follows: 26 cystic, 10 infiltrative, 8 focal erosions, and 6 spina ventosa (which means tubular expansion of the shaft of short tubular bones of the hands and feet). Peritoneal reaction was seen in 4 and sequestrum formation in 4. Four lesions crossed the growth plate and one had a pathological fracture. Soft tissue swelling was noted in all patients. All patients were cured of their active tuberculosis osteomyelitis. The author has also reported the sequelae of the tuberculous osteomyelitis after cure as follows: four patients had short legs, one a short arm, and one a short thumb. A vascular necrosis occurred in two femoral heads and one navicular bone. Coxa vera was noted in two hips. In another large series of extraspinal tuberculous osteomyelitis, Bahulkar and colleagues (2002) reported 74 patients from all age groups that were seen over a period of 25 years. The long tubular bones were affected in 39 patients, short tubular bones in 24, and flat bones in 11 patients. The three most common sites reported in this series were; the humerus in 10, 34.3.4 tarsal bones in 10, and pelvic bones in 5. Extraspinal Tuberculous Osteomyelitis These authors confirmed the diagnosis by histopathology and/or microbiology of biopsy specimens. Extraspinal tuberculous osteomyelitis is rare and All patients responded well to a full course of checomprises approximately of 2% to 3% of all cases of motherapy. osteoarticular tuberculosis. Localization of tuberculous infection in the bone without joint involvement can occur but is rare, and it can affect any bone. Long 34.3.5 or short tubular bones, flat bones such as the clavicle Tuberculous Osteomyelitis of the Chest Wall and pelvis, small round bones such as the patella, talus, and navicular can be affected with tuberculosis. Tuberculous osteomyelitis of the ribs, sternum and Tubular long bones such as the femur, tibia, humerus, lateral end of the clavicle are rarely reported. Tuberradius, and ulna can be affected in the metaphysis, culous osteomyelitis of the sternum may occur in the diaphysis, or epiphysis. (Figs. 35.2, 3, 4,10,32) absence of an underlying pleural, lung, or mediastiThe presenting clinical features include pain, swell- nal tuberculosis. (Fig. 34.4 and Fig. 36.7a-l). ing of the bone with warmth and tenderness, swelling One of our patients, a 36-year-old woman, preof the surrounding soft tissue with abscess and sinus sented with painless swelling in the anterior chest formation. The initial diagnosis of such patients is wall over the sternum. Her symptoms had started often difficult. It is commonly mistaken for all types 3 months before presentation. As the swelling graduof bone pathology. Rasool (2001) reviewed 42 children ally increased in size, the patient noticed fever, chills, with extraspinal tuberculous osteomyelitis seen over loss of appetite, weight loss, but she did not have any a 16-year period and found 50 lesions. In five patients respiratory symptoms. The patient was under weight, osteomyelitis was multifocal. The metaphysis of a long chronically unwell, with swelling over the manubone was affected in 25 patients (60%), the diaphysis brium sterni. It was not acutely inflamed and not in 3 (7%), the epiphysis in 4 (10%). Short tubular bones tender, but fixed with fluctuation. Chest radiography of hands and feet were affected in 8 (19%). Flat bones was reported as normal. Right lateral radiography were affected in 7 (17%) and small round bones in 3 of the manubrium showed soft tissue swelling and (7%). (Khanna et al. 1980; Sinnott et al. 1990; Franco bone erosion (See Fig. 35.28a, b. The left lateral view 2001; Garcea et al. 1994). showed larger erosion with a pathological fracture. Tubular long bones were affected in the following In another patient of ours, the sternum was affected descending order: femur in 17, tibia in 6, humerus as part of a multifocal tuberculosis that involved the

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Fig. 34.4. A sinus scar formation secondary to tuberculous osteomyelitis of the ribs on the left chest wall in a 40-yearold patient

chest wall, mediastinal lymph nodes, and vertebral body erosion with paravertebral and spinal canal soft tissue swelling. There was a small subcutaneous presternal cold abscess (Fig. 35.29a, b). In both patients the diagnosis was confirmed by tissue biopsy and abscess drainage showing granulomas and positive culture of the bacilli. Sarlak et al. (2001) described a 43-year-old Turkish man with discharging sinuses over the sternum for 18 months. The patient sought medical advice during this period with no diagnosis but only surgical debridements. Chest radiography and CT of the thorax showed destruction of the anterior border of the sternum, while other thoracic organs were normal. The diagnosis was eventually confirmed with tissue biopsies showing granulomatous lesions. Sternal tuberculosis was reported after coronary artery bypass graft surgery in a 58-year-old man from Greece. Although the pulmonary granulomatous nodule was excised during the cardiac operation, the patient refused further investigation of it. One year later, he presented with weakness, fatigue, weight loss, and pus discharge from the sternum which was sterile. The patient presented 10 months later with heart failure, and a CT of the chest showed sternal osteomyelitis and right upper lobe infiltrates. Sputum and pus cultures were both positive for acid-fast bacilli. Tuberculous osteomyelitis of the ribs, with discharging sinuses and involvement of underlying lungs and pleura is rare. We noted that the retromammary region or areas close to it seems to be the

M. M. Madkour et al.

site commonly reported by other authors as well (see Fig. 34.3). Huang et al. (2001) reported a 4-year-old girl with fever, cough, and chills treated with antibiotics as bronchopneumonia. Chest radiography and CT showed a soft tissue lesion in the third rib, which was not detected on physical examination. Excisional biopsy of the lesion was diagnosed as enchondroma and lymphadenitis, and tuberculosis was not diagnosed. One year later, a painless nonerythematous mass near the right nipple area over the previous third rib location was the presenting clinical feature detected by the family. Cystic lesion was found this time on physical examination. Incisional biopsy showed granulomatous lesions and urine culture yielded acid-fast bacilli. In New York, Adler and colleagues (l993) reported tuberculous osteomyelitis of the chest wall in four patients, of the rib in two, sternum in one, and costal cartilage in one. Underlying pleural or pulmonary parenchymal tuberculosis was noted in two patients. Plain radiography looked normal despite bone destruction and a diagnosis was only made by CT scan. In a large series on eight women with tuberculous osteomyelitis of the rib, Supe and colleagues (2002) reported the role of CT scan in the diagnosis. The age of these women ranged from 12 to 44 years, and they presented with a palpable nontender mass in the posterior aspect of the breast which had appeared 1 month to 2 years before presentation. None of these women had constitutional symptoms or had tuberculosis. The authors reported that CT scan depicted an abscess in seven patients, which was aspirated. The eighth patient had an ulcer, which was biopsied. A well-marginated abscess with rim enhancement was the CT scan finding in all eight patients. The lateral end of the clavicle is rarely reported as a site for tuberculous osteomyelitis. Basanagoudar and colleagues (2001) from India reported a 30-yearold female with pain in the right shoulder after a minor trauma. Shoulder radiography was misinterpreted as fracture of the lateral end of the clavicle. The same lesion was reported as a giant cell tumor during a repeat of radiography. However, a discharging sinus developed later and the culture yielded Staphylococcus aureus and the diagnosis was made as chronic osteomyelitis with discharging sinus superimposing on preexisting giant cell tumor. Incisional biopsy showed granulomatous lesions. The patient responded to 15 months of chemotherapy. The sinus healed and the full range of shoulder movement was achieved 4 months after starting chemotherapy. These authors reviewed the literature on tuberculous

Extraspinal Musculoskeletal Tuberculosis

osteomyelitis of the lateral end of the clavicle and found 16 cases reported between 1932 and 1996. The mandible is an extremely rare site of tuberculous osteomyelitis. Bhatt and Jayarkishnan (2001) reported a 4-year-old girl who was referred to a dental clinic with a I-month history of right cheek swelling with submandibular lymph node enlargement after dental extraction. Radiography revealed poorly defined radiolucency at the optical region of the mandible. Biopsy showed granuloma formation. Chest radiography did later revealed left lung tuberculosis with mediastinal lymphadenopathy. The father of this child had had spinal tuberculosis 1 year earlier.

34.3.6 Tuberculous Tenosynovitis, Bursitis, and Myositis Tuberculous tenosynovitis and bursitis are rare conditions and have a great propensity to mimic other diseases. Because of its rarity, failure in considering tuberculosis as a possible cause is common, leading to misdiagnosis and delay in giving the appropriate treatment. Clinicians have to have a high degree of vigilance in order to make the diagnosis. Symposium tendons, bursae, and muscle involvement secondary to bone and joint tuberculosis are well recognized but rarely occur without bone and joint involvement (Hoffman et al. 1996; Asaka et al. 1996; Abdelwahab and Kenan 2000; Esenyel et al. 2000; Toda et al. 1998; Soler et al 2000; Hassan et al. 1993; Del Giglio 1997; Bonomo et al. 1995).

34.3.7 Epidemiology Tuberculous tenosynovitis and bursitis occur in approximately 1% of all cases of osteoarticular tuberculosis (Jaovisidha et al. 1996). Jaovisidha and colleagues (l996) described the imaging findings of 21 patients with proven tuberculous tenosynovitis and bursitis. Tenosynovitis was found in 12 patients, and most commonly affected the tendon sheath of the hands and wrists. The mean age was 46.3 years with male predominance. Tuberculous bursitis was found in 9 patients, most frequently around the hip, particularly in the trochanteric bursa. The mean age was 51.5 years with male predominance. Other authors have reported rare cases of tuberculous bursitis (Ihara et al. 1998). In our own series, 80 patients had extraspinal musculoskeletal tuberculosis; two patients had teno-

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synovitis affecting the Achilles tendon and elbow (see Figs.35.2a-d and 35.33). Tuberculous bursitis of the greater trochanter was found in one patient (see Figs. 35.5, 35.8, and 35.9). Discharging sinuses, and cold abscesses in the gluteal region and groin were seen in nine patients (see Figs. 35.6,35.17,35.19, 35.22,35.35, and 35.39).

34.3.8 Pathogenesis Tuberculous tenosynovitis and bursitis are most commonly caused by M. tuberculosis. Rarely, it may be caused by nontuberculous mycobacterial organisms. The mode of transmission of the bacilli may be through a hematogenous route or by direct spread from adjacent bone and joint tuberculosis (Jaovisidha et al. 1996; Bocanegra 1994; Donovan and Sosman 1940; Briede 1945; Chafetzet et al. 1982; Hoffman et al. 1996). After the entry of bacilli, serious fluid exudate or thickened granulation tissue proliferation with thickening of the sheath may take place depending on the virulence of the organisms and host resistance. As the disease progresses, caseation and fibrosis of the sheath may occur, and the tendon itself may be affected leading to spontaneous rupture (Pimm and Waugh 1957). Granulation tissue, caseation, and abscess formation may spread along the tendon and break through the skin, discharging a straw-colored fluid. Secondary bacterial infection may superimpose itself (Fig. 35.40). In the bursae, a similar inflammatory process may take place leading to an increase in size due to inflammatory fluid, with subsequent formation of rice bodies and calcifications (Kim et al. 2002).

34.3.9 Clinical Features and Diagnosis Tuberculous tenosynovitis has no distinct clinical feature. Its onset is usually gradual and insidious with slowly progressive swelling at the involved site. The duration of symptoms before presentation may be up to several years (Jaovisidha et al. 1996; Goldberg and Avidor 1985; Abdelwahab et al. 1993; Robins 1967). Symptoms of mild pain and slight limitation of motion become apparent as the disease progresses. Symptoms of carpal tunnel syndrome due to tuberculous tenosynovitis of the flexor tendons of the wrist joints has been reported (Lee 1985; Suso et al. 1988; AI-Qattan et al. 1994; Skoll and Hudson 1999). Clini-

600

cal presentation of de Quervain's-like disease due to tuberculous tenosynovitis of the abductor pollicis longus and extensor pollicis brevis and the first dorsal retinacular compartment has been reported. Chen and Eng (1994b) described a 35-year-old man with pain, tenderness, and swelling over the radial styloid for 2 months, for whom Finkelstein's test was positive. He was diagnosed as having de Quervain's disease and treated with intraretinacular injection of steroid. Symptoms improved temporarily but the swelling progressed. Tenosynovectomy was performed and histology revealed granuloma while microbiological examination was negative. Antituberculous treatment was given for 12 months and the patient improved with no recurrence at follow-up. Asaka and colleagues (1996) reported a 74-year-old woman who presented with a mass lesion on the flexor side of the right forearm near the elbow joint. She was otherwise asymptomatic but had a strong family history of tuberculosis and a positive tuberculin test. Her chest CT showed right upper lobe infiltrate, and she was started on antituberculous chemotherapy. The mass did not change in size during therapy and increased in size after discontinuation of treatment. Ultrasonography, CT, and MRI of the mass showed encapsulated cystic lesion. Aspiration biopsy was nonspecific and the diagnosis was confirmed as tuberculous by doing a PCR on the abscess material. Tuberculous bursitis may present with persistent and slowly progressive dull pain, commonly affecting bursae that are subject to trauma. The most common sites affected are bursae around the hip and subdeltoid, but it may affect other bursae (Jaovisidha et al. 1996). Tuberculous bursitis over the greater trochanter of the femur may present with insidious persistent dull pain over the hip and a limp during walking. The time interval between the onset of symptoms and presentation may be months or years. A soft tissue swelling with fluctuation may be found. Constitutional symptoms may be lacking. Imaging modalities may be helpful in determining the extent of the lesion and are useful for guided tissue biopsy purposes. In a report by Ihara and colleagues (1998),it was found that for a 27-year-old woman with tuberculous bursitis of the greater trochanter, imaging modalities were helpful in revealing a multicystic soft tissue mass. An open biopsy was performed to exclude malignancy, and fluid and tissue biopsies confirmed the diagnosis by positive culture of the bacilli. Tuberculous myositis is extremely rare and its diagnosis is confirmed by raised serum creatine kinase (CK), EMG, and histopathological features of tuberculous myositis (Derkash and Makley 1979;

M. M. Madkour et al.

Pouchot et al.1990; Abdelwahab and Kenan 2000). Tuberculous myositis may be treated successfully by chemotherapy alone, but may also be complimented with surgical procedures such as surgical decompression of carpal tunnel syndrome drainage, tenosynovectomy, debridement or excision of bursae (Cramer et al. 1991; AI-Qattan et al. 1994; Bonomo et al. 1995; Del Giglio 1997; Hassan et al. 1993; Soler et al. 2000; Toda et al.1998).

34.4 Multifocal Osteoarticular Tuberculosis Multifocal or disseminated bone and joint tuberculosis is a well-recognized pathological entity although rarely reported. It is almost always misdiagnosed initially even in the endemic areas, and the correct diagnosis is often delayed (Aggarwal et aI. 2001; Morris et aI. 2002; Alexander and Mansuy 1950; Arslan 1999; Ip et aI.1993; Lachenauer et aI.1991; Murray 1954; Ormerod et aI. 1989; Tuli and Sinha 1969; Yip et aI. 1996; Eid et aI. 1994; Wessels et aI. 1998). In the Indian population, the incidence of multifocal osteoarticular involvement is 7% to 10% of all cases of osteoarticular tuberculosis (Kumar and Saxena 1988). In developed countries such as those in North America, the incidence is not known (Eid et aI. 1994; Tsui et aI. 1993; Aggarwal et aI. 2001; Morris et aI. 2002). A hematogenous mode of transmission of the bacilli to the bone is thought to be the most common. Tuberculous lymphadenitis with caseation and abscess formation frequently found in patients with multifocal osteoarticular disease favors the possibility of a lymph-born mode of transmission of the bacilli (Morris et al. 2002). Multifocallocalization of infection in the bone depends on host immunity. It is suggested that the lesions occur at different times and multifocallesions are seen at different stages of development (Morris et al. 2002; Aggarwal et al. 2001; Kumar and Saxena 1988). A primary source of infection is not always found in these patients. In their series of 48 patients with multifocal osteoarticular tuberculosis, Kumar and colleagues (1988) found that plain chest radiography revealed a primary focus in 19% of cases, abdominal disease was present in 8%, and for the remaining 73% no primary focus could be found. It can affect all age groups particularly children and young adults in endemic developing countries and the elderly in developed countries (Table 34.2). The disease affects both sexes equally (Table 34.2).

Extraspinal Musculoskeletal Tuberculosis

601

Table 34.2. Multifocal musculoskeletal tuberculosis (analysis of 8 reports) Author (year) Country of study

No. of

Age in

Sex

cases (%) years Kumar and Saxena (1988) Kumar and Saxena (1988) Kumar and Saxena (1988) Kumar and Saxena (1988) Case Illustration

India India India India

48 cases 13 (27%) 14 (29%) 21 (44%)

4-42

Patient's country Sites of tuberculosis of origin

Equal India numbers

4

Female

Case Illustration

31

Male

Tsui et al. (1993) Hong Kong

13

Female China

32

Female Philippines

Muradali et al. (1993) Canada

38

Female Somalia

Muradali et al. (1993) Canada Muradali et al. (1993) Canada

16 26

Female Philippines Male Ghana

Eid et al. (1994) USA Tsau et al. (1995) Taiwan

34 57

Male Male

Wessels et al. (1998) South Africa

Male S.Africa 6 months 4-60 12 Males India 6 Females

Muradali et al. (1993) Canada

Aggarwal et al. (2001) India Aggarwal et al. (2001) India Aggarwal et al. (2001) India Aggarwal et al. (2001) India Aggarwal et al. (2001) India Morris et al. (2002) India

4

18

9

Yemen Taiwan

Female India

The metaphysis of long bones are often the initial site as an endarteritis particularly in children (Rasool et al. 1994). The multiplicity of various sites as reported by several authors is noted in Table 34.2. The clinical and imaging manifestations are nonspecific. Pain is the most frequent presenting feature and may precede constitutional symptoms. A high level of vigilance by the attending clinician is essential in sorting out the long list of differential diagnosis. Chemotherapy and surgical intervention can cure this pathological entity of tuberculosis.

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Multiple bone involvement Multiple joint involvement Multiple bone and joint involvement Long bones of upper and lower limbs, short tubular bones of both hands Phalanx of (L) index finger, phalanx of (R) little finger, (R) olecranon, (L) medial malleolus (L) scapula, (R) 3rd rib, (L) 5th rib, skull, (R) middle ear, C7, TI, TI2, U vertebrae (R) rib, (L) 5th rib, sternum, (L) tibia, bilateral sacroiliac joints, (L) sternoclavicular joint, T2, T6, Til, TI2, Ll, L2 vertebral bodies, bilateral pleural effusion (L) 5th rib, 3rd thoracic vertebra, bilateral mediastinallymphadenopathy Sternomanubrial joint, Ll vertebra (L) sacroiliac joint, (L) 1st rib, (L) 3rd rib, (L) medial condyle, (L) kidney and ureter Lateral end of (L) clavicle, (R) iliac crest Pubic bone, (L) sacroiliac joint, (L) medial condyle, (L) kidney and ureter Skull, humeri, femora, tibiae, radii, ulnae, metatarsals, metacarpals, phalanges, liver, spleen lungs 5 spine (3 patients) 2 long bones (2 patients) 26 bones of hands and feet (15 patients) 10 joints (9 patients) 1 axial nonvertebral (1 patient) Skull, sternum, (R) first metatarsal, pulmonary

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603 Lee AS, Campbell JAB et al (1995) Tuberculosis of the knee in children. J Bone Joint Surg 77B:313-3l8 Lee KE (1985) Tuberculosis presenting as carpal tunnel syndrome. J Hand Surg (Am) 10A:242-245 Leibert E, Schluger NW et al (1996) Spinal tuberculosis in patients with human immunodeficiency virus infection: clinical presentation, therapy and outcome. Tuber lung Dis 77:329-334 Madkour MM (2001). Osteoarticular brucellosis. In: Madkour MM (ed). Madkour's Brucellosis, 2nd edn. Springer, Berlin Heidelberg New York Malhan K, Kumar A et al (2001) Use of polymerase chain reaction in diagnosis of occult tuberculosis of the fibula. Acta Orthop Belg 67:510-512 . Manzaneque l, Marin I et al (1992) Osteoarticular tuberculosis of the symphysis pubis presenting as a hypogastric cystic mass in a woman with primary Sjogren's syndrome. Br J Rheum 31:495-496 Martini M (1988) Tuberculosis of the bone and joints. Springer, Berlin Heidelberg New York Martini M, Adjrad A (1988) Tuberculosis of ankle and foot joints. In: Martini M (ed) Tuberculosis of the bones and joints. Springer, Berlin Heidelberg New York, pp 138-148 Martini M, Gottesman H et al (1980) Results of conservative treatment of tuberculosis of the elbow. Int Orthop 4:83-86 Martini M, Adjrad A et al (1986a) Tuberculous osteomyelitis: a review of 125 cases. Int Orthop 10:201-207 Martini M, Benkeddache Y et al (1986b) Tuberculosis of the upper limb joints. Int Orthop 10:17-23 Martini M, Bondjeman A et al (1986c) Tuberculous osteomyelitis: a review of 125 cases. Int Orthop 10:202-208 Morris BS, Varma R et al (2002) Multifocal musculoskeletal tuberculosis in children: appearances on computed tomography. Skeletal Radio131:1-8 Muradali D, Gold WL et al (1993) Multifocal osteoarticular tuberculosis: report of four cases and review of management. Clin Infect Dis 17:204-209 Murray RO (1954) Observation on cystic tuberculosis of bone. Proc R Soc Med 47:133 Negusse W (1993). Bone and joint tuberculosis in childhood in a children's hospital, Addis Abeba. Ethip Med J, 31:51-61 Newton P, Sharp J et al (1982) Bone and joint tuberculosis in greater Manchester 1969-79. Ann Rheum Dis 41:1-6 Nicklas BJ, latta DK et al (1996) Mycobacterial skeletal infection of the foot. JAPMA 86:280-287 Ong Y, Cheong PY et al (1998) Delayed diagnosis of tuberculosis presenting as small joint arthritis - a case report. Singapore Med J 39: 177-179 Ormerod lP, Grundy M et al (1989) Multiple tuberculous bone lesions simulating metastatic disease. Tubercle 70:305-307 Parkinson RW Hodgson SP et al (1990) Tuberculosis of the elbow: a report of three cases. J Bone Joint Surg (Br) 72:523-524 Patel DA (2001) The supratrochlear lymph nodes: their diagnostic significance in a swollen elbow joint. Ann R Coll Surg Engl 83:425-426 Pouchot J, Vinceneux P et al (1988) Tuberculosis of the sacroiliac joint: clinical features, outcome, and evaluation of closed needle biopsy in 11 consecutive cases. Am J Med 84:622-628 Pouchot J, Vinceneux P et al (1990) Tuberculous polymyositis in HIV infection. Am J Med 89:250-251 Ragni MV, Crosset lS et al (1995) Postoperative infection following orthopaedic surgery in human immunodeficiency virus-infected hemophiliacs with CD4 counts < or = 2001 mm 3• J Arthroplasty 10:716-721

604 Rasool MN (2001) Osseous manifestations of tuberculosis in children. J Pediatr Orthop 21:749-755 Rasool MN, Govender S et al (1994) Cystic tuberculosis of bone in children. J Bone Joint Surg 76B:113-117 Resnick D (1988) Diagnosis of bone and joint disorders, vol 4, 2nd edn. Saunders, Philadelphia, pp 2661-2686 Rieder HL, Snider DE Jr, Cauthen GM (1990) Extrapulmonary tuberculosis in the United States. Am Rev Respir Dis 141: 347-351 Rossmann MD, MacGregor RR (1995) Tuberculosis: clinical management and new challenges. McGraw-Hill, New York, pp 182-183 Ruggieri M, Pavone V et al (1997) Tuberculosis of the ankle in childhood: clinical, roentgenographic and computed tomography findings. Clin Paediatr 36:529-534 Sant M, Bajaj H (1991) Role of histopathology in the diagnosis of tuberculous synovitis. J Indian Med Assoc 90:263-264 Sarlak AY, Giindes H et al (2001) Primary sternal tuberculosis: a rare unhealed case treated by resection and local rotational flap. Thorac Cardiovasc Surg 49:58-59 Shah AA, Ahmed S et al (1992) Bone tuberculosis in Abbottabad. JPMA 42:180-181 Shanmugasundaram TK (1983) Tuberculosis of hip. In: Shanmugasundaram TK (ed) Bone and joint tuberculosis. Kothandaram, Madras, India, pp 59-72 Silva JF (1980) A review of patients with skeletal tuberculosis treated at the University Hospital, Kuala Lumpur. Int Orthop 4:79-81 Singh SB, Saraf SK et al (1992) Osteoarticular tuberculosis in children. Indian Paediatr 29:1133-1137 Sinnott JT, Cancio MR et al (1990) Tuberculous osteomyelitis masked by concomitant staphylococcal infection. Arch Intern Med 150:1865-1868 Sipsas NV, Panayiotakopoulos GD et al (2001) Sternal tuberculosis after coronary artery bypass graft surgery. Scand J Infect Dis 33:387-388 Skoll PJ, Hudson DA (1999) Tuberculosis of the upper extremity. Ann Plast Surg 43:374-378 Soholt ST (1951) Tuberculosis of the sacro-iliac joint. J Bone Joint Surg (Am) 33:119-130 Soler R, Rodriguez E et al (2000) Magnetic resonance imaging of pyomyositis in forty-three cases. Eur J RadioI35:59-64 Soler R,Rodriguez E et al (2001) MRI of musculoskeletal extraspinal tuberculosis. J Comput Assist Tomogr 25:177-183 Stecher DR, Gusis SE et al (1992) Tuberculous arthritis in the course of connective tissue disease: report of 4 cases. J RheumatoI19:1418-1420 Sueyoshi E, Uetani M et al (1996) Tuberculous tenosynovitis of the wrist: MR findings in three patients. Skeletal Radiol 25:569-572 Sub JS, Lee JD et al (1996) MR imaging of tuberculous arthritis: clinical and experimental studies. J Magn Res Imag 1:185-189 Supe AN, Prabhu RY et al (2002) Role of computed tomography in the diagnosis of rib and lung involvement in tuberculous retromammary abscesses. Skeletal RadioI31:96-98 Suso S, Peidro L et al (1988) Tuberculous synovitis with "rice bodies" presenting as carpal tunnel syndrome. J Hand Surg (Am) 13A:573-576 Tenth Report of the Medical Research Council Working Party

M. M. Madkour et al. on Tuberculosis of the Spine (1986) A controlled trial of six-month and nine-month regimens of chemotherapy in patients undergoing radical surgery for tuberculosis of the spine in Hong Kong. Tubercle 67:243-259 Toda K, Yasunaga Y et al (1998) MR image and CT scan of a tuberculous abscess in the gluteus maximus muscle. Comput Med Imag Graph 22:425-427 Tsay MH, Chen MC et al (1995) Atypical skeletal tuberculosis mimicking tumor metastases: report of a case. J Formos Med Assoc 94:428-431 Tuli SM (1997) Tuberculosis of the Skeletal System (Bones, Joints, Spine and Bursal Sheaths), 2nd edn. Jaypee Brothers Medical, New Delhi Tuli SM, Sinha GP (1969) Skeletal tuberculosis: 'unusual lesion'. Ind J Orthop 3:5-18 Valdazo JP, Ruiz FP et al (1990) Tuberculous arthritis. Report of a case with multiple joint involvement and periarticular tuberculous abscesses. J RheumatoI17:399-40 1 Veerken H, Bermejo A (1992) The impact of the HIV epidemic on tuberculosis control programmes in developing countries. Trop Doc 22:64-67 Versefeld GA, Solomon A (1982) Diagnostic approach to tuberculosis of bones and joints. J Bone Joint Surg Br 64:446-449 Visuthikosol V, Kruavit A et al (1996) Tuberculous infection of the hand and wrist. Ann Plast Surg 37:55-59 Vohra R, Kang HS (1995) Tuberculosis of the elbow: a report of ten cases. Acta Orthop Scand 66:57-58 Wang CT, Sun JS et al (2000) Mycobacterial infection of the upper extremities. J Formos Med Assoc 99:710-715 Watts HG, Lifeso RM (1996) Current concepts review: tuberculosis of bones and joints. J Bone Joint Surg (Am) 78: 288-298 Weir MR, Thorton GF (1985) Extrapulmonary tuberculosis: experience of a community hospital and review of the literature. Am J Med 79:467-478 Wessels G,Hesseling PB et al (1998) Skeletal tuberculosis: dactylitis and involvement of the skull. Pediatr RadioI28:234-236 Wilkinson AG, Roy S (1984) Two cases of Poncet's disease. Tubercle 65:301-303 Wilkinson MC (1969) Tuberculosis of the hip and knee treated by chemotherapy, synovectomy, and debridement: a followup study. J Bone Joint Surg 51A:1343-1359 . Williams CS, Riordan DC (1973) Mycobacterium marinum (atypical acid-fast bacillus) infections of the hand: a report of six cases. J Bone Joint Surg 55A:I042-1050 Wilson IN (1953) Tuberculosis of the elbow: a study of 31 cases. J Bone Joint Surg (Br) 35:551-560 Wobeser WL et al (1996) Evaluation of Roche Amplicor PCR assay for mycobacterium tuberculosis. J Clin MicrobioI34:134-139 Wolinsky E (1994) Conventional diagnostic methods for tuberculosis. Clin Infect Dis 19:396-401 Wright T, Sundaram M et al (1996) Tuberculous osteomyelitis and arthritis. Orthopedics 19:700-702 Yao DC, Sartoris DJ (1995) Musculoskeletal tuberculosis. Radiol Clin North Am 33:679-689 Yip KMH,Lin J et al (1996) Cystic tuberculosis of the bone mimicking osteogenic sarcoma. Tuberc Lung Dis 77:566-568 Yoon CT, Chung HW et al (2001) MR findings of tuberculous dactylitis. Eur J RadioI39:163-167

3S Imaging of Musculoskeletal Tuberculosis MOHAMMED ABD EL BAGI, MONA AL SHAHED, M. MONIR MADKOUR

CONTENTS 35.1 35.1.1 35.1.2 35.1.3 35.1.3.1 35.1.4 35.1.4.1 35.1.4.2 35.1.4.3 35.1.4.4 35.1.4.5 35.1.4.6 35.2 35.2.1 35.2.2 35.2.3 35.2.4 35.2.5 35.2.6 35.3 35.3.1 35.3.2 35.3.3 35.3.4 35.3.5 35.3.6 35.3.7 35.3.8 35.4 35.4.1 35.4.2 35.5

Introduction 605 Overview 605 Pathology 606 Clinical Presentation 608 Laboratory Tests 609 Classification of Musculoskeletal Tuberculosis 609 Tuberculosis Arthritis 609 Tuberculosis Osteomyelitis 609 Tuberculosis of Muscles 610 Tuberculous Tenosynovitis 610 Tuberculous Bursitis 610 Cystic Tuberculosis of Bone 610 Imaging 611 Plain Radiographs 611 Sinogram 612 Isotope Scanning 614 Ultrasound 614 Computed Tomography (CT) 614 Magnetic Resonance Imaging (MRI) 616 Radiologic Presentation 616 Tuberculosis of the Knee 616 Tuberculosis of the Hip 617 Tuberculosis of the Pelvis and Sacroiliac Joints 618 Chest Wall Tuberculosis 618 Tuberculosis of the Hands and Feet 620 Tuberculosis of the Elbow 621 Tuberculosis of the Shoulder 621 Tuberculosis of the Ankle 622 Interventions 622 Biopsies 622 Drainage 623 Summary 623 References 624

M. ABD EL BAGI, MB BCh, DMRD, FSRRCSI Senior Consultant, Department of Radiology, Riyadh Armed Forces Hospital, P.O. Box 7897, Riyadh 11159, Saudi Arabia M. M. MADKOUR, MD, DM, FRCP Consultant, Department of Medicine, Riyadh Armed Forces Hospital, P.O. Box 7897, C-119, Riyadh 11159, Saudi Arabia M. AI SHAHED, MBBS, FRCR Senior Consultant Radiologist, Department of Radiology, Riyadh Armed Forces Hospital, P.O. Box 7897, Riyadh 11159, Saudi Arabia

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

35.1

Introduction 35.1.1

Overview

Tuberculosis is one of the rare bone infections (RBI). This term refers to conditions where only a small percentage of cases have bone manifestations or where the infective organism is altogether rare (Abd El Bagi et al. 1999). Incidence of RBI can increase if predisposing factors prevail: for example, diabetes, immunocompromise, drug abuse, steroids therapy, immigration, undernourishment, and overcrowding. Osteoarticular tuberculosis is rare, occurring in 1-3% of all tuberculosis patients and is present in 30% of all extrapulmonary tuberculosis cases (Engin et al. 2000). Resurgence of tuberculosis is blamed on HIV infection and the development of multidrug resistance. Following the decline of tuberculosis in the second half of the last century in response to new efficient chemotherapeutic agents, osteoarticular tuberculosis was often overlooked, leading to a delay in diagnosis sometimes of many years (Yao and Sartoris 1995). Skeletal tuberculosis is almost invariably secondary. The original site is usually intrapulmonary or in the mesenteric glands. Occasionally the bone infection is by contiguity from a nearby joint or infected soft tissues. In some instances there is no apparent primary lesion. Skeletal involvement may follow the initial constitutional symptoms by 1-2 years. However, we have seen cases where the bone lesions preceded the chest disease. In one of our patients, miliary tuberculosis developed 6 months after the onset of knee infection. Concomitant pulmonary tuberculosis was reported in 12-50% of cases (Hugosson et al. 1996). This is more common in children. Bone lesions are usually solitary because sensitization of the patient to the tubercle bacilli occurs before the onset of skeletal lesions (Kumar and Saxena 1988). Multiple lesions can occur in 1-15% of cases (Watts and Lifeso 1996). Any bone in the body can be affected. The commonest bone involved is the spine in 50-70%

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of cases, particularly the thoracic vertebrae in 50%, but lumbar vertebrae involvement is not uncommon (Table 35.1). Actually the first lumbar vertebra was considered to be the most common site (Resnick and Niwayama 1988). Spinal tuberculosis is discussed in detail elsewhere. The articulation of the lower limbs is more commonly affected by tuberculosis than that of the upper limps. The commonest peripheral site of extraspinal tuberculosis is the knee (Abd EI Bagi et al., 2002). Previously the hip was thought to be the most commonest (Hugosson et al. 1996). These two large joints of the hip and knee together represent 10% of all cases of osteoarticular tuberculosis, while small joints of the hand, ankle, and foot are infected in 2-4% of cases (McGuiness 1999). Trauma has been associated with tuberculosis in 30-50% of cases (Rasool et al.1994). The pattern of osteoarticular tuberculosis has changed over the years (Resnick and Niwayama 1988). Initially the disease was usually encountered in children and young adults. Currently patients of all ages

Fig.35.1. Multifocal TB arthritis. Frontal radiograph of the pelvis on a 50-year-old female complaining of chronic pain in low back and pelvic bones with progressive discomfort on walking. There is widening, erosion, and periarticular sclerosis of the right sacroiliac joint (small arrows). Both sides-the iliac and sacral-of the joint are involved. There is asymmetry of the pubic symphysis associated with marginal erosions, widening of the joint space, and periarticular reactive sclerosis (long arrow)

are affected if there are predisposing causes. The disease is rare in the first year oflife. All forms of tubercu10sis are more common in the young where the disease is prevalent, and less common in the elderly where the disease is rare. Osteoarticular tuberculosis affects both sexes equally. Spinal disease is more common in males. Monoarticular disease is the rule (Resnick and Niwayama 1988), but we have seen cases with multiple joint involvement (Fig. 35.1) (Muradali 1993). In adults, tuberculosis usually originates in the epiphyses and spreads to the neighboring joint. Actual joint involvement is slower than in pyogenic infection or brucellosis, due to the lack of proteolytic enzymes (Fig. 35.2a-d) (Davidson and Horowitz 1970). Tuberculosis very rarely arises in the shaft of long bones. In children it starts in the metaphyses due to the increased vascularity in this region (Fig. 35.3) (Edeikin et al.I963). It may however cross the physes into the epiphyses (Fig. 35.4), which is an important sign differentiating it from pyogenic infection. Bone infection with acid-fast tuberculosis bacillus causes a destructive, caseating necrosis leading to cold abscess formation and sinus tracts. The radiologic signs of bone tuberculosis are variable. Tuberculosis can mimic pyogenic infections, traumatic lesions, collagen, or degenerative disease (Goldblatt and Cremin 1978).At times it could be confused with tumors (Abdel Wahab et al. 1991). Although bone tuberculosis may present in classical well-described radiologic changes, a significant number may present in a bizarre fashion taxing the diagnostic acumen of the radiologist (Goldblatt and Cremin 1978).

35.1.2 Pathology

Various body organs respond to the tuberculosis bacillus differently. The Mycobacterium usually reaches the bone marrow via hematogenous seeding. Bone

Table 35.1. The distribution of musculoskeletal tuberculosis Authors

Davidson and Horowitz (1970)

Goldblatt and Cremin (1978)

Watts and Lifeso (1996)

Hugosson et al. (1996)

Geographic location Spine Hip Knee Pelvis Femur and tibia Ankle and foot Others Multiple sites

USA 50% 15% 15%

Colored South Africans 59.9% 10.6% 8.2% 4.2% 5% 2.6% 9.5%

USA 50% 5% 5% 12% 10% 8% 8%

Middle East 71.5% 3.4% 11.3% 4.5% 2.2% 4.5% 2.6%

20% 8.2%

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c

a

b

~----~"'d

Fig. 35.2. a TB osteomyelitis of the right tibia in an adult. Right ankle radiographs of a 63-year-old diabetic male complaining of joint pain and swelling for 2 years. He received various medical treatments. There is a soft tissue swelling (long white arrows) and periarticular osteoporosis. Note the large erosion above the medial malleolus (open arrowhead) and the smaller erosion in the lateral malleolus and talus (small arrowheads). There is a faint periosteal reaction (small arrows). There is no sequestrum. The joint space has been spared any damage. b Lateral radiograph. The soft tissue swelling is surrounding the tendo calcaneus (long white arrows). Vascular calcification is present due to the diabetes. c Follow-up frontal radiograph after 6 months of treatment. The cortex is consolidated (arrow) and the periostitis has disappeared. Yet, there is a residual multilobular cystic area in the tibia and a smaller subarticular lesion in the talus. d Lateral radiograph showing resolution of the previous large soft tissue swelling, which was surrounding the tendo calcaneus (a). Vascular calcification is more apparent

infection could be initiated by trauma. Either overt or occult trauma can lead to local hemorrhage, vascular stasis, or cellular effusion, creating a suitable medium for bacterial growth. The initial process is an endarteritis. The tissue reaction to the tuberculosis bacillus forms a small follicle, the "tubercle:' Centrally these are multinucleated giant cells surrounded by clusters

of epithelial cells with elongated nuclei. Peripherally there are abundant lymphocytes and mononuclear cells whose presence is characteristic of tuberculosis. The bacillus produces "tuberculin:' which incites the process of caseating necrosis. This causes resorption of the trabecular lamellae. It should be noted that epithelial granulomas or granulomatous bone

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Fig. 35.3. TB osteomyelitis of the lower end of the right tibia in a child. Frontal radiograph of a child complaining of pain and swelling above the right ankle not responding to antibiotic treatment. There is a large metaphyseal lytic lesion with a periosteal reaction, subperiosteal bone deposition, and a soft swelling tissue. The periostitis is not florid and there are no sizable sequestra

Fig. 35.4. Metaphyseal TB focus eroding the physis into epiphyses. Frontal radiograph of the knee of a child who presented with knee pain and swelling. There is a small lytic lesion in the lateral aspect of the lower femoral metaphyses surrounded by minimal reactive sclerosis (black arrow heads). There is another well-defined lytic lesion at the lateral margin of the lower femoral epiphyses (long white arrow). The infection has crossed the physeal plate, a feature which indicates TB rather than pyogenic infection

lesions are not pathognomonic for tuberculosis. They represent a histologic nonspecific response to antigenic stimuli and can be seen in brucellosis, sarcoidosis, lymphoma, neoplasm, or autoimmune disorders (Resnick and Niwayama 1988). Such granulomatous reactions are not always proven as tuberculosis. The bacilli are scarce at the infected sites. Not uncommonly the diagnosis is made on clinical, laboratory, and radiologic correlation. Yet, biopsy and aspirations are mandatory. However, biopsies are not always positive (Davidson and Horowitz 1970). Some clinicians would repeat the biopsy to assess the response of a doubtful granuloma to treatment. Regression of a suspicious granuloma on treatment is considered evidence of tuberculosis. In countries where tuberculosis is highly prevalent and where medical facilities are limited, findings suggestive of the disease may not have a biopsy in order for the physician to make the diagnosis and institute treatment. There, biopsy is reserved for cases that do not respond to treatment (Watts and Lifeso 1996).

Agranuloma takes a few days to develop and become visible even to the naked eye as a white nodule in the bone marrow (Dutchie and Nelson 1996). This may slowly regress or heal by fibrosis and fatty replacement. Progression leads to caseating necrosis, which may form a cold abscess (Glassroth 1993). Periosteal hyperemia occurs at a very early stage in the disease. This stage is usually missed by the time imaging is performed. The process ultimately leads to periosteal thickening and bone deposition subperiosteally (Fig. 35.3).

35.1.3 Clinical Presentation There is no typical clinical presentation for musculoskeletal tuberculosis. The clinical signs and symptoms of osteoarticular tuberculosis could be: 1. Localized signs: pain, swelling, tenderness, limitation of movements, joint stiffness, muscle wasting, and sinus formation.

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2. Systemic symptoms of tuberculosis infection: fever, chills, night sweats, weight loss, anorexia, or malaise. 3. Signs due to concomitant disease: e.g., cough and hemoptysis in pulmonary disease, or kyphosis and paraplegia in spinal disease. 4. Atypical presentation: e.g., pyrexia of unknown origin (PUQ).

protein (CRP) and polymerase chain reaction (PCR) are more sophisticated tests and claim higher accuracy. Another sensitive new test is the enzyme-linked immunosorbent assay (ELISA).

Pain and swelling are the most common presenting symptoms. Joint pains may be greater at night when the protective muscle spasm is relaxed and inflamed surfaces may rub over each other. Swellings are usually cold in contrast to septic arthritis, brucella, or pyogenic abscesses. Soft tissue swelling could be due to a joint effusion, bursitis, inflammatory mass, lymphadenopathy, or subcutaneous cold abscess. Muscle weakness or wasting is noted in chronic or neglected cases. Sinus formation is a sign of skin disruption by expanding cold abscess. We had cases where a sinus was the first presentation. Pathologic fractures are rare presentations. Joint stiffness, limb shortening, and ankylosis are late sequelae.

35.1.4.1

35.1.3.1

35.1.4.2

Laboratory Tests

Tuberculosis Osteomyelitis

These are discussed in detail elsewhere. The simplest are ESR and the Mantoux test. Special stain microscopy and guinea pig cultures are routine. C-reactive

Pain and swelling are the presenting features. Regional lymphadenopathy can be seen. Peripheral osteoarticular tuberculosis predominantly involves the bones in

35.1.4 Classification of Musculoskeletal Tuberculosis

Tuberculosis Arthritis Tuberculosis arthritis is commonly monoarticular. It usually presents as gradually worsening arthritis (Fig. 35.5). Sometimes a soft tissue swelling is noticed. In many cases the use of nonsteroidal anti-inflammatory drugs offers some response and a false sense of security (Vohra et al. 1997). The reactive form of tuberculous arthritis, "Poncet's rheumatism:' can mimic juvenile rheumatoid arthritis (Wihlborg et al. 2001). This identification was, however, previously questioned (Resnick and Niwayama 1988).

Fig. 35.5. a TB of the talus. Radiograph of a 29-year-old female who presented with joint pain, limitation of movement, and fever. There was no obvious soft tissue swelling. Frontal view showing a cystic erosion in the medial side of the talus (arrowhead) associated with narrowing of the ankle joint. Note scalloping of the medial margin of the distal end of the fibula (open arrows). There is no periosteal reaction. b Lateral radiograph confirming presence of the cystic erosion in the talus (arrow). Patient had previous temporary releif by steroid treatment

a

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combination with joints in 62-84% of cases, while purely osseous lesions without joint involvement occur in 16-38% (Hugosson et al. 1996). Tuberculous osteomyelitis may not show radiographic changes in the early stage. Radioisotope studies are more sensitive. An eccentric osteolytic lesion with little or no reactive bone is characteristic (Vohra et al.1997) (Fig. 35.5a, b). Sclerosis and periostitis are less than those occurring in pyogenic osteomyelitis. Presence of a sinus that does not heal on antibiotic treatment should raise the possibility of tuberculous osteomyelitis. Biopsy is mandatory under all circumstances. Location of tuberculous osteomyelitis could be epiphyseal, metaphyseal, or in the diametaphysis. 35.1.4.3 Tuberculosis of Muscles

Tuberculosis of skeletal muscles is an unusual finding even in patients with widespread disease (Derkash and Makley 1979). The psoas muscle is the exception. A cold abscess may form (Fig. 35.6). Primary hematogenous tuberculosis of the muscle is very rare. Pain is not a feature. The disease is not usually associated with miliary tuberculosis (Wilbur et al. 1995). Localized swelling is the usual presentation. Slowly developing cellulitis and muscle weakness are important. Tuberculous myositis should be considered in the expanding spectrum ofHIV-infection manifestations in the presence of muscular symptoms (Pouchot et al.1990). The differential diagnosis of tuberculous myositis includes polymyositis, bacterial infections, lymphoma, and Kaposi's sarcoma particularly in AIDS patients. 35.1.4.4 Tuberculous Tenosynovitis

Previously, invasive contrast studies like arthrography, tenography, or bursography were the only ways to examine tendons and bursae (Jaovisidha et al.1996). Modern imaging enables explicit demonstration of these soft tissue structures. Tuberculous tenosynovitis has a gradual clinical onset. It presents as limitation of movement and soft tissue swelling. The condition can be confused with soft tissue tumors. High resolution ultrasound and MRI provide useful information. Tendon sheath of the hands and wrist are the most common site for tuberculous tenosynovitis. Kanavel described the various stages of tuberculous tenosynovitis (KanaveI1923). The earliest is the hygromatous "watery phase" followed by the "caseous" serofibrinous phase. The fungoid "cheesy" form is the third stage.

35.1.4.5 Tuberculous Bursitis

Primary tuberculous bursitis is an important clinical entity. The most common site is at the greater trochanter of the femur (Fig. 35.7). MRI is particularly useful in demonstrating bursitis (Fig. 35.8). A histologic diagnosis should be reached by aspiration and biopsy to exclude nontuberculous infections and collagen diseases (Fig. 35.9). Tuberculous bursitis and tenosynovitis have seldom been described in the literature Oaovisidha et al. 1996). 35.1.4.6 Cystic Tuberculosis of Bone

This type of osteomyelitis is reported more in children than adults (Harisinghani et al. 2000). According to Rasool the multicystic variety is more common than the solitary cystic lesions (Rasool et al. 1994). He described the confusion with Jungling's disease or osteitis tuberculosa multiplex cystoids of sarcoidosis which he considered to be a manifestation of tuberculosis. These lesions were renamed as osteitis multiplex cystoids sarcoidosa by Komins in 1952 (Rasool et al. 1994). This multicystic type of presentation is rare in our experience. We see more of the solitary cystic from (Figs. 35.3, 35.5, 35.10). Cystic tuberculosis is in the differential diagnosis of other benign cystic lesions, eosinophilic granuloma, plasmacytoma, and tumors. Tuberculous cysts are well defined and may not have a sclerotic rim. They could be single or multiple and may expand in size. In children these are common in long bones while in adults they are commoner in flat bones like the pelvis and the scapula. They tend to be

Fig. 35.6. Intramuscular cold abscess. A young adult male who presented with pain and swelling in the left groin. Axial postcontrast CT scan of the upper third of the thigh showed multilocular cold abscess with enhancing rim and fluid content distending the adductor muscles

Imaging of Musculoskeletal Tuberculosis

Fig. 35.7. Subtle TB bursitis. A young adult male who presented with chronic left hip pain. On the axial CT scan of the hips at the level of the greater trochanters, there is slight distension, thickening, and irregularity of the walls of the left greater trochanter bursa (arrowhead). See Fig. 35.8 for MRI image and Fig. 35.9 for diagnostic aspiration of the same patient

611

Fig. 35.8. Subtle TB bursitis. T2-weighted MRI sequence of the hips at the level of the greater trochanters. Well-defined hyperintense fluid collection in the left trochanteric bursa (black arrow head). This MRI belongs to the same patient shown in Figs. 35.7 and 35.9

smaller and less expansile in adults. The bone expansion is due to formation of granulation tissue. Cystic tuberculosis does not necessarily mean that these are fluid-filled lesions (Cremin and Jameism 1995). The term "pseudocystic" tuberculosis was used previously (Clinton and Young 1955).

35.2

Imaging 35.2.1 Plain Radiographs

Plain radiography remains the cornerstone for imaging of tuberculosis infection of bones and joints (Ridley et al. 1998). However, no specific radiographic feature is pathognomonic for musculoskeletal tuberculosis. Therefore nonradiologic evidence is always necessary to confirm diagnosis. Signs include soft tissue swelling, osteoporosis, and osteosclerosis. Appreciation of soft tissue swelling or displacement of fat planes could be the earliest sign (Figs. 35.11-12). Osteoporosis develops at an early stage due to hyperemia. Subtle narrowing of the joint space and faint erosions are also early signs (Fig. 35.14). Osteosclerosis is characteristic of the chronic form of the disease. The joint space may be widened initially, but it is usually normal in contrast to rheumatoid disease where joint space narrowing is the rule. Erosions and cystic lesions eventually develop (Fig. 35.15). Sequestra are usually small when they occur and can be seen in opposing articular surfaces (so-called kissing sequestra,

Fig. 35.9. CT-guided aspiration biopsy for the left trochanteric bursa for the patient shown in Figs. 35.7 and 35.8. The procedure was performed under local anesthesia. Aspirate was positive for TB culture. Note position of the needle (white arrows) within the small infected trochanteric bursa (black arrowhead)

see Fig. 35.15). Periosteal reaction is usually limited (Figs. 35.2, 35.3). Later in the disease the Phemister triad becomes evident, namely osteoporosis, marginal erosions, and joint space narrowing (Figs. 35.15, 35.16) (Resnick and Niwayama 1988). Soft tissue calcification can be seen on plain radiographs but CT is more sensitive (see Fig. 35.22b). Bony ankylosis may develop at a later stage. In rheumatoid disease, joint space narrowing is early and predominant. Rheumatoid disease is usually symmetric and bilateral. Gout does not provoke osteoporosis. Pyogenic infections are more rapidly progressing than tuberculosis and lead

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to early joint space narrowing and more periostitis. In pigmented villonodular synovitis the joint space is preserved and there is no osteoporosis. MRI shows characteristic signs. Brucellosis may be coendemic with tuberculosis but synovial infection is the earliest and most significant manifestation (AI Shahed et al. 1994). In children, the late occurring synovial involvement leads to chronic hyperemia with overgrowth of the epiphyses and premature fusion. This finding may simulate juvenile rheumatoid arthritis (Haygood and Williamson 1994).

35.2.2 Sinogram The skin overlying a superficial cold abscess becomes progressively thinner and may ultimately yield, forming a sinus (Fig.35.17). Injection of water-soluble contrast media under fluoroscopy can demonstrate the size, depth, and direction of the sinuses. These may form fistulae if adjacent to a hollow viscus. Fig. 35.10. Cystic TB osteomyelitis. Lateral radiograph of the right knee of an adult male who presented with a discharging sinus. There is a large well-defined lytic lesion eroding the upper end of the tibia and sparing the epiphyses. Little reactive sclerosis is present. No significant periosteal reaction, which is commoner in tumors and pyogenic osteomyelitis. No large sequestra. (see Fig. 35.18a-c)

Fig.35.11. Early radiographic signs of TB arthritis of the left knee. Frontal radiograph of the knees of a child who presented with limping, pain, and swelling. There was no history of trauma. Soft tissue swelling due to a joint effusion was evident on the plain films (black arrow heads) before any bony changes could be visible. This finding is nonspecific. Isotope bone scan was suggestive of focal infection (see Fig. 35.12). Diagnosis was confirmed by aspiration and culture

Fig. 35.12. Isotope bone scan for detecting early signs of TB infection. A three-phase 99mTc MDP isotope scan for the child shown in Fig. 35.11 was positive for infection. There is increased activity in the vascular phase as well as in the blood pool phase (black arrowhead)

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a"'__

b

Fig. 35.13. a Lateral radiograph of the left elbow for a 47-year-old male who presented with slowly developing joint swelling and limitation of movement. There is a large swelling of soft tissue in the arm (arrows) associated with elevation of the anterior and posterior fat pads (open arrowheads). The elevation of fat pads is commonly seen with post-traumatic joint effusion. Minimal haziness of the olecranon tip was missed (open black arrow). b Same patient shown in Fig. 35.l3a, after 2 months. An erosion at the olecranon tip has become apparent (arrow). The soft tissue swelling of the lower arm and the elevation of the fat pads have decreased

Fig. 35.14. Early findings on plain film of TB arthritis. Frontal radiograph of the left knee of an adult with chronic knee pain. There was slight narrowing of the medial joint compartment. Small marginal erosion is noted (arrow). Such findings can be missed. A high level of clinical vigilance is necessary to initiate relevant tests to exclude low-grade infection like TB

Fig. 35.15. Late findings on plain film of advanced TB arthritis. Frontal radiograph of the right knee of an adult who suffered chronic knee pain. There is periarticular osteopenia,joint space narrowing, and numerous marginal erosions. These together constitute the Phemister triad. Small "kissing" sequestra are noted at the lateral compartment of the knee joint originating from erosion of the opposing articular surfaces

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Fig.35.16. TB of the right hip. Hip radiograph of a 53-year-old male who presented with right hip pain, limping, and night sweats. The radiograph shows osteoporosis narrowing of the joint space and numerous articular surface erosions (open arrows). Note the large swelling of soft tissue (long arrows). These findings represent the Phernister triad. Diagnosis was confirmed by aspiration biopsy

35.2.3 Isotope Scanning

A three-phase technetium methylene diphosphonate 99m ( Tc MDP) scan is usually the first test performed to diagnose osteoarticular infection whether due to tuberculosis or otherwise (Figs. 35.12, 35.18). It is a sensitive test but a negative scan cannot exclude presence of tuberculous bone infection. Indium-labeled white blood cells in WBC scan, technetium hexamethylenepropyleneamine T2 oxime (99m Tc HMPAO), and the nonspecific indium-labeled immunoglobulin scan are also widely used to localize infections. When bone infection is not the initial presentation in patients known to have tuberculosis or where diagnosis of tuberculosis is not established, e.g., cases of pyrexia of unknown origin (POU), gallium citrate 67Ga scan is the test of choice. The use of 67Ga in tuberculosis was well described by Hamilton and Nabulsi (1999). It can detect skeletal and all extraskeletal sites of tuberculosis infection including lymph nodes and visceral lesions but is nonspecific for infections and can cause these to be confused with lymphoma and malignancies. Isotope scanning is more sensitive than morphologic imaging but findings are nonspecific. They should be reviewed in conjunction with clinical signs and other imaging findings. A specific advantage is the ability to

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Fig. 35.17. Contrast sinogram. An adult male presented with chronic knee pain and a discharging sinus. Lateral radiograph of the knee after administration of water-soluble contrast medium via a soft catheter advanced through the sinus opening at the fossa poplitea. Note the large erosion in the upper end of the tibia and multiple ill-defined erosions in the lower end of the femur due to TB arthritis

demonstrate multiple sites of osteoarticular involvement. In this respect, scintigraphy has totally replaced radiographic skeletal surveys. Positive multiple foci should be differentiated from metastatic disease.

35.2.4 Ultrasound

Ultrasound is a quick, simple, inexpensive, widely available, non-ionizing imaging technique that can easily be used in different clinical settings, including the emergency department, radiology department, and intensive care unit (Bureau et al. 1998). High resolution probes are now available providing excellent soft tissue details for detection of joint and periarticular pathology including joint effusions, bursitis, cold abscesses, and soft tissue calcification (Fig. 35.19). Ultrasound helps to exclude thrombophlebitis, which can be confused with bone and joint infections.

35.2.5 Computed Tomography (CT)

Computed tomography (CT) is superior to MRI in demonstrating details of bone destruction, detec-

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Fig.35.18a-c. Isotope bone scan. a Vascular phase of 99mTc MDP isotope bone scan vascular phase showing increased tracer accumulation at the TB infection site in the upper end of the right tibia as early as the arterial phase first pass. b Blood pool phase taken after 5 min of radiotracer administration showing a doughnut appearance of progressive increased tracer accumulation. c Mediolateral view in the delayed static phase showing persistent increased tracer accumulation at the infected site in the upper end of the right tibia. This isotope bone scan belongs to the patient shown in Fig. 35.10

Fig.35.19. Subcutaneous cold abscess. An adult male patient presented with chronic swelling of the right buttock and loss of weight. Ultrasound scan of the gluteal region showing a well-defined cold abscess with thick fluid contents and multiple wall calcifications. Note the acoustic shadow of the calcified granuloma adherent to the posterior wall of the cold abscess (similar to the effect of gall stones)

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tion of small sequestra, and minute soft tissue calcification (see Fig. 35.22a, b below). It is particularly important in patients where MRI is contraindicated. CT has a broader spectrum than MRI by demonstrating subcutaneous, intraosseous, bowel involvement, lymphadenopathy lesions, and lung disease in a single extended exam.

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35.2.6 Magnetic Resonance Imaging (MRI)

Magnetic resonance imaging (MRI) is superior in sensitivity and specificity for infections when compared to isotope scintigraphy due to the superb anatomical detail and the high soft tissue contrast resolution. Subtle changes of bone marrow signal or enhancement can only be demonstrated by MRI. The use of contrast enhancement helps to differentiate between noninfective conditions ofinternal derangement, like osteochondritis dissecans, and infective arthritis. Differentiation can be difficult on plain films (Fig. 35.20) but easier on MRI (Fig. 35.21a, b). Specific changes of arthropathies can be shown by MRI, e.g., small signal void bodies or blooming effect in pigmented villonodular synovitis. Soft tissue involvement is best demonstrated by MRI. Demonstration of periarticular disease by MRI is a useful asset. An example is trochanteric bursitis (Figs. 35.8).

35.3 Radiologic Presentation

Fig. 35.20. TB mimics. Lateral radiograph of a knee for a young adult patient who presented with painful knee. There are faint subarticular erosions. These were initially diagnosed as osteochondritis dissecans (see Figs. 35.21a, b)

a

35.3.1 Tuberculosis of the Knee

The knee is the most common site for tuberculous and nontuberculous osteoarticular infections. It is

b Fig.35.21. a Noncontrast coronal Tl-weighted MRI demonstrating two very well defined subchondral cystic erosions with little surrounding low signal change due to focal edema. This was still considered to be due to osteochondritis. b Postcontrastenhanced fat-saturated Tl-weighted image showing intense contrast enhancement all over the medial femoral condyle. This is not a feature of osteochondritis. There is also a small joint effusion with significant synovial enhancement. Presence of infection was suggested. This was proved to be due to TB after synovial biopsy. Note a small enhancing focus at the posterior margin of the tibia under the tibial insertion of the posterior cruciate ligament. This MRI belongs to the patient shown in Fig. 35.20

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also the most common site for malignant tumors, severe on the subchondral bone which erodes the cardegenerative disease, and internal derangements. tilage from beneath (Ainslie and Bateman 1991). This It is therefore important to diagnose the cause of in turn slowly leads to joint space narrowing. These symptoms in the knee accurately. This is why MRI "arthritic" subchondral erosions (Fig.35.16, 35.23) are different from the "osteomyelitic" cystic erosions, is commonly used. Kerri and Martini classified the radiologic stages of which may not affect the joint or articular cartilage knee tuberculosis (Kerri and Martini 1985). In stage (Fig. 35.10, 35.23) (Lee et al.1995). 1 there may be slight osteopenia with or without soft tissue hypertrophy (Fig. 35.11). Stage 2 is described as osteomyelitic stage with cystic erosions of the epiphy- 35.3.2 sis or metaphysis, but a normal joint space. In stage Tuberculosis of the Hip 3, arthritis ensues with joint space narrowing and disorganization which may progress further to stage The hip is the most common extraspinal site of 4 (Fig. 35.15). We believe ankylosis should be consid- tuberculosis infection in children. It is also the most ered stage 5. This classification is a good predictor of common site of septic arthritis in this age group. the outcome of the disease (Lee et al. 1995). In stage 1 Scrutiny of plain films is essential to avoid missing hip and 2, protective immunity causes synovial hypertro- infections (Fig. 35.24). Both conditions, namely tuberphy, synovitis, and granuloma formation. In stages 3 culosis and pyogenic hip infections, are debilitating if and 4, there is tissue destroying hypersensitivity most not treated at an early stage (Figs. 35.25, 35.26). Shanmugasundaram (1983) described the radiologic presentations of tuberculosis of the hips. In type 1, the hip looks normal. The disease is restricted to the synovium. A traveling acetabulum is noted in type 2, while a frankly dislocated hip was noted in type 3. In type 4, a, Perthes' like configuration of the capital epiphyses with sclerosis and total head involvement is seen but no associated metaphyseal changes like Perthes' disease. Type 5 presents as protrusio acetabuli. Type 6 is an atrophic head with decreased volume, while type 7 shows mortar and pestle appearance (Fig. 35.25). a

b Fig. 35.22. a TB of the right sacroiliac joint. Bone setting of an axial CT scan of the pelvis at the level of the sacroiliac joints. There is widening and erosions of the articular surfaces with formation of small "kissing sequestra" (long arrow) from either of the articular surfaces. There is a large right gluteal abscess (black arrowheads) in continuity with soft tissue swelling of the right iliacus muscle (small arrow). b Soft tissue setting of same patient showing sacroiliac joint erosions, iliacus muscle swelling, right gluteal abscess, and soft tissue calcification

Fig. 35.23. TB of the right knee. Lateral radiograph of the knee of a 37-year-old male who complained of knee pain and swelling. There is extensive subarticular permeation of both femoral condyles (arrows). Note patella erosions (arrowheads) and the soft tissue swelling (open arrows)

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Fig. 35.24. TB of the left hip, early changes. Frontal radiograph of the hips of a teenager complaining of left hip pain and limping. There is slight nonconcentric narrowing of the superior joint space. This was associated with nonhomogeneous density of the metaphysis in the left femoral neck. This stage of the TB infection can be missed. Diagnosis was made after open biopsy

Fig. 35.26. Missed case of septic arthritis in the left hip. Advanced articular surface erosions with avascular necrosis due to a missed diagnosis. Both septic arthritis and TB arthritis have serious sequelae on the joints if untreated. Open biopsy was negative for TB bacilli on staining and culture

Fig.35.25. Advanced TB left hip (stage 7). Missed case of severe TB arthritis of the left hip showing avascular necrosis and fissuring of the left femoral head ending in the mortar and pestle appearance. Peculiarly there was still good range of hip joint movement

Campbell and Hoffman have reviewed, confirmed, and slightly modified the abovementioned classification (Campbell and Hoffman 1999). They considered the irregular head of type 6 as type 1b and a destroyed head of type 6 as type 2. Type 3 refers to fibrosis and ankylosis while their type 4 refers to bone ankylosis. We believe the Shanmugasundaram classification is more elaborate and easier to apply. Despite the bizarre appearance of the hips, both Shanmugasundram and Campbell found good prognosis in the advanced cases because of the good range of movement.

35.3.3 Tuberculosis of the Pelvis and Sacroiliac Joints Primary tuberculous sacroiliitis is rare. Unlike ankylosing spondylitis which is usually bilateral, tuberculosis generally involves only one sacroiliac joint

(Chapman et al. 1979). It usually occurs due to spread from the lower lumbar spine. The disease starts in the synovial part of the joint at its lower third. The disease may be missed on plain films due to bowel overlap. An isotope scan is the examination of choice initially. CT provides accurate delineation (Fig. 35.22). Differential diagnosis includes pyogenic infection, collagen disease, and fungal infection. Aspiration biopsy is essential. The ilio-psoas muscle is usually involved and a cold abscess is common. We encountered some cases of multiple pelvic infection (Fig. 35.1). Involvement of the pubic symphysis is rare. CT is a very useful tool for examination of the pubic symphysis (Fig. 35.27).

35.3.4 Chest Wall Tuberculosis Chest wall involvement usually results from hematogenous infection but more rarely from direct spread of pleural or lung parenchymal disease. Tuberculosis occasionally involves the sternoclavicular joint or a rib, leading to bone destruction and abscess formation (Kim et al. 2001). This is seen in less than 2% of musculoskeletal tuberculosis cases (Adler et al.I993). Plain films are not always as successful in revealing this condition, as can be seen in Fig. 35.28a, b. CT is the examination of choice following a positive nuclear scan (Fig. 35.29a, b). Findings include bone

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Fig.35.27. TB pubic symphysis. An adult male patient presented with suprapubic pain and swelling. Axial postcontrast CT scan of the pelvis at the level of the inferior margin of the symphysis pubis. There are bilateral pubic bone erosions associated with subcutaneous small cold abscess formation

a

Fig. 35.28. a TB of the manubrium sterni. Right lateral view of the sternum of a 36-year-old female who presented with chest wall swelling and fever. Chest X-ray was reported as normal. Lateral radiograph of the manubrium demonstrated a soft tissue swelling (arrow) and a bone erosion (white arrowhead). Note presence of periostitis (long arrow). b Follow up left lateral view of the sternum for the same patient in (a) showing the extent of soft tissue swelling (white arrow), large erosion (e) and a pathologic fracture (open arrowhead)

a Fig. 35.29. a Multifocal TB of the chest wall, mediastinal lymph nodes, and vertebral body. An adult male patient who presented with fever. Anterior chest wall swelling and backache. Axial postcontrast CT of the thoracic inlet at the level of the sternoclavicular joints. There is a small subcutaneous presternal abscess on the right side of the midline (black arrowhead). An enlarged left retroclavicular lymph node is seen (long arrow). b Postcontrast CT scan of the upper chest at the level of the aortic arch in the same patient demonstrating D3 vertebral body erosion with a small paraspinal soft tissue component. There is epidural encroaclunent onto the spinal canal

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or costal cartilage erosions, soft tissue enhancement, lymphadenopathy, abscess formation, calcification, and underlying lung diseases (Adler et al. 1993). Good radiographs can depict the lesions (Fig. 35.28a, b). In one series, tuberculosis of the ribs was as frequent as 7% of all musculoskeletal tuberculosis cases (Watts and Lifeso 1996). This high incidence was not supported by other authors or by our own experience. MRI is also sensitive for chest wall infections but may be subject to motion artifacts (Fig. 35.30).

35.3.5 Tuberculosis of the Hands and Feet Tuberculous mycobacterial infection of the short tubular bones of the hand and foot, "dactylitis:' is a disease of childhood (Chapman et al. 1979). It is more common in the hands than the feet. The most frequent locations are the proximal phalanx of the index and middle fingers and the metacarpals of the middle and ring fingers (Hardy and Hartman 1947). Painless swellings appear on the dorsum of the hands and feet. Soft tissue changes precede the bone changes. Ballooning of the cortex, periostitis and cortical destruction can lead to what is called spina ventosa "wind filled sail sign" (Clark 1990). We rarely see this appearance. Cystic lesions can be seen (Figs. 35.5,35.31). An erosive dactylitis is now more common (Fig. 35.32). (Abd El Bagi et al. 1999). Differentiation from the hand-foot syndrome of sickle

Fig. 35.30. TB sternoclavicular joint. Postcontrast fat -suppressed Tl-weighted MRI of the sternoclavicular joint. There is erosion of the right clavicular head (arrowhead) with a surrounding enhancing soft tissue swelling (long arrow). There is also right paratracheal adenopathy (open arrow). This MRI belongs to the same patient as that in Fig. 35.29a, b

Fig. 35.31. TB tarsal bones. Oblique radiograph of the right foot of an adult female who presented with chronic foot pain. There is multilocular expansile cystic lesion of the tarsal navicular

Fig. 35.32. TB dactylitis. Frontal radiograph for the metatarsals and toes of an adult male who presented with pain and swelling of the dorsum of the foot. Patient is not diabetic. There is erosion of the base of the middle metatarsal (large black arrowhead). Minimal periosteal reaction noted (small black arrowheads). Diffuse soft tissue swelling is noted (open white arrows)

Imaging of Musculoskeletal Tuberculosis

cell disease is important where both diseases are endemic. Sickle cell dactylitis is characteristically bilateral (Wessels et al. 1998). Other differential diagnosis includes hemangioma and sarcoidosis. Congenital syphilis is no longer prevalent.

35.3.6 Tuberculosis of the Elbow Tuberculous arthritis of the elbow was reported to be more common than that of the wrist or shoulder (Resnick and Niwayama 1988). Muscle wasting

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becomes prominent as limitation of movement progresses. Tuberculous bursitis could be the presenting feature. This can mimic a soft tissue mass (Figs. 35.13, 35.33, 35.34).

35.3.7 Tuberculosis of the Shoulder A peculiar variety of "caries sicca" was described. It presents with osteoporosis, muscle wasting, and pain. Alternatively an erosive form develops (Fig. 35.35). Bursitis could be the presenting feature.

Fig. 35.33. TB of the elbow. A 65-year-old male presented with a slowly progressing tense mass in the right cubital fossa. This was clinically suspected to be a tumor. High resolution US demonstrated that the mass is cystic and multilocular

a Fig. 35.34. a TB of the elbow. T2-weighted axial MRI of the right elbow confirmed the multilocular cystic nature of the cubital fossa lesion as seen by ultrasound in Fig. 35.33. No solid component. Note the transcondylar hyperintense signal in the lower humerus due to early bone involvement (open white arrows). b Sagittal postcontrast fat-saturated Tl-weighted image showed enhancement of the walls and septations of the multilocular lesion. This is a sign of infection. US-guided aspiration for culture was positive for TB

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Cystic erosions are common (Figs. 35.2, 35.5), while articular surface erosions are late manifestations (Fig. 35.36a, b). Periostitis which is rare in tuberculosis can be provoked by weight-bearing stress (Fig. 35.2a). Subluxation can occur (Fig. 35.37).

35.4 Interventions 35.4.1 Biopsies

Fig. 35.35. TB of the scapula. A 25-year-old male presented with a chronic sinus at the scapular region. Axial CT scan demonstrated a subglenoid bone erosion (black arrowhead) associated with inflammatory changes and focal swelling of the subscapularis muscle anterior to the neck of the scapula (long white arrow). Diagnosis was confirmed by CT-guided biopsy

35.3.8 Tuberculosis of the Ankle Being a weight-bearing joint, the ankle is subject to repeat trauma. Tuberculosis infection starts in the bones and later involves the joint. The talus, calcaneum, or cuboid can be the source of infection. The patient usually presents with soft tissue swelling.

a

Tissue diagnosis is not easily established in tuberculosis, though it is imperative. The selection of biopsy sites is important. Cold abscesses and necrotic tissue do not usually yield bacilli. Stains from joint aspirates may also be negative for bacilli. The presence of a high blood cell count, low glucose, and pure mucin clot formation is diagnostic of tuberculous joint aspirate. Guinea pig cultures are more reliable than Ziehl-Neelsen stains (Glassroth 1993). Either US or CT can be used for biopsy or drainage procedures. Ultrasound does not involve exposure to ionizing radiations. US-guided procedures are quicker than CT-guided procedures and allow the freedom of bedside use. US provides real-time guidance. It is particularly suitable for superficial lesions and synovial biopsies (Fig. 35.38). CT is however superior for biopsies of intraosseous and deeply seated lesions inaccessible for US guidance. We have no experience with MRI-guided interventions,

b Fig. 35.36a, b. TB of the ankle. A 49-year-old male complained of chronic right ankle joint pain and swelling (open arrows) and articular surface erosions (small arrowheads). There is diffuse decrease of bone density. No periosteal reaction

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Fig. 35.37. Frontal radiograph of the right ankle of a 51-yearold male who complained of joint pain and swelling. There is a large soft tissue swelling (arrowheads). The lateral malleolus is osteoporotic and nonhomogeneous. Note the slight medial subluxation of the tibia over the talus

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Fig.35.38. TB synovitis. Adult male presented with unexplained chronic knee pain and swelling. US-guided synovial biopsy of the knee was performed. There was only a trace of joint effusion (not shown here) but there was significant synovial thickening (black arrowheads). Histopathology and culture of tissue biopsies were positive for TE. This film demonstrated the thickened hypoechoic synovium (black arrowheads). Note position of the biopsy needle (open white arrow) tip at the thickest site of the synovium (black arrowheads)

which require MRI-compatible nonferromagnetic titanium needles and instruments. Recent reports of large series indicate successful biopsy samples using a closed configuration magnet (Salmonowitz 2001). In general, unless a biopsy sample is accurately taken from a granuloma, the margins of cystic lesions, or the synovium, the histologic results are likely to be equivocal. (Versefeld and Solomon 1982). Biopsies are very important where multidrug-resistant organisms occur (Watt and Lifeso 1996).

35.4.2 Drainage

Percutaneous drainage of tuberculous abscesses was said to be not very common elsewhere (Dinc et al. 1996). We frequently perform this procedure, whenever a cold abscess is detected (Fig. 35.39). This prevents sinus and fistula formation and relieves local symptoms. A specimen is sent for microscopy and culture. Common sites are psoas compartments, the hips, and gluteal regions. The source of infection could be in the lumbar spine, pelvic bones, or sacroiliac joints (Pouchot et al. 1988). We tend to use the smallest size catheter that can possibly match the fluid thickness, and we puncture the skin and abscess at two different points. These precautions help to avoid forming persistent sinus.

Fig. 35.39. Percutaneous drainage of a cold abscess. Tense cold abscess tracking from the left groin was distending the adductor muscles of the left thigh. CT scan of the upper third of the thigh showing drainage catheter in situ

35.5

Summary

Musculoskeletal tuberculosis is an important cause of morbidity in developing countries with resurgence in industrial countries. Diagnosis of tuberculosis infection of bone joints and adjoining soft tissues is a real challenge, which requires a high degree of clinical vigilance. The combination of careful clinical history, elaborate laboratory tests, and radiologic findings can

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lead to an early diagnosis to prevent serious bone and joint destruction. Diagnosis should be confirmed by aspiration and biopsy samples for microscopy, culture, and histopathology. These could be negative at times. Alternatively, biopsy samples should be taken from the primary site or other extraskeletallesions particularly abdominal lymph nodes. We suggest an algorithm for handling the various presentations of osteoarticular tuberculosis using a structured diagnostic pathway.

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M. Abd El Bagi et al. Edeiken J, De Palma AF, Moskowitz H, Symthe V (1963) Cystic tuberculosis of bone. Clin Orthop 28: 163-168 Engin G, Acunas B, Acunas G, Tunaci M (2000) Imaging of extrapulmomary tuberculosis. Radiographics 20:471-488 Glassroth J (1993) Diagnosis of tuberculosis: a comprehensive interventional approach. In: Reichman LB, Hershfield ES (eds) Tuberculosis: a comprehensive international approach, Dekker, New York, pp 149-165 Goldblatt M, Cremin B (1978) Osteoarticular tuberculosis, its presentation in colored races. Clin Radiol 29:669-677 Hamilton D, Nabulsi J (1999) Radionuclides in the evaluation of extrapulmonary tuberculosis. In: McGuiness F (ed) Clinical imaging of non pulmonary tuberculosis. Springer, Berlin Heidelberg New York, pp 176-187 Hardy JB, Hartman JR (1947) Tuberculous dactylitis in childhood: a prognosis. J Paediatr 30:146-156 Harisinghani MG, McLoud TC, Shepard JA, Ko JP, Shroff MM, Mueller PR (2000) Tuberculosis from head to toe. Radiographics 20:449-470 Haygood TM, Williamson SL (1994) Radiographic findings of extremity tuberculosis in childhood: back to the future? Radiographics 14:561-570 Hugosson C, Nyman RS, Brismar J, Larson SG, Luidahl S, Lundstedt C (1996) Imaging of tuberculosis V: peripheral osteoarticular and soft tissue tuberculosis. Acta Radiol37: 512-516 Jaovisidha S, Chen S, Ryu KN, Siriwongpairat P, Pekanan P, Sartoris D (1996) Tuberculous tenosynovitis and bursitis imaging findings in 21 cases. Radiology 201:507-513 Kanavel AB (1923) Tuberculous tenosynovitis of the hand. A report of 14 cases of tuberculous tenosynovitis. Surg Gynaecol Obstet 37:635-647 Kerri 0, Martini M (1985) Tuberculosis of the knee. Int Orthop 9:153-157 Kim HY, Song KS, Goo JM, Lee JS, Lee KS, Lim T-H (2001) Thoracic sequelae and complications of TE. Radiographies 21:839-860 Komins C (1952) Multiple cystic tuberculosis: a review and revised nomenclature. Br J RadioI25:1-8 Kumar K, Saxena MB (1988) Multifocal osteoarticular tuberculosis. Int Orthop 12:135-138 Lee As, Campbell JAB, Hoffman EB (1995) Tuberculosis of the knee in children. J Bone Joint Surg 77B:313-318 McGuiness F (1999) Osteoarticular and soft tissue tuberculosis in clinical imaging of non-pulmonary tuberculosis. Springer, Berlin Heidelberg New York, pp 176-187 Muradali D, Gold WL, Vellend H, Becker E (1993) Multifocal osteoarticular tuberculosis: report of four cases and review of management. Clin Infect Dis 17:204-209 Pouchot J, Vinceneux P, Barge J et al (1988) TB of the sacroiliac joints clinical features: outcome and evaluation of needle biopsy in 11 consecutive cases. Am J Med 84:622-628 Pouchot J, Vinceneux P, Barge J et al (1990) Tuberculous polymyositis in HIV infection. Am J Med 89:250-251 Rasool M, Governder S, Naidoo K (1994) Cystic tuberculosis of bone in children. J Bone Joint Surg Br 76(B):113-117 Resnick D, Niwayama G (1988) Osteomyelitis, septic arthritis and soft tissue infections: the organisms in diagnosis of bone and joint disorders, vol 4, 2nd edn. Saunders, Philadelphia, pp 2661-2686 Ridley N, Shaikh MI, Remedios D, Mitchell R (1998) Radiology of skeletal tuberculosis. Orthopaedics 21: 1213-1220 Salmonowitz E (2001) MR imaging guided biopsy and thera-

Imaging of Musculoskeletal Tuberculosis peutic interventions in a closed configuration agent: single centre series of 361 punctures. AJR 177:159-163 Shanmugasundaram TK (1983) Bone and joint tuberculosis. Kothandaram and Co., Madras Versfeld G, Solomon A (1982) A diagnostic approach to tuberculosis of bones and joints. J Bone Joint Surg Br 64(B):446-449 Vohra R, Kang H, Dogra S, Saggar R, Sharma R (1997) Tuberculous osteomyelitis. J Bone Joint Surg Br 79(B): 562-566 Watts H, Lifeso R (1996) Tuberculosis of bones and joints. J Bone Joint Surg 76(A):288-298

625 Wessels G, Hesseling P, Beyers N (1998) Skeletal tuberculosis dactylitis and involvement of the skull. Paediatr Radiol 28: 234-236 Wihlborg C, Babyn P, Ranson M, Laxer R (2001) Radiologic mimics of juvenile rheumatoid arthritis. Paediatr Radiol 31:315-326 Wilbur A, Gorodetsky A, Hibbeln J,Aizenstein R (1995) Tuberculous myositis: CT and sonographic findings in two cases J Clin Ultrasound 23:495-499 Yao D, Sartoris D (1995) Musculoskeletal tuberculosis. RCNA 33:679-689

36 Tuberculosis of the Skin AIDA

J. AL KUDWAH

CONTENTS 36.1 36.1.1 36.1.2 36.1.3 36.2 36.2.1 36.3 36.3.1 36.3.1.1 36.3.1.2 36.3.1.3 36.3.1.4 36.3.1.5 36.3.1.6 36.3.1.7 36.3.1.8 36.3.1.9 36.4 36.4.1 36.4.1.1 36.4.1.2 36.4.2 36.4.2.1 36.4.2.2 36.4.3 36.4.3.1 36.4.3.2 36.4.3.3 36.5 36.6 36.6.1 36.6.2 36.6.3 36.6.4 36.6.5 36.6.6 36.6.7 36.7 36.7.1

Tuberculous and Nontuberculous Infections 627 History 627 Epidemiology 627 Classification of Mycobacteria 628 Tuberculosis of the Skin 628 Etiopathogenesis 628 Tuberculosis of the Skin Due to M. tuberculosis / M. bovis 629 Clinical Variants 629 Primary Inoculation Tuberculosis (Tuberculous Chancre) 629 Acute Miliary Tuberculosis of the Skin 631 Lupus Vulgaris 632 Tuberculosis Verrucosa Cutis 635 Scrofuloderma 636 Tuberculosis Cutis Orificialis 637 Metastatic Tuberculous Abscess (Gumma) 639 BCG Vaccination and Cutaneous Tuberculosis 641 Congenital Tuberculosis 641 The Tuberculids 642 Tuberculosis-specific Tuberculids 642 Papulonecrotic Tuberculids 642 Lichen Scrofulosorum 643 Tuberculosis Nonspecific Tuberculids 644 Erythema Induratum 644 Erythema Nodosum 645 Nontuberculids 646 Lupus Miliaris Disseminatus Faciei (Acne Agminata) 647 Rosacea-like Tuberculid 647 Lichenoid Tuberculid 648 Cutaneous Tuberculosis in the Immunocompromised 648 Atypical Mycobacterial Cutaneous Infections 648 M. marinum Infection 649 Mycobacterium ulcerans Infections 649 Mycobacterium kansasii Infection 650 Mycobacterium scrofulaceum Infection 651 Mycobacterium avium-intracellulare Complex Infection 651 Mycobacterium fortuitum Complex Infection 652 Mycobacterium haemophilum Infection 653 Treatment of M. tuberculosis Skin Infections 654 Dermatologic Considerations 654 References 654

A. J. AL KUDWAH, MD, DD, FRCP (Ed) Consultant Dermatologist, Department of Dermatology, Riyadh Armed Forces Hospital, P.O. Box 7897, C-1l7, Riyadh 11159, Saudi Arabia

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

36.1 Tuberculous and Nontuberculous Infections 36.1.1 History

Tuberculosis has been a recognized ailment of mankind from ancient history. The most ancient documentation is from the Pharaonic dynasties, 2000-3000 years B.C. It is one of the most important human infections because of its prevalence and its being one which causes more suffering for humans than all bacterial genera combined (Tapeiner and Wolff 1999; Sehgal 1994). DNA of Mycobacterium tuberculosis has been detected in Peruvian mummies (Gawkrodger 1998). Cutaneous tuberculosis was first documented by Laennec where he described his own prosector's wart (Laennec 1962) in 1826.

36.1.2 Epidemiology

Tuberculosis of the skin has a worldwide distribution. It constitutes a small portion of all cases of extrapulmonary tuberculosis which in itself is a small fraction (1 0%) of all tuberculous infections. It has been more prevalent in regions with cold and humid climates but is recognized in the tropics (Anonymous 1991; Marcoval et al. 1992). The improvement in socioeconomic standards and living conditions in European and North American countries, immunization programs, and the use of three or four drug regimens of treatment have caused a steady decline in its incidence over the last decades; it parallels the decline in incidence of pulmonary tuberculosis. Resurgence and increased incidence of cutaneous tuberculosis in the United States is mainly due to the AIDS epidemic, and this increase could be explained either by endogenous reactivation or increased susceptibility to reinfection with M. tuberculosis or low virulence mycobacteria (atypical) because of impaired cellular immunity. In the United States, until the 1980s, skin tuberculosis was a rare disease; in Europe the incidence now is less

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than 0.5%. In Germany only 300-400 new cases are estimated to occur every year. In India the incidence is 0.15% (Tapeiner and Wolff 1999). In our experience over the last 10 years (1993-2002) a total of 23 cases of cutaneous tuberculosis were seen among a total of 20,000 new dermatologic cases attended to by our hospital for the same period (0.12%).

36.1.3 Classification of Mycobacteria Mycobacteria are slender, unencapsulated, nonmotile, nonsporulating, weakly positive acid-fast anaerobic rods. The tubercle bacillus takes the form of slender, curved, delicate, beaded or banded rods, 1-4 11m long and about 0.5 11m in diameter (Sehgal and Wagh 1990a). They occur either singly, in pairs, or in clumps. Their highly complex waxy coating determines the mycobacterial physiologic properties (e.g., resistance to degradation following phagocytosis) and may influence the pattern of host response (Citron and Girling 1987; Higuchi et al. 1981). They are difficult to stain, also due to their cell wall high lipid content, but once stained with basic dyes (e.g., carbolfuchsin), they retain the color and resist decolorization with acid and alcohol, thus the name "acidfast bacilli." Runyon (1965, 1974) classified the mycobacteria other than tuberculosis (MOTT) according to their rate of growth and pigment-production ability with or without light. Since then more studies have been made and the genus Mycobacterium stands among the best classified bacterial genera. Table 36.4 shows the classification of the atypical mycobacteria (Runyon 1965,1974). Slow growers are divided according to their pigment-forming properties in culture: group I photochromogens capable of pigment production on light exposure, group II scotochromogens which are able to produce pigment without exposure to light, group III nonchromogens, non-pigment producers, and group IV including all rapid growers. A different classification could be used for clinical purposes which divides mycobacteria into obligate and facultative human pathogens and nonpathogens (Tapeiner and Wolff 1999).

36.2

Tuberculosis of the Skin Cutaneous tuberculosis has been described long before Robert Koch identified M. tuberculosis (see

Laennec 1962). It is caused by M. tuberculosis, M. bovis, or under certain circumstances by the bacille Calmette-Guerin (BCG). Various classifications of the clinical variants exist but none of them has been entirely satisfactory. These classifications were based on the mode of the infection, immunologic state of the host, and whether mycobacteria have been cultured and identified from the skin lesions or not. This resulted in a number of conditions with no culturable connection to tuberculosis but some have shown therapeutic response to the use of antituberculous treatment, while others show spontaneous resolution, response to other antibiotics, or to nonspecific measures such as bed rest. These are called tuberculids (Table 36.2). In this chapter an attempt to take into consideration variables that govern the outcome of the infection as well as the route of infection will be discussed, clinico-immunologic classification of the various cutaneous manifestation of the tuberculous process is seen in Table 36.1.

36.2.1 Etiopathogenesis The clinical presentation is determined by the outcome of the host immune responses, mycobacterial virulence, and the route of entry of the bacilli. The host has inherent or acquired ability to control infection. Susceptibility is decreased in populations where there is contact with TB for many generations. Such contact results in partially immunized individuals through natural infections. Blacks as well as carriers of HLA-BI5 major histocompatibility antigen are more susceptible to the disease. The age, an intact immune system, as well as socioeconomic and environmental factors are also of importance (Tapeiner and Wolff 1999). Once the host is invaded by the mycobacterium, the interaction between host immune responses and mycobacterial factors such as its virulence and the size of the inoculum will determine the outcome. Either there is unchecked multiplication, with the disease becoming apparent, or this process is arrested. Antigen-presenting cells engulf the bacteria and through the antigens displayed on their surface, they activate the T lymphocytes which release cytokines. These in turn activate macrophages that engulf the mycobacteria and kill them. Few organisms are killed in each cycle, and in the very early stages resistance depends on rapidly repeated cycles. Cytotoxic T cells lyse infected phagocytic cells with the subsequent release of surviving organisms which are phagocytosed again,

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Table 36.1. Clinico-irnmunologic classification of cutaneous tuberculosis Clinical presentation

Sensitization Route of infection of the host Exogenous Hematologic Lymphatic Contiguous

Primary tuberculous infection Tuberculous chancre Nonsensitized + Acute disseminated miliary TB Nonsensitized Postprimary tuberculous infection Reinfection Lupus vulgaris Pre-sensitized + Tuberculosis verrucosa cutis Pre-sensitized + Reactivation Scrofuloderma Pre-sensitized Tuberculosis cutis orificialis Pre-sensitized

+ +

+ + ++

autoinoculation

Reactive eruptions "True" tuberculids

Pre-sensitized

+

Table 36.2. Suggested classification of tuberculids Tuberculosis-specific tuberculids (TSTs) Conditions in which M. tuberculosislbovis plays a significant role Papulonecrotic tuberculid Lichen scrofulosorum Tuberculosis-nonspecific tuberculids (TnSTs) Conditions in which M. tuberculosislbovis is one of several other etiopathogenic factors Erythema induratum Erythema nodosum Nontuberculids (conditions previously described as tuberculids but for which recent evidence suggests no relationship to tuberculosis) Lupus miliaris disseminatus faciei Rosacea-like tuberculids Lichenoid tuberculids

and so on. A few organisms die also at the time of lysis of infected macrophages (Tapeiner and Wolff 1999; Gawkrodger 1998). The balance between lymphokines that activate macrophages and lymphokines that are toxic, necrogenic, or both will determine the final clinical picture of the infection. Different clinical entities have different bacterial numbers as seen histologically. It is difficult to determine whether the small bacterial number has caused, for example, lupus vulgaris or the host immunity has checked or decreased the number in that clinical entity. The route of infection and the targeted tissue properties (e.g., structure and vascular supply), determine, in addition to the hypersensitivity status of the host, the clinical variant exhibited dermatologically. The skin involvement could be exogenous or endogenous. Infection originating from an endogenous source can reach its destination hematologically, lymphatically, contiguously, or by autoinoculation. Local injury may act as a localizing factor.

36.3 Tuberculosis of the Skin Due to M. tuberculosis / M. bovis 36.3.1 Clinical Variants 36.3.1.1 Primary Inoculation Tuberculosis (Tuberculous Chancre) Tuberculous chancre (TC) is the result of mycobacterial infection of the skin at the site of inoculation in an unsensitized host who lacks natural or acquired immunity. The skin lesion and the affected regional lymph nodes constitute the tuberculous primary complex of the skin.

Incidence TC is a rare form of skin tuberculosis nowadays, but in 1930 it constituted 0.40% of all primary tuberculous lesions. In Asia where socioeconomic and living conditions are poor, the incidence remains high. Most patients are children, but this condition may affect adolescents and young adults, particularly those working in the medical field. It can be an occupational hazard for those people. Pathogenesis M. tuberculosis gains access into the skin and rarely the mucosa, through minor cuts, trauma, or pyodermas - as it cannot penetrate intact skin. It has been know to follow minor surgical procedures, such as circumcision (Holt 1913) when performed

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630 Table 36.3. Etiologic factors in erythema nodosum Infections

Systemic diseases

Drugs

Bacterial

Benign

Streptococcal infection M. tuberculosis

Enteropathies Connective tissue diseases Sarcoidosis Behyet's disease

Halides Pregnancy Sulfonamides Oral contraceptive pills

Yersinia enterocolitica Viral and chlamydial Chlamydia psittaci Epstein-Barr virus

Miscellaneous

Malignant Myeloproliferative disorders

Hepatitis B virus Parapox virus

Mycoses Superficial and deep mycoses

by a tuberculous rabbi, nose and ear piercing or tattooing where unsterilized needles were used. It can also be transmitted sexually through contact with individuals who have genitourinary tuberculosis. Mouth-to-mouth resuscitation has been reported to cause primary mucosal inoculation tuberculosis, and unpasteurized milk infected with bovine mycobacteria has caused oral lesions following trauma or tooth extraction (Tapeiner and Wolff 1999; Sehgal and Wagh 1990; Moschella 1985). Conjunctival and penile involvement has been reported. The skin lesion develops 2-4 weeks after inoculation, and regional lymph nodes become infected 3-8 weeks later. As the host's acquired immunity is built up, the process is localized to that area. Clinical Features The initial lesion presents a small brownish papule or nodule that rapidly enlarges and then breaks down to form a sharply demarcated, ragged ulcer with undermined reddish-blue edges, and a granular hemorrhagic base that is studded with miliary abscesses or covered with a necrotic fragmented membrane. As the lesion matures it becomes more indurated with thick adherent crust. Spontaneous but slow healing may take place. Apparent healing may conceal active infection beneath, which will eventually break through the surface giving granulating ulcers or sinuses (Tapeiner and Wolff 1999). Conjunctival lesions can either be shallow ulcers or fungating edematous granulations clinically known as phlyctenular conjunctivitis. Oral ulcers are characteristically painless and affect teeth sockets or the gum. Subcutaneous abscesses can result from the use of unsterilized needles. Painless paronychia can be caused by a primary tuberculous infection. Regional

Table 36.4. Classification of atypical mycobacteria A. Slow growers: Runyon group I - Photochromogens M. kansasii M. marinum

M. simiae Runyon group II - Scotochromogens

M. szulgai M. scrofulaceum M. xenopi Runyon group III - Nonchromogens M. avium-intracellulare complex M. genavense M. haemophilum

M. malmoense M. ulcerans B. Rapid growers: Runyon group IV M. fortuitum complex

lymph nodes enlarge slowly and occasionally may be the only clinical symptom. They are firm and painless, subside slowly, and often calcify. Cold abscesses may occasionally develop after weeks or months, they break through the skin forming discharging sinuses. Rarely, this may progress to miliary tuberculosis with fatal outcome. Constitutional symptoms may be present. Occasionally the process assumes a more acute course simulating a pyogenic infection (Moschella 1985). Course The chancre will heal slowly, taking up to 12 months, with scarring. Rarely, lupus vulgaris or tuberculosis verrucosa cutis develops at the site of a tuberculous chancre. Scars mark the sites of previously discharging liquefied lymph nodes which are calcified in 50% of cases. Calcification by itself is not a sign of cure.

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Hematogenous spread from breakdown of such foci will cause infection of other organs (Wolff 1921; Duken 1933), and depending on the size of the inoculum, and the age and immune response of the host, miliary tuberculosis may occur. Erythema nodosum develops in 10% of patients (Tapeiner and Wolff 1999; Gawkrodger 1998; Miller and Cashman 1955). The primary tuberculous complex imparts satisfactory immunity and high sensitivity in the host as shown by a positive tuberculin skin test. Histopathology

The early lesion of TC shows features of acute inflammation with necrosis. Mycobacteria are easily detected. The lesion, as well as the regional lymph nodes, show granulomatous morphology with caseation. Bacilli disappear 3-6 weeks later.

(intrauterine transmission) miliary tuberculosis has been reported, but organisms have not been cultured from lesions (McCray and Esterly 1981). Tuberculin skin testing may be negative. Clinical Features

The morphology of skin lesions in AMTS is often deceptive. There are usually disseminated bluish red to brown discrete pinhead papules, vesicles, pustules, or hemorrhagic lesions in a severely ill patient. Papules are capped by tiny vesicles that rupture or dry up forming a crust which upon removal shows a small umbilication (Fig. 36.1 a, b). Vesicles as such may become necrotic and form small ulcers (Sahn and Neff 1974). Erythematous subcutaneous nodules have been reported (Kounis and Constantinidis 1979). A search for other tuberculous infection should be made (Rietbroek et al. 1991).

Diagnosis and Differential Diagnosis

A high degree of suspicion is needed to avoid erroneous diagnosis. A persistent, painless, nonhealing ulcer with unilateral lymph node involvement should arouse suspicion of the tuberculous nature of the lesion, especially in a child, medical, or paramedical professional, particularly in endemic areas. Earlier lesions will show acid-fast bacilli in histologic specimens or smears. Diagnosis is confirmed by culture, though treatment should be initiated without awaiting results. The chancre should be differentiated from tularemia, primary complex of syphilis, sporotrichosis, cat scratch fever, and, when sinuses develop, from actinomycosis and ulcerative lesions of other mycobacterial infections (Pereira et a1. 1976). 36.3.1.2 Acute Miliary Tuberculosis of the Skin

Acute miliary tuberculosis of the skin (AMTS) is also known as tuberculosis cutis miliaris disseminata. It is a rare form of cutaneous tuberculosis subsequent to an acute hematogenous dissemination of the organism, occurring primarily in infants, children, and immunocompromised patients (Tapeiner and Wolff 1999). Pathogenesis

The initial focus of infection is either pulmonary or extrapulmonary. It may follow infection that reduced immunologic defenses, like measles, other exanthems, and AIDS (Tapeiner and Wolff 1999). Congenital

Fig.36.1. a Acute miliary tuberculosis of the skin. Multiple red to brown discrete scaly and crusted papules are seen on the trunk. Central crusts can be seen in some of the lesions. Courtesy of Dr. M. Enani, Department of Medicine, RKH. b Postinfiammatory hyperpigmentation of the previously involved skin of the same patient. Courtesy of Dr. M. Enani, Department of Medicine, RKH

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Course AMTS is usually fatal if the diagnosis is missed or delayed. Very young patients usually experience a downhill course. Favorable outcome has been reported and only happens if antituberculous therapy is instituted immediately upon suspicion, with supportive management. Cutaneous lesions heal with white depressed scars that have a brownish halo (Tapeiner and Wolff 1999; Schermer et al. 1969).

solely for the treatment of patients with lupus vulgaris because of the high prevalence of these cases in the 1940s and 1950s. It is now uncommon in Europe, infrequent in the East, and rarely reported in the United States (Goh et al. 1974). Women appear to be affected two to three times as often as men (Horwitz 1960; Kalkoff 1950). All age groups are uniformly affected (Tapeiner and Wolff 1999; Gawkrodger 1998), but in developing countries the majority of cases are in the 2nd and 3rd decade of life (Singh 1974; Sehgal et al. 1987; Pandhi et al. 1977).

Histopathology Pathogenesis Acute phase histologic findings are nonspecific. Necrosis, nonspecific inflammatory infiltrate, which at times forms small abscesses, and occasionally signs of vasculitis are seen. Mycobacteria may be present in and around blood vessels. If the patient's immune responses develop there will be lymphocytic cuffing of blood vessels and even granuloma with tubercle formation. Diagnosis An unusual exanthematous rash in a gravely ill patient who has tuberculosis or contact with a patient who has tuberculosis should arouse suspicion. These patients are usually very ill, and the rash may go often unnoticed (Tapeiner and Wolff 1999). Confirmation of diagnosis may be achieved by histology and microbiologic methods. PCR may be helpful in the diagnosis when available. 36.3.1.3 Lupus Vulgaris

Lupus vulgaris (LV) is one of the most common forms of cutaneous tuberculosis and the earliest recognized expression of the disease. It is a postprimary tuberculous infection: in other words, it occurs in a patient who has been sensitized to mycobacterium through a previous infection or vaccination and has developed high sensitivity but moderate immunity. It is a chronic, progressive condition with variable clinical expression and little tendency to spontaneous healing. Incidence Lupus vulgaris was reported early in the last century. A predilection for the northern European countries has been noted, as cool, humid climate favors its development. Specialized hospitals were available

Lupus vulgaris is a postprimary tuberculous infection and thus the skin is affected through either direct inoculation, hematogenous, lymphatic, or contiguous spread. Hematogenous dissemination could be from a distant tuberculous focus, this method could be implicated in cases in which only old pulmonary primary complex is found where disseminated mycobacteria are seeded in the skin awaiting suppression of the immune system of the host by various stimuli (Ustvedt and Ostensen 1951). Facial lesions, for example, might be explained by lymphatic spread from the mucous membranes of the nose and throat. Rarely, it may follow primary inoculation tuberculosis or BCG vaccination. Contiguous spread would explain lupus vulgaris appearing in skin over tuberculous lymphadenitis or joint involvement. It is preceded by scrofuloderma in 30% of cases (Kalkoff 1950; Horwitz 1959). The organisms are usually difficult to culture and difficult to demonstrate in histologic sections. Clinical Features Early lesion of LV may appear as is an asymptomatic solitary, tiny, reddish brown, soft, flat plaque. The lesions gradually enlarge and become more infiltrated with a darker brownish color (Fig. 36.2b). Slow peripheral extension produces gyrate shapes. The surface might remain smooth or become covered by fine scales. Apple-jelly nodules, a diagnostic feature, can be demonstrated by diascopy and when probed reveal a soft consistency. This feature might not be appreciated in patients with dark complexion (Banerjee 1956).The lesion runs an indolent course of peripheral extension in some areas while involuting with scarring in others. Fresh lesions may appear in apparently healed, scarred areas (Horwitz and Christensen 1960). The head and neck are affected in 80-90% of patients (Horwitz 1959; Kanan and Ryan 1976), particularly around the nose or on the

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Tuberculosis of the Skin

b

a

Fig. 36.2. a Lupus vulgaris. A reddish brown infiltrated plaque with superficial microabscesses and scales over the buttock of a patient with multiple tuberculous foci. Atrophic depressed scars of healed areas (arrows) are seen. Short arrow shows tethered skin of healed fistula. b Close-up of the lesion. c Lupus vulgaris. After treatment lesions appear less infiltrated and areas of scarring can be seen. There is a rim of postinflammatory hypopigmentation surrounding the lesions

cheek. Ear lobules are frequently affected. The arms and legs are affected to a lesser extent, while the trunk is the least involved except in cases with disseminated lupus vulgaris (Fig. 36.2a, c). Although lesions are usually solitary, two or more sites may be affected and at times satellite lesions appear adjacent to the primary one. Five clinical patterns can be observed in lupus vulgaris depending on the local tissue response (Gawkrodger 1998): 1. Plane forms manifest as flat, smooth surfaced or scaly plaques with polycyclic or serpiginous borders. Larger lesions may show irregular scarring with islands of activity that might persist indefinitely, and at times it might cover large areas of the body. The edge often becomes thickened and hyperkeratotic. 2. Hypertrophic tumor-like forms show deeply infiltrating tumorous growths that are soft in consistency or hyperkeratotic. Scaling and scarring are absent. There is marked soft tissue destruction with resultant edema, lymphatic stasis, vascular dilatation, and recurrent erysipelas leading to gross deformities (Tapeiner and Wolff 1999). 3. Ulcerative forms are mutilating because of extensive tissue necrosis, scarring, and ulceration, and if nasal or auricular cartilages are involved, extensive destruction takes place with contractures and deformities.

""_.. . .---c 4. Vegetating forms result from granulation tissue at areas of extensive ulceration and necrosis. Infiltration is marked but scarring is minimal. 5. Papular and nodular forms occur in disseminate lupus following a transient impairment of immunity, e.g., after measles (lupus postexanthematus) through hematogenous spread. Mucosal Lupus Vulgaris The buccal, pharyngeal, nasal, and conjunctival mucosae can be involved primarily through lymphatic spread or by extension from neighboring skin lesions. Small, soft, gray-pink papules, ulcers, or granulating masses are often present, which bleed easily. Advanced lesions may destroy the cartilage of the nasal or the larynx, resulting in collapse of the nasal septum and laryngeal stenosis, respectively. Cicatricial deformity of the soft palate may also occur (Tapeiner and Wolff 1999; Moschella 1985; Ihin et al. 1983). Course Lupus vulgaris is a slowly progressive chronic infection that might be neglected by the patient because ofthe initiallack ofsymptoms. Older patients may show extensive lesions because they probably have had the disease for longer periods or, if they were infected when older, the

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disease may have progressed more rapidly (Harrison and Marks 1980). If untreated it progresses relentlessly, leaving in its wake scarring, destruction, contractures, and deformities. Joint immobility, cicatricial ectropion, microstomia, nasal deformity, and laryngeal stenosis are some examples of what happens when such cases are neglected. The most serious complication in long-standing (l0-50 years) lupus vulgaris is the development of, most frequently, squamous and, less commonly, basal cell carcinomas. Sarcomas have also been described and their incidence was estimated as approximately 10% (Hekel and Seyss 1951), and it is believed that they have no relationship to previous X-ray therapy. An associated pulmonary or extrapulmonary tuberculosis may be present in up to 11 % in anyone series (Kanan and Ryan 1975). Tuberculous lymphadenitis was reported in up to 40% of patients with LV, and pulmonary, bone, and joint tuberculosis was reported in 10-20% in another series. LV may be regarded as a symptom of another site of tuberculous disease running a serious course (Clasen and Horwitz 1960). Histopathology LV lesions display typical tubercle formation with sparse caseation that is normally present in the upper dermis (Fig. 36.3a-c). The mycobacterium bacilli are often hard to demonstrate in sections but occasionally may be numerous. Secondary changes especially in

long-standing cases often supervene, such as epidermal thinning and atrophy, acanthosis, hyperkeratosis, and occasionally pseudoepitheliomatous hyperplasia. The dermis may show nonspecific inflammation disguising the tuberculous nature of the lesion, especially when necrosis and inflammation are present. Dormant lesions are often indistinguishable from sarcoidal infiltrates when epitheloid granulomas dominate in sections of tissue specimens (Tapeiner and Wolff 1999). Fibrosis with small epitheloid foci, that eventually disappear, may be seen in involuting lesions. Diagnosis and Differential Diagnosis Morphologically, the classic soft, brownish red lupus vulgaris plaque with its apple-jelly nodules noted on diascopy does not present a diagnostic problem. Early lesions must be distinguished from discoid lupus erythematosus, lymphocytoma, and Spitz nevus. In older lesions sarcoidosis, tertiary syphilis, leprosy, deep mycotic infections, lupoid leishmaniasis, and chronic vegetating pyodermas should be considered. Other differential diagnoses include psoriasis, Bowen's disease, and Wegener's granulomatosis. Facial lesions might resemble rosacea (Warin and Wilson-Jones 1977). Histologic examination and culture are mandatory for confirming the diagnosis. Tuberculin test is strongly positive except in early phases of postexanthematic lupus (Fig. 36.4) (Sundt 1925).

a Fig. 36.3. a Skin biopsy exhibiting granulomatous inflammation involving the superficial and deep part of the dermis with some accentuation around the adnexa. (H&E 4) Courtesy of Dr. A. Al-Ajlan, dermatopathologist, RKH. b High power shows a granulomatous inflammation with pseudoepitheliomatous hyperplasia at the edge of the granuloma. (H&E 10). Courtesy of Dr. A. AI-Ajlan, dermatopathologist, RKH. c Higher power shows a granulomatous inflammation with lymphocytic rimming. (H&E 40). Courtesy of Dr. A. AI-Ajlan, dermatopathologist, RKH

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Tuberculosis of the Skin

Fig. 36.4. PPD skin test showing a strong reaction with 3 em of induration. There is pus formation in the center

36.3.1.4 Tuberculosis VerrUCOSQ Cutis

Tuberculosis verrucosa cutis (TVC) is a verrucous skin lesion that occurs as postprimary tuberculosis in the previously sensitized host who has a moderate to high degree of immunity, through an exogenous route. Rene Laennec (1781-1826) described his "prosector's wart" (Marmelzat 1962). The name "verruca necrogenica"was coined by Samuel Wilson (1824-1911). Other synonyms have been used, including anatomist tubercle, lupus verrucosus, and butcher's wart (Sehgal and Wagh 1990). Incidence It is one of the common types of skin tuberculosis encountered in the East, in Hong Kong it accounts for 40% of the cases (Wong et al. 1968).

over the radial border of the back of the hand, and fingers, as noted among European patients. The ankles, knees, and buttocks are more likely to be affected in children in Eastern endemic countries (Tapeiner and Wolff 1999).The initial lesion may appear as an asymptomatic indurated warty papule or papulopustule with a purple inflammatory halo. It gradually enlarges to form a hyperkeratotic warty plaque that might assume an irregular shape because of uneven spread with finger-like projections. The verrucous hyperkeratotic surface might be traversed by clefts and fissures. Though it is usually firm, areas of softening, especially in the center, will discharge pus and keratinous material through these fissures that extend deep into the infiltrated brownish red base (Hirsh and Johnson 1984; Platou and Lennox 1956; Tapeiner and Wolff 1992; Gawkrodger 1998). Tuberculosis verrucosa cutis is usually a single lesion but multiple lesions may occur. In contrast to the cutaneous primary complex, lymph node involvement is rare but may occur as the result of secondary bacterial infection (Tapeiner and Wolff 1999). A variation in the clinical expression of the disease may be seen in a deeply destructive papillomatous and sclerotic form, which may cause deformity of the limbs (Tapeiner and Wolff 1999). An exuberant granulomatous variant was described in patients from Eastern countries (Mitchell 1954; Wong et al. 1968). Psoriasiform and keloidal morphology has been observed (Gawkrodger 1998). Course

Pathogenesis This infection can result from direct inoculation of mycobacteria via minor skin trauma coming in contact with soil that has been contaminated with infected sputa (Mitchell 1954; Wong et al.I968).Acute inoculation by the patient's own infected sputum is another possibility. Accidental infection occurs in certain professional groups: for example, physicians, pathologists, medical students, and laboratory and postmortem attendants. This constitutes an occupational hazard in these professions. Butchers and farmers can be similarly infected (Tapeiner and Wolff 1999; Gawkrodger 1998; Sehgal and Wagh 1990), but in these cases, M. bovis is the most common cause. Clinical Features The lesions of TVC may occur on areas that are subject to trauma, such as the hand, particularly

A slow and gradual resolution of the lesion may take place and the course may extend over many years if untreated. Spontaneous remission often occurs with atrophic sunken scars (Tapeiner and Wolff 1999; Gawkrodger 1998) and occasionally shows central clearing with peripheral activity. A secondary bacterial infection may give rise to acute inflammatory changes. Active pulmonary, osseous, or glandular disease may coexist in these patients. Histopathology A striking pseudoepitheliomatous hyperplasia with marked hyperkeratosis and dense inflammatory infiltrate is common. Abscesses form in the upper dermis, subepidermally or within the pseudoepitheliomatous rete ridges. Typical tubercles are uncommon. Mycobacteria are found only occasionally.

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Diagnosis and Differential Diagnosis Early TVC lesions should be differentiated from warts or seborrheic keratoses. Hyperkeratotic lupus vulgaris elicits the apple-jelly nodules and a has predilection to other sites. Hypertrophic lichen planus is usually pruritic and other cutaneous or mucosal lesions might be found. Localized lichen simplex chronicus is also pruritic, and lesions mature as itching continues. Deep mycotic infections such as blastomycosis, chromomycosis, chromoblastomycosis, and actinomycosis, iododerma, bromoderma, leishmaniasis, tertiary syphilis, and pyodermas due to other organisms should be considered and differentiating tests should be undertaken. Nontuberculous mycobacteria as causative agents (esp. M. marinum) can only be differentiated by culture and PCR. 36.3.1.5 Scrofuloderma

Scrofuloderma occurs as a postprimary reactivation tuberculosis. An underlying tuberculous lymphadenitis or osteomyelitis may lead to cold abscess formation with affection of overlying skin by contiguous spread leading to its breakdown and sinus formation. It was initially described by French writers who termed it scrofulous gumma (Grange 1988; Segal and Wagh 1990). The ancient Egyptian doctors described scrofuloderma about 5000 years ago (see chapter "Tuberculosis in Ancient Egypt") Incidence In patients with tuberculous lymphadenitis, scrofuloderma remains relatively common in endemic countries. It is the most common form of tuberculosis of the skin in Mexico (Amezquila 1963) and other tropical countries, and in the immigrants from these places. All age groups are affected but the prevalence is higher among children, adolescents, and the elderly (Tapeiner and Wolff 1999).

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nal, axillary, inguinal, epitrochlear, and retroauricular. It can result also from accidental or intentional introduction of bacilli in the subcutaneous tissue by trauma or injections in patients with previous latent or manifest infection (Chien and Wiggins 1954). Clinical Features The initial cutaneous lesion of scrofuloderma is an asymptomatic bluish red, firm subcutaneous nodule or deep subcutaneous infiltrate that is freely mobile in the earlier stages of the disease. As the infiltrate enlarges, the tissue becomes matted and doughy. After a period of time liquefaction occurs, and the lesion becomes fluctuant. The skin breaks down to form linear or serpiginous ulcers with granulating, uneven floors and undermined, inverted (rolled in) bluish edges (Fig. 36.5). The discharge could be watery and purulent or caseous. Many intercommunicating fistulae lead to the formation of subcutaneous soft pockets filled with discharge. These pockets alternate with slightly firmer gummatous nodules. Scarring develops with dense fibrous bands that bridge ulcerative areas or occasionally normal skin, giving on examination a plague with knobby fibrosis at some areas and discharging sinuses or fluctuant masses in others. The face and neck are the most common sites affected, in particular the parotid, submandibular, and supraclavicular regions and the lateral aspects of the neck corresponding to the groups of cervical lymph nodes. Other groups oflymph nodes could be affected (Fig. 36.6a, b). Lesions on the extremities or on the trunk accompany tuberculous disease of pharyngeal bones and joints, the sternum, the ribs, and the spine (Fig. 36.7a-i). Course Spontaneous resolution does occur but the process is protracted (indolent). Inflammatory and ulcerative

Pathogenesis As the skin over a tuberculous focus get involved, it breaks down discharging seropurulent discharge. The most common focus is a lymph node, but tuberculosis of bones and joints, tuberculous epididymitis, and lacrimal gland or duct tuberculosis have been implicated. Cervical tuberculous lymphadenopathy is the most common site, but other groups of lymph nodes can be the source of such focus, like paraster-

Fig.36.5. Scrofuloderma. A broken down skin with bluish rolled-in margins and granulating uneven floor

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sis and tularemia by culture; syphilitic gumma which form deep craters when ulcerated; and severe forms of acne conglobata and hydradenitis suppurativa. Infection by M. scrofulaceum must be excluded as it is poorly responsive to antituberculous treatment and affected lymph nodes have to be surgically excised. Diagnosis is confirmed by bacterial culture. 36.3.7.6

Tuberculosis Cutis Oriticialis a

Tuberculosis cutis orificialis (TCO) is a rare postprimary form of cutaneous tuberculosis affecting the mucous membranes and adjacent skin due to autoinoculation of mycobacteria from an advanced tuberculous infection of internal organs in a pre-sensitized individual who has impaired cellular immunity. Incidence It is a rare form of cutaneous tuberculosis affecting only 0.2% of patients with internal disease (Bryant 1939). Men are more frequently affected, particularly among middle-aged or elderly patients.

b Fig. 36.6. a Scrofuloderma. Bilateral inguinal tuberculous lymphadenopathy which shows on the right side an enlarged lymph node and above it a scar of a lymph node biopsy while on the left there is a puckered scar of a previously draining liquefied lymph node. On the left upper thigh there is an area of scrofuloderma with dense fibrosis. b The left inguinal area of same patient as (a) after antituberculous treatment

lesions take years before complete healing with scarring. The thick fibrotic scars are so characteristic that diagnosis could be made even after healing. Lupus vulgaris may complicate preexisting scrofuloderma (Tapeiner and Wolff 1999).

Pathogenesis The underlying tuberculous disease is usually an advanced pulmonary, intestinal, or rarely a genitourinary infection. Large numbers of bacilli are shed from the foci, and trauma determines sites of inoculation. Histopathologic examinations at autopsy of patients with pulmonary tuberculosis revealed a higher incidence of oral involvement than expected, indicating that many mucosal lesions are undetected clinically (Katz 1941). Clinical Features

Histopathology The typical caseating granuloma could be seen at the periphery of an abscess or the margin of a sinus. The central changes are nonspecific showing massive necrosis and abscess formation (Fig. 36.8a, b). Tuberculosis bacilli are usually seen and can be cultured. Diagnosis and Differential Diagnosis Scrofuloderma has to be differentiated from deep fungal infections, e.g., sporotrichosis and blastomycosis (which yield typical fungal elements on culture); lymphogranuloma venereum (in the presence of negative LVG complement fixation test); from actinomyco-

The oral cavity is commonly affected in patients with pulmonary tuberculosis, the tongue, particularly the tip and lateral margins, being the most frequently involved. The soft and hard palate, the lips, teeth extraction sockets and the nose are other commonly affected sites. In patients with intestinal tuberculosis the area at and around the anus is involved while in genitourinary tuberculosis the vulva, glans, penis, and urinary meatus might be affected to varying degrees (Fisher 1977; Banerjee 1956; Nepomuceno 1971). The initial lesion is a small yellowish or reddish edematous nodule that rapidly breaks down to form an exquisitely painful shallow ulcer with a typical "punched out" look, undermined bluish edges and soft consistency.

e

f

g Fig.36.7. a Scrofuloderma. An indurated area with ulcers is seen over the tuberculous sternum and medial end of the left clavicle. b Abscess formation before breakdown. c The infiltrated plaque of scrofuloderma. d The necrotic purulent base of the ulcer is seen with granulation tissue evident in one. e Postcontrast-enhanced axial CT image of sternoclavicular region demonstrates destruction of the medial end of the left clavicle and associated abscess formation (arrow). fAxial CT image distal to (e) demonstrates destruction of the manubrium sterni and the left sternoclavicular joint (arrow). g Axial postgadoliniurn Tl-weighted MRI image demonstrates enhancement of the irregular wall of the tuberculous cavity (arrow). h Sagittal Tl-weighted MR image of the same patient demonstrates low signal intensity tuberculous abscess collection in the region of the left sternoclavicular joint (arrows). i Sagittal TZ-weighted MR image of the same level demonstrating high signal intensity collection (arrow) caused by tuberculous abscess

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a Fig. 36.8. a Histologic section of a scrofulodermatous tuberculous skin lesion exhibiting suppurative process with scattered multinucleated giant cells and aborted attempt at granuloma formation. b Close-up of the section showing epithelioid and multinucleated giant cells

The floor is covered by a pseudomembrane and often exhibits multiple yellowish tubercles and broken vessels. The surrounding mucosa is swollen, edematous, and inflamed. It seldom exceeds 2 em, may be single or multiple and show little tendency toward healing. These lesions are painful and may result in dysphagia. They signify poor prognosis.

of mycobacteria from a distant focus during periods of lowered or altered immunity, leading to the development of a single or multiple cutaneous-subcutaneous abscesses. It occurs mainly in malnourished children and adults who are immunocompromised. Pathogenesis

Course patients with orificial tuberculosis usually run a downhill course. The enlarging lesions reflect progression of internal disease and herald a most unfavorable prognosis. Anergy develops with loss of tuberculin skin sensitivity in terminal stages. Histopathology There is severe nonspecific inflammatory infiltrate and necrosis. Granulomatous tubercle formation is not seen except may be in the deep dermis. Mycobacteria are easily demonstrated. Diagnosis and Differential Diagnosis Aphthous ulcers, syphilitic lesions, and carcinoma should be excluded. There is usually abundant evidence of the disease elsewhere and the development of painful ulcers at mucocutaneous junctions will help in making the diagnosis (Tapeiner and Wolff 1999). Smears and histologic specimens show large numbers of bacilli. Bacterial culture confirms the diagnosis.

The bacilli lodge in subcutaneous tissue following periods of silent bacteremia and altered immunity particularly at sites of previous trauma resulting in the formation of one or more subcutaneous cold abscesses. Progressive organ tuberculosis and miliary tuberculosis usually precede abscess development, but they can develop without an obvious tuberculous focus. Clinical Features Early in the course of the development of the tuberculous gumma, a firm subcutaneous nodule forms that slowly softens becoming a fluctuant nontender subcutaneous abscess. The lesion may be single or multiple, appearing on the trunk, extremities, or head (Fig. 36.9a, b) (Tapeiner and Wolff 1999). Abscesses break down through the overlying skin to form ulcers with undermined edges and fistulas (Fig. 36.lOa, b). The discharge could be either purulent or serosanguinous (Fig. 36.11). The surrounding skin is bluish and tethered to the underlying mass resembling scrofuloderma. Rarely, secondary lesions develop along the draining lymphatics (Gawkrodger 1998).

36.3.1.7

Metastatic Tuberculous Abscess (Gumma)

Tuberculous Abscesses of the Breast

Tuberculous gumma (TG) is a postprimary tuberculous process that results from hematogenous spread

Mammary involvement is rare in either primary or postprimary cases of tuberculosis. The largest

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b

a .....- - Fig. 36.9. a Metastatic tuberculous abscess. An abscess formation with induration of the affected tissue and pusy discharge from the broken down areas. Courtesy of Dr. A. Al-Talaq. b A close-up view of the abscess. Courtesy of Dr. A. Al-Talaq

Fig. 36.10. a A healed tuberculous fistula showing tethering of the skin onto the underlying previously affected rib. b Closeup view of the area

a

numbers of these cases came from India and Turkey (Kakkar et al. 2000; Khanna et al. 2002; Goksoy et al. 1995). The clinical features include a breast lump, breast lump with sinus formation, or persistent abscess of the breast with or without associated lymph adenopathy. An underlying tuberculous process in the chest wall, pleura, or adjacent lymph nodes is often present. Course

Fig. 36.1 I. A tuberculous abscess. A serosanguinous discharge is seen

Depending on the general condition of the patient, the integrity of the cellular immunity, and the presence or absence of an advanced pulmonary or extrapulmonary tuberculous process, the patient may either be gravely ill or fairly asymptomatic apart from lesion-related complaints. Tuberculin skin test

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positivity is often lower than with other forms of postprimary tuberculosis but becomes absent in the very ill. Histopathology

There is abscess formation with necrosis in the center. Tubercles with granuloma formation are found at the periphery of the lesion and bacilli are usually seen by acid-fast staining. Diagnosis and Differential Diagnosis

The diagnosis of TG depends on microbiologic and histopathologic findings of specimens obtained from affected tissues. The differential diagnosis includes all forms of panniculitis, deep fungal infections including sporotrichosis, syphilitic gumma, and hydradenitis suppurativa. Tuberculous mastitis should enter in the differential diagnosis of any breast lump especially in areas where tuberculosis remains highly prevalent. 36.3.7.8 BCG Vaccination and Cutaneous Tuberculosis

BCG vaccination has substantially reduced the incidence of childhood tuberculosis (Curtis et al. 1984). Two weeks after the intracutaneous introduction of bacille Calmette-Guerin, an infiltrated papule develops. It gradually enlarges to 1 cm in size at 6-12 weeks, it ulcerates and slowly heals leaving a scar. Regional lymph nodes may enlarge but usually do not break down. Positive skin testing usually appears 5 to 6 weeks later. Complications related to BCG vaccination may occur and can be divided into nonspecific and specific (Dostrovsky and Sagher 1963; Jorgensen and Horwitz 1956). Nonspecific complications include keloid formation, epithelial cysts, granuloma, eczema, generalized hemorrhagic rashes, and erythema nodosum. The specific complication is the development of a localized or systemic tuberculous process caused by the attenuated bovine bacillus. The majority of cases are lymphoglandular and/or skin reactions that usually simulate "naturally" acquired mycobacterial infections. Horwitz and Meyer (1957) reported the development of nonfatal general complications in 1 or 2 persons/million, perforating regionallymphadenitis in 2% of vaccinated children in Denmark while postvaccinal lupus vulgaris developed in 5-10 persons/million (Horwitz and Meyer 1957;

Waaler and Rouillon 1974). BCG reactions are usually of milder nature than "spontaneous" tuberculosis of the skin and more often occur after revaccination (Jorgensen and Horwitz 1956; Izumi and Matsunaga 1982). Among these specific reactions are: 1. Lupus vulgaris: This form doesn't differ from the usual lupus vulgaris morphologically and follows the same course and responds to the same treatment. It develops near the vaccination site after a latent period of several months to years. Organisms can be recovered from the lesion in a quarter of patients. 2. Koch's phenomenon with necrosis and ulceration may develop in previously sensitized individuals and takes on a shorter time course. Regional lymphadenitis is common and constitutional symptoms may be present (Horwitz and Meyer 1957). 3. Local subcutaneous abscesses: This is a complication of faulty vaccination technique, where the bacillus is injected too deeply into the skin. Severe ulceration may ensue (Dostrovsky and Sagher 1963). 4. Severe regional lymphadenitis is definitely the most commonly occurring complication in the younger age group. 5. Scrofuloderma may develop as a complication of regional lymphadenitis, and suppuration may persist for 6-12 months. 6. Generalized tuberculid-like eruption has rarely been reported (Dostrovsky and Sagher 1963; Jorgensen and Horwitz 1956). 7. A tuberculous infection in a distant organ (lymph nodes, bone, and joints) has occurred occasionally (Rouillon and Waaler 1976). Other rare but serious reactions are anaphylactic reaction and hepatic dysfunction (Aungst et al.1975). Fatal disease secondary to generalized BCG tuberculosis is very rare (l per million vaccinations) among immunocompromised patients. 36.3.7.9 Congenital Tuberculosis

Congenital tuberculosis is still being reported in endemic sub-Saharan African countries (see chapter on childhood tuberculosis). It should be considered in an infant with febrile systemic illness who exhibits discrete, erythematous lesions with central necrotic dell. The diagnosis can be confirmed by histologic and microbiologic means.

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36.4 The Tuberculids These are generalized eruptions that develop in response to an internal focus of tuberculosis giving rise to lesions that are usually transient, symmetric, and disseminated. Darier (1896) designated the name initially to a dissimilar group of eruptions that were thought to be tuberculous in origin (Darier 1896). Many of the previously called "tuberculids" do not fulfill the criteria for "true tuberculids" and they are not related to tuberculosis and represent small indolent granulomas. The following criteria have to be fulfilled for a condition to be a true tuberculid: 1. The lesion should show a tuberculoid histology. 2. Mycobacteria should not be demonstrated in the lesion. 3. Tuberculin skin testing is highly positive. 4. Lesions resolution following treatment with antituberculous drugs. 5. Presence of a concomitant focus of a tuberculous infection elsewhere in the body. Pathogenesis Tuberculids are probably due to hematogenous spread of tubercle bacilli in patients with a moderate to high degree of immunity. The underlying tuberculous process might not be evident and the general health is usually excellent. Changes in the immune status of the patient, stasis, skin temperature, and blood supply affect the development of the eruptions. Bacilli are not seen in the lesions because of their small number or due to their rapid destruction (Miescher 1955). Mycobacterial DNA has been demonstrated in papulonecrotic tuberculids and erythema induratum of Bazin using polymerase chain reaction (PCR) (Victor et al. 1992; Degitz et al. 1993).

36.4.1 Tuberculosis-specific Tuberculids 36.4.1.1 Papulonecrotic Tuberculids

losis. Morrison and Fourie (1974) reported 91 cases seen in South Africa over a 17-year period (Degitz et al. 1993). Children and young adults are usually affected. Pathogenesis The bacilli enter the blood circulation periodically where they are opsonized and settle preferentially in skin capillaries. Immune complexes form in an Arthus-like reaction to be followed by a delayed hypersensitivity response to the mycobacteria. Clinical Features Papulonecrotic tuberculid involves recurrent, symmetric, firm, dusky red, pinhead- to pea-sized papules that appear in crops with predilection to extensor surfaces of the extremities, in particular the knees, tips of elbows, buttocks, and lower trunk, and the dorsal surfaces of hands and feet. The face, ears, and penis may be involved sometimes alone (Kumar and Sharma 1987; Nishigori et al. 1986). Papules show a central depression which is followed by crust formation that upon removal leaves a craterlike ulcer. It probably signifies localized necrosis. In some cases the papules heal rapidly (within weeks) while in others they form ulcers that heal after many months. Healing ends with the development of white punched-out scars that might show marginal hyperpigmentation. Fresh outbreaks follow healing/healed lesions and the disease process may last for years. Spontaneous resolution may occur. It affects young adults predominantly but has been seen in infants and young children. Often there are no symptoms related to other organ involvement but fever, malaise, and other constitutional symptoms might precede the eruption. In some cases it has followed BCG vaccination (de Bruyne et al. 1953) and in others transition into lupus vulgaris has occurred and has an association with erythema induratum (Morrison and Fourie 1974; Jordaan et al. 1994). Tuberculous arteritis with subsequent gangrene has been reported. Course

Papulonecrotic tuberculids (PnT) are symmetric necrotizing papules appearing in crops, affecting the extremities, and healing with scars.

The clinical picture is governed by the individual immune responsiveness and the number and virulence of the mycobacteria. The underlying tuberculous

Incidence

focus may not be apparent and extracutaneous tuber-

PnT have become rare in recent literature. It is not so uncommon in areas with high prevalence of tubercu-

culosis has been found in only 30-40% of cases (Simon 1959). Prompt response to antituberculous therapy has been described (Morrison and Fourie 1974).

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36.4.1.2 Lichen Scrofulosorum

Histopathology In a well-developed PnT lesion there is a wedgeshaped necrosis in the upper dermis extending to and involving the epidermis, the dermis, and sometimes the subcutaneous tissue. The inflammatory infiltrate surrounding the area is usually tuberculoid, but may be nonspecific. Obliterative and sometimes granulomatous vasculitis is a cardinal feature leading to thrombosis and complete occlusion of the vascular channel. Recanalization has been observed (Tapeiner and Wolff 1999).

This is a lichenoid eruption of 2-S-mm erythematous, grouped, scaly often perifollicular papules in a patient with high sensitivity to M. tuberculosis. Incidence Lichen scrofulosorum (LSc) is a rare form of tuberculosis. It was first recognized by Hebra (Rauschkolb 1934). Children are usually affected as well as adolescents and adults.

Diagnosis and Differential Diagnosis Pathogenesis The clinical features of PnT are classical, but because of the rarity of the condition today and the frequent absence of an obvious focus of tuberculosis, it may deceive the unwary (Tapeiner and Wolff 1999). Diagnosis should be confirmed histologically or by using PCR when available. A therapeutic test is usually decisive. Differential diagnoses include insect bites that are usually itchy and less symmetric. Prurigo nodules are also itchy and differ in distribution. Papular secondary syphilis is more widely distributed with palm and sole involvement. Serologic testing for syphilis is essential. Leukocytoclastic vasculitis rash is less indurated, more red in color, might show dark central vesiculation depending on severity, but histopathologic findings may help in reaching a diagnosis despite some similarities. Pityriasis lichenoides et varioliformis acuta (PLEVA) may present a diagnostic challenge but is more wide spread, involving the trunk, palms, and soles.

Lichen scrofulosorum is usuallyassociated with chronic tuberculous infection of lymph nodes, bones, or both. Rarely, it is associated with pulmonary tuberculosis. It results from hematogenous spread of mycobacteria. It has been observed following BCG vaccination (Curtis et al. 1984). Clinical Features Lesions of lichen scrofulosorum consist of small, firm, yellow to reddish brown follicular or perifollicu1ar papules. They may be flat topped or scaly, or bear a minute horny spine. Rarely, they may be surmounted by a tiny pustule. Grouping of individual lesions results in the formation of discoid plaques usually on the trunk where they may persist unchanged for long periods, involuting slowly over months without scarring (Fig. 36.12a, b) (Tapeiner and Wolff 1999; Goldschmidt and Grekin 1990).

b

a

Fig. 36.12. a Lichen scrofulosorum grouped follicular and perifollicular scaly papules. b Close-up view of the grouped papules

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Course

Superficial dermal tuberculoid granulomas usually develop around hair follicles and sweat ducts, but may also develop independent of the adnexa (Montgomery 1937). It often abuts on and erodes the epidermis. There is no caseation usually, and bacilli are not seen.

not edematous, skin, it has long been accepted that transient mycobacteremia produces a reaction that is both induced by and superimposed upon the basic circulatory disorder. The pathogenic significance of the vasculature is clearly demonstrated by the vasculitic histologic pattern. Vessels of these patients react abnormally to changes in ambient temperature, thus cutis marmorata is common and the association of the rash with cold exposure. Mycobacterial DNA using PCR has been demonstrated in 20-50% of the cases. The peripheral T lymphocytes of patients with EI show an exaggerated response to PPD skin testing. T cells predominate in biopsy specimens suggesting aT-cell mediated response to a tuberculous antigen (Kuramato et al. 1990; Oller et al. 1993).

Diagnosis and Differential Diagnosis

Clinical Features

Biopsy will show the tuberculoid pathology. Lichen nitidus lesions are smaller, shinier, and more peripheral. Keratosis pilaris and lichen spinulosa papules are usually skin colored and truly follicular. Lichen planus, secondary syphilis, and sarcoidosis should also be excluded.

In the initial stages, there are slightly tender erythematous indurations appearing on the back of the lower legs of young to middle-aged women on a background of erythrocyanotic circulation. Affected legs tend to be plump and follicular perniosis may be present. Regression of these lesions occurs during the warmer months at first, but as the condition progresses the indurations give rise to indolent, mildly tender, ill-defined, dull red, deep nodules. These nodules often persist for months and may either dry up and heal or soften to form deep persistent, ragged ulcers with bluish margins (Goldschmidt and Grekin 1990). Resolution is usually slow because of the circulatory dysfunction. It may take weeks and ends in scarring (Forstrom and Hannuksela 1970).

Patients are usually well, due to the lack of constitutional symptoms. Chronic plaques may persist unchanged for months. Antituberculous treatment results in complete resolution, though slower and less dramatically than with other tuberculids. Histopathology

36.4.2 Tuberculosis Nonspecific Tuberculids 36.4.2.7 Erythema Induratum

Erythema induratum (EI) is a chronic recurring nodular and ulcerative disorder that affects the calves of the legs, occurring secondary to tuberculosis elsewhere in the body. Other stimuli such as ischemia or infection can provoke this reactive pattern. These are better called nodular vasculitis (Montgomery et al. 1945; Eberhartinger 1963). Incidence Cases of nodular vasculitis in general comprise 0.10.2% of dermatologic patients seen in a university hospital in Europe (Montgomery et al. 1945; Eberhartinger 1963). It affects predominantly women with peaks in adolescence and at menopause. There is also a seasonal prevalence in winter and early spring. Pathogenesis As most patients with this condition have erythrocyanotic lower extremities and thick, firm, but

Course At any given time, all stages of activity of current lesions as well as the depressed white scars of previous ulcers can be seen in anyone case. The disease may persist for years. A search should be made for active tuberculosis elsewhere, e.g., at nasopharyngeal, renal, or endometrial sites. Diagnosis and Differential Diagnosis The constellation of indurated ulceration of the skin over the calves on a background of erythrocyanotic circulation is characteristic. Occasionally the circulatory disturbance is not obvious. A high index of suspicion is required to make an early diagnosis, and confirmation can be achieved by histology and PCR. Differential diagnoses include nodular vasculitis of nontuberculous origin which lacks response to anti-

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tuberculous treatment. Erythema nodosum affects primarily the shins of the legs, and is of short duration and rapid resolution. Syphilitic gumma is usually unilateral, single or forming a small group of lesions; serologic tests and histology are decisive. Nodose lesions due to iodide and bromide resemble erythema nodosum or cause ulcers with vegetating bases. Histopathology The histologic features of EI are those of nodular vasculitis with areas of tuberculoid granulomas, fat necrosis, and foreign body giant cell reaction. Changes due to perniosis can usually be seen (Wall and Smith 1981). 36.4.2.2 Erythema Nodosum

Erythema nodosum (EN) is a reaction pattern manifesting as acute erythematous tender nodules affecting extension aspects of legs especially over the shins and less commonly the thighs and forearms. Tuberculosis is only one of many infections that can lead to its development and infections are among many other etiologic factors. Incidence The average hospital incidence of EN (regardless of it etiology) in the UK is about 0.5% of new skin cases seen. The prevalence of certain infections will be reflected in the incidence of this reactive pattern according to geographic differences and seasonal variations (Ellis et al. 1982; Riska and Selnoos 1964; Ross et al. 1971). The age of onset is between 20 and 45 years with a peak from 20 to 30. There is a female preponderance with a female to male ratio of 3-6: 1 (depending on geographic location and differences in etiologic factors) that is less dramatic in children.

of gravitational effect, cooling, and the lack of muscular pump, (3) a lymphatic system that is unable to meet any increase in fluid load and has no mechanical advantage. Immune complexes are deposited in the blood vessel wall causing physical damage manifesting itself in the characteristic "bruising" seen in many EN lesions. Granulomas are formed around vascular channels. The damage to the blood vessel wall is not complete, so that a degree of blood flow is maintained, thus avoiding the necrosis, ulceration, and scarring that is seen in erythema induratum. Once immune complexes are cleared, healing takes place with initial postinflammatory hyperpigmentation that also eventually disappears. Etiology Antigenic stimuli for the development of erythema nodosum can be categorized into infections, drugs, benign and malignant systemic disease, and a few miscellaneous disorders. See Table 36.3. Clinical Features The skin lesions appear as erythematous, raised, hot, tender nodules on the anterior aspect of the lower legs (shins) which are fairly classical (Fig. 36.13). The elevation at the center is more pronounced than that at the periphery. Their color changes from red to dusky red with a purplish tinge, during the 2nd week of the eruption, to yellowish green like a bruise, most marked during the 3rd week, before subsiding with postinflammatory hyperpigmentation without ulceration or scarring. The inflammation subsides between the 4th and 6th week. The lateral aspects of the legs, thighs, and the extensor aspects of the arms, face, and any area of the body with subcutaneous fat can be involved but less frequently. The eruption is

Pathogenesis A delayed hypersensitivity reaction results in the formation of immune complexes (IC). IC are deposited in and around venules of the deep dermis. The slow-flowing, rich but highly permeable capillary bed of the adipose tissue favors their deposition. This sequence of events results in the development of erythema nodosum lesions at sites of predilection. This "reaction" pattern is elicited by many triggering factors. There is a predilection for the shins because of the combination of (1) relatively sparse arterial supply, (2) sluggish flow in the venous system because

Fig. 36.13. Erythema nodosum. Classic lesions are seen over the shins

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often preceded by fever of 38-39°C, chills, malaise, Histopathology and arthralgia. Lesions continue to erupt for about 10 days. Bed rest is important to minimize the aching The pathology is that of septal panniculitis. There of the legs and the ankle swelling. Recovery may take is usually a septal lymphohistiocytic infiltrate with several weeks. Episcleral lesions (phlyctenular con- few neutrophils, but rarely do neutrophils predomijunctivitis), hilar lymphadenopathy and arthropathy nate. There is often small as well as medium-size (in 70% of patients) may develop during the course of vessel invasion with inflammatory infiltrate with or the eruption, which may persist for a long time after without extravasation of erythrocytes. Involvement resolution of the skin lesions. Familial cases occur in of fat lobules is limited to their periphery, so fatty tuberculous families and streptococcal cases. Upper tissue necrosis does not occur. At a later stage, giant respiratory tract infection may precede the eruption cells are present either alone or in association with by 7-14 days and medications given for it might be a few histiocytes but true granulomas are very rare. erroneously blamed for the eruption. Attention to In the chronic migratory type, granulomas are more specific points in the history might lead to identifi- pronounced and vascular changes not as much, but cation of the possible etiologic factor. there is no caseation. Erythema nodosum migrans is a variant of the condition that is also known as subacute nodular Diagnosis and Differential Diagnosis migratory panniculitis (Bafverstedt 1954; Vilanova and Pinol-Aguade 1959; Rostas 1980). The eruption is Post-traumatic phlebitis and cellulitis might often unilateral, and lesions are fewer in number, less resemble erythema nodosum but they are usually tender, and persist longer than in classic erythema unilateral. Nodular vasculitis elicits smaller, tender, nodosum, affecting the lateral aspect of the leg rather and chronic lesions that resolve slowly and lead to than the anterior shin. The lesion progresses and depressed scars on the calves usually on the back and extends laterally over a period of weeks or months sides of the legs. The very early infiltrated plaques of changing its configuration. Its outline becomes pyoderma gangrenosum may be difficult to differenirregular, forming crescents or arciform patterns tiate without the presence of an associated disease. with bright erythematous borders and brownish Insect bites with abnormal reaction are irregular in violaceous centers (Rostas 1980). Bruising does not distribution. Granulomas secondary to Trichophyton occur and trauma might determine the initial site infection of the feet are situated lower over the legs. In familial Mediterranean fever a erythema nodo(Gawkrodger 1998). sum-like lesion may occur. Course Treatment Crops of new lesions can occur for up to 6 weeks. Mild cases resolve in 3 weeks and severe ones take Spontaneous resolution of EN usually occurs. Bed longer. Aches and pain in the legs, and ankle edema rest is important and supportive bandaging should especially towards the evening, may occur especially be used when the patient is ambulatory. If eruption is severe, anti-inflammatory drugs may be of use. if the patient remains ambulant. The use of systemic steroids is potentially dangerous because of a possible underlying infection, and Laboratory Investigations may only be necessary if the eruption is extensive and Laboratory abnormality in EN may be lacking but an severe. Oral potassium iodide has been used as well elevated erythrocyte sedimentation rate is common. as hydroxychloroquine (Horio et al.1983; Schulz and Depending on the clinical history, physical findings, Whiting 1976; Jarrett and Goodfield 1996). age of the patient, and the geographic location, a decision is made on what further tests to do. A full blood count, blood chemistry as well as a chest x- 36.4.3 ray are needed in all erythema nodosum patients. A Nontuberculids skin biopsy is mandatory. The standard punch biopsy is inadequate as frequently the subcutaneous fat is In these conditions the tuberculous etiology has not not included. An excisional biopsy deep enough to been proven and no mycobacteria have been recovinclude subcutaneous fat is needed to confirm the ered from the lesions although they exhibit tuberculoid features on histology. Tuberculin skin testing diagnosis.

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sensitivity is low and in the absence of an underlying tuberculous infection they are not an id reaction. The incidence of past tuberculous infections among patients with these conditions does not exceed that of the general population. Three clinical entities are recognized and discussed below.

unit with a striking similarity to tuberculosis. Damage to the vessel wall with extravasation of red blood cells and leukocytoclasia (nuclear dust) are seen in the early lesions.

36.4.3.7 Lupus Miliar;s D;ssem;nafus Fac;e; (Acne Agm;nafa)

LMF needs to be differentiated from classic rosacea which shows background erythema and telangiectasia with polymorphic lesions, and from acne vulgaris with its comedonal hallmark and pleomorphism. Lewandowsky's rosacea-like eruption has more peripheral distribution and smaller papules; perioral dermatitis does not usually involve periorbital areas; sarcoidosis; lupus vulgaris is less symmetric and less florid; and papular granuloma annulare involves a more generalized papular eruption. The combination of the brownish red papules and the pitted atrophic scars in the center of the face is characteristic. Histology will help to establish the diagnosis.

This is a chronic popular eruption of the face with spontaneous involution after a variable period of 12-24 months. Pathogenesis It appears that this is either due to a reaction to a factor yet unidentified or due to many etiologic triggers giving rise to a single morphologic entity. Implicated factors include zirconium, sebum, follicular contents, and even Demodex folliculorum (Ueki and Masuda 1979; Pinkus and Mehregan 1981). Most cases are currently believed to represent a sarcoidal form of rosacea. Clinical Features Lupus miliaris disseminatus faciei (LMF) occurs predominantly in young adults and adolescents of both sexes, particularly of Japanese origin. It consists of multiple discrete indolent, dull brown follicular or nonfollicular dome-shaped papules with yellowish center. Their size ranges between 1 and 3 mm in diameter and they are symmetrically distributed preferentially in the central "muzzle" area of the face: the lower portion of the forehead, temples, periorbital areas, bridge of the nose, cheeks, nasolabial folds, perioral areas, and chin. Occasionally dissemination occurs to involve arms, legs, trunk, and axillae. The papules are initially soft and translucent, become firm, may crust or pustulate before resolving with scar formation. Apple-jelly nodules similar to those of lupus vulgaris are demonstrated by diascopy. Course The natural history is that of spontaneous resolution with scarring.

Diagnosis and Differential Diagnosis

Treatment There is no single effective treatment. Tetracyclines may be beneficial in some patients. Dapsone has been used successfully in others (Kumanu et al. 1983) and appears to shorten the expected natural duration and prevent the eruption of new crops of lesions, which has also been achieved with the use of oral steroids (O'Driscoll and Morgan 1974). 36.4.3.2 Rosacea-like Tuberculid

This is also known as Lewandowsky's rosacea, and it is largely agreed today that this is a micropapular form of rosacea with histologic tuberculoid features (Lewandowsky 1917). Clinical Features Women aged 20-50 are affected with these numerous tiny, slightly indurated, flattened papules on a background of persistent erythema. The lesions are more peripheral than classic rosacea affecting the outer aspect of the cheeks and forehead. Occasionally the rash involves the whole face. Treatment

Histology Tuberculoid follicles with central caseation are seen in the mid-dermis in relation to the pilosebaceous

Gradual and slow spontaneous resolution is common. Tetracyclines may be of help but the response is sluggish compared with rosacea.

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36.4.3.3 Lichenoid Tuberculid

Lichenoid tuberculid (LT) was originally described by Ockuly and Montgomery (1950), and it is likely that the majority of their cases were sarcoidal reactions. Only a few additional cases have been described (Ockuly and Montgomery 1950; Kowalenko 1963; Schuhmachers 1967). Clinical Features The skin lesions of LT present as symmetric, small, reddish purple flat-topped papules that suddenly appear, affecting the extremities rather than the trunk, with a tendency to dissemination in middleaged patients. The papules are 3-5 mm in diameter and might be surmounted by a fine scale. Grouping of lesions has been noted and when coalesced, annular configuration ensues. It resolves spontaneously leaving brownish macules with no scarring. Diagnosis and Differential Diagnosis The clinical picture can only be differentiated from other similar eruptions histologically. It should be distinguished from lichen planus, pityriasis lichenoides chronica, and sarcoidosis.

36.5 Cutaneous Tuberculosis in the Immunocompromised Patients who have impaired immune responses due to various causes, as well as patients with HIV infections, are at the risk ofexhibiting unusual, atypical, and severe forms of cutaneous tuberculosis which do not fit in the aforementioned categories. It is imperative that any cutaneous lesions developing in immunosuppressed patients should be biopsied for histologic, bacterial, and fungal studies. Histologically well-formed granulomas are uncommon, but AFBs are seen in abundance. The skin biopsy culture may yield either M. tuberculosis, M. bovis, or atypical mycobacteria. Patients usually respond to antituberculous drugs but some die despite appropriate treatment. BCG vaccination of the patients has resulted in disseminated disease, and targeted benefits as well as definite risks have to be carefully weighed in immunocompromised patients (Watson and Gill 1990; Tarantola and Mann 1987; Lane and Fauci 1985).

36.6

Atypical Mycobacterial Cutaneous Infections Atypical mycobacteria are widely distributed organisms and are present in nature as environmental saprophytes found in animal and human feces, soil, vegetation, and water in lakes, rivers, swimming pools, and aquariums. They are usually nonpathogenic to man, eliciting an immune response without overt infection, as they are of low virulence. A degree of impaired host immunity is needed for the development of the disease. The outcome of the infection is determined by the organisms' virulence, the inoculum load, and the host immunity. The most common target organs are the lungs, bones, joints, and less frequently the skin, where trauma is essential for the introduction of the infective organism. Infection with the atypical mycobacteria runs a more benign and limited course than that caused by M. tuberculosis. Transmission from person to person is exceedingly rare and as the reservoir of the organism is large, control methods known to be effective in tuberculosis are ineffective in the control of atypical mycobacterial infections. With the decreased incidence of mycobacterial infection of the skin especially in developed countries there seems to be a relative increase in infections caused by other mycobacteria (Palenque 2000). History Only recently did the pathogenicity of slowgrowers other than M. leprae and M. tuberculosis become recognized: Infections clinically mimicking those caused by M. tuberculosis and the strict and often unusual culture requirements are in part responsible for this delay in recognition. In 1948, M. ulcerans was identified as the cause of an ulcerating skin condition in Australia. Ten years later it was recognized to be the etiologic agent of the "Buruli ulcer" in the Buruli district of Uganda. M. marinum was isolated from patients with swimming pool granulomas in 1954, although had been known since 1926 (Clancey et al. 1961; MacCullum et al. 1948; Linell and Norden 1954). The identification of rapid-growers atypical mycobacteria as human pathogens was reported earlier, when DaCosta isolated an organism from a postinjection abscess in 1938 and named it M. fortuitum (DaCosta Cruz 1938).

Tuberculosis of the Skin

Pathogenesis An alteration in the host immune status, or trauma or damage to a particular organ including the skin, is a prerequisite for the development of infection in most cases. Pulmonary infections are frequent in patients with preexisting lung disease and are pathologically indistinguishable from M. tuberculosis-caused infections. Skin and lymph node infections can be granulomatous, suppurative, or mixed, mimicking tuberculosis, sporotrichosis, leishmaniasis, or other diseases (Tapeiner and Wolff 1999). The most commonly encountered atypical mycobacterial skin infections are discussed below.

36.6.1 M. marinum Infection

Also known as "swimming pool granuloma" or "fish tank granuloma;' this is a granulomatous eruption caused by M. marinum which is found in fresh water and salt water (Findlay 1980). It may be also found in heated water in temperate climates, in the sea or natural ponds in warmer regions, in diseased fish, mud, and even cWorinated water where chlorination appears sufficient (Beurey et al.1981). It can occur sporadically or in small community outbreaks depending on the source. Clinical Features M. marinum is only pathogenic to abraded skin, and areas of predilection are the back of the hands and on the fingers of fish fanciers, and on the feet, elbows, and knees of swimmers (Hautmann and Lotti 1994). The incubation period is usually 2-3 weeks but ranges from 1 week to 2 months (Huminer et al. 1986). The usual initial presentation is that of a solitary, tender, bluish red nodule or pustule that may ulcerate and break down to form a crusted ulcer, or may suppurate into an abscess or remain warty. Lesions are usually solitary but occasionally there are multiple lesions along the draining lymphatics giving rise to a sporotrichoid pattern. Dissemination may occur in immunosuppressed patients (Gombert et al. 1981). Regional lymph nodes may enlarge slightly but usually do not break down. Spontaneous healing usually takes place within a few months to 2 years with residual scarring. Histopathology The histologic features vary from nonspecific acute or chronic inflammation to a more specific tuber-

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culoid inflammatory infiltrate. Fibrinoid rather than caseation necrosis is seen and Langerhans giant cells are not always present. Intracellular acid-fast bacilli may be seen. Diagnosis and Differential Diagnosis A high index of suspicion is needed. The clinical history and histopathology are suggestive of the diagnosis. Confirmation is obtained by demonstrating the organism in culture from biopsy specimen. PPD testing with M. marinum antigen is of little diagnostic value because of its antigenic cross-reactivity (Tapeiner and Wolff 1999). Other granulomatous infections should be considered in the differentials: for example, other mycobacterial infections, deep fungal infections, tertiary syphilis and yaws, and leishmaniasis. Verruca vulgaris and cutaneous neoplasia are other possibilities. Treatment M. marinum is poorly susceptible to antituberculous drugs. Three drug regimens have proved successful in the treatment: (I) tetracyclines 500 mg 3-4 times daily, (2) rifampicin 600 mg and ethambutol 1,000 mg daily, or (3) sulfamethoxazole and trimethoprim 960 mg twice daily. Minocycline (or doxycycline) 200 mg daily is considered the drug of choice by many clinicians (Brown and Sanders 1987). Treatment is recommended for many months. Surgical excision when feasible is effective (Wolinsky et al. 1972).

36.6.2 Mycobacterium ulcerans Infections

This is a cutaneous ulcerative process caused by M. ulcerans that is also known as "Buruli ulcer." The disease is most common in wet, moldy, or swampy areas of the subequatorial regions with cases clustered in the Nile riverbed areas of Uganda. Person-to-person transmission does not seem to occur (Yeager 1985). Pathogenesis The organism is introduced into the skin by microabrasions, pricks, or cuts from certain plants (Feldman 1974). The infection is confined to the skin as the organism is unable to survive the warmer core body temperature (like M. marinum). A toxin produced by M. ulcerans mayor may not be responsible for the ulceration and necrosis typical of this infection. Heal-

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ing is always preceded by the reversal of the patient's anergic state when tested by M. ulcerans antigens.

A. J. Al-Kudwah

dermal necrosis. There is no typical caseation or tubercle formation in these lesions. Acid-fast bacilli are commonly noted in tissue biopsies.

Clinical Features Diagnosis and Differential Diagnosis M. ulcerans affects mostly African children and young adults, with a female predominance. A pain- The diagnosis in endemic areas is not difficult less subcutaneous swelling develops after a nearly because of a high index of suspicion. The histologic 3-month incubation period. The swelling becomes features and culture of the organism from tissue larger and well defined, forming a nodule that is firm specimens confirm the diagnosis. The differential and mobile. It eventually ulcerates forming a shallow diagnosis is made according to the presenting clinical necrotic ulcer with deeply undermined, sometimes picture. The subcutaneous nodule has to be differenhyperpigmented, edges. There is rapid and irregular tiated from lipomas, subcutaneous cysts, panniculiextension with the ulcer reaching a diameter of sev- tis, nodular vasculitis, foreign body granuloma, and eral centimeters over a course of a few weeks. The appendageal tumors. Ulcers have to be differentiated floor of the ulcer is formed by necrotic fat and there from necrotizing cellulitis, pyoderma gangrenosum, may be mucoid clear discharge (Gawkrodger 1998). deep fungal infections, suppurative panniculitis, or The ulceration may extend into deeper structures, cutaneous neoplasia. involving the muscle and bone. It is of interest to note that despite the large size of the ulcer, the patient con- Treatment tinues to feel well with no constitutional symptoms In the early stages, simple excision is the treatment or lymphadenopathy (Grange 1980). Itching is occasionally a feature, thus the local of choice. Larger ulcers require a wider excision with name "mputa matadi" (the itching stone) in Ghana. skin grafting. Hyperbaric oxygen (Krieg et al. 1975) The lesions affect the head, neck, and trunk in chil- and local heat therapy (Meyers et al. 1974) in order dren, and extremities in adults. Van der Werf (1990) to increase affected limb temperature to levels above made the observation that affection of the left leg in that needed for survival of the viable organism have particular in adult Ghanaian farmers has to do with been tried. Therapeutic attempts with rifampicin the common farming stance with the left leg forward. and trimethoprim-sulfamethoxazole can be of value The introduction of the infection takes place near the separately or in combination (Standford and Philipps ground where feet are vulnerable to pricks, thorns, 1972). Clofazimine has been shown to be ineffective and grasses, while the right arm is significantly more (Revill et al. 1973). affected in children because the use of the right hand is a cultural imperative (van der Werf and van der Graaf 1990). Ulcers are usually single, and satellite 36.6.3 lesions may develop. The course is prolonged with Mycobacterium kansasii Infection ulceration persisting for months or years. Eventual healing is with scarring Contractures and severe M. kansasii is the atypical mycobacterium that is deformity may result from fibrosis, dystrophic calci- closely related to M. tuberculosis. It is frequently fication, as well as lymphedema (Gawkrodger 1998; associated with chronic pulmonary disease in adult Tapeiner and Wolff 1999). white men, but any age, sex, or race can be affected (Lichtenstein et al. 1965). Its prevalence is higher in temperate areas. Cutaneous involvement usually Histopathology occurs after minor trauma, in immunocompetent The histologic features are those of necrosis of the as well as immunocompromised hosts in whom an dermis and the subcutaneous tissue with a charac- extracutaneous focus is more likely to be also present teristic extensive involvement of the fat as in septal (Hirsch and Saffold 1976). panniculitis. The subcutaneous necrotic fat becomes surrounded by granulation tissue and giant cells. Clinical Features Muscles are usually spared probably because of their higher temperature. The deep dermis usually Skin lesions due to M. kansasii infection are clinically shows leukocytoclastic vasculitis affecting small and variable and most frequently present as verrucous medium-size vessels which probably account for the nodules with sporotrichoid spread. Papulopustules,

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abscesses, crusted ulcers or cellulitis-like lesions have been reported (Hirsch and Saffold 1976; Dore et al. 1979; Owens and McBride 1969; Banker 1974). Disseminated disease may occur in immunosuppressed patients (Beyl et al. 1980; Owen and Toone 1970), and in these patients periorificial skin infection may develop as the organism may be present in nasopharyngeal secretions (Ahn et al. 1976). These lesions might progress slowly, be chronic and persistent, or spontaneously regress (Tapeiner and Wolff 1999). Histopathology The histologic appearance is indistinguishable from that of M. tuberculosis. Differential and Differential Diagnosis Confirmation of the diagnosis is by identification of the organism by bacterial culture. PPD skin testing is not helpful in the diagnosis. The differential diagnoses include tuberculosis, sporotrichosis, and other atypical mycobacterial infections.

from tap water and soil. Children probably accidentally inhale or ingest the organism while playing. Clinical Features Children between the ages 1 and 3 years are primarily affected. The submandibular and submaxillary lymph nodes are targeted rather than the tonsillar and anterior cervical lymph nodes typical of M. tuberculosis infection. Constitutional symptoms are usually lacking and mild neck pain is usually the most common presenting symptom. The involvement is often unilateral where the glands gradually enlarge over many weeks then soften and ulcerate draining their contents. Occasionally there are sporotrichoid lesions due to lymphatic spread and multiple skin abscesses following hematogenous seeding of the organism (Murray-Leisure et al. 1897). Histopathology The histologic features are similar to lymphadenitis caused by M. tuberculosis with tubercle granuloma formation.

Treatment Diagnosis and Differential Diagnosis M. Kansasii is more susceptible to antituberculous drugs than other atypical mycobacteria but not as susceptible as M. tuberculosis. Care should be taken to avoid the emergence of resistant strains, and rifampicin has to be included in any regimen used with at least the standard dosage and duration recommended. Persistent isolates are susceptible to slightly higher concentrations (Ahn et al. 1981; Hobby et al. 1967; Pezzia et al. 1981). The currently recommended regimen for pulmonary and extrapulmonary M. kansasii infection is isoniazid (300 mg), ethambutol (15 mg/kg), and rifampicin (600 mg) daily for 18 months (Hautmann and Lotti 1994). In disseminated cases, in addition to the three-drug regimen, streptomycin 1 gm twice weekly can be added for the first 3 months (Snider et al. 1987). Minocycline 200 mg daily has been used successfully in one case (Dore et al. 1979).

The clinical picture of unilateral lymphadenopathy with a normal chest roentgenogram is suggestive of the diagnosis. Confirmation may be achieved by bacterial culture from tissue biopsy. Differential diagnosis includes all infective and noninfective causes of cervical lymphadenopathy. Appropriate hematologic, serologic, and histopathologic tests should be employed. Treatment Surgical excision is the treatment of choice of affected lymph nodes as M. scrofulaceum is not very sensitive to antituberculous-drug treatment. Multiple antituberculous drugs should be given to patients with Widespread disease until the sensitivity tests results are available.

36.6.5 36.6.4

Mycobacterium scrofulaceum Infection Mycobacterium scrofulaceum infection commonly affects the cervical lymph nodes in children and resembles scrofuloderma. The organism is widely distributed in the environment and has been isolated

Mycobacterium avium-intracellulare Complex Infection These organisms may cause lung involvement in patients with preexisting pulmonary disease, but osteomyelitis and cervical lymphadenitis may also occur. Disseminated infections are rare but their

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incidence is rising sharply as this infection is one of the most common causes of opportunistic infections in AIDS patients (Collins 1989; Lerner and Tapper 1984). However, primary cutaneous infection is rare. It is ubiquitous in the natural world, and more than 20 subtypes have been identified with immunologic techniques. It has been isolated from normal human feces in as many as 30% of tested cases. Pathogenesis M. avium-intracellulare complex is of low virulence for the immune-competent host but causes disseminating disease in the immunocompromised patients. It is transmitted through air into the lungs, or through water and food into the gut. Trauma is needed for the rare cases of primary cutaneous infection to occur.

al. 1988). Antituberculous drugs are used in disseminated cases but are less effective because of 10-100 times less activity against M. avium-intracellulare complex (compared with M. tuberculosis), larger dosage and more drugs are used concomitantly but with the risk of higher toxicity (Hautmann and Lotti 1994). Ciprofloxacin, clarithromycin, and azithromycin have been reported to be effective (Mandell and Sande 1990; Frank and Cabie 1995). Acquired drug resistance develops 2-7 months after commencing treatment, so a combination with other antituberculous drugs is recommended. Treatment is for life. Prophylaxis in HIV-positive patients with rifampicin 300 mg daily is recommended (Gawkrodger 1998).

36.6.6 Mycobacterium fortuitum Complex Infection

Clinical Features Post-traumatic inoculation of the skin is rare and may cause purulent leg ulcers, folliculitis, ulcerated nodules, panniculitis, abscesses, or even scaly nondescript plaques (Cox and Stransbough 1981). More commonly, the cutaneous involvement is secondary to disseminated disease with clinical presentation similar to the primary infection but more generalized and severe. The survival time of AIDS patients who are infected with M. avium-intracellulare complex is about 4 months (Horsbugh et al. 1991).

This is the only rapid grower which has been found to cause human disease in the form of subcutaneous abscesses following trauma or surgery. M. fortuitum, M. chelonae, and M. abscessus (which make up the complex) are commonly found in water, milk, soil, dust, marine life, fish, frogs, cows, and the saliva of healthy humans. Pathogenesis

Histologic features are those of noncaseating granulomas. Acid-fast bacilli may be found in the specimen and inside giant cells.

Infection may occur following trauma or surgical intervention. Infection can be disseminated in immunocompromised patients. The organism has the ability to infect a wide variety of human tissue (Hautmann and Lotti 1994). All subtypes share the affinity for the skin and soft tissues, in addition M. abscessus has an affinity for the lungs.

Diagnosis and Differential Diagnosis

Clinical Feature

Culture of the organism from various body fluids and tissue specimens such as urine, sputum, skin, lymph nodes,bone marrow, and liver is mandatory for the diagnosis. The differential diagnoses include other atypical mycobacterial infections, deep fungal infections, and other chronic granulomatous skin conditions.

In the primary cutaneous infection, following trauma by 1-2 months, a painful erythematous nodule forms, which matures into an abscess that may rupture draining a clear fluid. The process may remain localized, or in cases of compromised immunity, disseminated cutaneous disease may result in either multiple recurring abscesses on the extremities or generalized maculopapular eruption, a sporotrichoid pattern of spread has been noted. Constitutional symptoms are either mild or absent. Postinjection abscesses are probably the most common skin lesions caused either by M. chelonae or M. fortuitum. It has followed injections of vitamins, insulin, steroids, and inoculations (DaCosta Cruz 1938; Inman et al. 1969; Lau 1986; Borghans and Stanford

Histopathology

Treatment Purely cutaneous-limited lesions are best treated with surgical resection whenever feasible because of poor susceptibility to chemotherapeutic agents. Response to treatment with tetracycline or minocycline has been reported (Karinuma and Suzuki 1994; Noel et

Tuberculosis of the Skin

1973). The source of infection seems to be contaminated injection solutions (Tapeiner and Wolff 1999). Surgical procedures (e.g., mammoplasty, ophthalmic operations, median sternotomy, or percutaneous catheterization), or other procedures (e.g., hemodialysis and endoscopic examinations) can be followed by the introduction of the organism into the tissues and subsequent development of infection. Awide range of clinical presentations has been reported, including cellulitis, subcutaneous abscesses, osteomyelitis, lymphadenitis, synovitis, meningitis, mastoiditis, hepatitis, keratitis, prosthetic valve endocarditis, and bacteremia, thus eliciting the affinity of this organism to many body tissues. It is possible that trauma and surgical procedures may produce localized disease in the immune-competent patients. Impairment of immunity due to diabetes, chronic renal failure, or corticosteroid and other immunosuppressive agents will promote dissemination either as a disseminated cutaneous infection or as a systemic disease (Baack and Brown 1991; Wallace et al. 1992). HIV infection does not seem to impart an increased susceptibility to this infection (Palenque 2000). Histopathology The histologic features are those of the simultaneous occurrence of polymorphonuclear microabscesses and granuloma formation with foreign-body-type giant cells and are considered characteristic for this infection. This is known as «dimorphic inflammatory response" (Tapeiner and Wolff 1999). Caseation is usually absent, but necrosis occasionally may be present. Acid-fast bacilli can be seen in approximately one third of the patients.

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The M. fortuitum complex organisms are resistant to most standard antituberculous drugs (Wallace 1989). M. fortuitum is more susceptible to amikacin, doxycycline, sulfonamides, cefoxitin, imipenem, or ciprofloxacin. M. chelonae is usually sensitive to erythromycin, cefoxitin, and tobramycin, while M. abscessus is usually sensitive to amikacin, cefoxitin, and clarithromycin. In systemic disease an initial empirical treatment with the combination of intravenous amikacin and cefoxitin is recommended until the result of an in vitro sensitivities test is available. Oral treatment can then be commenced (Palenque 2000). Triple therapy is usually used with immunosuppressed patients.

36.6.7 Mycobacterium haemophilum Infection The organism is a rare cause of disease with the skin being most commonly involved. It requires culture media supplemented with hemin or ferric ammonium citrate, hence the name. Its prevalence is increasing, and it has been identified as the causative organism of subcutaneous granulomatous absc .sses or ulcers in immunocompromised hosts. Clinical Features M. haemophilum infection is manifested by multiple, tender, often violaceous cutaneous nodules situated commonly over joints of the extremities. Facial and chest lesions have been described, as well as joint effusions, tenosynovitis, and weight loss. Histopathology

Diagnosis An unusual cold abscess that is resistant to conventional treatment should arouse suspicion of atypical mycobacterial infection especially in the tropics. These abscesses should be differentiated from foreign-body reactions and deep mycosis. Culture of the organism from biopsy material serves a dual purpose: it confirms the diagnosis and helps the clinician make an informed decision on the choice of which antimicrobials to use as different subspecies have markedly different susceptibilities.

Tissue specimens exhibit dimorphic inflammatory response similar to M. fortuitum complex with no caseation necrosis. Diagnosis and Differential Diagnosis Culture of the organism from tissue specimens with particular attention to the temperature and media requirement will confirm the diagnosis. The differential diagnosis should include other atypical mycobacterial infections, panniculitis, and foreign-body granulomas.

Treatment

Treatment

Surgical debridement or excision of a localized disease may be sufficient, but is probably better combined with appropriate antibiotics (e.g., amikacin or doxycycline).

Treatment is often disappointing as lesions may persist despite therapy or relapse when medications are stopped. The severity of immunosuppression often

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influences the outcome (Kristjansson et al. 1991). Sensitivity tests suggest that the organism may be sensitive to rifampicin, ciprofloxacin, clarithromycin, and p-aminosalicyclic acid (Tapeiner and Wolff 1999; Darling et al. 1994). A number of other mycobacteria have been implicated in a diversity of cutaneous/subcutaneous lesions such as nodules, abscesses, ulcers, panniculitis, and draining sinuses usually in the immunocompromised host. They are primarily opportunistic pulmonary pathogens with the skin secondarily infected through hematogenous spread. These include M. simiae, M. malmoense, M. smegmatis, M. gordonae, M. thermoresistible, M. flavescens, and M. szulgai. Most are resistant to antituberculous drugs, and cultures from various specimens should aid in using the appropriate chemotherapeutic agents.

36.7 Treatment of M. tuberculosis Skin Infections The treatment of cutaneous tuberculosis is not different from that of tuberculosis elsewhere, although additional measures might need to be taken to optimize patient care. Patients have to be fully evaluated in search of an underlying tuberculous process. Attention has to be given to the patient's general condition as well as to any coexisting illnesses that might adversely affect the ongoing tuberculous process: for example, diabetes, immunosuppressive medications, and superadded infections.

36.7.1 Dermatologic Considerations Whenever an extracutaneous infection coexists with a cutaneous infection, a full antituberculous regimen must be followed. This will help avoid emergence of multidrug-resistant organisms. Because of that danger, the older, single-drug therapy with isoniazid, of lupus vulgaris and tuberculosis verrucosa cutis is better avoided, despite high cure rates. Surgical excision of isolated small lesions of lupus vulgaris or tuberculosis verrucosa cutis may be effective. Plastic surgery is needed to correct disfigurement left by healed extensive lupus vulgaris. Surgery in scrofuloderma is needed to debride dead and infected tissue so as to reduce morbidity and shorten the duration of chemotherapy (Gawkrodger 1998; Tapeiner and Wolff 1999).

A. J. Al-Kudwah

Acknowledgements. I would like to thank my son M. Monir Madkour for his diligent help with MedLine searches and computer skills. Also I would like to thank Amr, Rasha, and Reem Madkour for their help and support, each one in his or her own way. Above all, I would like to thank my husband for giving me this opportunity.

References Ahn CH et al (1976) Ventilatory defects in atypical mycobacteriosis. Am Rev Respir Dis 113:273 Ahn CH,Loweli JR,Ahn SA et al (1981) Chemotherapy for pulmonary disease due to mycobacterium kansasii efficacies of some individual drugs. Rev Infect Dis 3:1028-1034 Amezquila R (1963) Tuberculosis cutanea: aspectos clinicos y epidemiologicos en Mexico. Acta Lepro116:1 Anonymous (1991) Epidermiologic notes and reports: Mycobacterium haemophilum infection, New York City Metropolitan Area, 1990-1991. Arch Dermato1127:1628 Aungst CW et al (1975) Complications of BCG vaccinations in neoplastic disease. Ann Intern Med 82:666 Baack BR, Brown RE (1991) Atypical mycobacterium softtissue infection on the dorsal radial wrist: a possible complication of steroid injection for de Quervain's disease. Ann Plast Surg 27:73-76 Bafverstedt B (1954) Erythema nodosum migrans. Acta Derm Venereol (Stockh) 34:181 Banerjee BN (1956) Common clinical manifestations of tuberculosis of the skin in the tropics. Ind J DermatoI2:7-13 Banker DJP (1974) Mycobacterial skin ulcers. Br J Dermatol 91:473-474 Beurey J, Weber M, Vignaud JM et al (1981) Mycobacterioses cutanees: enquete epidemiologique. Ann Dermatol Venereol 108:439-442 Beyl BE et al (1980) Cutaneous mycobacteriosis: analysis of 34 cases with a new classification of the disease. Medicine (Baltimore) 60:95 Borghans JGA, Stanford JL (1973) M. Chelonei in abscesses after injection of diphtheria-pertussis tetanus-polio vaccine. Am Rev Respir Dis 107:1-8 Brown JW, Sanders CV (1987) Mycobacterium marinum infections: a problem of recognition not therapy (editorial)? Arch Intern Med 147:817-818 Bryant JC (1939) Oral tuberculosis. Am Rev Tubercle 39:738 Chien JTT, Wiggins ML (1954) Self-inoculation with M. tuberculosis and P. aeruginosa by a diabetic woman. Am Rev Tuberc 69:818 Citron KM, Girling DJ (1987) Tuberculosis. In: Weatherhall DJ, Ledinghan JGG, Warrell DA (eds) Oxford textbook of medicine, vol I, 2nd edn. ELBS/Oxford University Press, Oxford, 5.278-5.299 Clancey JK et al (1961) Mycobacterial skin ulcers in Uganda. Lancet 2:951 Clasen K, Horwitz 0 (1960) The morbididty for pUlmonary tuberculosis in patients suffering from extrapulmonary tuberculosis disease, lupus vulgaris cutis. Adv Tuberc Res 10:237 Collins FM (1989) Mycobacterial disease, immunosuppression

Tuberculosis of the Skin and acquired immunodeficiency syndrome. Clin Microbiol Rev 2:360-377 Cox SK, Stransbough LJ (1981) Chronic cutaneous infection caused by mycobacterium intercellulare. Arch Dermatol 117:794 Curtis HM et al (1984) Incidence of childhood tuberculosis after neonatal BCG vaccination. Lancet 1:145 DaCosta Cruz J (1938) "Mycobcterium fortuitum" un novo bacilo acido resistente patogenico par 0 homem. Acta Med Rio de Janeiro 1:297-301 Darier MJ (1896) Les "tuberculids" cutanees. Ann Der Syphiligr (Paris) 7:1431-1436 Darling TN, Sidhu-Malik N, Corey GR et al (1994) Treatment of Mycobacterium haemophilum infections with an antibiotic regimen including clarithromycin. Br J Dermatol 131 :379-390 De Bruyne JI, van Creveld S, Prakken JR (1953) Papular tuberculids after BCG vaccination. Acta Derma Venereol (Stockh) 33:385-390 Degitz K, Messer G et al (1993) Successful treatment of erythema induratum of Bazin following rapid detection of mycobacterial DNA by polymerase chain reaction. Arch DermatoI129:1619-1620 Dore N, Collins JP, Mankiewicz E (1979) A sporotrichoid-like M. kansasii infection of the skin treated with minocycline hydrochloride. Br J Dermatoll0l:75-79 Dostrovsky A, Sagher F (1963) Dermatological complications of BCG vaccination. Br J Dermatol 75:181 Duken J (1933) Ober Verlaufsarten der extrapulmonalen Primartuberkulose. Z Kinderheilkd 55:687 Eberhartinger C (1963) Das Problem des Erythema induratum Bazin. Ein Beitrag zur Kenntnis der rezidivierenden subakuten nodosen Gefassprozesse am Unterschenkel. Arch Klin Exp Dermato1217:196 Ellis ME, Pope J, Mokashi A et al (1982) Compylobacter colitis associated with erythema nodosum. Br Med J 285:937-940 Feldman RA (1974) Primary mycibacterial skin infection: a summary. Int J Dermatol 13:353 Findlay GH (1980) Mycobacterial infections other than leprosy. In: Rook A, Savin JA (eds) Recent advances in dermatology, 5th edn. Churchill Linvingstone, Edinburgh, pp 59-81 Fisher JR (1977) Miliary tuberculosis with unusual cutaneous manifestations. JAMA 238:241-242 Forstrom L, Hannuksela M (1970) Anti-tuberculous treatment of erythema induratum of Bazin. Acta Derm Venereol (Stockh) 50:143-147 Franck N, Cabie A (1995) The reemergence of tuberculosis and atypical abscesses due to mycobacterial diseases. Curr Opin Dermatol 249-253 Gawkrodger DJ (1998) Mycobacterial infections. In: Rook, Wilkinson, Ebling (eds) Textbook of Dermatology,vol 28, 6th edn. Blackwell Science, Oxford, pp 1181-1214 Goh YS, Ong BH, Rajan VS (1974) Tuberculosis cutis in Singapore: a two year experience. Sing Med J 15:223-226 Goksoy E, Duren M, Durgun V, Uygun N (1995) Tuberculosis of the breast. Eur J Surg 161:471-473 Goldschmidt H, Grekin RC (1990) Mycobacterial diseases. In: Andrew's diseases of the skin. W. B. Saunders Company, Philadelphia, London, Toronto, Montreal, Sydney, Tokyo. Clinical dermatology, chap 16, 8th edn. pp 375-388 Gombert MD et al (1981) Disseminated mycobacterium marinum infection after renal transplantation. Ann Intern Med 94:435-486

655 Grange JM (1980) Mycobacterial disease. Arnold, London, pp 80-82 Grange JM (1988) Lupus and lepros. Int J Dermatol 59: 111-112 Harrison PV, Marks JM (1980) Lupus vulgaris and cutaneous lymphoma. Clin Exp DermatoI5:73-77 Hautmann G, Lotti T (1994) Atypical mycobacterial infections of the skin. Dermatol Clin 657-668 Hekel K, Seyss R (1951) Die malignen tumoren in lupo vulgaris. Hautarzt 2:349 Higuchi M, Suga M, Dannenberg AM et al (1981) Persistence of protein, carbohydrate and wax components of tubercle bacilli in dermal BCG lesions. Am Rev Respir Dis 123: 397-401 Hirsch FS, Saffold OE (1976) M Kansassii infection with dermatologic manifestations. Arch Dermatol 112:706-708 Hirsh BC, Johnson WC (1984) Pathology of granulomatous diseases. Int J DermatoI23:237-246 Hobby GL, Redmond WB, Runyon EH et al (1967) A study of pulmonary disease associated with mycobacteria other than M. tuberculosis; identification and characterization of the Mycobacteria. Am Rev Respir Dis 95:954-971 Holt LE (1913) Tuberculosis acquired through ritual circumcision. JAMA 61:99 Horio T, Danno K, Okamoto H et al (1983) Pottassium iodide in erythema nodosum and other erythematous dermatoses. J Am Acad DermatoI9:77-81 Horsburgh C,Harlick J, Ellis E (1991) Survival of patients with acquired immune deficiency syndrome and disseminated mycobacterium avium complex infection with and without anti-mycobacterial chemotherapy. Am Rev Respir Dis 144: 557-559 Horwitz 0 (1959) The localization of lupus vulgaris of the skin. Acta Tuberc Scand 47:175 Horwitz 0 (1960) Lupus vulgaris cutis in Denmark 1895-1954: its relation to epidemiology of other forms of tuberculosis. Acta Tuberc Scand 49: 1 Horwitz 0, Christensen S (1960) Numerical estimates of the extent of the lesion of lupus vulgaris cutis and their significance for epidemiologic and clinical research. Am Rev Respir Dis 82:862-872 Horwitz 0, Meyer J (1957) The safety record of BCG vaccination and untoward reactions observed after vaccination. Adv Tuberc Res 8:245 Huminer D, Pitlik SD, Block C et al (1986) Aquarium borne M. marinum skin infection. Arch DermatoI122:698-703 Ihin CW, Choi CK, Suh JI (1983) LUpus tumidus involving facial skin, nasal cavity, throat and eye. Dermatologica 166:38-39 Inman PM, Beck A, Brown AE et al (1969) Outbreak of infection abscesses due to M. abscessus. Arch Dermatol 100: 141-147 Izumi AK, Matsunaga J (1982) BCG vaccine-induced lupus vulgaris. Arch Dermatol 118: 171 Jarrett P, Goodfield MJD (1996) Hydroxychloroquine and chronic erythema nodosum (letter). Br J Dermatol134:373 Jordaan HF, van Niekerk DJ et al (1994) Papulonecrotic tuberculid. A clinical histopathological and immunohistochemical study of 15 patients. Am J DermatopathoI16:474-485 Jorgensen BB, Horwitz 0 (1956) Dermatological complications of BCG vaccination. Acta Tuberc Scan 32:179 Kakkar S, Kapila K, Singh MK, Verma K (2000) Tuberculosis of the breast: a cytomorphologic study. Acta eytol 44:292-296

656 Kalkoff KW (1950) Die Tuberculose der Haut. Thieme, Stuttgart Kanan MW, Ryan TJ (1975) Endonasallocalization of blood borne viable and non-viable particulate matter. Br J Dermatol 92:475-478 Kanan MW, Ryan TJ (1976) The localization of granulomatous diseases and vasculitis in the nasal mucosa. In: Ryan TJ (ed) Microvascular injury. Saunders, London, pp 195-220 Karinuma H, Suzuki H (1994) Mycobacterium avium complex infection limited to the skin in a patient with systemic lupus erythematosus. Br J Dermatol130:785-790 Katz HL (1941) Tuberculosis of the tongue. Q Bull Seaview Hosp 6:239 Khanna R, Prasanna GV, Gupta P, Kumar M, Khanna S, Khanna AK (2002) Mammary tuberculosis: report on 52 cases. Postgrad Med J 78:422-424 Kounis NG, Constantinidis K (1979) Unusual tuberculous skin manifestations. Practitioner 222:390-393 Kowalenko W (1963) Ober ein lichenoides Exanthem unklarer Pathogenese (zur Kenntnis des "Lichenoid Tuberculid" von Montgomery). Dermatol Wochenschr 147:13 Krieg RE et al (1975) The treatment of mycobacterium ulcerans infection by hyperbaric oxygenation. Aviat Space Environ Med 46:1241 Kristjansson M, Bieluch VM, Byeff PD (1991) Mycobacterium haemophilum infection in immunocompromised patients case report and review of the literature. Rev Infect Dis 13: 906-910 Kumanu K, Tani M, Murata Y (1983) Dapsove in the treatment of miliary lupus of the face. Br J Dermatoll09:57-62 Kumar B, Sharma VK (1987) Papulonecrotic tuberculides on glans penis. Dermatologica 174:151-152 Kuramato Y, Aiba S, Tagami H (1990) Erythema induratum of Bazin as a type of tuberculid. J Am Acad Dermatol 22: 612-616 Laennec RTH (1962) Traite de L'auscultation mediate et des maladies des peumons et du coevr, vol 1. Asselin and Cie, Paris, 1826, pp 649-650. Quoted in Marmelzat WL. Laennec and the «prosector's wart». Arch DermatoI86:122-124 Lane HC, Fauci AS (1985) Immunologic aspects of acquired immuno-deficiency syndrome. Adv Host Def Mech 5: 131-148 Lau JH (1986) Hand infection with M. chelonei. Br Med J 292: 444-445 Lerner CW, Tapper MC (1984) Opportunistic infection complicating acquired immunodeficiency syndrome. Medicine 63:155-164 Lewandowsky F (1917) Ober rosacea-ahnliche Tuberkulide des Gesichtes. Korresp Bl Schweiz Arz 47:1280 Lichtenstein MR, Takimura Y, Thompson JR (1965) Photochromogenic mycobacterial pulmonary infection in a group of hospitalized patients in Chicago. Am Rev Respir Dis 91: 592-595 Linell F, Norden A (1954) Mycobacterium balnei: a new acidfast bacillus occurring in swimming pools and capable of producing skin lesions in humans. Acta Tuberc Scand 33: 1

MacCullum P et al (1948): New mycobacterial infection in man: clinical aspects. J Pathol Bacteriol 60:93 Mandell GL, Sande MA (1990) Antimicrobial agents. Drugs used in the chemotherapy of tuberculosis and leprosy. In: Goodman, Gilman et al (eds) The pharmacological basis of therapeutics, 8th edn. Pergamon, New York, p 1146

A. J. Al-Kudwah Marcoval J, Servitje 0, Moreno A et al (1992) Lupus vulgaris: clinical, histopathologic and bacteriologic study of 10 cases. J Am Acad Dermatol 26:404-407 Marmelzat WL (1962) Laennec and the prosector's wart. Arch DermatoI86:74-76 McCray MK, Esterly NB (1981) Cutaneous eruptions in congenital tuberculosis. Arch Dermatol 117:460 Meyers WM et al (1974) Heat treatment of mycobacterium ulceran infections without surgical excision. Am J Trop Med Hyg 23:924 Miescher G (1955) Uber katamnestische Untersuchungen bei Fallen mit Tuberkulid. Dermatologica 110:23 Miller FJW, Cashman JM (1955) The natural history of peripheral tuberculosis lymphadenitis associated with a visible primary focus. Lancet 1:1286 Mitchell PG (1954) Tuberculosis verrucosa cutis among Chinese in Hong Kong. Br J Dermatol 66:444-448 Montgomery H (1937) Histopathology of various types of cutaneous tuberculosis. Arch Dermatol Syphilol 35:698 Montgomery H et al (1945) Nodular vascular diseases of the legs. JAMA 128:335 Morrison JGL, Fourie ED (1974) The papulonecrotic tuberculid from Arthus reaction to lupus vulgaris. Br J Dermatol 91:263-270 Moschella SL (1985) Mycobacterial infections. In: Moschella SL, Hurley HJ (eds) Dermatology, 2nd edn. Saunders, London, pp 921-946 Murray-Leisure KA, Egan N et al (1897) Skin lesion caused by mycobacterium scrofulaceum. Arch Dermatol 123: 369-370 Nepomuceno DR (1971) Tuberculosis of the anal canal: report of a case. Dis Colon Rectum 14:313-316 Nishigori C, Taniguchi S, Hayakawa M (1986) Penis tuberculosis papulo-necrotic tuberculides on the glans penis. Dermatologica 17:93-97 Noel SB, Ray MC, Greer DL (1988) Cutaneous infection with M. avium intracellulare scrofulaceum intermediate: a new pathogenic entity. J Am Acad DermatoI19:492-495 O'Driscoll T, Morgan G (1974) Acne agminata of the eye lid. Proc Roy Soc Med 67:869 Ockuly OE, Montgomery H (1950) Lichenoid tuberculid: a clinical and histopathologic study. J Invest Dermatol 14: 415 Oller MW, Thomas P, Korting HC et al (1993) Erythema induratum of Bazin: evidence of T-lymphocyte hyper-responsiveness to purified protein derivative of tuberculin. Arch DermatoI127:496-473 Owen DS, Toone E (1970) Soft tissue infection by group I atypical mycobacteria. South Med J 63: 116 Owens DW, McBride ME (1969) Sporotrichoid cutaneous infection with M. kansasii. Arch Dermatoll00:54-58 Palenque E (2000) Skin disease and nontuberculous atypical mycobacteria. Int J Dermatol 39:659-666 Pandhi RK, Bedi TR, Kanwar AJ et al (1977) Cutaneous tuberculosis: a clinical and investigative study. Ind Dermatol 22: 99-107 Pereira CA, Webber B, Orson JM (1976) Primary tuberculous complex of the skin. JAMA 235:942 Pezzia W, Raleigh JW, Bailey MC et al (1981) Treatment of pulmonary disease due to mycobacterium kansasii: recent experience with rifampin. Rev Infect Dis 3:1035-1039 Pinkus H, Mehregan AH (1981) Guide to dermato histopathology, 3rd edn. Appleton-Century-Croftis, New York, p 231

Tuberculosis of the Skin Platou RV, Lennox RH (1956) Tuberculous cutaneous complexes in children. Am Rev Tuberc 74:160-172 Rauschkolb JW (1934) Tuberculosis of the skin. Arch Dermatol Syphilol 29:398 Revill WD et al (1973) A controlled trial of the treatment of mycobacterium ulceras infection with clofaxzimine. Lancet 2:873 Rietbroek RC, Dahlmans RP, Smedts F et al (1991) Tuberculosis cutis miliaris disseminata as a manifestation of miliary tuberculosis: literature review and report of a case of recurrent skin lesions. Rev Infect Dis 13:265-269 Riska N, Selnoos 0 (1964) Clinically diagnosed sarcoidosis in Finland in 1960. Acta Tuberc Scand 44:267-275 Ross PW, Christy MK, Knox JDE (1971) Sore throat in children: its causation and incidence. Br Med J 624-626 Rostas A (1980) Erythema nodosum migraus in a young woman. Arch Dermatol116:325 Rouillon A, Waaler H (1976) BCG vaccination and epidemiological situation. A decision making approach to the use of BCG. Adv Tuberc Res 19:65 Runyon EH (1965) Pathogenic mycobacteria. Adv Tuberc Res 14:235 Runyon EH (1974) Ten mycobacterial pathogens. Tubercle 55: 235-248 Sahn SA, Neff TA (1974) Miliary tuberculosis. Am J Med 56: 459-505 Schermer DR, Simpson CG, Haserick JR et al (1969) Tuberculosis cutis miliaris acute generalisata. Arch Dermatol 99:64-69 Schuhmachers R (1967) 2 Falle eines lichenoiden Tuberculids (Lichen scrophulosorum). Hautarzt 18:81 Schulz EJ, Whiting DA (1976) Treatment of erythema nodosum and nodular vasculitis with potassium iodide. Br J DermatoI94:75-78 Sehgal VN (1994) Cutaneous tuberculosis. Contemp Trop DermatoI12:645-668 Sehgal VN, Wagh SA (1990a) Cutaneous tuberculosis. Current concepts. Int J DermatoI29:237-251 Sehgal VN, Wagh SA (1990b) The history of cutaneous tuberculosis. Int J Dermatol 29:666-668 Sehgal VN, Srivastava G, Khurana VK et al (1987) An appraisal of epidemiologic, clinical bacteriologic, histopathologic and immunologic parameters in cutanneous tuberculosis. Int J DermatoI26:521-526 Simon VN (1959) Die Rolle des peripheren Lymphknoten in der Pathogenese der Tuberkulide. Hautarzt 10:303-309 Singh G (1974) Lupus vulgaris in India. Ind J Dermatol VenereoI40:257-260 Snider DE, Hopewell PC, Millis Jet al (1987) Mycobacteriosis and the acquired immunodeficiency syndrome . Am Rev Respir Dis 136:492-496 Standford JL, Philipps I (1972) Rifampicin in experimental

657 mycobacterium ulcerous infection. J Med Microbiol 5: 39 Sundt H (1925) A case of lupus disseminatus (post-exanthematic miliary tuberculosis cutis). Br J Dermatol37:316 Tapeiner G, Wolff K (1999) Tuberculosis and other mycobacterial infections. Fitzpatrick's Dermatol Gen Med 191: 2370-2394 Tarantola D, Mann JM (1987) Acquired immunodeficiency syndrome (AIDS) and expanded programmes on immunization. Special programme on AIDS. WHO, Geneva Ueki H, Masuda T (1979) Lupus miliaris disseminatus faciei. Hautarzt 30:353-355 Ustvedt HJ, Ostensen IW (1951) The relation between tuberculosis of the skin and primary-infection. Tubercle 32:36 Van der Werf TS, van der Graaf WTA (1990) Buruli ulcer in West Africa. Lancet 336:1440 Victor T, Jandann HF, VanNiekerk DJT et al (1992) Papulonerotic tuberculid: identification of mycobacterial tuberculosis DNA by polymerase chain reaction. Am J DermatopathoI14:491-492 Vilanova X, Pinol-Aguade J (1959) Subacute nodular migratory panniculitis. Br J Dermatol 71:45 Waaler H, Rouillon A (1974) BCG vaccination policies according to the epidermiological situation. Bull Int Union Tuberc 29:166 Wall LM, Smith NP (1981) Perniosis: a histopathological review. Clin Exp DermatoI6:263-271 Wallace RJ (1989) The clinical presentation, diagnosis and therapy of cutaneous and pulmonary infections due to the rapidly growing mycobacteria, M. fortuitum and M. chelonai. Clin Chest Med 10:419-429 Wallace RJ Jr, Brown BA, Onyi GO (1992) Skin, soft tissue and bone infections due to mycobacterium chelonei: importance of prior corticosteroid therapy, frequency of disseminated infections and resistance to oral antimicrobials other than clarithromycin. J Infect Dis 166:405-412 Warin AP, Wilson-Jones E (1977) Cutaneous tuberculosis of the nose with unusual clinical and histological features leading to delay in the diagnosis. Clin Exp Dermatol 2: 235-242 Watson JM, Gill ON (1990) HIV infection and tuberculosis. Br Med J 300:63-65 Wolff E (1921) Ober Zirkumzisionsuberkulose. Berlin Klin Wochenschr 58:1531 Wolinsky E et al (1972) Sporotrichoid M marinum infection treated with rifampin-ethambutol. Am Rev Respir Dis 105: 964 Wong Ko, Lee KP, Chin SF (1968) Tuberculosis of the skin in Hong Kong. Br J Dermtol 80:424-429 Yeager H Jr (1985) Other mycobacterium species. In: Mendell GL et al (eds) Principles and practice of infectious diseases, chap 207, 2nd edn. Wiley, New York

37 Abdominal Tuberculosis MOHAMMAD SULTAN KHUROO

and NAIRA SULTAN KHUROO

small intestinal obstruction and stricture. However, by the middle of the century all forms of tuberculosis 37.1 Epidemiology 659 had declined dramatically. This decline was caused by 37.2 Tuberculosis of Small Bowel and Colon 661 a number of factors, which included an increased stan37.3 Tuberculous Peritonitis 666 dard of living, pasteurization of milk, control of bovine 37.4 Tuberculosis of Mesenteric Lymph Nodes 670 37.5 Tuberculosis of Solid Abdominal Organs 671 tuberculosis. and introduction of antituberculous treat37.6 Tuberculosis of Other Gastrointestinal Sites 672 ment (O'Reilly and Daborn 1995). In fact, frequency of 37.7 Treatment 674 abdominal tuberculosis in the United States in 1960s and References 675 1970s dropped to such low levels that the disease was classified as a "rare" or Third World disease. However, since 1985 the number of reported cases of abdominal Tuberculosis remains one of the major health tuberculosis has dramatically increased. This was due problems in the world. WHO estimates that each to two reasons: (1) an increased incidence of all cases year 8 million new cases of tuberculosis occur and of tuberculosis (Brudney and Dobkin 1991; Cantwell approximately 3 million people die from the disease et al. 1994) and (2) an increased proportion of extra(WHO 1996). Tuberculosis is a disease of develop- pulmonary disease, especially abdominal tuberculosis ing countries; however, its incidence is increasing in (Farer et al.1979; Alvarez and McCabe 1984). From 1980 developed countries as well, mainly in the immigrant onward, reported cases of tuberculosis in the United population and in patients with AIDS (McKenna et States increased. The majority of these cases were in al. 1995; Barnes et al. 1991). Hispanics, blacks, prisoners, immigrants, refugees, and nursing home patients (McKenna et al. 1995; Cantwell et al. 1994; Nardell et al. 1986; Raviglione and O'Brien 2001; Bradney and Dobkin 1991). Multidrug-resistant 37.1 tuberculosis in AIDS patients contributed significantly Epidemiology to this increase in the occurrence of the disease (Edlin et al. 1994; Bloch et al. 1994; Gordin et al. 1996; Frieder et Abdominal tuberculosis is still prevalent in developing al.1993; Selwyn et al.1989; CDC 1990, CDC 1991; Small countries (Tandon and Prakash 1972; Bhansali 1977; et al.1993; Anand 1956). The impact of the disease was Kapoor 1998). There is confusion on the exact inci- seen particularly in urban areas. In 1979, there were dence of abdominal tuberculosis in such countries due 1,530 new cases of tuberculosis in New York City, and to problems of actual reporting, difficulty in diagnosis, by 1991 the city had 3,673 new cases of tuberculosis, a and inability to separate tuberculosis from Crohn's yearly increase that is three times the national average. disease, which can closely resemble it in its clinical The number of cases continued to increase and peaked manifestations. Abdominal tuberculosis was common in 1992. As a result of aggressive health care control in the United States early in the 20th century (Horvath policies, the number of cases has shown a gradual and Whelan 1998). It was the cause of most cases of downward trend. Another reason for high occurrence of abdominal M. S. KHURoo, MD, DM, FRCP (Edin), MACP tuberculosis was high proportion of extrapulmonary Professor, Consultant Gastroenterologist, Department of Med- disease (Farer et al. 1979; Alvarez and McCabe 1984). icine - MBC 46, King Faisal Specialist Hospital and Research In 1960s only 8% of patients with tuberculosis had Centre, P.O. Box 3354, Riyadh 11211, Saudi Arabia extrapulmonary manifestations. By 1986, extrapulN. S. KHuRoo, MBBS monary disease constituted 25% of all cases of tuberDepartment of Radiology, King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh 11211, Saudi Arabia culosis. The lung is the commonest site (over 85%) of CONTENTS

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

660

involvement in immunocompetent persons, while the disease predominantly affects extrapulmonary sites (over 50%) in patients with AIDS. As the urban epidemic of tuberculosis in the United States occurred in AIDS patients, abdominal tuberculosis revealed a significant resurgence. Mycobacterium tuberculosis is the pathogen for most cases of abdominal tuberculosis. Mycobacterium bovis, an organism transmitted by unpasteurized diary products, is the cause of a small percentage of cases in developing countries (Raviglione and O'Brien 2001; Marshall 1993). The route of infection occurs by one of the following mechanisms (Kapoor 1998; Horvath and Whelan 1998; Marshall 1993): 1. Swallowing of infected sputum. This occurs in patients with sputum-positive pulmonary disease and those with laryngeal involvement. This was the most important route of infection before the era of effective treatment. Autopsies in patients with pulmonary tuberculosis in the pretreatment era demonstrated intestinal disease in 55% to 99%. The frequency of intestinal disease was related to the severity of pulmonary involvement: 1% of patients with minimal pulmonary tuberculosis, 4.5% with moderately advanced disease, and 25% with far-advanced disease. In modern series, this mode of infection is less important and chest radiograph is completely normal in the majority of patients with intestinal tuberculosis. 2. Hematogenous spread from active pulmonary, miliary tuberculosis or silent bacteremia during the primary phase of tuberculosis. Most cases of abdominal tuberculosis occur as a result of reactivation of a latent focus in the small bowel or peritoneum. This focus is established perhaps previously, because of hematogenous spread from a primary focus in the lungs that subsequently healed completely (as they usually do without leaving any radiologic evidence of a lung lesion). Less commonly, hematogenous spread can occur from active pulmonary focus tuberculosis. Hepatosplenic tuberculosis almost always follows miliary seeding and is a manifestation of dissemination throughout the body. 3. Ingestion of contaminated milk or milk products. This mode of infection had been a common cause of spread of bovine tuberculosis in the past. However, pasteurizing and/or boiling milk has controlled this mode of transmission (O'Reilly and Daborn 1995). At present, Mycobacterium bovis is involved in a small percentage of intestinal disease

M. S. Khuroo and N. S. Khuroo

4.

5.

6.

7.

in developing countries, and this form of disease is rare in the West (Anand 1956). Contiguous spread from adjacent organs. Occasional cases of abdominal tuberculosis are related to contiguous spread from tuberculous lesions of adjacent organs. Peritoneal spread can occur from lesions in the fallopian tubes and intestines. Recent data showed that this is an infrequent mechanism in most patients with abdominal tuberculosis. More often, lymph node lesions spread the infection to the bowel wall or pancreas. Tuberculosis in patients with AIDS. Tuberculosis occurs with increased frequency in AIDS patients as the CD4 count drops below 400 cells per III (Jones et aI.1993).An autopsy study in West Africa found that 50% of adults dying of AIDS had active tuberculosis and in 85% of them the liver was involved. In fact tuberculosis is the most common specific hepatic HIV-associated lesion in such patients (Lucas 1994). The pathology of tuberculosis varies with the immune status of the patient (Bhargava et al. 1984; Edwards and Kirkpatrick 1986). In patients with intact immune systems, granulomas with Langhans giant cells and caseation or non-giant cell epitheloid granulomas are usually seen. In patients with extreme immune deficiency as commonly seen in terminal AIDS patients, the histologic pattern is that of nonreactive tuberculosis. Foci of granular necrosis are surrounded by degenerate swollen macrophages, and a large number of acid-fast bacilli are seen. An analysis using restriction-fragment-Iength polymorphisms to study the mode of infection of tuberculosis in patients with AIDS has shown that the disease is readily spread from index patients and progresses rapidly to active disease. There was no evidence that disease occurs from reactivation of a latent focus (Daley et al. 1992; Small et al. 1994). Liver disease and tuberculous peritonitis. Patients with cirrhosis of the liver with ascites have a higher chance (around 10%) of concomitant tuberculous infection (Aguado et aI.1990). In the United States, half of the patients with tuberculous peritonitis have underlying alcoholic cirrhosis as a cause of ascites formation (WHO 1990; Raviglione and O'Brien 2001; Lucas 1994). The mechanism of this infection in patients with liver disease is not known. It may be due to reactivation of a latent tuberculous focus in the peritoneum facilitated by lower immunity and coexistent ascites. Tuberculous peritonitis in patients undergoing long-term or continuous ambulatory peritoneal

661

Abdominal Tuberculosis

dialysis (CAPD). Tuberculous peritonitis has been subject. Abdominal tuberculosis may affect the gasreported as a complication of CAPD (Holley and Piraino 1990; Cheng et al.1989; Lui et al.1996; Lam et al. 2000). Talwani and Horvath (2000) reviewed the English-language literature and found 51 reported cases of CAPD-associated tuberculous peritonitis and added a 52nd case from their own experience (Lui et al. 1996). Defects in local immunity unique to CAPD may predispose to active tuberculosis in such patients. Removal of the CAPD catheter is not considered necessary for cure of the infection. Abdominal tuberculosis can occur at any age and is equally prevalent in males and females (Bhansali 1977; Kapoor 1998; Horvath and Whelan 1998). The majority of patients have symptoms present for 1 month to 1 year; however, around 20% of patients have symptoms for 1 month or less at the time of presentation. Low-grade fever, night sweats, anorexia, weight loss, general lassitude, and weakness occur in around two thirds of patients. Symptoms of disease at other sites occur in patients with active disease in extraabdominal organs. This is of particular significance in patients with active pulmonary tuberculosis or disseminated tuberculosis. Laboratory results reveal mild normocytic or microcytic anemia and normal white blood cell count (Pouchot et al. 1997). PPD is positive in most of the patients; however, it may be negative in immunosuppressed and malnourished patients (Bass et al. 1985; Huebner et al. 1993; American Thoracic Society 1981; Markowitz et al. 1993). Chest X-rays show active disease in about one fifth of patients. The evolution ofthe disease in a patient with abdominal tuberculosis depends upon route of infection, site of involvement, and underlying immune status of the gastrointe tinal

% n

II

100 7S

35% .•j ....."...

u·'"

so 2~

lIroccal

7% Lymph node

Fig.37.1. Sites of organ involvement in abdominal tuberculosis. The data are based on 596 patients with abdominal tuberculosis

trointestinal tract, peritoneum, lymph nodes, liver and spleen and pancreas singly or in combination.Abdominal tuberculosis in immunosuppressed patients poses special problems as disease has distinct bacteriologic and clinical characteristics. Gastrointestinal tuberculosis affects, in order of frequency, the ileocecal region, jejunum/ileum, colon, anorectum, stomach, appendix, duodenum, and esophagus (Marshall 1993). Reported sites of involvement of abdominal tuberculosis are shown in Fig. 37.1.

37.2 Tuberculosis of Small Bowel and Colon Pathogenesis (randon and Prakash 1972; Anand 1956). After the tubercle bacilli enter the gastrointestinal tract, they traverse the mucosa to lodge in the submucosa. There, the presence of the bacilli induces inflammatory changes, including serosal and subserosal edema, cellular infiltrate, and lymphatic hyperplasia. Eventually, the appearance of granulomata causes small papillary mucosal elevations. Lymphangitis, endarteritis, and fibrosis ensue, which lead to mucosal ulceration, caseating necrosis, and narrowing of the intestinal lumen. Mucosal ulceration may occur as a result of endarteritis of submucosal vessels. Infection can spread to mesenteric lymph nodes. As mentioned earlier, the most common site of involvement is the ileocecal region. The affinity of the bacilli for this site may be due to its relative stasis and abundant lymphoid tissue. The macroscopic appearances of intestinal lesions can follow one of the below-mentioned patterns. Such lesions are usually segmental, and multiple sites of involvement are common. Rarely, diffuse colonic involvement may simulate ulcerative colitis and Crohn's disease. Other characteristics include increased mesenteric fat and mesenteric lymphadenopathy, which can cause traction diverticula with narrowing, local fixation, and sinus tract development. a. An ulcerative lesion is characterized by multiple superficial ulcers. Ulcers are circumferential and usually surrounded by inflamed mucosa. This is the most common lesion, occurring in around 60% of such patients and is associated with a virulent clinical course. b. A hypertrophic lesion is characterized by scarring, fibrosis, and pseudotumor formation. This is seen in around 10% of such patients.

662

M. S. Khuroo and N. S. Khuroo

c. An ulcerohypertrophic lesion is characterized by an inflammatory mass with thickened and ulcerated mucosa. The lesion is most commonly seen in the ileocecal region. It causes cone-shaped deformity of the cecum, shortening of the ascending colon, and thickening of the ileocecal valve, where a wide gape is created. Overall this lesion is seen in 30% of such patients. d. Fibrous stricture occurs in some patients as a result of healed ulceration causing luminal narrowing and gut obstruction. In some cases this occurs after effective antituberculous therapy. Luminal narrowing may also occur due to extraintestinallymph node involvement without intrinsic intestinal lesions.

Clinical Manifestations. Abdominal symptoms depend upon the site of involvement of disease, pattern of pathologic changes, and underlying immunologic status of the host (Bhansali 1977; Kapoor 1998; Horvath and Whelan 1998; Marshall 1993). Involvement of small bowel and colon leads to single or multiple strictures through a number of underlying pathogenic mechanisms (see as above). Abdominal pain in such patients is characteristically described as a "ball of wind" moving around the umbilicus. It is associated with abdominal distension, inability to pass wind, and borborygmi. Following an episode of pain, diarrhea usually ensues. Steatorrhea and significant weight loss can occur due to bacterial overgrowth. Right lower quadrant mass and pain can occur in patients with hypertrophic ileocecal tuberculosis. Rarely, diffuse colonic disease can simulate symptoms of ulcerative colitis. Perforation and fistulae occur in a small percentage of patients. Massive bleeding from the lesion in the gut has been reported. Clinical exami-

nation reveals distended bowel loop and exaggerated bowel sounds. Plain X-ray of the abdomen reveals distended bowel loops with multiple fluid levels.

Diagnosis. Intestinal tuberculosis can be difficult to diagnose. The reasons for this include absence of a particular pattern of symptoms and signs. In fact, symptoms of the disease may be vague and signs nonspecific. Thus, a high degree of suspicion is needed. Even with adequate imaging, endoscopic examination and bacteriologic tools, diagnosis can correctly be made in only around 50% of patients with intestinal tuberculosis. The dominant reason for this is the inaccessibility of common sites of disease segments of the bowel, namely the ileum and ileocecal region. Moreover, the hallmark of tuberculous pathology, namely caseating granulomas, may be absent in the bowel wall and present in the draining lymph nodes (Tandon and Prakash 1972; Anand 1956). Laparotomy and resection of the involved segments with culture and animal inoculation of the organisms have been performed to make a diagnosis with precision in endemic areas. Therapeutic trial with antituberculous drugs is commonly used in developing countries to make a diagnosis. A number of clinical conditions closely simulate intestinal tuberculosis. These include Crohn's disease, amebiasis, carcinoma colon, Yersinia enterocolitis, gastrointestinal histoplasmosis, and periappendiceal abscess. A number of features may help to differentiate intestinal tuberculosis from Crohn's disease and Yersinia infection. These have been detailed in Table 37.1. The diagnostic algorithm to be followed for intestinal tuberculosis may vary with the exact site of disease involvement (Fig. 37.2). X-ray chest, PPD skin test, and flat abdominal films are usually used for the

Table 37.1. Differentiating features of abdominal tuberculosis from Crohn's disease and Yersinia infection Feature

Tuberculosis

Crohn's disease

Yersinia enterocolitica

Clinical course Stool culture Serology for Yersinia PPD X-ray of chest Ileal disease Ulcers Fistulae Granulomas

Prolonged Negative Negative Positive Positive Short Circumferential Unusual Large, many, caseating

Several weeks Positive Positive Negative Negative Short Normal endoscopy

Anal lesions Strictures Nodal involvement

Rare Usually <3 cm Often, independent of mural disease

Long intermittent Negative Negative Negative Negative Long Linear Common Small, few, noncaseating Frequent Long Only with transmural disease

Nil Intramural, multiple, large, with satellite Abscess

Nil Localized In children with ileitis

Abdominal Tuberculosis

663

I Suspect abdominal

tuberculosis X-ray chest

PPO

I Lymphadenopathy I

Luminal disease

'colonOSCO~y,

enter ileum, biopsy 'Barium enema 'Barium follow through 'Enteroclysis

!

•Ascitic fluid analysis 'Laparoscopy/ biopsy

•Fine needle aspiration biopsy

Culture & Direct Amplification Tests

initial investigations. Active pulmonary disease may help; however, it is seen in only a minority of patients. PPD skin test is positive in the majority of patients with abdominal tuberculosis, but is of limited value because it does not differentiate between active disease and previous exposure or vaccination. Furthermore, the PPD skin test may be negative in older or immunosuppressed patients (Lui et al. 1996; Lam et al. 2000). Careful examination of the flat abdominal films may give important clues to the nature and site of underlying pathology. Calcification of lymph nodes is of the speckled type, and rarely calcification of peritoneum may coexist. Episodes of abdominal pain are usually associated with dilated bowel loops with air fluid levels proximal to the site of stricture. Abdominal imaging by ultrasound, computed tomography, or magnetic resonance imaging is useful to define the bowel wall, abdominal lymph nodes, and changes in peritoneum, mesentery, and omentum. CT, with its ability to provide a comprehensive overview of abdominal structures, is the imaging modality of choice for such evaluations (Suri et al. 1999; Balthazar et al. 1990; Ha et al. 1999). The most common CT findings are mural thickening affecting the ileocecal region, either limited to the terminal ileum or cecum or, more commonly, simultaneously involving both regions (Fig. 37.3,38.10,38.12). This mural thickening is usually concentric, but is occasionally eccentric, and it predominantly affects the medial wall. In some patients, low-density areas, most likely to represent necrosis, may be noted within the thickened wall. Ileocecal involvement is usually associated with enlarged hypodense nodes in the adjacent mesentery. Skip areas of concentric mural thickening

Fig. 37.2. An algorithm which is useful to investigate most cases of abdominal tuberculosis

Fig. 37.3. Tuberculosis of colon. A 28-year-old male presenting with fever, abdominal pain, and loose motions of 18 months duration. He had a strong history of contact with an open case of pulmonary tuberculosis. General physical examination was unremarkable. Abdominal examination revealed fullness and vague tender mass in the right iliac fossa. ESR was 10 mm and PPD skin test was 7 mm. Plain X-rays of chest and abdomen were normal. Computed tomography of abdomen with oral and IV contrast shows thickened cecum (short arrow), a mass below the cecum (long arrow) and 2 lymph nodes of 1 em diameter each (arrowhead). A barium enema (Fig. 37.4a),colonoscopy (Fig. 37.5c), colonic biopsies from the lesion in the cecum (Fig. 37.6b) were performed. Colonic biopsy samples grew Mycobacterium tuberculosis on culture. He made rapid clinical improvement with antituberculous treatment

may be seen elsewhere in the small bowel, usually affecting the ileal loops. These segments may also show luminal narrowing with or without proximal dilatation. The presence of such lesions in combina-

664

tion with ileocecal involvement should strongly suggest the diagnosis of tuberculosis. Barium enema and small bowel follow-through may show mucosal ulceration, strictures, deformed cone-shaped and retracted cecum, incompetent ileocecal valve, a wide gap between a thickened ileocecal valve and a narrowed ileum (Fleischner's sign), and a fibrotic terminal ileum that empties into a rigid contracted cecum (Stierlin's sign) (Fig. 37.4, 38.9) (Suri et al.1999; Balthazar et al. 1990; Ha et al.1999). Small bowel enema (enteroclysis) has a special advantage in defining the site and number of small bowel strictures (Fig. 38.5, 38.6, 38.7) Colonoscopy has been used in patients with colonic and ileocecal tuberculosis (Singh et al. 1998; Bhargava et al. 1992; Shah et al. 1992; Misra et al. 1999; Kalvaria et al. 1988). It has the advantage that targeted biopsies from endoscopic abnormalities can be taken for histology, culture, and molecular techniques (Kochhar et al. 1991; Pulimood et al. 1999; Jost et al. 1995; Anand et al. 1994; Kashima et al. 1995; Pfyffer et al. 1996; Yajko et al. 1995; Tevere et al. 1996; Rich et al. 1996; Simon et al. 1993; Schluger et al. 1994; Bradley et al. 1996; Wobeser et al. 1996; Carpentier et al. 1995; Vlaspolder et al. 1995; Shah et al.1998). Colonoscopic examination in 50 patients of colonic tuberculosis revealed ileocecal disease in 16, ileocecal and contiguous ascending colon disease in 14, segmental colonic disease in 13, ileocecal disease and nonconfluent involvement of another part of the

a

M. S. Khuroo and N. S. Khuroo

colon in 5, and pancolitis in two patients (Singh et al. 1996). The colonoscopic appearances include mucosal nodules and ulcers, stricture with nodules and ulcerations, and mucosal nodules with or without pseudopolypoid folds (Fig.37.5). Nodules vary in size from 2 to 6 mm and have a pink surface. These are scattered and at places densely packed. Friability of mucosa over nodules is unremarkable. Ulcers may be from a few millimeters to 2 em long and are superficial with sharply defined irregular margins. Ulcers are covered with slough, which is difficult to wash away. The surrounding mucosa is nodular and hyperemic and blends imperceptibly with normal mucosa. When the ileocecal valve is involved, it is edematous, deformed, patulous, and easily admits the endoscope into the diseased terminal ileum. With diffuse colonic involvement, mucosa from rectum to cecum is hyperemic and friable and shows areas of circumferential ulcerations of different sizes along the entire length of the colon. Biopsy samples should be taken from ulcer edge, ulcer base, nodules, and from adjacent normal mucosa. Endoscopic mucosal biopsies from the colon and terminal ileum may show a mixture of pathologic changes and include (l) characteristic and diagnostic caseating granulomas in about 25% of patients, (2) noncaseating granulomas in about 35%, (3) ulceration with nonspecific granulation tissue and infiltration with polymorphs forming microabscesses in around 60%, (4) variable mucosal reparative changes in around

b Fig. 37.4a, b. Tuberculosis of colon. a Barium enema shows filling defect (arrowhead) and cone shaped deformity (long arrow) of the cecum. AppendiX is normally filled. b Barium enema shows lack of distensibility and nodular defects of the hepatic flexure, transverse and splenic flexure (arrowheads)

665

Abdominal Tuberculosis

a

c

Fig. 37.5a, b. Tuberculosis of colon. Colonoscopic views in three patients. a A transversely placed ulcer in the descending colon (arrows). b An infiltrative and nodular lesion in the transverse colon (arrows). c Hypertrophic nodular mass in the cecum (arrows)

b

20%. Characteristic granulomas show caseous necrosis in the center, are often large, with marked variations in size, and usually tend to be confluent (Fig. 37.6). The granulomas seem to be enlarged by expansion of individual granulomas or by confluence of numerous satellite granulomas. This is in sharp contrast to sarcoid

granulomas seen in Crohn's disease which are small in size, closely adjacent but discrete, and do not become confluent (Tandon and Prakash 1972). Endoscopic mucosal biopsy rarely shows M. tuberculosis organisms on smear, and routine culture yields a growth of bacilli in only 6% to 40% of speci-

a

b Fig. 37.6a, b. Tuberculosis of colon. a Histologic examination of colonic biopsy revealed dense lymphoplasmocytic infiltrate in lamina propria and a well-formed granuloma (arrows) consisting of epitheloid histiocytes and multinucleated giant cells. b Histologic examination of colonic biopsy showing moderate lymphoplasmocytic infiltrate in the lamina with infiltration and destruction of crypts (arrow). No granulomas were seen

666

mens (Singh et al. 1996; Bhargava et al. 1992; Shah et al.1992; Misra et al.1999; Kalvaria et al.1988). Recent technologic developments have introduced a number of improvements in the ability of clinical laboratories to cultivate and identify Mycobacterium tuberculosis complex more quickly and precisely than previously. These developments include more rapid detection of growth Oost et al. 1995) and tests to identify RNA or DNA of M. tuberculosis complex directly in clinical samples (Anand et al. 1994; Kashima et al. 1995; Pfyffer et al. 1996; Yajko et al. 1995; Tevere et al. 1996; Rich et al.1996; Simon et al.1993; Schluger et al.1994; Bradley et al. 1996; Wobeser et al. 1996; Carpentier et al. 1995; Vlaspolder et al. 1995; Shah et al. 1998). Exploitation of such tools for intestinal tuberculosis will make the diagnosis easier and more frequent.

37.3 Tuberculous Peritonitis Pathogenesis (Marshall 1993; Singh et al. 1969). Peritoneal seeding by tubercle bacilli causes granulomas, which appear as multiple, whitish miliary nodules «5 mm) scattered over the visceral and parietal peritoneum. In addition, the peritoneal lining along with the omentum and mesentery is thickened and adhesions develop with abdominal organs. A majority (>95%) of patients develop exudative free or loculated ascites; however, a small group of patients may have a more advanced dry fibroadhesive (plastic) or purulent form of disease. Plastic peritonitis causes adhesions and matting of bowel loops, mass formation due to matting of bowel loops, adenopathy, mesenteric and omental thickening (omental cake). Purulent peritonitis is usually secondary to tuberculous salpingitis and causes abscess formation due breakdown of caseous lesions in lymph nodes, mesentery, or omentum. These abscesses are present within matted bowel loops and thickened omentum and mesentery. Fistulae, both cutaneous and enteric, are common when such abscesses rupture either through the skin or into the bowel. Clinical Manifestations (Marshall 1993; Singh et al. 1969; Manohar et al. 1990). Tuberculous peritonitis in its ascitic form presents insidiously with progressive abdominal distension. Diffuse abdominal pain (65%), fever (71%), and weight loss (38%) are seen in a variable percentage of patients. Clinical examination reveals shifting dullness, abdominal tenderness, and transverse solid epigastric intra-abdominal mass. The last is caused by rolled-up, thickened omentum infil-

M. S. Khuroo and N. S. Khuroo

trated with tubercles. The encysted form of the disease produces a localized cystic mass usually in the central or lower abdomen, resembling a mesenteric cyst in children and ovarian cyst in females. Plastic peritonitis produces matted small bowel loops with thickening of, and adhesions with omentum and mesentery. Patients often present with recurrent attacks of subacute intestinal obstruction. Acute intestinal obstruction may sometime supervene. Dilated bowel loops produce bacterial overgrowth and cause steatorrhea and wasting. Abdominal examination reveals single or multiple bowel masses which are resonant to percussion (thickened and matted bowel loops). Solid mass may be caused by thickened mesentery. Patients with purulent peritonitis are very sick, wasted, and in moribund clinical status. Abdomen examination reveals tenderness, guarding, multiple bowel masses, and usually a fecal fistula commonly near the umbilicus. Patients with tuberculous peritonitis with cirrhosis of the liver present with similar clinical features to those without liver disease. However, patients with liver disease are younger (42±8 years vs 54±15 years, p
Diagnosis. Diagnosis of tuberculous peritonitis is mainly focused on the differential diagnosis of ascites and a well-established algorithm has been developed in clinical practice to do so (Runyon et al. 1992). The index of suspicion of tuberculous peritonitis should be high in following circumstances: a. Residence in developing countries or immigration to a Western country from a developing country b. Recent exposure to open tuberculosis c. Underlying cirrhosis d. Patients on long-term or continuous ambulatory peritoneal dialysis e. Immunosuppressed patients, especially AIDS, and patients with liver or renal transplants

667

Abdominal Tuberculosis

The value of a chest X-ray, PPD, and flat abdominal films has been discussed {Fig. 37.7). Abdominal imaging, especially CT scan, is useful for an initial investigation to give a comprehensive view of the abdominal organs. Ascitic fluid analysis gives an important lead to the possibility of infectious etiology. Laparoscopy and peritoneal biopsy is the investigation of choice to confirm the diagnosis of tuberculosis. CT findings include changes in the peritoneal lining and cavity, mesentery, and omentum (Suri et al. 1999). Peritoneal lining shows smooth uniform thickening. Nodular implants with irregular thickening of the peritoneum are unusual and more often suggest peritoneal carcinomatosis {Fig. 37.8, 38.l9a,b). Peritoneal fluid may be free or loculated and shows high-density signals (25-45 HU), possibly explained by high protein and cellular contents of the fluid. However, tuberculous ascites may also be near water density, perhaps reflecting an earlier transudative stage of immune reaction. Mesenteric infiltration can range from mild involvement in the form of linear soft tissue strands, thickened and crowded vascular

bundles, a "satellite" appearance, and subtle increase in mesenteric fat density, to more extensive involvement resulting in diffuse infiltration with soft tissue density masses involving the leaves of mesentery surrounding the adjacent bowel loops. Omentum infiltration may cause thickening, smudged appearance, or omental "cake" formation. Retroperitoneal and mesenteric nodes may be enlarged and caseate to form large mesenteric abscesses (Fig. 37.9). Ascitic fluid may be collected from either flank or centrally below the umbilicus with a blind peritoneal needle puncture and aspiration (Runyon 1986). In patients with minimal fluid collection or those with thick abdominal wall due to obesity, ultrasoundguided fluid collection may be done {Goldberg et al. 1970). Ascitic fluid examination should include gross inspection, biochemical tests, cytology, and smear and culture for tuberculosis. Fluid for a cell count should be sent to the laboratory in an anticoagulant tube (i.e., containing heparin/ethylenediaminetetraacetic acid) to prevent clotting (Hoefs 1990). Before the 1980s, the ascitic fluid total protein concentration

a

b Fig. 37.7a, b. Tuberculous peritonitis. A 50-year-old woman presenting with low-grade fever, weight loss, diffuse abdominal pain, and abdominal distension of 6 months duration. Clinical examination revealed abdominal tenderness and free fluid in the peritoneum. ESR was 60 mm and PPD skin test was 25 mm. X-ray chest revealed right apical infiltration and scarring. Ascitic fluid analysis revealed low-gradient lymphocytic exudate. a Laparoscopic examination revealed adhesions, peritoneal exudates, and multiple small (3 to 5 mm), whitish, elevated lesions on the visceral and parietal peritoneal surface. In this photograph multiple such lesions are shown on the liver surface. The results of a peritoneal biopsy from this patient are shown in Fig 37.10 b Plain X-ray of abdomen showing plaque-like calcification in the right and left upper quadrant (peritoneum - thick arrow), nodular calcification in the abdomen (lymph nodes - arrowheads), and incidental atherosclerotic linear calcification along the aortic wall (arrow).

668

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M. S. Khuroo and N. S. Khuroo

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b Fig. 37.8a, b. Tuberculous peritonitis. Computed tomography (CT) scans of two patients with documented tuberculous peritonitis. a Contrast-enhanced CT of abdomen shows thickening and fat infiltration of the omentum (omental plaque--arrowheads). b Contrast-enhanced CT of abdomen showing irregularity and fatty infiltration of the mesentery (arrowheads)

b

a

Fig. 37.9a-c. Tuberculous retroperitoneal mass. A 30-year-old woman presented with fever and night sweats of 3 months duration. Clinical examination was unremarkable. Plain X-ray of chest was normal. PPD skin test was 15 mm. Contrast-enhanced spiral CT of abdomen (a and b) showed 9x5 cm mass (long arrows) behind the stomach and displacing it anteriorly. a Arterial phase revealed celiac artery (thin arrow) within the mass, which was not involved by the lesion. b Late venous phase revealed minimal contrast uptake by the lesion (arrows). c Histologic examination of the resected specimen revealed extensive necrotizing granulomatous lesion (arrow) with giant cells (arrowhead)

Abdominal Tuberculosis

was used to classify ascites into exudate (>25 gIl) and transudate «25 gil). This classification does categorize ascites into various etiologic groups with a high degree of precision. Attempts at using combinations of lactic dehydrogenase (LDH) and serum-ascitic fluid ratio of LDH and protein have not been shown to improve accuracy of classifying ascitic fluid into exudate and transudate. The serum-ascites albumin gradient (SAAG) has proven in multiple studies to categorize ascites better than total protein concentration and better than other parameters (Runyon et al. 1992; Mauer and Manzione 1988). An SAAG of 11 gIl or more is classified as high gradient ascites, and an SAAG of less than 11 gIl is classified as low gradient ascites. If the SAAG is high, the patient has portal hypertension as the cause of ascites, with 97% accuracy. If the SAAG is low, portal hypertension can be excluded as the cause of portal hypertension, with 97% accuracy. The accuracy of this test is not influenced by ascitic fluid infection, diuretic therapy, therapeutic paracentesis, albumin infusion, and etiology of liver disease. Tuberculous ascitic fluid is usually opalescent due to high protein content and cell count (Marshall 1993; Holley and Piraino 1990; Singh et al.1969; Manohar et al.1990; Runyon et al.1992). However fluids with a cell count ofless than I,OOO/cm 3 (1.0 x109/1) may be almost clear. Fluids with counts of over 50,OOO/cm 3 (50 x 109Il) look purulent. Fluid may be sanguineous (RBC> 10,0001 mm 3) or frankly hemorrhagic (RBC>20,OOO/mm 3). Bloody ascitic fluid due to underlying disease should be differentiated from traumatic tap. The latter is only streaked with blood and frequently clots. In contrast, nontraumatic blood-tinged ascitic fluid is homogeneous and does not clot. Tuberculous ascitic fluid is uniformly of low gradient variety with a SAAG of less than 11 gil and has a high cell count (150 to 4,OOO/mm 3 ) with lymphocytic predominance. Tuberculous fluid in patients with chronic peritoneal dialysis is typically neutrocytic rather than lymphocytic. Ascitic fluid adenosine deaminase is an enzyme involved in the catabolism of purine bases (conversion of adenosine to inosine) (Marinez-Vazques et al. 1986; Pettersson et al. 1984; Hillebrand et al. 1996). Levels of ascitic adenosine deaminase are increased in tuberculous peritonitis as a result of stimulation of T lymphocytes in response to cell-mediated immunity to mycobacterial antigens. A number of studies have shown that at a cut-off of >33 VII, the sensitivity and specificity in tuberculous ascites are about 100% and 95%, respectively. A cut-off of >50 VII may even be preferable because sensitivity remains excellent and false positives are almost eliminated. Ascitic

669

adenosine deaminase has been proposed as a useful test in detecting peritoneal tuberculosis. However, in the Vnited States, where more than half of patients with tuberculous peritonitis have underlying cirrhosis, ascitic adenosine deaminase has been found to be too insensitive to be helpful. Examination of an acid-fast, stained smear of ascites will identify the organism in less than 3% of cases. The chances of culturing M. tuberculosis from the ascitic fluid are less than 20%. Culturing of ascitic fluid concentrated by centrifugation may increase the yield of culture. Culture reports are available by 4 to 8 weeks, which limits their diagnostic usefulness (Runyon et al. 1992). Laparoscopy with directed biopsies is an excellent study for diagnosis of tuberculous peritonitis and should be done in all patients with low-gradient ascites, lymphocytic ascites, and in those with high risk or high index of suspicion of tuberculosis (Singh et al.1969; Bhargara et al.1992; Geake et al.I98l). The laparoscopic appearances include: a. Thickened peritoneum with loss of usual shiny luster, miliary yellowish tubercles of uniform size (about 4-5 mm) diffusely distributed over parietal peritoneum and loops of the bowel, multiple adhesions between organs and peritoneum: this pattern is seen in around 66% of patients. b. Thickened parietal peritoneum with loss of luster, multiple adhesions between liver, peritoneum, and loops of the bowel: this pattern is seen in around 21 %of patients. c. Fibroadhesive pattern with marked thickening of parietal peritoneum, peritoneum may show yellowish nodules and cheesy material, thick adhesions may fix the viscera to anterior abdominal wall, sometimes it may not be possible to enter the peritoneal cavity: this pattern is seen in 13% of patients. Laparoscopic biopsies from abnormal-appearing lesions detect caseating granulomas in 85-90% of patients (Fig. 37.10). Mycobacterium can be cultured in 40% of patients. Laparoscopy in patients with peritoneal tuberculosis appears to be relatively safe; complications occurred in around 3% of patients, including bowel perforation, intraperitoneal bleeding, and subcutaneous hematoma. Blind peritoneal biopsies in patients with free ascites can be performed to obtain tissue for histology and culture. The procedure is reasonably safe and incidence of complications is low. The yield for positive diagnosis is lower than with laparoscopic-targeted biopsies. It is recommended in centers where laparoscopy is not

670

M. S. Khuroo and N. S. Khuroo

involvement of the bowel wall by the caseous lymph node. A tuberculous mesenteric abscess gives rise to a palpable cystic mass. Enlarged lymph nodes in the ileocecal lymph nodes give rise to a palpable mass in the right iliac fossa.

Fig. 37.10. Tuberculous peritonitis. Peritoneal biopsy showing extensive necrosis (thick arrow) with giant cells (long arrow)

available or in patients who refuse for laparoscopy. Minilaparotomy with peritoneal biopsies is recommended for patients with extensive peritoneal adhesions and for those patients for whom laparoscopy is nondiagnostic (Levine 1968; Shukla et al.1982).

37.4 Tuberculosis of Mesenteric Lymph Nodes Pathogenesis (Tandon and Prakash 1972; Marshall 1993). Tuberculosis of the mesenteric lymph nodes

is considerably less common than intestinal or peritoneal involvement. Tubercle bacilli reach the nodes by way of Peyer's patches. Single or multiple lymph nodes along the mesentery may be involved. Lymph nodes are rounded or oval and readily mat together and calcify. Breakdown may occur giving rise to tuberculous pus in the mesentery. The bowel loop may become adherent, or disease may spread to the bowel wall or pancreas.

Clinical Manifestations (Mann et al. 1997). Tuberculosis of the mesenteric lymph nodes may present with systemic symptoms of the disease only (see above) without abdominal complaints. Sometimes nonspecific abdominal pain may accompany these symptoms. Abdomen lymph nodes may be palpable on deep palpation as firm, discrete, tender, bean-like masses most frequently to the right of and near the umbilicus. Sometimes reactivation of infection in the lymph nodes may cause pain and tenderness in

the right iliac fossa resembling subacute appendicitis. Subacute intestinal obstruction may result from adhesions with a bowel loop or stricture as a result of

Diagnosis (Suri et al. 1999; Batra et al. 2000). Abdominal imaging (ultrasound and CT scan) is the investigation of choice for patients with tuberculosis of mesenteric lymph nodes (Fig. 37.11, 38.24a-c). In fact, imaging is often the tool which first points to this possibility when patients with vague abdominal symptoms are being investigated. Differential diagnosis includes other causes of lymph node enlargement including lymphoma, metastases, Whipple's disease, etc. Mesenteric and peripancreatic lymph nodes are commonly affected sites, reflecting the lymphatic drainage of commonly affected sites in the small bowel and liver. Isolated tuberculous retroperitoneal lymphadenopathy is uncommon and most patients also have affected lymph nodes at other sites. CT scan appearances of enlarged lymph nodes are as follows: a. Enlarged nodes with hypodense centers and peripheral hyperdense rims. This is the commonest appearance and occurs in around 70% of patients. b. Conglomerate mixed density nodal masses, most likely representing multiple confluent nodes due to perinodal spread of inflammation. c. Enlarged nodes of homogeneous density, most often associated with low density nodes at other sites.

Fig.37.11. Tuberculous lymphadenopathy. Ultrasound abdomen in A 30-year-old woman with abdominal pain and palpable abdominal masses showing multiple pre-aortic lymph nodes. Histology of the resected lymph nodes is shown in Fig. 37.12

Abdominal Tuberculosis

671

d. Increased number (>3 in one CT section) of normal sized or mildly enlarged mesenteric nodes of homogeneous density, usually located along the mesenteric vessels or adjacent to the bowel loops. e. Nodal calcification with characteristic distribution and appearance. Whenever tuberculous lymphadenopathy is suspected, diagnosis is confirmed by ultrasound or CTguided fine-needle aspiration biopsy and examining the aspirated material and/or core biopsy sample for histology, smear, and culture (Fig. 37.12). A biopsy can also be performed with a laparoscopy or minilaparotomy if radiologically guided biopsies cannot be done for reasons of access through a bowel loop.

37.S Tuberculosis of Solid Abdominal Organs

Fig.37.12. Tuberculous lymphadenopathy. Histologic examination of the resected lymph node showing caseating granulomatous inflammation (thick arrows) with multiple giant cells (thin arrows) and surrounding lymphocytic infiltration

4. Nodular disease. In this entity, single or multiple focal masses develop in the liver and are seen as low-density nonenhancing lesions with or without Hepatobiliary Tuberculosis. Hepatobiliary tuberculoperipheral rim enhancement. Such appearances sis is seen in number of situations: need to be differentiated from lymphoma, fungal infection, and metastasis. Diagnosis is confirmed 1. Incidental. Liver involvement is seen at autopsy in 25 to 50% of patients dying from active pulmoby image-guided fine-needle aspiration biopsy of the lesion (Herman et a!. 1995; Achem et a!. 1992; nary tuberculosis. An autopsy study from West Buxi et a!. 1992). Africa found that 50% adults dying of AIDS have active tuberculosis and in 85% of them the liver 5. Tuberculous liver abscess. Tuberculous abscesses is involved (Lucas 1994). in the liver are extremely rare. The clinical picture and imaging resemble those of a pyogenic 2. Miliary form. This occurs due to hematogenous or amebic liver abscess. Culture of the aspirated spread of the tubercle bacilli. The liver is involved material confirms the diagnosis by growth of by multiple granulomas. Miliary tuberculosis tubercle bacilli (Rahmatulla et al. 2001). presents with fever, night sweats, anorexia, weakness, and weight loss. Physical signs include 6. Tubular disease. These patients present with obstructive jaundice due to involvement of the bile ducts. hepatomegaly, splenomegaly, and lymphadenopathy. Elevation of serum alkaline phosphatase and Bile ducts may be involved by an enlarged tubercuother abnormal values in liver function tests are lous lymph node compressing the bile duct or diffuse detected in patients with severe hepatic involveinvolvement of the intrahepatic ducts by tubercle ment. Liver biopsy revealed granulomas in a high bacilli. ERCP reveals multiple intrahepatic biliary strictures, areas of dilatation, beading and ectasia, percentage of patients and usually gives a clue to diagnosis (Raviglione and O'Brien 2001). resembling sclerosing cholangitis or cholangiocarci3. Granulomatous hepatitis. Patients present with noma. Biliary stricture may occur at hilar region or unexplained fever, jaundice, hepatomegaly, eledistal common bile duct with dilatation of the intravated alkaline phosphatase, and abnormality of hepatic ducts (Alvarez 1998; Hickey et al. 1999). other liver function tests. Imaging of the liver may be normal or reveal nonspecific abnormalities. Splenic Tuberculosis. Tuberculosis of the spleen presLaparoscopy is useful and shows cheesy, white, ents with fever, night sweats, asthenia, and loss of irregular nodules on the liver surface. Biopsy from weight. The spleen is enlarged and is clinically palsuch lesions reveals caseating granulomas. Granu- pable. Portal hypertension may ensue. Tuberculous lomatous hepatitis with multiple granulomas in the splenic abscess is rare and presents as splenomegaly liver may also be seen following vaccination with with a heterogeneous mass on ultrasound or CT. bacille Calmette-Guerin, especially in persons with Splenic puncture will yield cold abscess and culture grows the organisms (Mann et al. 1997). impaired immune response (Campos et al. 1996).

672

Pancreatic Tuberculosis. Pancreatic tuberculosis presents with a wide spectrum of symptoms such as abdominal pain, weight loss, fever, and obstructive jaundice. Abdominal ultrasound or CT detects pancreatic masses closely mimicking pancreatic carcinoma (Fig. 37.13). Diagnosis is only revealed with a fine-needle aspiration biopsy and culture of the aspirated material(Harland and Varkey 1992).

37.6 Tuberculosis of Other Gastrointestinal Sites Esophageal, gastric, duodenal, and isolated appendicular tuberculosis are rare. Anal tuberculosis is rare in the West; however, it comprises 16% of the cases of fistulae-in-ano in developing countries (Marshall 1993).

M. S. Khuroo and N. S. Khuroo

Esophageal tuberculosis usually results from extension of the disease from mediastinal lymph nodes or spread from a pulmonary focus. Rarely, disease may occur without a primary contiguous focus of disease. Esophagus reveals ulceration, nodularity, strictures, sinus-track formation, and fistulae with trachea or bronchus. Esophageal tuberculosis presents with dysphagia, odynophagia, choking, and aspiration due to tracheoesophageal or bronchoesophageal fistula and upper gastrointestinal bleeding. Bleeding from esophageal infiltration and ulceration is usually of no major consequence; however, massive bleed from aortoesophageal fistula complicating tuberculosis has been reported. Chest X-ray and CT scan of the chest are helpful in identifying active pulmonary lesion and mediastinal masses. Barium-swallow findings include ulcerations, stricture, pseudotumor masses, fistulae, sinuses, and traction diverticula. Upper gastrointestinal endoscopy with biopsy is the diagnostic procedure of choice and

a

c

Fig. 37.13a-c. Pancreatic tuberculosis. Contrast-enhanced spiral computed tomography of abdomen (a and b) shows a hypodense mass (long arrow) in the head of pancreas. Arterial phase (a) revealed displacement of the hepatic artery (arrowhead), and portal venous phase (b) revealed displacement of the portal vein (arrowheads). c Spiral computed tomography of the abdomen in another patient revealed a well-defined hypodense mass (long arrow) in the pancreas. Hepatic artery (arrowhead) and portal vein (small arrow) are well defined without displacement and involvement

Abdominal Tuberculosis

673

Fig. 37.14. Esophageal tuberculosis. Endoscopic view of esophagus shows ulceration, narrowing, and whitish exudates and pseudomembrane (arrow)

Fig.37.15. Gastric tuberculosis. Endoscopic view of stomach showing ulceration (arrowhead), nodularity (thick arrow), and bridging mucosal lesions (long arrows)

usually reveals the etiologic nature of the esophageal disease (Fig. 37.14). In patients with mediastinallyrnphadenopathy, endoscopic ultrasound has made a major advance in identifying the nodes, and biopsies can be taken from these lesions for histology and culture under endoscopic ultrasound guidance (Tassios et al. 1995; Eng and Sabanathan 1991; Sutton 1990). Gastric tuberculosis usually occurs in the absence of pulmonary disease. This has been attributed to the presence of acid and paucity of lymphoid tissue in the stomach. Disease causes ulceration, nodularity of the mucosa, a tumor-like mass, and extensive submucosal infiltration and fibrosis causing linitis plastica. The antrum is the most common site of involvement. Gastric tuberculosis presents with nonspecific symptoms including abdominal pain, nausea, vomiting, and gastrointestinal bleeding. Such symptoms are usually confused with peptic ulcer or gastric neoplasm. Fever, night sweats, and weight loss may point to the possibility of tuberculosis. Barium meal and upper gastrointestinal endoscopy reveal ulceration, gastric outlet obstruction, nodular masses, and rigid nondistended stomach suggestive of linitis plastica (Fig. 37.15). Diagnosis is usually confirmed at histologic examination of the resected stomach (Lin et al. 1999; Rathnaraj et al. 1997; Quantrill et al. 1996; Goh et al. 1994; Raskin 1976). Duodenal tuberculosis commonly occurs secondary to extraintestinal lymph node involvement and causes segmental narrowing of the lumen. However ulceration, nodularity, and masses may develop due to mucosal disease. Duodenal tuberculosis usually

causes duodenal stricture and presents as abdominal pain, vomiting, and gastric stasis. Barium meal examination (Fig. 37.16, 38.1, 38.2, 38.3) and upper gastrointestinal endoscopy define the type of involvement of the duodenum. Biopsies are usually not helpful and show nonspecific changes. Diagnosis is confirmed at histologic examination of resected diseased segment (Marshall 1993).

Fig. 37.16. Duodenal tuberculosis. Barium-meal examination of stomach and duodenum showing duodenal loop irregularity and narrowing (arrow) and an ulcer in the duodenal bulb (arrowhead)

674

Appendix involvement is common in patients with ileocecal tuberculosis. Isolated appendicular tuberculosis causes subacute inflammation. Isolated appendicular tuberculosis presents as nonspecific abdominal pain and right iliac fossa tenderness and simulates other clinical conditions involving organs in this region (AI-Hilaly et al.1990). Anal tuberculosis causes ulcers, fissures, fistulae, abscesses, and warty or hypertrophic growths. Active pulmonary tuberculosis is found in around 15% of such patients. Anal tuberculosis presents with a variety of appearances namely ulcers, fissures, fistulae, abscesses, and wart or hypertrophic growths (Fig.37.17, 38.16, 38.17). Crohn's disease causes similar appearances and in view of its higher occurrence in the West is the usual clinical diagnosis (Candela et al. 1999; Chung et al. 1997; Harland and Varkey 1992).

M. S. Khuroo and N. S. Khuroo

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37.7

Treatment

Standard Drug Regimen. Patients with abdominal tuberculosis should receive a standard antituberculous drug regimen (Raviglione and O'Brien 2001). Therapy is highly successful and cure occurs in around 90% patients with tuberculosis of ileum and colon and over 95% patients with tuberculous peritonitis and tuberculosis of lymph nodes. Careful consideration needs to be given to selection of initial drugs for therapy, compliance issues, modification of drug regimen based upon drug susceptibility testing, and monitoring of the therapy and drug toxicity. These do not differ in any way from those of treating pulmonary tuberculosis. Short-course regimens are divided into an initial or bactericidal phase and a continuation or sterilizing phase. The initial phase consists of 2-month therapy with isoniazid, rifampicin, and pyrazinamide, followed by a 4-month therapy with isoniazid and rifampicin. If drug resistance is suspected on epidemiologic or other grounds, ethambutol (or streptomycin) should be included for the initial2-month therapy or until the drug susceptibility tests become available. Treatment may be given daily throughout the course of therapy, or three times weekly throughout the therapy, or daily for the first 2 months followed by twice weekly for the next 4 months. Direct observed therapy (DOT) requires an intermittent dosage schedule and increases compliance. Provision of drugs in combined formulations is useful, as patients have to swallow only one tablet

Fig. 37.17a, b. Anorectal tuberculosis. a Resected specimen of the rectum showing mucosal hypertrophy, nodularity (arrowheads), and strictures (arrows). b Histologic examination of the lymph node from the specimen revealed extensive caseating granuloma (arrow) with giant cells (arrowhead)

daily. It eradicates drug formulation errors, increases compliance and reduces chances of drug resistance. Pyridoxine should be added to the regimen given to persons at high risk of vitamin deficiency, namely alcoholics, malnourished persons, pregnant and lactating mothers, and patients with such conditions as chronic renal failure, diabetes, and HIV infection, because such patients are prone to neuropathy. A significant proportion of patients with abdominal tuberculosis are given therapy without positive cultures for tubercle bacilli. These patients need treatment with a standard regimen. Monitoring of response to treatment in abdominal tuberculosis is usually assessed by clinical parameters.

Course of Action When the Diagnosis Is Unclear. The diagnosis of tuberculosis may remain unclear despite the diagnostic efforts described above (Marshall 1993). This can occur in as many as 50% patients in developing countries, where diagnostic tools are not freely available and culture techniques have not been refined. Either of two possible actions can be taken in such cases: namely, therapeutic antituberculous trial or diagnostic exploratory laparotomy. In patients with clinical disease highly suggestive of

a

675

Abdominal Tuberculosis

tuberculosis, a history of exposure to tuberculosis, a strong positive PPD, evidence of tuberculosis on chest X-ray, and residence or origin from developing countries, therapeutic antituberculous therapy is feasible. Rapid clinical response to medical therapy is seen. If the patient fails to respond within 2 weeks, a laparotomy is indicated. However many clinicians suggest prompt diagnostic laparotomy in absence of definite nonoperative diagnosis, since diseases like Crohn's disease, lymphoma, and malignancy can mimic tuberculosis in every possible way. Moreover the criteria for response are based on clinical criteria and fraught with errors.

Indications for Surgery. Surgery is indicated in a select group of patients with complications of abdominal tuberculosis (Bhansali 1977; Kapoor 1998; Marshall 1993; Shah et al. 1992). The most common indication for surgery is multiple and/or long strictures which are unlikely to respond to medical therapy. Rarely, strictures may become critical during antituberculous therapy. The surgical resection of strictures should be conservative. Strictureplasty is the standard treatment for single and especially multiple ileal strictures. An alternative is to do an endoscopic balloon dilatation of colonic or accessible terminal ileal strictures (Bhasin et al. 1998). Resection or bypass should be avoided as these may precipitate short bowel or blind loop syndrome. For hypertrophic ileocecal tuberculosis needing surgery, right hemicolectomy has been the treatment of choice in the past. Other reasons for surgical intervention include free perforation, confined perforation with abscess and fistula, massive bleeding and intra-abdominal cold abscesses. Therapy in Patients with AIDS and Other Immunosuppressed Patients. Patients with immunosuppressed conditions including AIDS respond well to the standard 6-month regimen (Raviglione and O'Brien 2001; Small et al. 1991). Treatment may be prolonged to 9 months if the response is graded as suboptimal. Rifampicin shortens the half life of HIV protease inhibitors, indavir or nelfinavir, and therefore is contraindicated when antiviral therapy is being given concomitantly. In such situations, rifabutin (150 mg/day or 300 mg twice weekly) is given instead of rifampicin.

Therapy in Patients with Liver Disease. Patients with liver disease pose a special problem because of the hepatotoxicity of isoniazid, rifampicin, and pyrazinamide (Raviglione and O'Brien 2001). These

drugs should be avoided and if absolutely essential should be used in reduced dosage under close supervision. Patients with severe hepatic dysfunction may be treated with ethambutol and streptomycin and if required with reduced doses of isoniazid and rifampicin under close monitoring for drug toxicity. Pyrazinamide in patients with severe hepatic disease is contraindicated.

Adjunctive Glucocorticoid Therapy. Some clinicians administer glucocorticoids for 2 to 3 months along with antituberculous treatment on the assumption that this therapy will decrease fibrosis during healing. This may in turn reduce stricture formation in intestinal tuberculosis and adhesions in peritoneal tuberculosis. However, this has not been substantiated by any well-conducted therapeutic trial. In fact, large series of patients with intestinal tuberculosis have been treated without glucocorticoids and no strictures showed up in the follow-up. In other series, patients treated with or without adjunctive glucocorticoids did equally well (Dooley et al.).

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676 Bhargara DK et al (1992) Peritoneal tuberculosis: laparoscopic palleons and its diagnostic accuracy. Am J Gastroenterol 87:109-112 Bhargava DK et al (1984) Cell mediated immune response in intestinal tuberculosis. Ind J Med Res 80:264-269 Bhargava DK et al (1992) Endoscopic diagnosis of segmental colonic tuberculosis. Gastrointest Endosc 38:571 Bhasin DK et al (1998) Endoscopic balloon dilation of ileal stricture due to tuberculosis. Endoscopy 30:S44 Bloch AB et al (1994) Nation-wide survey of drug-resistant tuberculosis in the United States. JAMA 271:665 Bradney K, Dobkin S (1991) Resurgent tuberculosis in New York City: human immunodeficiency virus, homelessness and the decline of tuberculosis control programs. Am Rev Respir Dis 144:745 Bradley S, Reed S, Catanzaro A (1996) Clinical efficacy of the amplified mycobacterium tuberculosis direct test for the diagnosis of pulmonary tuberculosis. Am J Respir Crit Care Med 153:1606 Brudney K, Dobkin J (1991) Resurgent tuberculosis in New York City. Am Rev Respir Dis 144:745 Buxi TB et al (1992) CT apperances in macronodular hepatosplenic tuberuclosis: a review with five additional new cases. Comput Med Imag Graph 16:381-387 Campos JM et al (1996) Disseminated Bacillus CalmetteGuerin infection in HIV-infected children: case report and review. Pediat AIDS HIV Infect 7:429-432 Candela F et al (1999) Perianal disease of tuberculous origin: report of a case and review of the literature. Dis Colon Rectum 42:110-112 Cantwell MF et al (1994) Epidemiology of tuberculosis in the United States. JAMA 272:535 Carpentier E et al (1995) Diagnosis of tuberculosis by Amplicor Mycobacterium tuberculosis test: a multicenter study. J Clin Microbio133:3106 Carr WJ, Kyle RA, Bowie EW (1964) Hematologic changes in tuberculosis. Am J Med Sci 248:709 CDC (1990) Outbreak of multidrug-resistant tuberculosisTexas, California, and Pennsylvania. MMWR Morb Mortal Wkly Rep 39:369 CDC (1991) Transmission of multidrug-resistant tuberculosis from an HIV-positive client in a residential substanceabuse treatment facility-Michigan. MMWR Morb Mortal Wkly Rep 40:129 Centers for Disease Control and Prevention (1998) Prevention and treatment of tuberculosis among patients infected with human immunodeficiency virus: Principles of therapy and revised recommendations. MMWR Morb Mortal Wkly Rep 47:1 Cheng IK, Chan PC, Chan MK (1989) Tuberculous peritonitis complicating long-term peritoneal dialysis: report of 5 cases and review of the literature. Am J Nephrol9:155 Chung CC et al (1997) Anal and perianal tuberculosis: a report of three cases in 10 years. J R Coli Surg Edinb 42:189-190 Daley CL et al (1992) An outbreak of tuberculosis with accelerated progression among persons infected with human immunodeficiency virus: an analysis using restrictionfragment-Iength-polymorphisms. N Engl J Med 326:231 Dooley DP, Carpenter JL, Rademachar S Adjunctive corticosteroid therapy for tuberculosis: a critical reappraisal of the literature. Clin Infect Dis 25:872-887 Edlin BR et al (1994) An outbreak of multidrug-resistant tuberculosis among hospitalized patients with the acquired

M. S. Khuroo and N. S. Khuroo immunodeficiency syndrome. N Engl J Med 330:1710 Edwards D, Kirkpatrick CH (1986) The immunology of Mycobacterial diseases. Am Rev Respir Dis 134:1062 Eng J, Sabanathan S (1991) Tuberculosis of the esophagus. Dig Dis Sci 36:536-540 Farer LS, Lowell LM, Meador MP (1979) Extrapulmonary tuberculosis in the United States. Am J Epidemiol 109:205 Frieder IR et al (1993) The emergence of drug-resistant tuberculosis in New York City. N Engl J Med 328:521 Geake TMS et al (1981) Peritoneoscopy in the diagnosis of tuberculous peritonitis. Gastrointest Endosc 27:66-68 Goh SH et al (1994) Gastric ulceration with acute bleeding from tuberculosis of the stomach-a case report. Ann Acad Med 23:903-906 Goldberg BB, Goodman GA, Clearfield HR (1970) Evaluation of ascites by ultrasound. Radiology 96:15 Gordin FM et al (1996) The impact of human immunodeficiency virus infection on drug-resistant tuberculosis. Am J Respir Crit Care Med 154:1478 Ha HK et al (1999) Intestinal tuberculosis with abdominal complications: radiologic and pathologic features. Abdom Imaging 24:32 Harland RW, Varkey B (1992) Anal tuberculosis: report of two cases and literature review. Am J Gastroenterol 87: 1488-1491 Herman P et al (1995) Nodular form oflocal hepatic tuberculosis: case report. J Trop Med Hyg 98:141-142 Hickey N et al (1999) Acute hepatobiliary tuberculosis: a report of two cases and a review of the literature. Eur Radiol 9:886-889 Hillebrand DJ et al (1996) Ascitic fluid adenosine deaminase insensitivity in detecting tuberculous peritonitis. Hepatology 24:1408 Hoefs JC (1990) Diagnostic paracentesis: A potent clinical tool. Gastroenterology 98:230 Holley HL, Piraino BM (1990) Complications of peritoneal dialysis: Diagnosis and management. Semin Dial 3:245 Horvath KD, Whelan RL (1998) Intestinal tuberculosis: return of an old disease. Am J Gastroenterol 93:692 Huebner RE, Schein MF, Bass JB (1993) The tuberculin skin test. Clin Infect Dis 17:968 Jones B et al (1993) Relationship of the manifestations of tuberculosis to CD4 cell counts in patients with human immunodeficiency virus infection. Am Rev Respir Dis 148:1292 Jost KC et al (1995) Identification of Mycobacterium tuberculosis and M. avium complex directly from smear-positive sputum specimens and BACTEC 12B cultures by high-performance liquid chromatography with fluorescence detection and computer-driven pattern recognition models. J Clin Microbiol 33:1270 Kalvaria I, Kottler RE, Marks IN (1988) The role of colonoscopy in the diagnosis of tuberculosis. J Clin Gastroenterol 10:516 Kapoor VK (1998) Abdominal tuberculosis. Postgrad Med J 74:459 Kashima K et al (1995) Detection of anti-cord factor antibodies in intestinal tuberculosis for its differential diagnosis from Crohn's disease and ulcerative colitis. Dig Dis Sci 40: 2630 Kim KM et al (1998) Intestinal tuberculosis: clinicopathologic analysis and diagnosis by endoscopic biopsy. Am J Gastroenterol 93:606

Abdominal Tuberculosis Kochhar R et al (1991) Colonoscopic fine needle aspiration cytology in the diagnosis of ileocecal tuberculosis. Am J Gastroenterol 86: 102 Lam MF, Tang SC, Lai KN (2000) Tuberculous peritonitis in patients on continuous ambulatory peritoneal dialysis (editorial). Int J Artif Org 23:154 Levine A (1968) Needle biopsy diagnosis of tuberculous peritonitis. Am Rev Respir Dis 97:889-894 Lin OS et al (1999) Isolated gastric tuberculosis of the cardia. J Gastroenterol Hepatol 14:258-261 Lucas SB (1994) Other viral and infectious diseases and HIV-related liver disease. In: MacSween RNM, Anthony PP, Scheur PJ, Burt AD, Portmenn B (eds) Pathology of the liver, 3rd edn. Churchill Livingstone, Edinburgh, pp 269-316 Lui SL et al (1996) Optimal treatment and long-term outcome of tuberculous peritonitis complicating continuous ambulatory peritoneal dialysis. Am J Kidney Dis 28:747 Mann CV, Russell RCG, Wilhams NS (1997) Barley and Love's Short practice of surgery, 22nd edn. Chapman and Hall, pp 708,728,772-773,777,799 Manohar A, Simjee AA, Pettengill KE (1990) Symptoms and investigative findings in 145 patients with tuberculous peritonitis diagnosed by peritoneoscopy and biopsy over a five year period. Gut 31:1130 Marinez-Vazquez JM et al (1986) Adenosine deaminase activity in the diagnosis of tuberculous peritonitis. Gut 27:1049 Markowitz N et al (1993) Tuberculin and anergy testing in HIV-seropositive and HIV-seronegative persons. Ann Intern Med 119:185 Marshall JB (1993) Tuberculosis of the gastrointestinal tract and peritoneum. Am J Gastroenterol 88:989 Mauer K, Manzione NC (1988) Usefulness of the serum-ascites albumin gradient in separating transudative from exudative ascites: another look. Dig Dis Sci 33:1208 McKenna MT, McCray E, Onorato I (1995) The epidemiology of tuberculosis among foreign-born persons in the United States, 1986 to 1993. N Engl J Med 332:1071 Misra SP et al (1999) Colonic tuberculosis: clinical features, endoscopic appearance and management. J Gastroenterol Hepatol 14:723 Nardell E et al (1986) Exogenous reinfection with tuberculosis in a shelter for the homeless. N Engl J Med 315:1570 O'Reilly L, Daborn C (1995) The epidemiology of Mycobacterium bovis infections in animals and man: a review. Tuberc Lung Dis 76 [Suppll]:1 Pettersson T, Ojala K, Weber TH (1984) Adenosine deaminase in the diagnosis of pleural effusions. Acta Med Scand 215:299 Pfyffer GE et al (1996) Diagnostic performance of amplified Mycobacterium tuberculosis direct test with cerebrospinal fluid, other non-respiratory, and respiratory specimens. J Clin Microbiol 34:834 Pouchot J et al (1997) Reliability of tuberculin skin test measurement. Ann Intern Med 126:210 Pulimood AB et al (1999) Endoscopic mucosal biopsies are useful in distinguishing granulomatous colitis due to Crohn's disease from tuberculosis. Gut 45:537 Quantrill SJ, Archer GJ, Hale RJ (1996) Gastric tuberculosis presenting with massive hematemesis in association with acute myeloid leukemia. Am J GastroenteroI91:1259-1260 Rahmatulla RH et al (2001) Tuberculous liver abscess: a case report and review of literature. Eur J Gastroenterol Hepatol 13:437-440

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Raskin MM (1976) Some specific radiological findings and consideration oflinitis plastica of the gastrointestinal tract. CRC Crit Rev Clin Radiol Nucl Med 8:87-106 Rathnaraj S, Singh SK, Verghese M (1997) Gastric tuberculosis presenting with hematemesis. Indian J Gastroenterol 16: 110-111 Raviglione MC, O'Brien RJ (2001) Tuberculosis. In: Braunwald E, Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson JL (eds) Harrison's Principles of internal medicine, 15th edn. McGraw-Hill, New York, pp 1024-1035 Rezeiq MA et al (1998) Pancreatic tuberculosis mimicking pancreatic carcinoma: four case reports and review of the literature. Dig Dis Sci 43:329-331 Rich JA et al (1996) Polymerase chain reaction detection of Mycobacterium tuberculosis in formalin-fixed tissue. Am J Respir Crit Care Med 153:1419 Runyon BA (1986) Paracentesis of ascitic fluid: a safe procedure. Arch Intern Med 146:2259 Runyon BA et al (1992) The serum-ascites albumin gradient is superior to the exudate-transudate concept in the differential diagnosis of ascites. Ann Intern Med 117:215 Runyon BA Ascites and spontaneous bacterial peritonitis. In: Feldman M, Sleisenger MH, Scharschrnidt BF (eds) Gastrointestinal and liver disease; pathophysiology, diagnosis and management, 6th edn. Saunders, Philadelphia, pp 1310-1333 Schluger NW et al (1994) Clinical utility of the polymerase chain reaction in the diagnosis of infections due to Mycobacterium tuberculosis. Chest 105:1116 Selwyn PA et al (1989) A prospective study of the risk of tuberculosis among intravenous drug users with human immunodeficiency virus infection. N Engl J Med 320:545 Shah S et al (1992) Colonoscopic study of 50 patients with colonic tuberculosis. Gut 33:347 Shah S et al (1998) Rapid diagnosis of tuberculosis in various biopsy and body fluid specimens by the AMPLICOR Mycobacterium tuberculosis polymerase chain reaction test. Chest 113:1190 Shakil AO et al (1996) Diagnostic features of tuberculous peritonitis and presence of chronic liver disease: a case control study. Am J Med 100: 179 Shukla AS et al (1982) Peritoneal biopsy for diagnosis of abdominal tuberculosis. Postgrad Med J 58:226-228 Simon VA, Hale Y, Taylor A (1993) Identification of Mycobacterium tuberculosis and related organisms by HPLC with fluorescence detection. LCGC-Magazine of Separation Science 11:144 Singh MM, Bhargava AN, Jain KP (1969) Tuberculous peritonitis: evaluation of pathogenic mechanisms, diagnostic procedures and therapeutic measures. N Engl J Med 20: 1091-1094 Singh V et al (1996) Clinicocolonoscopic profile of colonic tuberculosis. Am J Gastroenterol 91:565 Small PM et al (1991) Treatment of tuberculosis in patients with advanced human immunodeficiency virus infection. N Engl J Med 324:289 Small PM et al (1993) Exogenous reinfection with multidrugresistant mycobacterium tuberculosis in patients with advanced HIV infection. N Engl J Med 328:1137 Small PM et al (1994) The epidemiology of tuberculosis in San Francisco: a population-based study using conventional and molecular methods. N Engl J Med 330:1703 Suri S, Gupta S, Suri, R (1999) Computed tomography in abdominal tuberculosis. Br J Radiol 72:92-98

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38 Imaging of Gastrointestinal Tuberculosis MONA S. AL SHAHED and MOHAMMED ABD EL BAGI

CONTENTS 38.1 38.1.1 38.1.2 38.1.3 38.1.4 38.1.4.1 38.1.4.2 38.1.4.3 38.1.5 38.2 38.2.1 38.2.2 38.2.3 38.2.4 38.2.5 38.2.6 38.3 38.3.1 38.3.1.1 38.3.1.2 38.3.1.3 38.3.1.4 38.3.1.5 38.3.1.6 38.3.1.7 38.3.1.8 38.3.2 38.3.3 38.3.4 38.3.4.1 38.3.4.2 38.4 38.5 38.6 38.7

Introduction 679 Scope 679 Overview 680 Pathogenesis 680 Determinants of Imaging Strategies 680 Status of Clinical Doubts or Certainty 680 Population Status 680 Organ-specific Localization 681 Clinical Presentations 682 Imaging Techniques 682 Plain Radiographs 682 Barium Studies 682 Ultrasound 682 Computed Tomography 682 Magnetic Resonance Imaging 682 Radioisotope Scans 683 Radiologic Manifestations of Gastrointestinal TB 683 Alimentary Tract Tuberculosis 683 TB of Esophagus 683 Tuberculosis of the Stomach 683 TB of the Duodenum 683 TB of the Jejunum and Ileum 684 Ileocecal TB 684 TB of the Appendix 687 Tuberculous Colitis 687 Anal TB 688 Peritoneal TB 688 TB Lymphadenitis 690 TB of the Parenchymal Organs 691 TB of the Liver and Spleen 691 Pancreatic TB 693 Imaging of Complications of Gastrointestinal TB 694 Mimics and Differential Diagnosis 694 Summary 696 Algorithms 697 References 697

M. AL SHAHED, MBBS, FRCR Senior Consultant Radiologist, Department of Radiology, Riyadh Armed Forces Hospital, P.O. Box 7897, Riyadh 11159, Saudi Arabia M. ABD EL BAGI, MB BCh, DMRD, FSRRCSI Senior Consultant, Department of Radiology, Riyadh Armed Forces Hospital, P.O. Box 7897, Riyadh 11159, Saudi Arabia

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

38.1

Introduction

38.1.1 Scope This chapter addresses the imaging of abdominal tuberculosis, which specifically encompass the gastrointestinal tract, the peritoneum and its reflections, the lymphatic system, and the solid visceral organs (Akhan and Pringot 2002). Imaging of the genitourinary system organs is discussed elsewhere. The retroperitoneum is unavoidable in this review, but no dedicated description is provided.

38.1.2 Overview Abdominal tuberculosis (TB) remains common in developing countries (MacGregor 1993; Aston 1990; Rohweddler 1989; Suri et aI.1999), and there has been a recent resurgence in developed counties (Marshall 1993). TB is probably as old as humanity itself (MacGregor 1993). Abdominal TB has long been known in history. Correct and early diagnosis of abdominal TB is crucial because untreated disease carries a 50% mortality rate. Unfortunately, sometimes the disease may not be diagnosed before the patient's death (Lingenfelser et al. 1993; Bankier et al. 1995; Hulnick et al. 1985). However, once diagnosed, it is a curable disease with a favorable prognosis (Bernhard et al. 2000). The problem of multidrug-resistant strains is discussed elsewhere. In spite of the advances in imaging modalities, the diagnosis of abdominal TB remains a real challenge even to the experienced physician because many patients present with vague, nonspecific signs or symptoms (Sheikh et al. 1995; Haddad et al. 1987). Some unfounded concepts have led physicians to overlook the diagnosis of abdominal TB. Such concepts include the assumption that abdominal TB is rare and a disease of the poor or that it is always associated with pulmonary TB (AI Quorain et al.

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1993). Clinical tests are often inconclusive or misleading (Bankier et al. 1995). Intestinal TB is diagnosed when histologic tests reveal caseating granulomas or acid-fast bacilli. However, the sensitivity for revealing these granulomas with caseating necrosis or acid-fast bacilli is low at approximately 32% and 50%, respectively, by histologic tests (Kim et al.1998). This augments the role of imaging in diagnosis. Even laparoscopy may be resorted to for diagnosis, which renders the clinical examination an invasive experience for the patient (Lam et al. 1999). Growth of tuberculosis in cultures of tissue or ascites fluid takes a long time. Clinicians may wish to make an earlier decision depending on clinicoradiologic correlation. A clinical diagnosis of intestinal TB is sometimes made by therapeutic trial of antituberculous treatment, especially in endemic areas (Park et al. 2000). This does not exclude the contribution of imaging because the response to the therapeutic test must be monitored by clinical and radiologic follow-up. According to Manahour, abdominal TB develops in 2% to 4% of patients with pulmonary tuberculosis (Manahour et al.1990).At our own institution, Karawi and colleagues reported an incidence of 130 cases of alimentary tract tuberculosis (16%) out of 820 patients with TB seen over a period of 8 years (AI Karawi et al. 1995). Incidence of gastrointestinal TB is higher (50%) in patients with AIDS (Chaisson and Sul Kin 1989). Abdominal TB is the second most common extrathoracic site of involvement in the body (AI Karawi et al. 1995). One of the major historical and diagnostic problems with abdominal TB is that it is a great mimic Oadvar et al. 1997; Panton et al. 1985). TB is a differential diagnosis in a variety of abdominal conditions. These will be highlighted below. Due to awareness of the resurgence of the "new tuberculous disease" (Marshall 1993; Snider and Roper 1992) the characteristics of abdominal TB have been well described in different patient populations (Kim et al. 1998; Marshall 1993; Gilinsky et al. 1983).

M. S. Al Shahed and M. Abd EI Bagi

tubercle bacilli to lymphoid tissue, and in most cases CT scans are positive for lymphadenopathy. Hematogenous spread can reach any part of the gastrointestinal tract. The last method of local spread is by direct invasion of nearby organs either microscopically or by gross fistulae and sinuses. The gross pathology conforms easily with radiologic findings in the various types and presentations of TB including (1) ulcerative disease, (2) hypertrophic, (3) ulcerohypertrophic (Paustian and Bockus 1959), and (4) stricture (Bhansali 1977).

38.1.4 Determinants of Imaging Strategies 38.7.4.7

Status of Clinical Doubts or Certainty The index of clinical suspicion dictates the pathway, the end point, and the choice of radiologic examinations (Fig. 38.1). When gastrointestinal TB is suspected, the whole spectrum of radiographic procedures are activated in a sequential manner starting with plain films, ultrasound (US), and computed tomography (CT). This may end up with image-guided biopsies.When gastrointestinal TB is the most probable diagnosis, which entails the presence of specific clinical signs (e.g., ascites, mass, or bowel obstruction), a choice of an imaging technique has to be made accordingly. For lymphadenopathy you may proceed directly to CT, whereas if there is ascites, you may start with US. For suspected alimentary tube lesions, barium studies are necessary although CT may suffice. When the diagnosis is confirmed by laboratory tests, or endoscopic or percutaneous biopsies, the aim of imaging is to assess the extent of disease, which entails the use of CT. When patients are put on a therapeutic trial of antituberculous drugs, a baseline investigation is documented. Treatment response is judged by a comparative follow-up examination using the same technique that was used in the baseline study, in correlation with clinical progress.

38.1.3 Pathogenesis

38.7.4.2

The pathologic mechanism and route of infection determine the manifestations of gastrointestinal TB. Swallowing infected sputum or contagious unpasteurized milk can manifest as ulcerative disease particularly in the terminal ileum and colon due to the abundance of lymphatic tissue (Marshall 1993). The stomach esophagus and duodenum are least involved due to rapid transit and the low pH. There is an apparent affinity of

The type of community setting dictates the level and index of clinical suspicion. The availability of imaging tools in the community is a determinant of the diagnostic test choice and preference (Fig.38.2). We do not have experience with TB in developed countries, nor do we have much experience with gastrointestinal TB in immunocompromised patients. We actually see more fungal infec-

Population Status

Imaging of Gastrointestinal Tuberculosis

Fig.38.1. Gastroduodenal tuberculosis. Adult male patient presented with gastric outlet obstruction. Barium meal showing widening of duodenal loop, narrowing of the descending duodenum and thickening of the mucosal fold (arrow). There is partial obstruction at the pylorobulbar region

tions in patients who receive intensive therapy with immunosuppressants. In our clinical settings, patients who have pulmonary TB are not examined for gastrointestinal tuberculosis unless there are grave or overt abdominal symptoms of a surgical nature. Most of the abdominal complaints in these patients are usually attributed to drug intolerance. Patients who are diagnosed to have gastrointestinal TB by endoscopic biopsies are usually scheduled for CT to assess the extent of extraluminal disease and to exclude complications. The last group of patients are those investigated for obscure symptoms, for example, pyrexia of unknown origin or suspicion of a malignant disease (Lundstedt et al. 1996). Because TB is a great mimicker (Jadvar et al. 1997), the diagnosis might even come as a surprise from the biopsy results. Ga67 scanning plays a useful role in the screening of such patients supplemented by CT for the suspected site of tracer accumulation. 38.1.4.3 Organ-specific Localization

As far as initial imaging is concerned, an anatomical localization of a single or multiple lesions is the starting point in building up evidence for diagnosis of TB (Fig. 38.3). Barium studies are important in patients with gastrointestinal TB (Palmer et al. 1985). Most proximal and most distal "hollow viscus" parts of the alimentary tube are usually amenable to endoscopic examination by gastroscopy or colonoscopy. How-

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Fig.38.2. Post-contrast-enhanced CT of the same patient at the level of the stomach antrum, demonstrating transmural thickening at the stomach outlet "hypertrophic nodular form" (arrow). Note striation of the peritoneal fat (open arrow)

Fig.38.3. CT at the level of the third part of the duodenum showing diffuse wall thickening and mucosal edema secondary to direct infiltration (arrow). Note enlarged lymph node (curved arrow), between the aorta (a) and inferior vena cava (v)

ever, confusion with Crohn's disease or malignancy is most likely to happen (Marshall 1993). This is also true with barium studies or a combination of the two (Kim et al. 1998). If a chest X-ray or CT shows a concurrently active TB, then the diagnosis is settled radiographically (Marshall 1993). Parenchymal organ or abdominal wall TB are amenable to ultrasound examination. This can be supplemented by CT. Mesenteric TB imaging depends on whether we are dealing with a wet type, for which the ease and high yield of US is helpful, or the dry type, which is usually easier to assess by CT. For the mixed or

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fibrotic type, a combination of the two techniques is complementary. Lymphadenopathy is more accurately assessed by contrast CT because overlapping bowel gas hinders a US examination.

38.1.5 Clinical Presentations Abdominal TB may present in many ways, ranging from nonspecific abdominal symptoms to acute surgical emergencies or nonspecific clinical signs (Fig. 38.4). Patients presenting with any of the spectrum of abdominal symptoms may end up going through a whole series of tests before a diagnosis is reached. Subacute intestinal obstructions are more common than acute obstruction, which gives time for proper contrast studies by barium or CT. Abdominal masses are first examined by US to see if solid or cystic, but CT remains the mainstay for characterization and depiction of the extent of the disease.

1993). Ascites may not be large enough to be detectable by radiographs. Calcified granulomas in solid visceral organs or lymph nodes are fairly specific but not pathognomonic. Where basic radiographic setups are barely available, as in the peripheral clinics of deprived communities, and TB is prevalent, plain radiographs can be the first line of investigation.

38.2.2 Barium Studies These are useful in patients with gastrointestinal TB (Palmer et al. 1985). Fluoroscopic barium studies are available in most developing countries. Specific radiologic signs in barium studies have been well described (Kolawole and Lewis 1975; Werbelloff et al. 1973). These are, however, not diagnostic on their own. A disadvantage of barium studies is the inability to assess extraluminal disease (Hulnick et al. 1985). Filling defects, masses, ulcerations, strictures, and fistulous tracts can be well outlined by barium meal, swallow, follow-through, or enema. At times, small bowel enemas may be resorted to.

38.2 Imaging Techniques 38.2.1 Plain Radiographs Plain abdominal radiographs are usually considered unhelpful because they are less sensitive compared with other imaging modalities (Denton and Hossain

38.2.3 Ultrasound As a simple and quick examination, ultrasound is usually recommended as the first examination in abdominal TB, particularly if fluid or a mass is suspected (Gompels and Darlington 1978). Presence of ascites enhances the ultrasound examination. Ultrasound is the initial screening test for solid organ involvement.

38.2.4 Computed Tomography CT is the most sensitive and specific tool for detecting a wide spectrum of lesions of abdominal TB (Denton and Hussain 1993). CT is essential in many situations where endoscopic studies and or barium examinations are nonspecific (Makanjoula 1998).

38.2.5 Magnetic Resonance Imaging Fig. 38.4. TB jejunum. CT at the level of the superior mesenteric artery origin. Note the diffuse wall thickening of jejunal loops with marked mucosal edema (arrows)

The use of MRI in diagnosis of gastrointestinal TB is limited. It is particularly useful in solid organ disease

Imaging of Gastrointestinal Tuberculosis

(Mercusot et al. 1995) and when multiple organs are involved especially the combination of abdominal disease with spinal lesions (See Fig. 38.31b).

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presence of a preexisting gastric mucosal ulceration or tumor paves the way for TB infection (Denton and Hossain 1993; Al Hadeedi et al. 1990). Radiologic features of gastric TB are nonspecific (Akhan and Pringot 2002). Ulcerations are the most common 38.2.6 findings. Gastric TB may present with signs of gasRadioisotope Scans tric outlet obstruction due to inflammatory changes, fibrosis, or enlarged lymph nodes (Thoeni and Gallium 67 citrate is considered the best radiophar- Margulis 1979). The hypertrophic form can mimic maceutical for imaging of mycobacterium infections malignancy. Gastric TB should be differentiated (McAfee 1996; Yang et al.1992). However, the specific- from gastric carcinoma, non-Hodgkin's lymphoma, ity of gallium scintigraphy is low, although it is sensi- leiomyoma, Kaposi's sarcoma, gastritis, syphilis, or tive for occult TB and should be followed by CT or sarcoidosis (Denton and Hossain 1993; Jadvar et al. US. Gallium 67 citrate scanning is useful in obscure 1997). Exclusion of Crohn's disease from ulcerative presentations like pyrexia of unknown origin (PUO), TB needs scrutiny and clinical correlation, with unexplained weight loss, and bone disease. preference for TB where the disease is endemic (AI Karawi et al. 1995). Rarely, gastric TB can present as linitis plastica, which can lead to confusion with scirrhous carcinoma, sarcoidosis, syphilis, lymphoma, 38.3 radiation injury, or corrosive ingestion (Jadvar et Radiologic Manifestations al.1997). of Gastrointestinal 18 Sinus formation and fistula are rare in gastric TB (Thoeni and Margulis 1979; Denton and Hossain 38.3.1 1993). The chest radiograph can be normal in over Alimentary Tract Tuberculosis 50% of cases. Gastric TB is rare (about 2%) in patients with pulmonary disease (Tromba et al. 1991). This is 38.3.7.7 due to the relatively low pH of gastric juice and the TB of Esophagus rapid gastric emptying. Barium studies can demonstrate ulcers, masses, or outlet obstruction (Fig. 38.1). Primary esophageal TB is rare even in endemic US or CT can demonstrate other visceral lesions, areas (Marshall 1993). However, it has recently been lymphadenopathy, or ascites. Although the diagnoreported in AIDS patients (de Silva et al. 1990). sis can be confirmed by endoscopic biopsy, gastric Esophageal TB is usually secondary to compres- TB is often not suspected until the time of surgery sion or fistulation by mediastinal lymph nodes (Mc (Tromba et al.1991). Antropyloric disease can extend Namara et al. 1987). Such patients complain of pain- into the duodenum and vice versa (Fig. 38.2). ful dysphagia (Akhan and Pringot 2002). Barium swallow can readily demonstrate esopha- 38.3.7.3 geal narrowing, ulceration, or fistulae. CT can depict TB of the Duodenum the extraluminallesion and the extent of the disease in the mediastinum and lungs (Willifort et al. 1983; Duodenal TB is rare, occurring in about 1-3% of Dantew et al. 1987). The reasons for the rarity of patients suffering gastrointestinal TB (Lundstedt et esophageal TB have previously been described, al.1996). Barium studies may demonstrate duodenal including the lack of stasis due to the rapid transit of narrowing, dilatation, or distortion (Fig. 38.1). Narfood and the protective salivary coat over the strati- rowing is most common at the third or fourth part of fied epithelium (McGuinness 2000). the duodenum (Akhan and Pringot 2002). The pylorobulbar region can be deformed in continuation of 38.3.7.2 the duodenal disease (Fig. 38.2). Thickening of the Tuberculosis of the Stomach overlying mesenteric root can be demonstrated by US or CT (Denton and Hossain 1993; Hulnick et al. Gastric TB is also rare (Tromba et al.1991), though a 1985). Duodenal obstruction is a likely presentation little more common than that of esophagus (Marshall (Bhansali 1977; Gupta et al. 1988). 1993). The antropyloric region and distal body are Duodenocolic fistula can occur but duodenoaorthe sites usually involved (Leder and Low 1995). The tic fistula is exceedingly rare (Edie and Pollack 1968).

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Mesenteric adenopathy at the root of the mesentery can cause compression or invasion of the third and fourth parts of the duodenum. CT is an excellent examination for these lymph nodes (Fig. 38.3). 38.3.1.4 T8 of the Jejunum and Ileum

The jejunum and ileum are the second most common GIT site after ileocecal TB (Marshall 1993). It is usually associated with peritonitis (Leder and Low 1995). Isolated jejunal stricture can occur. Diffuse jejunal wall thickening is readily demonstrated by CT (Fig. 38.4). Barium studies can demonstrate sites of strictures, separation of bowel loops, bowel wall thickening, or fistulae (Fig. 38.5). Ulcerations can sometimes be detected in barium studies (Pringot et al. 1984). Skip lesions with intervening normal or dilated bowel segments are common. Internal fistulae (Fig. 38.5) are a cause of malabsorption (Bhansali 1977). 38.3.1.5 Ileocecal T8

Ileocecal involvement is the most common presentation of gastrointestinal TB occurring in as much as 80-90% of cases (Jadvar et al.1997; Makanjuola 1998;

Fig. 38.5. Multiple skip lesions of tuberculous enteritis: Barium follow-through demonstrating diffuse jejunal wall thickening causing separation of bowel loops (small arrows). Note areas of circumferential luminal narrowing (curved arrow). Also note an unusual barium location delineating a fistula tract (long arrow). The terminal ileum is incompetent, fixed, and irregular (arrowheads). The cecum shows multiple polypoid nodules due to small granulomas (medium size arrow)

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Balthazar et al. 1990) (Fig. 38.6). This is attributed to the abundance of lymphatic tissue, as well as the relative stasis (Leder and Low 1995). Early signs of the disease include mucosal edema, spasm, and hyperperistalsis (Park et al. 2000). This stage can be missed, especially if there is no associated ascites or obvious lymphadenopathy. We have previously reported this stage of "dry type" ileocecal TB, which was missed in barium studies and even CT (Abd El Bagi and Al Karawi 1997) (Fig. 38.7). Ultrasound is a useful test because it allows simultaneous clinical examination by the radiologist for localization of any tender spot, which gives a clue to the site to be examined critically by ultrasound (Fig. 38.8). Ileocecal TB has characteristic signs, which can be demonstrated by barium studies, US, or CT (Jadvar 1997; Balthazar et al. 1990; Hulnick 1985). The terminal ileum can be thickened (Fig. 38.8) or patulous (as shown in Fig. 38.7) (Jadvar 1996). At a later stage the terminal ileum becomes irregular and immobile. Deep ulcerations can be demonstrated, which could cause confusion with Crohn's disease. However, TB ulcers tend to be larger than those of Crohn's disease. The confusion can be exacerbated when there is a fistula or skip lesions (Figs. 38.5, 38.6). Eventually the terminal ileum becomes narrowed with thick walls, "Fleischner's sign". The cecum becomes coned and contracted on barium examinations, "Stierlin's

Fig. 38.6. TB ileum, cecum, terminal ileum, and appendix. This image demonstrates fistulous communication with an abscess cavity in the right iliac fossa as a result of perforated appendicular abscess (small arrows). Note tethering of bowel loops (open arrows), nodularity of the cecum (medium-size arrows) and the fistula tract (long arrow)

Imaging of Gastrointestinal Tuberculosis

Fig. 38.7. Ileocecal TB missed on barium follow-through. Note the cut-off of the lower pole of the cecum (arrow), which was considered due to fecal residue. The terminal ileum was considered normal. A patent terminal ileum does not exclude presence of TB

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Fig. 38.9. Ileocecal tuberculosis: barium enema showing ulceration and narrowing of the terminal ileum with marked thickening of the ileocecal valve (Fleischner's sign) (arrowheads). The cecum is shrunken, stenosed, and classically conical in shape (Stierlin's sign) (open arrow). Note submucosal polypoid pattern (long arrows) and deep ulcers (small arrows)

Fig. 38.8. Transabdominal US of the right iliac fossa showing edematous waIls of a patent terminal ileum (arrowheads) and a contracted lower pole of the cecum (arrow). No ascites was present: "dry type TB"

Fig. 38.10. CT of the cecum showing incomplete filling of the cecum and waIl thickening (large arrow). This was initially considered normal. Note presence of mesenteric lymph node enlargement (small arrow)

sign" (Leder and Low 1995) (Fig. 38.9). US can also show the cecal wall thickening (Lee et al. 1993) see (Fig. 38.11). Cecal wall thickening can be dismissed on CT as incomplete filling of the lower pole due to colonic residue (Fig. 38.10). The presence of associated signs like lymphadenopathy should raise the alarm (Fig. 38.10).

Contraction of the cecum may be complete, mimicking a lower pole mass (Fig. 38.12). The lower pole of the cecum may be amputated by filling defect or mass (Fig. 38.7). Marked cecal involvement is said to be more common in TB than in Crohn's disease (AI Karawi 1995). A combination of Crohn's disease and TB in the same patient has been reported (AI Karawi et al.1991).

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Fig. 38.11. US for TB of the cecum. Contracted thick coned cecum

Endoscopy and endoscopic biopsy are popular methods for diagnosis of TB, but double-contrast barium enema can provide detailed information (Ferentzi et al. 1988; Han et al. 1996). Radiologic features of TB can be similar to Crohn's disease, lymphoma, amebiasis, carcinoma, and even sarcoidosis (Thoeni and Margulis 1979). Crohn's disease tends to produce a more uniform pattern than the irregular changes of TB (Fig. 38.13). These can affect a longer segment. Engorgement of the mesenteric vessels can

M. S. Al Shahed and M. Abd El Bagi

Fig. 38.12. CT of cecal TB presenting as a small mass. Contracted cecum (c) mimicking a mass. Note enhancing mesocolon (small arrows). Presence of a patent terminal ileum (open arrow) does not exclude presence of TB

give the peculiar "comb sign" (Fig. 38.14). On CT, mural stratification with symmetric, concentric wall thickening (Fig.38.14) is characteristic of Crohn's disease (Meyers and McGuire 1995; Makanjuola 1998). Amebiasis does not usually involve the small bowel (Akhan and Pringot 2002). Cecal carcinoma is always limited by the ileocecal valve (Reeder.and Palmer 1994). The ambiguous situation of coexisting adenocarcinoma and TB of the cecum has been reported (Isaacs and Zissis 1997).

b

a Fig. 38.13. a Barium follow-through showing extensive uniform changes of Crohn's disease involving a very long segment of the ileum (arrowheads). b Magnified view of the terminal ileum. Note cobblestone edematous mucosa (large arrowheads) and the rose thorn ulcerations (small arrowheads). Compare the depth of the ulcers with the deeper ulcers in Fig. 38.9

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b

a Fig. 38.14. a CT of the terminal ileum showing extensive long segment involvement with Crohn's disease. Note the prominent mesenteric vasculature producing the "comb sign" (arrowheads). b Spiral CT of the terminal ileum showing characteristics of Crohn's disease. Note the transmural layering of "stratification" sign (open arrow). Note also the enlarged, beaded appearance of the vasa recta (small arrows)

38.3.1.6 TB of the Appendix

The appendix was reported to be involved in 5% patients in one series (Al Karawi et al. 1995). A lower incidence of 0.11% has been reported for nonendemic countries (Jaffe 1951). Involvement of the appendix is usually due to direct extension from the more common ileocecal tuberculosis (Singh et al. 1987). Tuberculosis limited to the appendix is rare and has no characteristic features. It can be mistaken for appendicitis or pelvic inflammatory disease, as it can perforate spreading the infection into the peritoneum (Reeder and Palmer 1994). An abscess may form (Fig. 38.6) with recurrent pain of mild or severe degree (Marshall 1993). 38.3.1.7 Tuberculous Colitis

Infection of the colon without involvement of the small bowel is reported in 9% of gastrointestinal TB cases (Thoeni and Margulis 1979). Colonic tuberculosis can take one of several forms including segmental ulcers, inflammatory strictures, hypertrophic lesions resembling polyps and masses (Chawla et al. 1971; Stock and Li 1964; Peh 1988). The early features of tuberculous colitis include spasm, hypersecretion, increased motility, lymphoid hyperplasia, thickened folds, and shallow ulcers (Park et al. 2000). Small aphthous ulcers are considered specific of Crohn's disease but has also been described in TB (Shah et al. 1992). Most of the radiologic signs of colonic TB were described in single-contrast studies. These include Stierlin's and Fleischner's signs. Lately, findings with double-contrast enemas (Fig. 38.15)

Fig.38.15. Double-contrast barium enema of a 45-year-old male adult patient presenting with fever, malaise, night sweats, and discharging sinus in the anterior abdominal wall. Barium enema demonstrates a track of barium originating from descending colon (large arrow). Note focal area of symmetric annular stenosis, napkin-ring appearance, in the descending colon above the sinus tract (small arrows)

have been reported (Nakano et al. 1992). Advanced features of tuberculous colitis in double-contrast studies include transverse ulcers, nodularity, polyps, and narrowing. Colonic lymphoid tissue follicles are oriented transversely, which is why the ulcers frequently adopt this orientation (Carrera et al. 1976). Rose thorn ulcer can occur and may not be visible on colonoscopy (Park et al. 2000). Symmetric narrowing of the colon gives the "napkin ring" sign (Leder and

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Low 1995) (Fig. 38.15). TB strictures show smooth transition to the nonaffected area with preservation of the haustral pattern (Park et al. 2000). Sometimes TB can simulate colonic tumors (Carrera et al. 1976). The changes of tuberculous colitis can be seen with other causes of inflammatory bowel disease. More extensive involvement can also be demonstrated by CT including edema, stricture formation, and other associated conditions like ascites (Fig. 38.16). Ha and colleagues used a combination of CT signs to differentiate TB peritonitis from peritoneal cardiomatosis "omental cakes" (Ha et al. 1996). Presence of little intervening thick ascites fluid can give the appearance of "sliced bread" in US. The walls of pocketed ascitic fluid or the lymph nodes may calcify (Fig. 38.20). For everyday practice, there is a considerable overlap between the different types of peritoneal involvement with TB (Suri et al.1999). Commonlya wide spectrum of multiple organ involvement is encountered in each case (Fig. 38.6).

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Fig.38.16. TB of the rectosigmoid region. CT of the pelvis demonstrating involvement of the rectosigmoid. Note significant narrowing (curved arrow) and edema of the wall (arrowheads). Also note creeping peritoneal fat to the area of infected bowel (small arrow). This also seen in Crohn's disease. Ascites is present (a)

38.3.1.8 Ana/TB TB of the anal canal is rare, representing less than 4% of abdominal TB (AI Karawi et al. 1995). However, higher incidence has been reported from India (Shukla et al. 1988). The disease may present with ulcers, fissures, abscess, hypertrophic lesions, or fistula (Marshall 1993).Anal TB can be confused with Crohn's disease due to the common belief that the latter is more common at this specific site. Biopsy and laboratory tests should be obtained, because access is easy.

38.3.2 Peritoneal T8

Involvement of the peritoneum is a very frequent finding in abdominal TB and was reported in 30% of the AI Karawi series and 57% of the Gilinsky series (AI Karawi et al. 1995; Gilinsky et al. 1983). However, isolated peritonitis is a rare manifestation of TB, occurring in less than 4% of patients (Leder and Low 1995). There are three well-recognized types of peritonitis TB (Hanson and Hunter 1985): (1) a wet ascitic type (Epstein and Mann 1982), (2) a dry plastic type (Abd EI Bagi and Al Karawi 1997), and (3) a fibrotic fixed type (Suri et al. 1999). The wet type is the most common type seen in as much as 90% of cases, with excess high attenuation ascites fluid, which can be free or pocketed (Fig. 38.17). CT measurement of ascitic fluid density is not always reliable, however (Bankier et al. 1995).

Fig. 38.17. Wet TB peritonitis (pocketed). CT scan of the midabdomen showing large, high density ascites localized anteriorly, displacing bowel loops posteriorly (a). Aspirate revealed acid-fast bacilli, and tuberculous peritonitis was diagnosed

Sonographically echogenic debris is seen as fine strands or particulate matter within the fluid (Lee et al. 1991). The dry or plastic type is seen in 10% of cases (Fig. 38.7). It can be missed due to lack of excess peritoneal fluid, which when present, enhances both the CT and US examinations (Fig. 38.18). The fibrotic fixed type is characterized by hypervascular peritoneum, matting of the loops, and omental masses referred to as omental cakes (Lee et al. 1991) (Fig. 38.18). The walls of an encysted ascitic fluid pocket may calcify (Fig. 38.20).

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a Fig.38.18. US of the ileocecal region showing dry-type TB with focal thickening of the medial wall of the cecum (C) and a trace of fluid (F), behind the terminal ileum (TE)

Fig. 38.19a, b. TB enteritis with lymphadenopathy and omental cakes. a CT of lower abdomen demonstrating enlarged lymph nodes (arrow) and thickened wall bowel loops (large arrowheads). Note the thickened peritoneum with mottled lowdensity masses and nodular soft tissue thickening along with hypervascularity of the peritoneal surface "pseudomyxoma peritoni appearance" (small arrowheads). b CT at more caudal levels demonstrates the pseudomyxoma peritoni appearance of the involved peritoneum (arrowheads), bowel wall thickening (arrows), and loculated ascites (a)

a

b

b

Fig. 38.20a, b. Tuberculous peritonitis (wet type). a Plain abdominal X-ray demonstrates generalized ground-glass density throughout the abdomen indicating presence of ascites. Note curvilinear calcification (arrowheads) in the upper abdominal region. b CT scan of the same patient showing lobulated fluid collection surrounded by calcified wall, initially mistaken for hydatid disease (arrowheads)

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38.3.3 TB Lymphadenitis Lymph node involvement in gastrointestinal and other abdominal infections with TB is a common finding. It has been reported in 33% of cases in one series (Lundstedt et al. 1996). With the frequent use of CT, lymphadenopathy was found to be the most common finding in abdominal TB, occurring in two thirds (Suri et al. 1999) of patients. An even higher incidence of 93% was reported (Demirkazik et al.1996). The mesenteric and peripancreatic group oflymph nodes are the most often involved (Suri et al. 1999) (Fig. 38.3). Various patterns of lymph node involvement have been observed in abdominal TB (Pombo et al. 1992). The most common pattern, in 40-70% of cases, is a hypodense center of lymph nodes with a peripheral enhancing rim on CT scanning (Leder and Low 1995) (Figs. 38.21, 38.30). These can be confluent due to perinodal inflammation or remain discrete. The second type is relatively homogenous with a low density on nonenhanced CT and shows relatively homogenous enhancing lymph nodes after intravenous-contrast administration. These are usually small, multiple, and rather discrete (Fig. 38.22). This pattern is probably a different stage of pathology representing noncaseating granulomas (Suri et al. 1999). Retroperitoneal lymph node involvement was previously considered rare in TB. But it can occur as a part of disseminated disease (Fig. 38.21,38.23,38.24). Sometimes a third pattern of lymph node involvement is seen. The lymph nodes, may show a heterogeneous central enhancement pattern due to the presence of central,

Fig. 38.21. Tuberculous adenopathy: CT scan of a patient demonstrating the characteristic appearance of tuberculous adenopathy manifesting as low attenuation center of caseous necrosis, surrounded by an enhancing rim reflecting peripheral highly vascular inflammatory reaction (n)

a

b Fig. 38.22a, b. Tuberculous adenopathy. a CT of the abdomen demonstrates multiple small,discrete lymph nodes with homogenous density (arrows). b Postcontrast CT of abdomen showing multiple small, discrete homogenously enhancing modes in a known TB patient after 4 months of treatment (arrow)

Fig.38.23. Post-enhanced CT of the abdomen demonstrating multiple enlarged lymph nodes with nonhomogeneous ring enhancement centrally, due to presence of necrotic foci (arrows)

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a

c

Fig.38.24a-c. Aggressive presentation of abdominal tuberculosis. a Post-enhanced CT of the abdomen demonstrates massive para-aortic adenopathy (n) surrounding the superior mesenteric artery (s). The inferior vena cava (v) is displaced by enlarged retrocaval lymph nodes. Note presence of ascites (small arrows). Also note the enhanced vascularity of the peritoneum (p). This appearance is consistent with fibrotic fixed type of peritonitis. b CT scan of the chest of the same patient demonstrating enlarged posterior and anterior mediastinal lymph nodes (arrows). c Chest X-ray of the same patient (b) showing fibronodular tuberculous lesion in the right upper lobe (arrow)

b

scattered, necrotic tissue (Fig. 38.23). CT is believed to be more accurate than US for assessment of lymph node enlargement in TB (Denton and Hossain 1993). However, US is usually a first line of investigation for abdominal conditions. US can detect discrete or confluent lymph node enlargement (Fig. 38.25). The application of color Doppler US can demonstrate the increased perinodal vascularity due to inflammatory periadenitis (Fig. 38.26), as well as the hyperemia of the omental layers. This phenomenon is not pathognomonic for TB and can occur in other benign or malignant conditions, including metastases, lymphoma, Whipple's disease, and Crohn's disease (Hulnick et al. 1985; Bankier et al. 1995). Although abdominal lymphadenopathy can reach a large size (Fig. 38.26, 38.27), obstruction due to extrinsic compression of the gastrointestinal tract is unlikely. Actually, intestinal obstruction in TB is commonly due to peritoneal adhesions (AI Karawi et al. 1995). Different stages of lymph node involvement can be demonstrated in the same patient (Fig. 38.28).

38.3.4 TB of the Parenchymal Organs 38.3.4.1 T8 of the Liver and Spleen

Hepatobiliary TB has been reported in 20% of abdominal TB patients (Lundstedt et al. 1996). As much as 80-100% of patients having miliary TB were proven to have hepatosplenic involvement at autopsy (Thoeni and Margulis 1979). Infection can reach the liver either by hematogenous spread of disseminated TB or locally via the portal vein from gastrointestinal lesions. The disease commonly presents as hepatosplenomegaly (Hulnick et al. 1985; Ramaiya and Walter 1993). There are three types ofhepatosplenic TB. The miliary spread is the most common presentation. The liver and spleen may become extensively infiltrated by small lesions in the order of 0.5-2 cm. The smaller size micronodular pattern may be below the resolution

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a

b

Fig. 38.25a, b. Tuberculous adenopathy. a Ultrasound examination of the abdomen showed lobulated hypoechoic homogenous mass in the right side of the lower abdomen, caused by enlarged matted lymph nodes (between cursers). b CT scan of the same patient demonstrates characteristic appearance of peripheral ring enhancement of the enlarged lymph nodes, which are totally matted together (arrowheads)

a

Fig. 38.26a, b. TB abdominal lymphadenopathy in a 50-year-old male who presented with diarrhea, weight loss, and malaise. On clinical examination he had a soft "doughy" abdomen and multiple masses were felt. a US examination of the abdomen showed multiple hypoechoic enlarged lymph nodes with necrotic center and thick wall, matted together in the para-aortic region (arrows). b On Doppler US these lymph nodes were avascular. Enhanced vascularity of the blood vessels surrounding the lymph nodes and the adjacent peritoneal/omental vessels was demonstrated (arrows)

of a US scanner and present as a diffusely bright liver or spleen (Andrew et al. 1982; Jadvar et al. 1997). On CT, a honeycomb pattern (Fig. 38.29) of uncountable low attenuation lesions with minimal enhancement can be seen (Choi et al. 1989). A larger macronodular pattern is less commonly encountered, while medium-size multiple lesions are easier to discern on US or CT (Fig. 38.30). These lesions are hypoechoic on US and hypodense on CT. Lately, increased echogenicity or higher attenuation may be noted, and calcification may be the

end result (Denton and Hussain 1993; Choi et al. 1989). The diffusely nodular TB of the liver and spleen should be differentiated from metastatic disease, lymphoma, and other infections particularly fungal infections. The second form of hepatosplenic TB is the solitary lesion, which can be a granuloma or a frank abscess formation (as shown in Fig. 38.31a) (Wilde and Kueh 1991; Choi et al. 1989). The appearance of the solitary lesion may show variation of density according to progression or regression of the dis-

693

Imaging of Gastrointestinal Tuberculosis

Fig. 38.27. Postenhanced CT examination of the abdomen showed massive adenopathy with characteristic appearance of low attenuation center and peripheral rim enhancement (n). Note small bowel wall thickening (arrowheads), ascites (a), and thickening of the peritoneum (small arrows)

Fig. 38.28. CT shows difference patterns of abdominal tuberculous lesions including lymphadenopathy (arrows). Note the thickened infiltrated peritoneum (large arrowheads), ascites (a), and the dilated bowel loops with edematous mucosa (small arrowheads). (Fibrotic-fixed type of peritonitis)

Fig. 38.29. Hepatosplenic tuberculosis, miliary type: Postenhanced CT of the abdomen demonstrating multiple tiny foci oflow attenuation, widely scattered throughout the spleen and the liver (arrowheads)

Fig. 38.30. Hepatosplenic tuberculosis, macronodular type: post-enhanced CT of the abdomen demonstrates splenomegaly with multiple low attenuation lesions of variable size throughout its parenchyma (arrowheads). Note associated adenopathy with necrotic center (arrow)

ease. On MRI imaging a solitary lesion in the liver or spleen demonstrates a hypointense signal on TIweighted images and an isointense or hyperintense nodule with a less intense rim on T2-weighted images (Mercusot et al. 1995). After IV-contrast administration, rim enhancement may be demonstrated (Fig.38.31b). Hepatosplenic TB can be a part of disseminated disease involving the spine, retroperitoneal structures like the adrenal glands or the psoas muscle (Fig. 38.31,38.32), or the gastrointestinal tract (Fig. 38.27).

38.3.4.2

Pancreatic TB Tuberculosis of the pancreas is rarely reported (Hulnick et al. 1985; Desai et al. I991). This could be a part of miliary tuberculosis or a site of reactivated disease (Desai et al. 2000). The pancreas may be inseparable from surrounding infected retroperitoneal lymph nodes (Lundstedt et al. 1996). However, focal pancreatic lesions in TB can be readily demonstrated by US or CT (Fig. 38.33). Confusion with

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a

Fig.38.31a-c. Multisystemic tuberculosis. Male patient presented with weight loss, back pain, fever, and night sweats. a US of the spleen showed a well-defined solitary hypoechoic mass consistent with tuberculous granuloma (arrow) (macro nodule presentation). b MRI of the spleen: Tl-weighted image after contrast enhancement demonstrates low signal intensity mass with rim enhancement (arrow). The examination also demonstrates tuberculous spondylitis and paraspinal abscess (large arrowheads). There is extension of the abscess into the vertebral canal (small arrowheads). c MRI of dorsolumbar spine of the same patient demonstrates tuberculous spondylitis, paraspinal abscess (large arrows) and the extension of the abscess into the vertebral canal (arrowheads)

pancreatic carcinoma can occur (Fig. 38.34). There is a tendency to involvement of the pancreatic head but the tail can, rarely, be involved (Lundstedt et al. 1996). This could be due to the abundance oflymph nodes in the region of the pancreatic head. In cases of pancreatic abscesses, clinical correlation and aspiration are necessary to differentiate between a pyogenic and tuberculous abscess.

38.4 Imaging of Complications of Gastrointestinal T8 Cold abscess formation is a common complication of gastrointestinal TB. The most serious complication of gastrointestinal TB is fistula formation. These can be demonstrated by a simple barium follow-through examination (Fig. 38.5, 38.6, 38.35), but a fistulogram can delineate the exact length and course of the fis-

c

tulous tract (Fig. 38.36). Intestinal complications of abdominal TB have been well described (Ha et al. 1999). Intestinal obstruction is considered the most common complication (Makanjuola et al. 1998).

38.5 Mimics and Differential Diagnosis Despite pattern recognition and imaging characteristics, TB is mimicked by and is a mimicker of many other conditions (Yassawy et al. 1987; Jadvar et al. 1997). In particular, differentiation from Crohn's disease is a problem. There are no radiologic or colonoscopic features of Crohn's disease that may not be mimicked by colonic TB (Lingenfelser et al. 1993). Invasive procedures using imaging-guided aspiration biopsies are necessary. However, the frequency of positive acid-fast smears is low (0-45%) (Leder and Low 1995). Measurement of ascitic fluid adenosine deam-

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695

a

b

c

d Fig.38.32a-d. CT manifestation of abdominal tuberculosis with multisystemic involvement. a Post-enhanced CT of the upper abdomen demonstrating ill-defined macronodular hypodense lesions in the liver displacing blood vessels (arrowheads). Note paraspinal abscess (small arrowheads). Also note tuberculous involvement of the right adrenal gland, which appeared enlarged with area of caseation (arrow). b CT scan at lower level demonstrates multiple hypodense lesions in the spleen (arrows). Note the left adrenal mass due to tuberculous involvement (arrowhead) appearing as a solid tumor with no evidence of necrosis. c CT scan at more caudal level demonstrates cold abscess in the left psoas muscle (arrowheads). d CT of the same patient at more caudal level demonstrating paraspinal abscess (arrows). Also note thickened bowel wall (small arrowheads) and large necrotic lymph node

Fig. 38.33. Tuberculosis of the pancreas. US examination demonstrates a well-defined hypoechoic mass in the region of the head of pancreas (arrow)

Fig. 38.34. CT scan of the same patient demonstrating a homogeneous mass of low attenuation in the region of the head of pancreas (arrows), mistaken for carcinoma. Tuberculosis was diagnosed after surgical intervention

696

Fig. 38.35. Extensive tuberculous peritonitis and enteritis: small bowel follow-through demonstrates widely separated bowel loops due to peritoneal lymph adenopathy and due to direct infiltration to the bowel loops. Opacification of the rectum (large arrow), has occurred before barium reached the left side of the colon indicating fistulous communication. The cecum is conical in shape due to stenosis (open arrow). Note multiple small bowel loops demonstrating wall edema and narrowing (small arrows)

ine activity sensitivity above 95% has a specificity of 96-98% (Voigt et al.I989). Adenosine deamine activity is a quick test, which together with histologic tests and serum PCR level determination have improved the diagnosis of abdominal TB (Marshall 1993). Laparoscopy is more invasive than imaging-guided aspiration biopsy but has a high yield of 72-79% (Menzies et al. 1985). Ha and colleagues described CT criteria for differentiation between tuberculous peritonitis and peritoneal carcinomatosis, including mesenteric modulation, and enhancement of the infiltrated omentum, omental line and splenic involvement. The overall sensitivity of CT for prediction of TB peritonitis was 69% and for peritoneal carcinomatosis was 91 % (Ha et al.1996). Other conditions like lymphoma and peritoneal mesothelioma should be excluded (Akhan and Pringot 2002). Castleman disease can cause abdominal lymphadenopathy but tends to cause dense homogenously enhanced large lymph nodes (Ferreiros et al. 1989). Whipple's disease tends to cause an exceedingly low attenuation of lymph nodes due to excessive fat deposition. Calcification is more commonly seen in old, healed lymph node infections than in the acute disease. It is important

M. S. Al Shahed and M. Abd El Bagi

Fig.38.36. Fistulogram using a soft catheter through a sinus tract in the left iliac fossa demonstrates the tract (arrowheads), which opens into the descending colon (arrow)

to note that a multitude of intra-abdominal lesions is common in gastrointestinal TB, which helps to clarify the nature of the disease.

38.6 Summary Gastrointestinal TB has a wide spectrum of clinical and radiologic manifestations. There are no pathognomonic radiologic signs. Gastrointestinal TB can mimic many other diseases. A high index of clinical suspicion is necessary. The radiologic approach should be systematic and structured in an objective and practical manner. We propose criteria and pathway algorithms to determine the imaging strategies, which should be adopted in various clinical situations and according to the type of patient. This entails assessing the clinical presentation (Algorithm 1), the level of clinical suspicion ofTB (Algorithm 2), the population setting (Algorithm 3), and the organ expected to be involved (Algorithm 4). Accordingly, the diagnostic pathway and the end point for all investigations should be decided. Modern serologic tests are sensitive and provide speedy assistance to a diagnosis. Image-guided microbiologic or histologic proof is essential for a definitive diagnosis.

Imaging of Gastrointestinal Tuberculosis

38.7 Algorithms 38.7.1 Algorithm 1. Clinical Presentation of Abdominal 18 38.7.2 Algorithm 2. Degree of Clinical Suspicion of Abdominal 18 38.7.3 Algorithm 3. Population Setting 38.7.4 Algorithm 4. Organ Involved with 18

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697 Choi BI,Im JG,Han Mc et al (1989) Hepatosplenic tuberculosis with hypersplenism: CT evaluation. Gastrointest Radiol14: 265-267 Dantew B, Frengley D, Wolinsky E et al (1987) Oesophageal tuberculosis mimicking gastrointestinal malignancy. Rev Infect Dis 9:140-146 Denton T, Hossain J (1993) A radiological study of abdominal tuberculosis in a Saudi population with special reference to ultrasound and computed tomography. Clin Radiol 47: 490-414 Dermirkazik FB,Akhan 0, Ozmen MN et al (1996) US and CT findings in the diagnosis of tuberculous peritonitis. Acta RadioI37:517-520 Desai DC, Swaroop VS, Mohandas KM et al (1991) Tuberculosis of the pancreas: report of three cases. Am J GastroenteroI86:761-763 Desai SR, Bhanthunmavin K, Hollands M (2000) Primary pancreatic tuberculosis: presentation and diagnosis. Aust NZ Surg 70:141-143 De Silva R, Stoopack PM, Roufman JP (1990) Oesophageal fistulas associated with mycobacterium infection in patients at high risk for AIDS. Radiology 175:449-443 Edie DGA, Pollack DS (1968) A complicated aorto-duodenal fistula. Br J Surg 53:314-317 Epstein BM, Mann JH (1982) CT of abdominal tuberculosis. AJR Am J Roentgenol139:861-866 Ferreiros J, Gomez-Leon N, Mata MI et al (1989) Computed tomography in abdominal Castleman's disease. J Comput Assist Tomogr 13:433-436 Ferentzi CV, Sieck JO, Ali MA (1988) Colonoscopic diagnosis and medical treatment of ten patients with colonic tuberculosis. Endoscopy 20:62-65 Gilinsky NH, Marks IW, Kottler RE et al (1983) Abdominal tuberculosis: a 10 year review S. Afr Med J 64:849-857 Gompels BM, Darlington LG (1978) Ultrasonic diagnosis of tuberculous peritonitis. BJR 51:1018-1019 Gupta SK, Jaain AK, Agrawal AK et al (1988) Duodenal tuberculosis Clin Radiol 39: 159-161 Ha HK, Jung JI, Lee MS et al (1996) CT differentiation of tuberculous peritonitis and peritoneal carcinomatosis. AJR 167:743-748 Ha HK, Ko GY, Ya ES et al (1999) Intestinal tuberculosis with abdominal complications: radiologic and pathologic features. Abdom Imaging 24:32-38 Haddad FS, GhossainA, Saway E et al (1987) Abdominal tuberculosis. Dis Colon Rectum 30:724-735 Han JK, Kim SH, Choi KY et al (1996) Tuberculous colitis: findings at double contrast barium enema examinations. Dis Colon Rectum 39:1204-1209 Hanson RD, Hunter TB (1985) Tuberculous peritonitis CT appearance. AJR 144:931-932 Hulnick DH, Megibow AJ, Naidich DP et al (1985) Abdominal tuberculosis: CT evaluation. Radiology 157:199-204 Isaacs P, Zissis M (1997) Colonic tuberculosis and adenocarcinoma: an unusual presentation. Eur J Gastroenterol HepatoI9:913-915 Jafee FA (1951) Tuberculous appendicitis: a clinicopathologic study of 17 cases. Am Rev Tuberc 64:182-191 Jadvar H, Mindelzun R, Eric W et al (1997) Still the great mimicker: abdominal tuberculosis. AJR 168:1455-1460 Kim KM, Lee A, Choi KY et al (1998) Intestinal tuberculosis clinicopathologic analysis and diagnosis by endoscopic biopsy. Am J Gastroenterol 93:606-609

698 Kolawole TM, Lewis EA (1975) A radiologic survey of tuberculosis of the abdomen (gastrointestinal tract). Am J Roentgenol Rad Ther Nucl Med 123:348-358 Lam KN, Rajasoorya C, Mak PK et al (1999) Diagnosis of tuberculous peritonitis. Singapore Med J 9:601-604 Leder RA, Low VHS (1995) Tuberculosis of the abdomen. Radiol Clin North Am 33:691-705 Lee DH, Lim JH, Ko YT et al (1991) sonographic findings in tuberculosis peritonitis of wet ascitis type. Clin Radiol 44: 306-310 Lee DH, Ko YT, Yoon Y et al (1993) Sonographic findings in intestinal tuberculosis. J Ultrasound Med 12:537 Lingenfelser T, Zak J, Marks IN et al (1993) Abdominal tuberculosis: still a potentially lethal disease. Am J Gastroenterol 88:744-750 Lundstedt C, Nyman R, Brismar J et al (1996) Imaging of tuberculosis II. Abdominal manifestations in 112 patients. Acta Radiol 37:489-495 MacGregor (1993) Tuberculosis from history to current management. Semin Roentgenol XXVIII(2):101-108 Makanjuola D (1998) Is it Crohn's disease or intestinal tuberculosis? CT analysis. Eur J RadioI28:55-61 Makanjuola D, AI Oraini I, Al Rashid R et al (1998) Radiological evaluation of complications of intestinal tuberculosis. Eur J RadioI26:261-268 Manahour A, Simjee AE, Haffejee AA et al (1990) Symptoms and investigative finding in 145 patients with tuberculous peritonitis diagnosed by peritoneoscopy and biopsy over a five year period. Gut 31:1130-1132 Marshall JB (1993) Tuberculosis of the gastrointestinal tract and periotoneum. Am J Gastroenterol 7:989-999 McAfee JG (1996) The year book of nuclear medicine. Editorial comment. Mosby, London, PP 94-95 McGuiness F (2000) Tuberculousis of the gastrointestinal tract and peritoneum: clinical imaging of non-pulmonary tuberculosis. Springer, Berlin Heidelberg New York, pp 105-137 McNamara M.,Williams CE, Brown TS et al (1987) Tuberculosis affecting the oesphagus. Clin RadioI8:419-422 Menzies R, Fitzgerald JM, Mulpeter K (1985) Laparoscopic diagnosis in ascites in Lesotho. Br Med J 291:473-475 Mercusot B, Arrive L, Rottenberg et al (1995) Imaging of hepatic tuberculoma. J Radiol 76:277-279 Meyers MA, Mc Guire PV (1995) Spiral CT demonstration of hypervascularity in Crohn's disease: vascular jejunization in Crohn's disease or the comb sign. Abdo Imaging 20: 327-332 Nakano H, Jaramillo E, Watanabe M (1992) Intestinal tuberculosis: findings on double contrast barium enema. Gastrointest Radioll08-114 Palmer KR, Patil DH, Basran GS et al (1985) Abdominal tuberculosis in urban Britain: a common disease. Gut 2: 1296-1305 Panton ON, Sharp R, English RA et al (1985) The great mimic still at large. Dis Colon Rectum 28:446-4450 Park SJ, Han JK, Kim JS et al (2000) Tuberculous colitis: radiologic colonoscopic correlation. AJR 175:121-128

M. S. Al Shahed and M. Abd EI Bagi Paustian FF, Bockus HL. (1959) So-called primary ulcerohypertrophic ileocaecal tuberculosis. Am J Med 27:509-518 Peh WCG (1988) Filiform polyposis in tuberculosis of the colon. Clin RadioI39:534-536 Pombo F, Rodriguez E, Mato J et al (1992) Patterns of enhancement of tuberculous lymph nodes demonstrated by computed tomography. Clin RadioI46:13-17 . Pringot J, Concette L,Ponette E et al (1984) Non stenotic ulcers of the small bowel. Radiographics 4:357-375 Ramaiya LI, Walter DF (1993) Sonographic features of tuberculous peritonitis. Abdom Imaging 18:23 Reeder M, Palmer P (1994) Miscellaneous disorder of the gastrointestinal tract. In: Freeny Rohweddler JJ (1989) Abdominal tuberculosis: a disease poised for reappearance. NY State J Med 89:252-254 Shah S, Thomas V, Mathan M et al (1992) Colonoscopic study of 50 patients with colonic tuberculosis. Gut 33:347-351 Sheikh M,Abu-Zeidan F,AI Hilaly M et al (1995a) Abdominal tuberculosis: comparison of sonography and computed tomography. J Ultrasound 23:413-417 Sheikh MY, Yosuf AH, Khalid TR et al (1995b) Co-existent tuberculosis and carcinoma of the colon. J Pakistan Med Assoc 45:305-306 Shukla HS, Gupta SC, Singh G et al (1988) Tubercular fistula in anal. Br J Surg 75:38-39 Singh MK, Arunabh S, Kapoor VK (1987) Tuberculosis of the appendix: a report of 17 cases and a suggested aetiopathological classification. Postgrad Med J 63:855-857 Snider DE, Roper WL (1992) The new tuberculosis. N Engl J Med 326:703-705 Stock F, Li FWP (1964) Granulomas of the large bowel simulating malignant disease. Br J Surg 51:898-901 Suri R, Gupta S et al (1999) Computed tomography in abdominal tuberculosis. BJR 72:92-98 Thoeni RF, Margulis AR (1979) Gastrointestinal tuberculosis. Semin RoentgenoI14:283-284 Tromba JL, Inglese R, Rieders B et al (1991) Primary gastric tuberculosis presenting as pyloric outlet obstruction. Am J Gastroenterol 86: 1820-1822 Voigt MD, Kalvaria I, Trey C et al (1989) Diagnostic value of ascites adenosine deaminase in tuberculous peritonitis. Lancet 1:751-754 Werbeloff L, Novis BH, Bank S et al (1973) The radiology of tuberculosis of the gastrointestinal tract. BJR 46:329-336 Wilde CC, Kueh YK (1991) Case report: tuberculous hepatic and splenic abscess. Clin RadioI43:215-216 Willifort ME, Thompson WM, Hamilton JD et al (1983) Oesophageal tuberculosis: findings on barium swallow and computed tomography. Gastroentrol RadioI8:119-112 Yang S-O, Lee YI, Chung DH et al (1992) Detection of extrapulmonary tuberculosis with gallium 67 scan and computed tomography. J Nucl Med 33:2118-2123 Yassawy MI, Al Karawi MA, Mohamed AE (1987) Alimentary tract tuberculosis: a continuing challenge to gastroenterologists. Report of 55 cases. J Gastroenterol Hepatol 2: 137-147

39 Genitourinary Tuberculosis M. MONIR MADKOUR

CONTENT 39.1 39.1.1 39.1.2 39.1.3 39.1.4 39.1.4.1 39.1.4.2 39.1.4.3 39.1.4.4 39.1.5 39.1.5.1 39.1.5.2 39.1.5.3 39.1.6 39.1.7 39.1.7.1 39.1.7.2 39.1.7.3 39.1.7.4 39.1.7.5 39.1.7.6 39.1.7.7 39.1.8 39.1.8.1 39.1.9 39.1.10 39.2 39.2.1 39.2.2 39.2.3 39.2.3.1 39.2.3.2 39.2.3.3 39.2.4 39.2.5 39.2.5.1 39.2.5.2

Urinary Tract Tuberculosis 699 Introduction 699 Epidemiology 700 Pathogenesis and Pathology of Renal Tuberculosis 701 Other Modes of Transmission 702 Renal Allografts 702 Sexual Transmission 702 Intrauterine Transmission 702 Direct Spread from Abdominal Tuberculosis 702 General Clinical Features of Urinary Tuberculosis 702 Symptoms 702 Signs of Urinary Tuberculosis 703 Other Clinical Features 703 Diagnosis of Urinary Tuberculosis 703 Imaging Modalities in Urinary Tuberculosis 703 Plain Radiography 703 Intravenous Excretory Urography 704 Ultrasound 704 Computed Tomography (CT) Scan 705 Magnetic Resonance Imaging (MRI) 707 Renal Scintigraphy 707 Cystoscopy 707 Polymerase Chain Reaction (PCR) 707 A Large Series of One Thousand Patients with Suspected GUTB 707 Treatment of Renal Tuberculosis 709 Surgery of Urinary Tuberculosis 709 Male Genital Tuberculosis 710 Epidemiology 710 Pathogenesis 711 Clinical Features 712 Clinical Features of Tuberculous Epididymo-orchitis 712 Clinical Features of Tuberculous Prostatitis and Seminal Vesiculitis 712 Clinical Features of Penile Tuberculosis 713 Diagnosis of Male Genital Tuberculosis 713 Imaging Features 713 Ultrasound and Color Doppler 713 CT and MRI 716

39.2.6 39.2.7 39.3 39.3.1 39.3.2 39.3.3 39.3.3.1 39.3.3.2 39.3.3.3 39.3.3.4 39.3.3.5 39.3.3.6 39.3.3.7 39.3.3.8 39.3.3.9 39.3.4 39.3.5 39.3.6 39.4 39.4.1 39.4.2 39.4.3 39.4.4 39.4.5

Tissue Biopsy and Fine-Needle Aspiration 716 Obstructive Azoospermia and Tuberculosis 717 Female Genital Tuberculosis 717 Epidemiology of Female Genital Tuberculosis 717 Pathogenesis of Female Genital Tuberculosis 718 Clinical Features of Female Genital Tuberculosis 719 Presenting Symptoms 719 Physical Signs 719 Tuberculosis of the Fallopian Tube and Ovary (Features and Investigations) 719 Tuberculosis of the Uterus (Features and Investigations) 720 Synechia Uteri: Asherman's Syndrome (Features and Investigations) 721 Tuberculosis of the Uterine Cervix (Features and Investigations) 721 Tuberculosis of the Vagina (Features and Investigations) 722 Tuberculosis of the Vulva (Features and Investigations) 722 Investigation of Female Genital Tuberculosis 722 Microbiology and Histopathology 723 Laparoscopy 723 Treatment of FGTB 723 Tuberculosis in Patients with Chronic Renal Failure, on Hemodialysis, or with Renal Transplant 723 Epidemiology 724 Clinical Features of Tuberculosis in these Groups 724 Investigations 724 Treatment of Genitourinary Tuberculosis 725 Dose Modification 725 References 725

39.1 Urinary Tract Tuberculosis 39.1.1 Introduction

M. M. MADKouR, MD, DM, FRCP Consultant, Department of Medicine, Riyadh Armed Forces Hospital, P.O. Box 7897, C-1l9, Riyadh 11159, Saudi Arabia

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

Genitourinary tuberculosis (GUTB) is a common site of extrapulmonary tuberculosis (EPTB). It accounted for 10% to 33% of extrapulmonary TB cases in various series (Garcia-Rodriguez et aI. 1994; Chattopadhyay et

700

al.1997; Alvarez and McCabe 1984; Weir and Thornton 1985). Clinical features of GUTB are often vague and insidious, and clinicians have to have a high index of suspicion to avoid the disastrous effect if this pathology is ignored. In developing countries, GUTB is a particular diagnostic problem and in developed countries it is expected to be on the rise with the resurgence of tuberculosis due to the spread of HIV (Nzerue et al. 2000). GUTB will eventually occur in 4% to 20% of all cases of pulmonary tuberculosis (Gow 1992). GUTB can be treated successfully with a short course of antituberculous drugs for 4-6 months. Such success is due to the relatively smaller number of organisms in renal tissue compared with those present in pulmonary disease. The kidney has a very good blood supply with high concentrations of the drugs in the urine, and there is good penetration of these medications to closed cavities (Gow 1979a,b).Although GUTB may affect one or more sites of the genitourinary tract, renal, male genital, and female genital disease will be discussed separately.

39.1.2 Epidemiology The epidemiology of urinary tract tuberculosis is difficult to determine because of the sparsity of symptoms related to the kidney, which is the most common site of involvement. Bacilliuria is also intermittent in nature therefore the prevalence of urinary tuberculosis is grossly underestimated. It has been estimated by many authors that among all patients with pulmonary tuberculosis, the genitourinary tract will be affected in 4% to 20% (Gow 1992, Lenk and Schroeder 2001). Mycobacterium tuberculosis is the most common cause of urinary tuberculosis. Occasionally Mycobacterium bovis may be the causative organism particularly in areas where raw milk is still consumed (Stoller 1985; Yates et al. 1993; Dankner et al. 1993; Cosivi et al. 1998). Other nontuberculous mycobacteria may also cause urinary tract infection particularly in HIV-infected patients. Urinary tract tuberculosis is more common among high-risk groups including Australian Aborigines, Native American Indians, immigrant health care workers, alcoholics, drug addicts, those living in shelters for the homeless, and those on immunosuppressive agents or with AIDS (CDC 1986,1985,1987,1995; Beck-Sague et al. 1992; Cantwell et al.1994; McKenna et al.1995; Nardell et al. 1986; Pearson et al. 1992; Selwyn et al. 1989,1992). Urinary tuberculosis occurs in all age groups but is most commonly found in the third and fifth decades

M. M. Madkour

of life at the time of its presentation. It is relatively uncommon among children and young adults (Ferrie and Rundle 1983; Chang et al. 1998). In India, Chattopadhyay and colleagues (1997) reported nine children (five boys and four girls) with genitourinary tuberculosis. Association with, or past history of, tuberculosis and was noted in three of these children (33%). Ferrie and Rundle (1983) reviewed 230 patients with genitourinary tuberculosis seen at the Royal Infirmary in Glasgow between 1970 and 1979. The authors reported 29 patients under the age of 25 years (10.8%). Past history of tuberculosis was found in 6.9% and positive family history in 27.6%. Both sexes were affected, with male predominance in most series at a ratio of2:1. The incidence of genitourinary involvement among all patients with tuberculosis may range between 2% and 5%, but the incidence is higher among patients with active pulmonary tuberculosis, ranging between 5% and 10% or higher. In Spain, genitourinary tuberculosis was noted to involve the most common site of extrapulmonary disease. Garcia-Rodriguez et al. (1994) reported 198 cases of extrapulmonary tuberculosis and found 81 cases to have genitourinary tuberculosis (40.9%), with male predominance (63%). Genitourinary tuberculosis accounted for 13.4% of all cases of tuberculosis and history of tuberculosis was present in 27.2%. The age distribution was more homogenous among different age groups in this series and was not restricted to older age groups. The authors noted that despite the decline in the prevalence of pulmonary tuberculosis in Spain, extrapulmonary localizations have increased from 18% in the late 1970s to 24% in 1986. In Saudi Arabia, the incidence of genitourinary tuberculosis has increased recently from 5% to 16% among those with extrapulmonary disease (see Figs. 3,4, and 5 in the chapter «Epidemiology of TB in Saudi Arabia"). Ethnic and racial differences in the incidence of genitourinary tuberculosis have been noted in different parts of the world. The Tuberculosis and Chest Diseases Unit of the British Medical Research Council conducted a survey in 1983 and reported in 1987 on tuberculosis based on notifications and bacteriology (National Survey - BMRC 1987). The survey indicated that genitourinary localization accounted for 27% of nonrespiratory tuberculosis among the European (white) patients and only accounted for 5% among those born in the Indian subcontinent (ISC): India, Pakistan, and Bangladesh. Ormerod (1993) reported a similar lower incidence of genitourinary tuberculosis among the ISC population living in the United Kingdom than among the European (white) population. He reviewed 1,163 notifications of tuberculosis

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monly located in the lung. M. bovis and nontuberculous mycobacteria can also affect the genitourinary system (Stoller 1985; Dahl et al. 1996). During primary pulmonary tuberculosis development, many authors believe that bacillemia occurs and metastatic seeding via hematogenous spread may occur to other sites (Balasubramanian et aI.1994). Even after healing of the primary complex in the lung, the bacilli may remain dormant in the new seeded areas in the lung and other organs. The exact mechanisms of protective immunity response against the development of the disease in humans have not been totally clarified (Ellner 1997). Reactivation of dormant granulomatous foci in the kidney or reinfection of both kidneys from postprimary pulmonary tuberculosis via hematogenous spread is the most common route of infection. The renal cortex of both kidneys at the periglomerular regions is the most common site of initial localization of microscopic miliary granulomas because of the high oxygen tension and rich blood supply. When the immune system is altered because of HIV, old age, diabetes mellitus, chronic renal failure, or the use of immunosuppressive agents, these dormant foci of granulomata containing viable organisms proliferate (Medlar 1926; Medlar et al. 1949; Berman et al. 1960; Christensen 1974; Psihramis and Donahoe 1986; Lazarus and Peraino 1984) and granulomas may enlarge in size. Enlarging granulomas may coalesce and form a large nodule that may in turn rupture and spread deeper into the renal tubules and produce medullary granulomas. Caseation and necrosis of these nodules may cause sloughing of the papillae with formation of a cavity or cavities. Debris passed from this process may obstruct a calyx, renal pelvis, pelviureteric junction, or the ureter. Such cavitations may be augmented by ureteric obstruction to form a cystic mass lesion. Tubercle bacilli are shed from these cavities and infect surrounding renal parenchyma and the collecting system. The ureter, urinary bladder, and urethra are infected through this antegrade method of spread, and bacilli may appear in the urine. Renal parenchymal healing with fibrosis, scarring, and calcification usually occurs in part of the kidney or all of it. Calyceal renal pelvis, ureteric, and bladder ulceration may occur and usually associated with fibrosis, scarring, calcifications, reduction in capacity, deformities, or obstruction. 39.1.3 As the disease advances, the renal cortex may be Pathogenesis and Pathology of Renal Tuberculosis totally lost particularly with ureteric obstruction and it becomes hydronephrotic nonfunctional Mycobacterium tuberculosis spread to the kidney (autonephrectomy) (Psihramis and Donahoe 1986; via hematogenous route from a primary focus com- Lazarus and Peraino 1984).

in Blackburn, Hyndburn, and Ribble Valley between 1978 and 1990 inclusive. Extrapulmonary tuberculosis was more common in the ISC ethnic group than in the white ethnic group (74% versus 24%, respectively). The ethnic white group accounted for 82% of genitourinary tuberculosis while patients in the ISC group accounted only for 15%. In another survey from Southeast England, Grange and colleagues (l995) conducted a survey to determine the ethnic differences in the incidence of genitourinary tuberculosis. These authors based their survey on positive bacteriologic culture rather than on the total notifications. A total of 7,536 new tuberculosis patient records of ISC and European ethnic origins were reviewed. The authors found the incidence of genitourinary tuberculosis in the ISC group was only 8% while in the European white ethnic group it was 25% with highly significant differences. However, they concluded that with elimination of the confounded factor of age, the occurrence of genitourinary tuberculosis was similar in both ethnic groups. In the United States, ethnic and racial differences in the incidence of genitourinary tuberculosis were also reported. Reider and colleagues (l990) reported the epidemiology of extrapulmonary tuberculosis according to age, sex, racial, and ethnic origin on data obtained from the Centers for Disease Control (CDC), Atlanta. The authors noted that genitourinary tuberculosis was less common in blacks than in nonHispanic whites, and more common among those born outside the United States. In Australia, there was definite evidence of ethnic and racial differences in the incidence of genitourinary tuberculosis. Dwyer and his colleagues (l987) reviewed 51 patients with extrapulmonary tuberculosis seen between 1980 and 1985. Ten patients had genitourinary tuberculosis (six were European immigrants and four were Australians) and none from Southeast Asia or among other immigrants to Australia. The authors also noted that in 1984, the incidence of extrapulmonary tuberculosis among all patients with tuberculosis in Australia was 24.3%. Recently, patients with AIDS were found to have a higher incidence of genitourinary tuberculosis than occurred in non-HIV-infected patients. Shafer and colleagues (l99l) from New York reported genitourinary tuberculosis in 37% of patients with AIDS and in 25% among non-HIV-infected patients.

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39.1.4 Other Modes of Transmission

39.1.4.3 Intrauterine Transmission

Although hematogenous spread of infection to the urinary tract is the most common route, there is documented evidence that other modes of transmission can occur.

Congenital renal tuberculosis in infants that has been transmitted via the intrauterine route has been reported. <;askurlu and colleagues (1998) from Turkey reported a male infant with persistent pyuria from the age of 1 year. Investigations showed a nonfunctioning right kidney as well as hydronephrosis in the left kidney. Tuberculosis was found in the resected right kidney. Family screening for tuberculosis showed no evidence of active tuberculosis. Because of the short duration for such severe destructive damage to occur in kidneys, right ureter, and urinary bladder with vesicoureteral reflux at this age, and in the absence of other sources, the authors considered intrauterine transmission was the presumed mode of transmission. Congenital or prenatally acquired tuberculosis may occur through hematogenous route with spread of the bacilli to the placenta leading to placental tuberculosis and then tuberculosis in the fetus. Hematogenous spread of tuberculosis from the infected placenta to the fetus via the umbilical cord vein to the liver may occur. Rupture of placental tuberculous caseation and necrosis into the amniotic fluid with subsequent in uterofetal aspiration is another mode of transmission of congenital tuberculosis (Myers et al.1981; Cantwell et al.1994). (See also the chapter on pregnancy and tuberculosis.)

39.1.4.1 Renal Allografts

Transmission of Mycobacterium tuberculosis bacilli to recipients by renal allograft obtained from cadaveric or living donors has been reported. Wajeh and his colleagues (1990) from Saudi Arabia reported one patient who developed tuberculosis after receiving a kidney donated by his living brother. The brother was found later to have active pulmonary tuberculosis. These authors also reported their experience of 403 renal transplant recipients at the King Faisal Specialist Hospital and Research Center in Riyadh over a 9-year period. They found 14 patients (3.5%) who developed tuberculosis after renal transplant. Tuberculosis was disseminated in nine (64.3%), pulmonary in four (28.6%), and genitourinary in one patient (7.1 %). A similar report from France indicated the development of disseminated tuberculosis in two allograft recipients (Mourad et al. 1985). The donor was a 46-year-old French man who was hospitalized for head injury and for whom a history of tuberculosis could not be obtained. The two recipients were on maintenance hemodialysis and did not have tuberculosis before the transplant. Both recipients developed tuberculosis 2 and 5 months after transplant, respectively. Mycobacterium tuberculosis grew from the urine of both patients in the absence of clinical evidence of genitourinary tuberculosis. 39.1.4.2 Sexual Transmission

Transmission of tuberculosis via sexual intercourse from a husband with renal tuberculosis to his wife has been reported (Richards and Angus 1998). These authors reported a 49-year-old Caucasian man with urinary bladder tuberculosis who was diagnosed retrospectively. His wife was being investigated for secondary infertility and during a laparoscopy, left tuberculous pyosalpinx was found. Subsequently, the husband was investigated and found to have urinary bladder tuberculosis. The authors found no other way for the transmission of tuberculosis except through coitus.

39.1.4.4 Direct Spread from Abdominal Tuberculosis

Spread of infection to the genitourinary tract may occur via direct contact with abdominal organs and tissue tuberculosis including adhesions due to tuberculous peritonitis or intestinal tuberculosis. It may also spread via intestinal or appendicular fistulas to the genitourinary tract (Silva et al. 1988; Tripathy and Tripathy 1990).

39.1.5 General Clinical Features of Urinary Tuberculosis 39.1.5.1 Symptoms

Renal tuberculosis is asymptomatic in up to 80% of patients (Simon et al. 1977) in comparison with the remaining 20% of cases of genital tuberculosis that are more symptomatic, with a better chance of being diagnosed earlier. Therefore, the treating clinician in

703

Genitourinary Tuberculosis

endemic areas should have a high index of suspicion to diagnose it at its early stage. History of recurrent urinary tract infections may be the only presenting feature even when the causative pyogenic organism, such as E. coli, is identified or sterile pyuria is present. This should alert the clinician to the possibility of urinary tract tuberculosis as a cause. Constitutional symptoms, such as the fever, sweating, loss of appetite, and weight loss described in 14-60% of patients, nut may be absent in patients with urinary tract tuberculosis (Garcia-Rodriguez et al. 1994). Symptoms of recurrent attacks of painless hematuria, or flank or abdominal pain may occur in isolation or in association with mild constitutional symptoms. However, the most common urinary symptoms at the time of presentation are related to urinary bladder involvement. Recurrent or persistent dysuria, frequency, urgency, nocturia, or suprapubic pain may be present. The incidence of these urinary symptoms with bladder irritation varies from one series to another with average occurrence in 20% to 95% of patients with urinary tuberculosis (Garcia-Rodriguez et al. 1994; Psihramis and Donahoe 1986). Rarely, acute urinary retention, weak urinary stream, periurethral abscess, sinus, or fistulas may be the presenting symptoms when the urethra is involved (Raghavaiah 1979; Indudhara et al. 1992). Symptoms related to pulmonary tuberculosis, or that in other systems or organs, may be also present. Past history or family history of tuberculosis should be obtained. 39.1.5.2 Signs of Urinary Tuberculosis

Physical signs in patients with urinary tract tuberculosis are often lacking. Occasionally flank tenderness on percussion, enlarged palpable renal mass, cold abscess with discharging nephrocutaneous fistula may be found. Suprapubic tenderness, perineal and urethral abscesses or fistulas, or mass at urethral meatus, may be seen. 39.1.5.3

39.1.6 Diagnosis of Urinary Tuberculosis The diagnosis of early urinary tract tuberculosis is difficult as it has no distinctive clinical, hematological (anemia) or biochemical features (raised urea in 1.2% to 2.6%) that could raise the suspicion of the treating clinician to the possibility of tuberculosis as a cause. At the time of diagnosis, most patients will have advanced disease. Unsuspected accidental discovery of urinary tuberculosis, while investigating other illnesses or during surgery has been noted in 7.5% to 56% of patients (Garcia-Rodriguez et al. 1994). The most important initial test that may lead to requesting further urinary tract investigations is urine analysis, done as a routine test. It is abnormal in 59.3% to 84% (pyuria and or hematuria) of patients with urinary tract tuberculosis (Webester and Wright 1985, Gow 1992). The second most important investigation is intravenous urography OVU), which may have features that raise the suspicion of tuberculosis as a cause. Urine smear and culture for acid-fast bacilli is the mainstay for diagnosing urinary tract tuberculosis. Ziehl-Neelsen staining of urine deposits is positive in 3-5 morning samples on separate days in about 0.2% to 50% of cases (Webster and Wright 1985; Gow 1992). Smear staining of urine sediments requires a minimum of 10,000 organisms/rnl to be able to identify the bacilli on microscopic examination. However, urine deposit staining may give misleading results due to contamination by saprophytic mycobacteria particularly M. smegmatis. Urine culture yield has been reported with a wide range of positivity from 25% to 100% (GarciaRodriguez et al. 1994; Moussa et al. 2000; Ferrie and Rundle 1983). These variations may be related to the intermittent bacilliuria. Bucholz, Salahuddin and Haque (2000) from Pakistan reported 55 patients with genitourinary tuberculosis. Positive urine culture was found in 57% and urinary bladder biopsy changes in 54%. Positive culture can also be obtained from draining perineal and urethral sinus discharge or abscesses. Concomitant presence of active pulmonary tuberculosis may provide another source for detecting bacilli in the sputum.

Other Clinical Features Clinical features of tuberculosis affecting various organs of the urinary and male and female genital tract will be discussed separately. Although these organs are often affected in more than one site of the genitourinary tract, it is my intention to discuss each organ separately in this chapter for the purpose of clarity.

39.1.7 Imaging Modalities in Urinary Tuberculosis 39.1.7.1

Plain Radiography In the early stage of the disease process, plain radiography appears normal. In advanced renal tuberculosis,

704

calcifications may be seen as stippling, curvilinear, lobar in pattern or may affect the entire kidney (Leder and Low 1995; Cohen 1986) (Fig. 39.1a, b). Calcifications may be so extensive that they affect the kidney, ureter, and urinary bladder (Figs. 39.la, b, 39.3a, b). 39.1.7.2 Intravenous Excretory Urography

Early in the disease, IVU may look normal. Imaging abnormalities were depicted in IVU in 65% to 95% of patients in different reported series (Garcia-Rodriguez et al. 1994). Although bilateral renal tuberculosis pathology is the rule (Figs. 39.1-39.3), unilateral abnormalities in IVU are not rare (Fig. 39.5). With early calyceal involvement, the outline of the calyces may look hazy, but later, ulceration and fibrosis deformities may appear more obvious. A cavity or multiple cavities may be seen when necrosis and sloughing of the papillae occurs. Parenchymal fibrosis and scarring may be depicted by IVU as well as by ultrasound. Obstruction of the pelvicalyceal and pelviureteric

a

M. M. Madkour

junctions leading to hydronephrosis can be easily discerned. In the advanced stages, autonephrectomy of the kidney may not be visualized (nonfunctioning) while the opposite side will be clearly seen by IVU and may also show evidence of involvement (Figs.39.1, 39.2, 39.4, 39.5). The ureter ulceration and fibrosis may be seen as straightened ureter, and hydroureter may be seen if ureterovesical reflux or obstruction at the lower end is present. Reduced bladder capacity and deformity can be noted by IVU (Fig. 39.2c) (McGuinness 2000). 39.1.7.3 Ultrasound

Ultrasonography may not be helpful in the early stage of renal tuberculosis. As the disease progresses, the size of the renal pelvis may be reduced by fibrosis or hydrocalyx, and strictures at various sites may cause hydronephrosis. Mass lesions and even pelviureteric obstructions can be demonstrated by ultrasound. The thickness of the urinary bladder wall, its capacity, and the caliber of the lower part of the ureter can be

-~~--b

Fig. 39.la, b. A 53-year-old male presented with 2 years of dysuria and micturition. He was told in the past that he had renal stones but these were not causing problems for him. At presentation he denied fever, chest symptoms, or contact with tuberculosis patients. His blood urea and creatinine were raised. a Abdominal radiograph shows lobar type of parenchymal calcification of the left kidney (putty kidney), amorphous calcification at the lower pole of the right kidney (white arrowhead). Calcification of the left ureter and the bladder (white arrows). The last two findings are infrequent in tuberculous involvement of these structures. Note calcified pelvic lymph node due to abdominal tuberculosis (curved arrow). b Intravenous pyelogram shows nonfunctioning left kidney and hydronephrotic right kidney. Note marked dilatation of the pelvis with irregular round filling defects due to granuloma (arrow). Granulomas causing filling defects also seen in the dilated lower pole calyx (arrowhead). Three morning urine cultures grew M. tuberculosis

705

Genitourinary Tuberculosis

Fig. 39.2a-c. A 49-year-old man presented with recurrent urinary tract infection for 6 months before presentation. He had had many antibiotics. He was referred to our hospital. He had fever, dysuria, and micturition. He had a past history of pulmonary tuberculosis 10 years earlier and was treated. a Chest radiography shows multiple calcified right paratracheal and right hilar lymph nodes (arrowheads). Parenchymal fibrotic bands are also seen radiating from the hilar regions (arrows). b Abdominal X-ray shows multiple irregular calcifications in a small right kidney (black arrowheads). Small calcific density is also seen in the left kidney (white arrowhead in b and c). c Intravenous pyelogram demonstrates nonfunctioning of the right kidney. Left hydronephrosis and hydroureter. Shrunken small-capacity urinary bladder with marked wall thickening (white arrow)

a __

~

-",".,.J

b

assessed with ultrasound. However, ultrasound does not assess renal function or calcifications. These are better depicted by plain radiography IVU or CT scanning (Premkumar et al. 1987; Cremin 1987). 39.1.7.4 Computed Tomography (CT) Scan

Axial CT with contrast can provide similar findings to those of IVU, in depicting features of renal tuberculosis particularly the pelvicalyceal ulcerations and wall thickening, focal caliectasis, and deformities due to fibrosis and strictures. It can provide more detailed morphology and some assessment of the renal function through the degree of cortical per-

fusion and enhancement (Premkumar et al. 1987; Birnbaum et al. 1990). Renal calcification patterns are better depicted by axial CT than by the use of IVU or ultrasound. An enhancement of an inflammatory granuloma seen on axial CT with contrast will differentiate it from caseating and necrotic material that does not enhance (Goldman et al. 1985; Feeney et al. 1994). Perinephric abscesses are much better depicted with greater detail by axial CT than by the use of IVU (Fig. 39.5) or ultrasound. Ureteric fibrosis, dilatation, wall thickening, and multiple strictures are better seen on CT than by IVU. A small, shrunken, deformed urinary bladder with a thick, irregular wall with occasional calcifications can readily be seen by axial CT (Valentini et al. 1998; Wang et al. 1997).

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M. M. Madkour

a Fig. 39.3a, b. A 28-year-old female presented with recurrent dysuria, fever, and constitutional symptoms for more than 3 years. a Abdominal radiograph showing lobar and curvilinear calcifications in the left kidney (arrowheads). There is also irregular calcification at the distal end of the left ureter due to calcified granulomas (curved arrow). This is an infrequent finding in ureteric tuberculosis. b Intravenous pyelogram showing partially functioning left kidney, narrow contracted renal pelvis due to fibrosis (arrow), and abnormal pooling of contrast around the deformed upper pole calyces (black arrowheads) in the right kidney

a

b Fig. 39.4a, b. A 32-year-old male presented with recurrent episodes of right flank pain and dysuria for over 3 years. He had ultrasound of the abdomen 3 years before presentation and was reported as normal. Urine cultures showed E. coli on one occasion. He had had many courses of antibiotics. a Abdominal radiograph showed no abnormal findings. b Intravenous pyelogram shows nonfunctioning right kidney and normal left collecting system and ureter. Filling defect noted in the bladder at the site of the ureterovesical junction caused by tuberculosis granulomas (arrowheads). Series of morning urine cultures for tuberculosis was positive. Cytoscopy showed inflammation at the ureterovesical orifice with mass. Biopsy showed caseating granuloma

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Genitourinary Tuberculosis

39.7.7.5 Magnetic Resonance Imaging (MRI)

MRI has the advantage over other imaging modalities in differentiating large granulomatous caseating mass lesions from other mass lesions of the kidney due to other causes. Caseating tuberculous lesions tend to be hypodense in T2 and fail to enhance. Other mass lesions of the kidney tend to be hypodense in Tl and show high signal intensity on T2- and Tl-gadolinium contrast images. MRI is however at a disadvantage in detecting calcification if compared with axial CT (Murata et al. 1996; Valentini et al. 1998). 39.7.7.6 Renal Scintigraphy

Assessment of renal function can be done by isotope renal scintigraphy. Renal perfusion, glomerular filtration rate, excretion, and drainage can be assessed by this method. It can be done by using either: 200-mBq Tc 99m DTPA, 100-mBq Tc 99m DMSA, or Cr 51 EDTA. The size of the kidney, renal parenchymal uptake and perfusion, its shape, pelvicalyceal and ureteric shape, obstruction, dilatations and drainage of the isotope through the ureter can be assessed. Cortical scarring or mass lesions may be seen as photodense areas but their nature cannot be differentiated by isotope scintigraphy (Fig. 39.5). 39.7.7.7 Cystoscopy

inflammation and stenosis. Biopsy from bladder lesions may be obtained for histopathologic and microbiologic investigations that may show granulomata with caseation and necrosis and may grow the bacilli. Piscioli et al. (1985) from Italy conducted a comparative study in 13 patients with tuberculosis of the bladder, diagnosed by cytologic findings of urinary sediment and positive histologic findings. Cytologic findings of urinary sediment were aimed at identifying epithelioid cells which were present in 38.5% and/or the identification of Langhans giant cells which were found in 84.6% of this series. Histologic diagnosis of the bladder tissue biopsy sample obtained by cystoscopy showed typical granulomas with Langhans giant cells in all 13 patients (100%) and culture was positive in 11 (84.6%) as reported by these authors.

39.1.8 Polymerase Chain Reaction (peR) Diagnosis of urinary tract tuberculosis depends on the gold standard of identifying the bacilli from the urine or tissue biopsies. The standard methods of urine sediments staining and culture remain unsatisfactory. The use of PCR for the diagnosis of active tuberculosis was mostly reported on sputum samples and only a few reports cite results on urine sediments (Missirliu et al.1996; Moussa et al. 2000). Detection of mycobacterial DNA by means of PCR requires only 1-10 organisms to yield a positive result while smear examination requires at least IO,OOOorganisms/ml.

When frank hematuria is the sole presenting feature, cystoscopy should be performed (Chattopadhyay et 39.7.8.7 al. 1997). Cystoscopy in such instances is done for the A Large Series of One Thousand Patients purpose of diagnosing or excluding urinary bladder with Suspected GUTS tumor. In one of our patients (from Buraidah, Saudi Arabia) who presented with severe painless hema- In a prospective comparative study on 1,000 patients turia and passing clots, cytoscopy showed a tumor with clinical suspicion of GUTB, the diagnosis was mass in the urinary bladder. Histology was reported confirmed in 347 patients (34.7%), by parallel peras transitional cell carcinoma and in another cystos- formances of conventional urine smear and culture, copy performed in another hospital it was reported radiometric liquid culture (BACTEC), and two differas squamous cell carcinoma and he was referred to ent assays of PCR (IS6110-PCR and 16S rRNA-PCR) the oncology department in our hospital for a third (Moussa et al. 2000). These patients attended the opinion and was found to have tuberculous cystitis. Urology and Nephrology Center, Mansoura UniverCystoscopy of urinary tuberculosis under general sity Hospital, in Egypt. Morning urine was obtained anesthesia may show inflammation, mucosal ulcer- on 3 consecutive days from each patient. Urine sediation, or necrotic mass that simulates bladder tumor. ments were stained for AAFB, cultured simultaneEdema, redness and inflammation of the trigone, ure- ously by using Lowenstein-Jensen (BACTEC), and teric orifices inflammation and stenosis, contracted examined by two different PCR assays (IS611O-PCR bladder with diminished capacity may be noted by and 16S rRNA-PCR). The results of these laboratory cytoscopy. The urethra may also show features of investigations are shown in Table 39.1.

f

h

Genitourinary Tuberculosis

..

709

Fig. 39.5a-h. A 65-year-old man presented in October 1995 with left hemiparesis and brain CT pre- and postenhancement showed (figure not included) multiple bilateral cortical infarcts in the centrum semiovale bilaterally, the left internal capsule, and the subcortical region of the left parietal lobe. There was no evidence of enhancing foci. In December 1995 he presented with upper abdominal pain. a Plain radiograph of the abdomen showed a dense irregular opacity in the left hypochondrium (arrow) and 2 smaller punctuate opacities just inferomedial to the large opacity (small arrows). These were interpreted as representing calcified hydatid cysts or old calcified hematomas. The lesions are probably located within the spleen and ultrasound was suggested but not done as abdominal pain settled. Bilateral carotid Doppler sonography showed calcified atheromatous plagues at left common carotid and right common carotid and right common carotid bifurcation. b On 24 June 1997 he presented with I-week history of fever, left loin pain, and dysuria. Patient came in April 1996 with left foot pain. Plain X-ray (not shown) showed calcification at the insertion of Achilles' tendon and vascular calcification. Chest X-ray demonstrates multiple calcified granulomas in both lung fields (arrowheads). Blunting of the left costophrenic angle due to small effusion (curved arrow). c On 25 June 1997 he had abdominal ultrasound. Ultrasound of the left hypochondriac region demonstrates irregular mixed echogenic mass-like lesion (arrows), medial and inferior to the spleen (arrowhead) interpreted as possible abscess collection. The left kidney could not be visualized clearly. d CT of the abdomen: axial section at the dome of the diaphragm demonstrates multiple foci of pleural calcification (arrowheads) and pleural thickening with small effusion (arrow). e CT of abdomen: axial section at a caudal level demonstrates irregular abscess collection (arrowheads) medial to the spleen (arrow). The perinephric abscess was aspirated and 40 ml of thick yellowish pus was drained. CT-guided biopsy samples were also obtained. Culture grew M. tuberculosis and histopathology showed granuloma. f At more caudal section the abscess is seen to extend to the posterior abdominal wall (arrowheads). g More inferior section shows atrophic left kidney with multiple foci of calcification (white arrow in c and d). The diagnosis of tuberculosis of the left kidney with autonephrectomy with atrophy and calcification noted first as nonsymptomatic left hypochondrium calcification in October, 1995. Only in June 1997, did the patient present with fever, left loin pain, and dysuria. h DMSA scintigraphy shows no evidence of tracer activity in the left kidney

Table 39.1. The results of AFB staining, PCR assays, relative to results of culture Test

Result

Results of Culture Sensitivity

Specificity PPV

NPV

52.06%

96.7%

99%

77.9%

95.59%

98.11%

96.66%

97.5%

87.05%

98.90%

97.83%

93.06%

Positive Negative AFB smear AFB smear IS6110-PCR IS6110-PCR 16S rRNA-PCR 16S rRNA-PCR

Positive Negative Positive Negative Positive Negative

189 174 347 16 316 47

21 616 12 625 7 630

ppv, Positive predictive value; NPV, Negative predictive value. [Reproduced: Courtesy of Professor M. A. Ghoneim, director, Urology and Nephrology Center, University of Mansoura, Egypt]

These authors recognized the factors that may alter PCR assays of the urine. False-negative results are known and found in 5% of the urine samples because of the presence of urinary enzyme inhibitors and contamination problems. These two obstacles were overcome in this study by lysis of the mycobacterial cell wall and by dUTP methods. The authors reported that IS611O-PCR assay was more sensitive than 16S rRNA-PCR. The detection limit of the former method was 10 organisms by agarose gel electrophoresis and only 1 cell by Southern blot hybridization. The sensitivity and specificity of methods used in this study are shown in Table 39.1. PCR is more sensitive than culture and its specificity is close to 99%. Detection of mycobacterial DNA can be achieved in 2-3 days.

39.1.9 Treatment of Renal Tuberculosis Treatment for renal, male genital, and female genital tuberculosis, and for other groups with renal diseases who are at risk, will be discussed at the end of this chapter.

39.1.10 Surgery of Urinary Tuberculosis Reconstructive surgical intervention may play an important role in the management of urinary tract tuberculosis. Antituberculous antibiotics should be

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initially given for a period of 4-6 weeks before any surgical intervention. Most surgical procedures for urinary tuberculosis may include emergency operative management for certain conditions (such as bilateral hydronephrosis, hydronephrotic solitary kidney), if renal insufficiency is getting worse and is occurring in association with abscess formation such as perinephric tuberculous abscess. Surgical procedures required may include drainage of hydronephrosis, abscess drainage, partial nephrectomy, reconstruction of upper urinary tract, bladder augmentation, or urethral reconstruction (Carl and Stark 1997; Gow and Barbosa 1984; Lazarus and Peraino 1984; Psihramis and Donahoe 1986). With advances in modern treatment in recent years, nephroureterectomy is rarely needed. Every effort should be made to preserve any remaining functioning renal tissue. Restoration of renal function to what may appear as obstructive nonfunctioning kidney may occur after the removal of obstruction or constriction in the urinary collecting system. Most reported series where nephroureterectomy was performed involved patients seen in the 1950s, 1960s, and 1970s (O'Flynn 1970; Gow 1979). At present there are only rare occasions where nephroureterectomy may still be indicated, despite antituberculous treatment, such as recurrent urinary tract infections, pain, persistent hematuria, failure of chemotherapy, development of hypertension, or if coexisting renal cancer is suspected. The role of nephroureterectomy in the treatment of a nonfunctioning kidney remains debated issue among authors. Some believe it may allow the use of a shorter course of chemotherapy, as viable bacilli were found in resected kidneys of patients treated for about 3 months. However, such a short period of medication would not eradicate the bacilli, but a longer course up to 2 years would achieve that goal. Operative procedures can be done by laparotomy or by laparoscopy. Partial nephrectomy is rarely needed except during fistulectomy with primary repair of the gut. Reconstructive surgery is most commonly used at present for pelviureteric, ureteric, or ureterovesical junction obstruction or stricture. Percutaneous nephrostomy may initially be required to relieve obstruction at the pelviureteric junction and to be followed later by pyeloplasty. Cystoscopic dilatation of strictures at the ureter or ureterovesical junction by means of an expanding ureteric catheter has been tried but commonly failed (Murphy et al. 1982). Ureteric stinting may be tried and if it fails then the stricture may be resected if it affects the short segment of the ureter with reanastomosis. Uretero-

vesical junction stricture may be resected, and the ureter can be reimplanted in the urinary bladder by using a reflux-preventing technique or by the use of Boari flap. Longer segments of ureteric stricture may require ureteroureterostomy, ureterocolic implant, or ureteral replacement using ileal segment. But the last has been found to be hazardous and has been associated with grossly dilated bowel segment, vesicoileal reflux, bacteruria, excessive mucous secretion in urine, and renal damage (Charghi 1979). Bladder augmentation has rarely been indicated in recent years. A bladder capacity of 100 ml or less may be associated with troublesome frequency symptoms, and enterocystoplasty, colocystoplasty, or cecocystoplasty may be indicated. Between 1959 and 1977, in a review of 59 patients with bladder tuberculosis, augmentation enterocystoplasty was performed on all of them (Dounis and Gow 1979). These authors reported operative mortality of 17% and postoperative complications in 50.8% of their patients. The use of part of the stomach for bladder augmentation (gastrocystoplasty) has been attempted. It has advantages over enterocystoplasty because it produces less mucous plaque, allows for easier ureteral reimplantation, and does not disturb the body electrolytes (Shamsa 1998). Tuberculous urethral strictures are extremely rare and may be managed by dilatation, urethrotomy, or urethroplasty (Raghavaiah 1979; Indudhara et al.1992). In conclusion, the need for surgery for urinary tract tuberculosis has declined remarkably in recent years due to the use of modern chemotherapy. Reconstructive surgery of the collective system is only required when stenotic lesions are not responding to antibiotics alone in the first 4 weeks.

39.2 Male Genital Tuberculosis 39.2.1 Epidemiology Genital organ tuberculosis in general (male and female) is more commonly reported than urinary tract tuberculosis. Mokhtar and Salman (1983) from Saudi Arabia reported genitourinary tuberculosis in 20 patients in their series of 125 patients with extrapulmonary tuberculosis (16%). Genital involvement was found in 16 patients (80%) (12 male and 4 female), while the urinary tract was involved in only 4 patients (20%). All 12 male patients had epididymo-orchitis.

Genitourinary Tuberculosis

Wechsler and colleagues (l960) reported on their series of 127 male patients with early symptoms and signs of genitourinary tuberculosis, and found epididymitis in 36%. Other authors have noted that the epididymis is the most common site of involvement in male genital organs (Ferrie and Rundle 1983; Petersen et al. 1993). While other authors reported that the epididymis and the prostate were the most common male genital site of tuberculosis. In Spain, Garcia-Rodriguez et al. (l994) reported on 81 patients with genitourinary tuberculosis (51 male and 30 female). Epididymitis was found in six patients (l1.8% of males) and the prostate was infected in one (2%). In India, Chattopadhyay et al. (l997) reported nine children (five boys and four girls) with genitourinary tuberculosis. Two of the boys (40%) had epididymo~orchitis with no evidence of renal involvement. Tuberculous epididymitis in a group of 214 patients with scrotal inflammation who were referred for ultrasonography was reported by Drudi et al. (l99l). They found 34 cases that were later identified to be due to tuberculous epididymo-orchitis (l6%). Wechsler et al. (l960) reported a series of 127 male patients with genitourinary tuberculosis and found tuberculous epididymo-orchitis in 36%. Male genital tuberculosis occurs mostly in young men, with 60% of patients between 20 and 40 years of age (Heaton et al.1989). Previous history of tuberculosis may be obtained in up to 70% of patients with epididymitis (Chung et al. 1997). The incidence of tuberculosis of the prostate in recent years with modern chemotherapy is not clearly determined but reported as low, while in the past, before the era of modern therapy, prostatic involvement ranged between 14% and 95%. In India, Mondal et al. (l990) reported their findings on 126 cases of transurethral fine-needle aspiration cytology of prostatic nodules suspected to be malignancies, and tuberculosis was found in four samples (3%). The incidence of tuberculosis in the vas deferens and seminal vesicles is not known, as they rarely occur in isolation. Penile tuberculosis is rare and the penis is the least commonly affected male genital organ, yet there are many single case reports or small series that have appeared in the literature. Penile tuberculosis may occur at any age from infancy to adulthood and among homosexuals with HIV (Lewis 1946; Annobil et al.1990; Dahl et al.1996).

711

mycobacterium was also found to cause male genital tuberculosis particularly in homosexuals with mv. These included M. kansasii, M. avium, M. celatum, and M. xenopi (Dahl et al. 1996). The route of transmission of the bacilli to male genital organs is commonly via hematogenous spread, direct spread from the urinary tract tuberculosis, or sexual intercourse (Sutherland 1982, 1985). Genital tuberculosis in males may be the sole primary site of the disease, without urinary tract involvement. The urine culture may be positive in up to 50% of patients with tuberculous epididymo-orchitis without any evidence of renal tract involvement (Ferrie and Rundle 1983). Carbal et al. (l985) reported two children with tuberculous epididymo-orchitis that had no evidence of renal or other sites of involvement. These authors reviewed the literature for similar findings to their own and found 24 children reported by others with tuberculous epididymo-orchitis without evidence of renal involvement. They also suggested that in children the transmission of infection to the epididymis is most likely via hematogenous route, while in adults transmission by direct spread from urinary tract disease is the most common. Early focal lesions may initially start at the tail or head, or may affect the entire epididymis. Inflammatory cell infiltrates, including epithelioid and polymorph nuclear cells with caseation and necrosis, may spread to the tunica vaginalis testis. Abscess formation may occur (Granadoz 1998) and may rupture through a single or multiple scrotal sinuses. The scrotal involvement may be by direct spread of infection leading to swelling, and the vas deferens may also be affected. Prostatic and seminal vesicle tuberculosis may be transmitted via hematogenous route or by direct extension of infection from tuberculous cystitis (Kim et al. 1993a; Gow 1992; Hemal et al. 2000). Sporer and Auerbach (l978) reviewed 1,000 autopsies (l972-1976) from New Jersey and found tuberculous epididymitis in 26 cases. None of these cases had evidence of urinary tract disease. They also reported three cases from their own series. In one, the kidney, bladder, and epididymitis were infected but not the prostate. In the second patient, the lungs and the right kidney were involved but not the prostate. In the third patient, the prostate and seminal vesicles were infected and urine culture was positive, yet there was no evidence of renal tuberculosis. 39.2.2 They also suggested that descending intracanalicular Pathogenesis spread may be excluded by the absence of pathologic changes of the bladder and ureter. They concluded Mycobacterium tuberculosis is the most common that the lateral or peripheral parts of the prostate cause of male genital tuberculosis. Nontuberculous were more often involved indicating the likelihood

712

M. M. Madkour

of hematogenous spread. They concluded that if descending infection was the route, then the disease would begin near the prostatic urethra and that was not the case in their findings. As the disease progresses and advances in the prostate, granulomatous nodules, caseation, necrosis, and abscess formation may occur. The prostatic tuberculous abscess may break through the urethra or the prostatic capsule (Kumar et al.1994). The vas deferens and the seminal vesicles may be involved via direct spread of infection from epididymal or prostatic tuberculosis. The vas deferens and the seminal vesicles may be affected in patients with renal tuberculosis in up to 60% of patients (Rains and Mann 1988). Transmission of tuberculosis to the penis may be either primary, when no tuberculosis elsewhere in the urogenital tract is found, or secondary, when other organs or systems are also affected. Primary tuberculosis of the penis may occur as a result of sexual intercourse with a partner having tuberculosis of the cervix or endometrium. Sengupta and Mukherjee (1982) reported two patients with penile tuberculosis, and sexual contact was definite in one of them. Lewis (1946) reported five patients with penile tuberculosis and reviewed 110 cases reported by other authors. He found that primary penile tuberculosis was reported in 89 cases (77.4%), secondary in 6.9%, hematogenous in 2.6%, while in 10 patients the source of infection was not known. Among the 89 primary cases, 72 were due to ritual methods of circumcision, 12 were definitely transmitted through vaginal sexual intercourse, 2 from oral genital sex, and 3 from different sources.

feature of the disease being insidious and progressive in the absence of constitutional symptoms or other features of tuberculosis in other organs in the body. Testicular pain or swelling may be associated with fever, sweating, loss of appetite, and weight loss. Scrotal abscess or discharging sinus may be the presenting feature. Unilateral involvement is the most frequently reported, but bilateral epididymal involvement may occur. The time interval between testicular symptoms and presentation to clinician may vary between 2 and 8 weeks (Izawa et al. 1999; Carbal et al. 1985). The epididymis is often swollen with nodularity, and it may be adherent to the testis and difficult to differentiate. Primary testicular tuberculosis without epididymal disease is rare. The testicular mass may be hard, similar to carcinoma. Tenderness may be slight and fluctuance of the mass may be detected. The scrotum may be normal, inflamed, indurated and adherent to the testicular mass. Scrotal sinus with seropurulent discharge may be noted at the time of presentation. The vas deferens may be thickened and beaded with multiple small nodules. Another rare presentation of tuberculous epididymitis is obstructive azoospermia leading to infertility (Abdel Razic and EI-Morsy 1990). Moon et al. (1999) treated 44 patients who presented with azoospermia. Seven of these cases were due to tuberculosis of the epididymis (15.9%). They also reported that sperm retrieval and intracytoplasmic injection (ICSI) from these patients resulted in successful pregnancies in a rate similar to that of nontuberculous patients.

39.2.3 Clinical Features

39.2.3.2 Clinical Features of Tuberculous Prostatitis and Seminal Vesiculitis

In male genital tuberculosis, systemic constitutional symptoms may be lacking. However, low grade fever, weight loss, or past history of tuberculosis may be present. Symptoms related to pulmonary or extrapulmonary tuberculosis may also be present. 39.2.3.1 Clinical Features of Tuberculous Epididymo-orchitis

Tuberculous epididymitis or epididymo-orchitis has no distinctive clinical features that differentiate it from other causes of testicular mass. A high index of suspicion by the treating clinician that tuberculosis may be the cause is important to avoid unnecessary orchiectomy. Epididymitis may be the sole presenting

The clinical features of tuberculous prostatitis include nocturia, dysuria, frequency, or urinary retention. Irritative bladder symptoms and hematuria may be the initial presenting manifestation. Rectal examination may reveal enlarged nontender prostate with firm or cystic swelling or with irregular hard multiple nodules of variable sizes simulating other pathologies such as carcinoma (Sporer and Auerbach 1978). Kumar et al. (1994) reported the clinical features of two patients with tuberculosis of the prostate. The first patient was a 29-year-old man with a 4-year history of dysuria, urinary retention, and difficulty in voiding of urine, and three episodes of hematuria. Rectal examination revealed cystic prostatic mass. Ultrasound showed bilateral hydronephrosis and

713

Genitourinary Tuberculosis

by transrectal imaging it confirmed the prostatic cyst which was aspirated. Histopathology of biopsy samples from kidney and prostatic cyst confirmed the tuberculosis. He was given 9 months antituberculous treatment. The second patient presented with rectal tenesmus, irritative voiding, and recurrent urinary retention. This patient had similar investigative findings and a prostatic tuberculous abscess that communicated with the urethra. He was also treated for 9 months with chemotherapy. The spermatic cords may be thickened and beaded and the seminal vesicles may be tender and craggy. 39.2.3.3 Clinical Features of Penile Tuberculosis

Symptoms of penile tuberculosis are not characteristic and patients may present with pain and swelling of the penis of gradual insidious onset. Constitutional symptoms may be lacking. Dysuria, urethral discharge, or tender masses in the groin may be the presenting symptoms. Erectile dysfunction in adults with penile tuberculosis may be a rare presenting symptom (Pal 1997; Murali and Raja 1998, Nishigori et al. 1986, Chatterjee et al. 1975). In infants who have been circumcised, the parents may note delayed healing of the wound, discharge, and pus oozing at the site of the wound and associated with fever (Lewis 1946; Annobil et al. 1990). Lewis (1946) reviewed the literature on penile tuberculosis, found 110 reported cases, and added five of his own. Most patients were Jewish infants who had undergone ritual circumcision and sucking of their penis by the operator to ensure hemostasis, a practice which has been abandoned in recent times. Annobil et al. (1990), reported a 4-month infant with penile tuberculosis. Circumcised at the age of 6 weeks by a "local barber" who spat several times on the razor during its sharpening. The wound did not heal and a penile ulcer and discharging sinus in both groins developed 3 weeks later. Culture of the discharge yielded M. tuberculosis. Family and contact screening were negative but the barber was not screened. Physical examination may show lesions on any part of the penis including ulcers, erythematous eruption, a plague, papulonodular lesion, necrotic area, subcutaneous nodules, chancre-like eruption, lupus vulgaris, penile orificial swelling, fistulas or sinuses, cold abscess, complete destruction of the glans penis, or even gangrene (Lewis 1946; Jaisankar et al. 1994; Annobil et al. 1990; Dahl et al. 1996; Nakamura et al. 1989; Pal 1997; Murali and Raja 1998; Atalay and Karaman 1997).

39.2.4

Diagnosis of Male Genital Tuberculosis The hemogram is usually normal and ESR may be raised. Biochemical parameters in the blood are usually normal. Urine microscopy and culture may yield M. tuberculosis. Screening for HIV should be carried out, particularly in homosexuals with penile tuberculosis (Dahl et al. 1996). Chest radiography may show an associated active pulmonary disease. Screening for associated renal tuberculosis should be done if genital TB is discovered. The diagnosis of male genital tuberculosis depends on a high index of suspicion in order to avoid unnecessary orchiectomy among patients with tuberculous epididymo-orchitis. Imaging features using various modalities are helpful in identifying the disease. Ferrie and Rundle (1983) reviewed 20 cases with tuberculous epididymo-orchitis and found that 50% had evidence of tuberculous infection in the urine. In this series IVU was done on 19 patients, and 14 had abnormal findings in the kidneys, ureters, and urinary bladder. Fine-needle aspiration and biopsies for histopathologic and microbiologic investigations are the most important diagnostic tools for male genital tuberculosis. Polymerase chain reaction (PCR) may also be helpful.

39.2.5

Imaging Features 39.2.5.7 Ultrasound and Color Doppler

Ultrasound of the scrotal mass may show epididymal enlargement predominantly in the tail, less frequently in the head, and perhaps the entire organ (Figs. 39.6-39.9). Marked heterogeneity of the echotexture with areas of calcification and small hydrocele may be depicted (Drudi et al. 1991). The testis may be enlarged, nonhomogeneous with central hypoechoic areas of variable sizes, however, these echographic appearances are impossible to differentiate from those of neoplasm (Figs. 39.6-39.9). An irregular margin between the testis and epididymis may also be present (Heaton et al. 1989; Chung and Harris 1991; Kim et al. 1993). The sinus tract may also be detected by ultrasound. Chung et al. (1997) reported the sonographic findings on 18 patients with tuberculous epididymitis and epididymo-orchitis. They reported abnormalities in 22 hemiscrotums of 18 patients. Unilateral epididymal abnormalities

714

M. M. Madkour

a

b

Fig. 39.6a, b. A 28-year-old man presented with fever, sweating, weight loss, and right testicular pain and swelling for a few months. He denied drinking raw milk and brucella serology and culture were negative. a Doppler ultrasound of both testes demonstrates enlargement of the right testis. There is a generalized reduction in its echogenicity and enhanced vascularity in comparison with the left testis. b Ultrasound of the right testis shows ill-defined area ofreduced echogenicity (arrowheads), this area demonstrates increased vascularity on Doppler ultrasound (arrow). Fine-needle aspirate showed caseating granuloma

Fig. 39.7. Tuberculous epididymo-orchitis. A 28-year-old male with left testicular pain and swelling for 2 months. He had constitutional symptoms with fever. Ultrasound of the scrotum demonstrates marked enlargement of the left epididymis (arrowheads), areas of necrosis (open arrow), and foci of calcification (arrow). The left testis is also involved (T), and there is moderate hydrocele (h). Fine-needle aspiration showed caseating granulomata

Genitourinary Tuberculosis

715

Fig. 39.8a, b. A 45-year-old man presented with left testicular dull aching pain and swelling for 7 months. a Ultrasound of the left testis demonstrates echolucent lesion (open arrows), containing floating echogenic foci consistent with debris (arrowheads). The wall of the lesion is thick and edematous (arrow). Testicular abscess was diagnosed. b Doppler ultrasound demonstrates increased vascularity around the wall of the abscess (arrowheads). Tuberculosis was diagnosed by fine-needle aspirate and positive culture

b

a Fig. 39.9a, b. A 36-year-old male presented with fever, weight loss, and left testicular painful swelling for 1 month duration. He was given antibiotics but was not responding to treatment. Hard left testicular mass was felt and was slightly tender. a Initial ultrasound of the left testis demonstrates ill-defined hypoechoic lesion (arrowheads) involving the epididymis and adjacent testicular tissue. Hydrocele is also noted (arrow). He was planned for orchiectomy but the patient refused the operation. b The patient came 1 month later with worsening of his left testicular symptoms. Ultrasound demonstrates localized abscess formation with irregular thick wall (arrowheads). Fine-needle aspiration showed caseating granuloma and the culture yielded

Mycobacterium tuberculosis

were found in 14 patients and bilateral in 4 patients. All of theepididymides involved were enlarged (diffuse in 9 and focal in 13). Decreased echogenicity was observed in 13, increased in 2, and mixed in 7. Draining sinuses were found in 4 and hydrocele in 12. The testis were involved in 8 cases and had diffuse enlargement of a hypoechoic testis and an ill-defined or well-demarcated hypoechoic lesion.

Colored Doppler may be helpful in differentiating tuberculous epididymitis from nontuberculous epididymal disease (Yang et al. 2000). Yang and colleagues (2000) from South Korea performed colored Doppler on 11 consecutive patients with histologically proven tuberculous epididymitis and epididymo-orchitis. Color Doppler ultrasound findings correlated well with histologic findings. It dem-

M. M. Madkour

716

onstrated no blood flow in the epididymal lesions except for focal linear or spotty flow signals in the peripheral portion. Transrectal ultrasound of the prostate may show hypoechoic areas with an irregular pattern in the peripheral zone of the prostate. The seminal vesicles may appear as enlarged and dilated but these ultrasound changes are not specific for tuberculosis. Calcifications, abscess formations, or cavities that are communicating from the prostate to the urethra or the seminal vesicles may be noted by ultrasound as well as by CT and MRI (Valentini et al.1998). 39.2.5.2 CTandMRI

In a contrast-enhanced CT of prostatic tuberculosis, areas of inflammation, caseation, or abscess formation will appear as hypoattenuation. However, these features are not specific for tuberculosis, but may be depicted in nontuberculous pyogenic prostatic abscesses. CT may depict seminal vesicle involvement better than ultrasound. A tuberculous prostatic abscess demonstrates peripheral enhancement (Engin et al. 2000). Low signal intensity in the prostate may appear as diffuse, radiating, or streaking ("watermelon skin" sign). Wang et al. (1997) noted that a CT of the prostate may show abscess and calci-

fication including in the seminal vesicles. If no calcification is present, then a CT of the upper urinary tract with contrast may show abnormalities, otherwise the abscess may look like other pyogenic abscesses. MRI of epididymal and testicular tuberculosis has the advantage of showing more detailed structural changes than ultrasound (Fig. 39.10), yet these are not specific for tuberculosis.

39.2.6 Tissue Biopsy and Fine-Needle Aspiration Tuberculous epididymitis or epididymo-orchitis is frequently diagnosed after orchiectomy and histologic examination for suspected malignancy (Ferrie and Rundle 1983). However, in endemic areas, particularly when other evidence of tuberculosis in other body organs is present, fine-needle aspiration under ultrasound guidance of epididymal tissue may spare the unnecessary orchiectomy as well as confirming the diagnosis. Fine-needle aspiration is also useful in the diagnosis of infertility caused by obstructive azoospermia due to tuberculous epididymitis. Transrectal fine-needle aspiration of the prostate mass, transurethral tissue resection, or incidental findings after prostatectomy for other indications are the usual diagnostic tools of tuberculous prostatitis.

b

a Fig. 39.10. a US of the left testis demonstrates ill-defined area of reduced echogenicity (arrowheads). Small amount of hydrocele noted (open arrow). band c MRls of the testis: sagittal (b) and axial (c) Tl-weighted images demonstrate irregular area of intensified signal (arrowheads) consistent with abscess formation

c

717

Genitourinary Tuberculosis

Other investigations should include urine culture, biopsy and culture of penile lesions and sinus discharge, chest radiography, and screening for renal tuberculosis.

39.3 Female Genital Tuberculosis

39.2.7 Obstructive Azoospermia and Tuberculosis

The frequency of female genital tuberculosis (FGTB) among the general population is difficult to determine. In many patients the disease is asymptomatic and only discovered accidentally (Schaefer 1976). Female genital tuberculosis is rare in the developed, industrialized world, but the incidence is rapidly rising (Miranda et al. 1996; Lueken et al. 1997). The frequency of involvement of different organs in the female genital tract has been reported by many authors (See Table 39.2). The incidence of female genital tuberculosis is much higher than the literature has suggested. Infertility is the most common presenting reason for investigations to find out the possible cause, therefore most of the reports on female genital tuberculosis were gathered from those infertile women. Agarwal and Gupta (1993) from India reported 501 females with genital tuberculosis. Young women aged 2030 years were the most commonly affected (82.3%), and sterility was the most common presenting symptom (68.5%). Menstrual disturbances were the second most common complaint in 22.7% of patients, abdominal mass in 3.5%, leukorrhea in 3.2%, abdominal pain in 1.2%, vaginal prolapse in 0.4%, and vulva ulcers in 0.2%. The uterus was involved in 99.5%, the tubes in 94%, the cervix in 81.5%, the ovaries in 62.5%, and the vulva in 0.2%. In an attempt to find the incidence of female genital tuberculosis among women admitted to a medical ward with bacteriologically proven pulmonary tuberculosis, Tripathy and Tripathy (1990) from

Male infertility due to obstructive azoospermia caused by tuberculosis of the epididymis, the vas deferens, seminal vesicle, or ejaculatory duct may be a presenting sequela of the disease (Abdel Razic and EI-Morsy 1990). Diagnostic procedures include history of tuberculosis, physical examination, plain chest radiograph, IVD, semen analyses and fructose measurement, hormonal assays, testicular biopsy, transrectal ultrasonography, and vasography (Wong et al. 1973). The incidence of tuberculosis as a cause of obstructive azoospermia and infertility due to ejaculatory duct obstruction was reported in 34% of a group of 50 infertile men from Korea (Paick et al. 2000). Microsurgical reconstruction ofthe epididymis or vas deferens, sperm retrieval, and intracytoplasmic sperm injection (leSI) can be successful in achieving fertilization and normal pregnancy outcome. Moon et al. (1999) from Seoul, Korea, reported 44 patients with destructive azoospermia that were divided into 2 groups: 7 patients with tuberculous obstructive azoospermia and 37 patients with nontuberculous obstructive azoospermia. The rates of fertilization and embryo cleavage, clinical pregnancy, embryo quality, and pregnancy outcome were comparable in these two groups. Infertility due to obstructive azoospermia caused by tuberculous epididymitis is still prevalent in Korea. It occurs in approximately 25% of those with obstructive azoospermia (Lee 1987).

39.3.1 Epidemiology of Female Genital Tuberculosis

Table 39.2. The frequency of organ involvement in female genital tuberculosis, as cited by different authors using various diagnostic methods Authors (year)

Diagnostic procedures of FGTB and no. of patients

Fallopian Uterus Ovaries Cervix tubes % % % %

Sutherland (1985) Agarwal and Gupta (1993) Tripathy and Tripathy (1990) Nogalez-Ortiz (1979)

Surgical findings 710 Clinical and pathologic specimens 501 Clinical and laparoscopy 37

100 94.7

90 99.5

20 62.5

1 91.5

NA Vulva 0.2

100

92

32

NA

Pouch of Douglas 22

Pathologic specimens 1436

100

79

11

24

Myometrium 20

Other organs or sites

718

India performed a pelvic laparoscopy on 62 patients. Of this group, aged between 15 and 45 years, 11 were nulliparous, 15 para 1, 15 para 2, 13 para 3, and 8 para 4 or more. Laparoscopic findings were normal in 25 women (40.3%) and abnormal with evidence of genital tuberculosis in 37 (59.7%). The uterus was abnormal in 34 women (bands and adhesion, hyperemia, tubercles nodules on the surface, and variations in the uterine size). Abnormalities in the tubes were noted in all 37 women (peritoneal adhesions, tubercles on the surface and/or blockage). Endometrial curettage showed histologic evidence of tuberculosis in 4 women. The authors however did not indicate if the nulliparous were among those with normallaparoscopic findings. Sutherland (1985) analyzed his own personal series of 710 cases of female genital tuberculosis. He noted that the fallopian tubes were involved in almost all cases, the endometrium in about 90%, the ovaries in about 20%, the cervix in about 1%, and there were no reports of tuberculosis in the vulva or vagina. The average age of FGTB patient was 31 years, the youngest 16 years and the oldest 72 years. Infertility was present in 84%, and only 16% of the married women gave a history of pregnancy. In Riyadh, Saudi Arabia, the incidence of female genital tuberculosis was reported to be 0.45% of all gynecologic admissions. Infertility with genital tuberculosis as its cause accounted for 4.2% of cases (Chattopadhyay et al.1986). In Spain, Nogales-Ortiz (1979) reviewed 78,000 gynecologic specimens studied between 1946 to 1977 and found the diagnosis of female genital tuberculosis in 1,436 cases (1.8%) of the total number of specimens. All patients presented with infertility (primary in 94% and secondary in 6%), fallopian tubes were affected in 100%, endometrium in 79%, myometrium in 20%, the cervix in 24%, and the ovaries in 11 %.

39.3.2 Pathogenesis of Female Genital Tuberculosis Hematogenous spread remains the most common route of transmission from primary tuberculous lesions most likely in the lung, similar to that observed in other forms of genitourinary tuberculosis. History of extragenital tuberculosis is found in more than 80% of these patients (Sutherland 1985). The fallopian tubes are the most favorable site, specifically on the mucosa. It usually affects both tubes at the same time. Direct spread from neighboring organs such as the gastrointestinal tract, peritoneum, or urinary tract is also common. Sexual intercourse was the primary

M. M. Madkour

source of transmission as reported by Sutherland (1985). He noted that "In my own series, 5 out of 128 husbands examined by a urologist had active genitourinary tuberculosis and transmission to their wives during sexual intercourse has occurred:' Seeding tuberculomas form in the mucosa of the fallopian tube bilaterally (Schaefer 1976; Saracoglu et aI.1992).As these advance and progress,caseation and necrosis with microabscess formation and blockage of the tubes may occur. The lumen may be distended and filled with purulent or serosanguinous fluid, and it may be calcified (Fig. 39.11). Direct spread to the uterus, cervix, and abdominal cavity may occur. Uterine endometrium and even to a lesser extent the myometrium may also be affected. This process is always associated with extensive fibrosis, adhesion to neighboring organs, calcification, and structural changes, and may even lead to fistula formations in the sigmoid colon, appendix, cecum, ileum, rectum, and the urinary bladder (Sbihi et al. 1980; Silva et al. 1988). Direct spread of infection to the genital organs may occur from contiguous abdominal tuberculous lymphadenitis, peritonitis, or other viscera (Schaefer 1976). Zamberletti et al. (1981) tried to find out the reasons for such poor prognosis as far as regaining fertility is concerned after treatment. They examined five fallopian tubes by electron microscope to determine the histomorphology. The authors noted mucosal damage and that the architecture of the folds and cellular population were compromised. The folds were low in height and their directions were not coaxial with the lumen of the tube. The number of ciliated cells was very low, even scarce, and the cilia were thin and disordered, with irregular heights. None of these findings were restored by antituberculous chemotherapy. The uterus may appear bulky or atrophic, calcified (Fig.39.11), hyperemic with tubercles on the surface (Tripathy and Tripathy 1990; Saracoglu et al. 1992). The ovaries are affected by adhesions from fallopian tubes rather than from uterine involvement. Cervix erosions and ulcers may occur by direct spread of tuberculous infection from the uterus. The cervix may also show a polyp, papillary growth, or granulation tissue formation. The vagina may be involved, although this is rare. Vesicovaginal fistula may be the presenting feature of female genital tuberculosis (Ba-Thike et al. 1992; Kutteh and Hatch 1992; Arora et al. 1994; Singh et al. 1988). Vaginal tuberculosis is usually caused by direct extension of the infection from uterine tuberculosis (Coetzee 1972; Ma et al.1997). Vulval lesion is rare and infection occurs as a result of direct spread from upper genital tract tuberculosis or from sexual intercourse.

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Genitourinary Tuberculosis

months. As pelvic pain becomes severe, it is aggravated by sexual intercourse and during menstruation. Lower abdominal pain may appear and episodic acute attacks may occur. Fatigue, malaise, low grade fever, loss of appetite, and weight loss may be noted. However, the presenting features of the disease may be menstrual disturbances such as amenorrhea, menorrhagia, oligomenorrhea, irregular periods, or dysmenorrhea in approximately 20% of patients (Agarwal and Gupta 1993). Postmenopausal bleeding may be the presenting feature in approximately 4%. Vaginal discharge may be a rare presenting feature. Vaginal dribbling of urine due to a vesicovaginal fistula may rarely be the presenting symptom (Ba-Thike et al.1992).An ulcer in the vagina is rarely a presenting feature. The frequency of symptoms at the time of presentation in some series is shown in Table 39.3. 39.3.3.2 Fig.39.11. A 50-year-old woman with past history of tuberculosis and infertility. Plain radiograph of the pelvis demonstrates calcification of the fallopian tubes (arrowheads)

39.3.3 Clinical Features of Female Genital Tuberculosis 39.3.3.1

Presenting Symptoms Female genital tuberculosis may pass unnoticed by the patient for years and only infertility, occurring in approximately 85% of cases, may be the first presenting symptom (Schaefer 1976; Sutherland 1982; Agarwal and Gupta 1993). Past history of tuberculosis mostly of the lung or less frequently of other systems is noted in approximately 50% of patients. Family history of tuberculosis may be found in 20% of patients suffering from female genital tuberculosis. Pelvic pain may occur in 50% of patients, but this is usually mild and the time interval between this symptom and seeking medical advice may be several

Physical Signs Physical signs may be lacking or point to features of pulmonary involvement, spinal tenderness, or "doughy" sensation during abdominal palpation. Lower abdominal tenderness may also be discovered on deep palpation. Bimanual pelvic examination may give the only positive signs if adnexal masses, which are tender, are felt. Other rare physical signs include leukorrhea and vulval ulcer. Bimanual pelvic examination may show normal findings, though, if the tubes are not enlarged. Tube ovarian mass may be felt with variable sizes. The mass may be firm or fluctuant and only slightly tender. Genital carcinoma may coexist with genital tuberculosis. 39.3.3.3

Tuberculosis of the Fallopian Tube and Ovary (Features and Investigations) Tubal tuberculosis is the leading cause of infertility in endemic areas of developing countries (Wang 1989, Punnonen et al. 1983). In India, Parikh et al. (1997)

Table 39.3. Female genital tuberculosis: the frequency of presenting symptoms Author (year)

Total Infertility: Pelvic!abdominal Vaginal Amenorrhea: number (%) number number (%) pain: number (%) bleeding: number (%)

Agarwal and Gupta (1993) Otieno (1983) Sutherland (1985) Saracoglu et al. (1992)

501

343 (68.5)

6 (1.2)

58 (U.S)

56 (11.2)

16 (3.2)

2 (0.4)

12

12 (100) 313 (44) 34 (47.2)

8 (66) 179 (25.2) 23 (31.9)

4 (33) 127 (17.9) 8 (1Ll)

12 (100) 36 (5) 1 (1.4)

5 (40) 26 (3.6) NA

NA 16 (2.2) 2 (2.8)

710 72

Vaginal Postmenopausal discharge: bleeding: number (%) number (%)

720

reported 300 women attending a specialized infertility center, with tubal factors as the cause of their infertility. One hundred and seventeen women were found to have tubal tuberculosis. In China, Yang et al. (1996) reported 1,120 women with tubal factor infertility, and tubal tuberculosis accounted for that infertility, in 63.6% of these women. In Turkey, Saracoglu et al. (1992) reported 72 women with pelvic tuberculosis. Hysterosalpingography were performed on 34 patients and tubal blockage was noted in 32 of them. Wang (1989) reported 66 women with infertility due to tubal obstruction as depicted by hysterosalpingography. During operations, tubal patency was found in 28.8% of women reported to have obstruction by hysterosalpingography. Tuberculosis as a cause of tubal obstruction was found in 31.3% of pathologic examinations of 48 specimens. The coexistence of tubal tuberculosis and primary carcinoma is rarely reported (Wiskind et al. 1992). Plain radiography of the pelvis may depict calcifications of the tubes and uterine (Fig. 39.11), and may depict peritoneal involvement as well as of the tuboovarian mass (Crowley et al. 1997; Tang et al. 1984; Svendsen et al. 1985). Hysterosalpingography may depict tubal obstruction and tuboappendiceal, tuboparietal, salpingosigmoid, or tubointestinal fistulas (Silva et al. 1988; Sbihi et al. 1980). Laparoscopy/ laparotomy is essential for the histopathologic analysis (Tripathy and Tripathy 1990). Pregnancy after antituberculous treatment of tubal destruction is very rare and IVF should be attempted. In vitro fertilization success or failure has been assessed. Marcus et al. (1994) reported 10 patients with genital tuberculosis with infertility. Clinical pregnancies after IVF were achieved in six patients and resulted in three live births, one ectopic pregnancy and one abortion. Patients with trophic endometrium achieved pregnancy in 42.9% of cases, and those with atrophic endometrium had a 0% success rate (no pregnancy). Similar findings were reported by Soussis et al. (1998) in 13 women with genital tuberculosis who had undergone IVE The ovaries are almost always involved as part of tube and uterine tuberculosis. Agarwal and Gupta (1993) reported two cases with purely ovarian involvement with multiple large cysts 6-10 cm in diameter filled with hemorrhagic and purulent fluid. 39.3.3.4 Tuberculosis of the Uterus (Features and Investigations)

Tuberculous endometritis may occur in isolation without other genital or extragenital involvement (Shireman 1992). Pregnancy may still occur despite

M. M. Madkour

endometrial tuberculosis, and it may progress to full term. Fetal congenital infection in the premature infant may be a sequela (Myers et al. 1981; Balasubramanian et al. 1999; Yip et al. 1999; Baumgartner et al. 1980). Postmenopausal endometrial tuberculosis is reported in up to 11 % of patients (Nogales-Ortiz 1979; Mantovani et al. 1998; Castelo-Branco et al. 1995; Dhillon et al. 1990; La Grange 1982). The most common cause of uterine tuberculosis is Mycobacterium tuberculosis but nontuberculous mycobacterium may also cause endometritis with similar clinical and pathologic features including irregular menses and infertility. Rao et al. (1992) reported 140 infertile women with endometrial biopsies. Positive cultures of organisms were found in 45%. Mycobacterium tuberculosis was identified in eight patients and nontuberculous mycobacterium organisms in 14 patients with M. scrofulaceum, M. kansasii, M. fortuitum and other cultured organisms also found in endometrial samples. Sterile endometrial specimens were noted in 76 patients. An endometrial biopsy is usually done to investigate either infertility or abnormal uterine bleeding and is an essential tool to determine the cause. Histopathologic examination and culture of endometrial samples may yield evidence of tuberculosis which may vary in its rate of positive yield from one series to another depending on the endemicity of tuberculosis and the vigilance of the reporting medical center. In Nigeria, Emembolu (1989) reported the microbiologic cultures of endometrial biopsy samples in 114 infertile women. Various organisms were grown in 42 patients and Mycobacterium tuberculosis was found in seven (16.7%) and represented the most common organism isolated as a cause of infertility. Adewole et al. (1997) from Nigeria analyzed the microbiologic and histopathologic findings of 7,211 endometrial specimens of women who presented with infertility or abnormal vaginal bleeding due to various causes, and found tuberculous endometritis in 0.49%. In Turkey, Aka and Vural (1997) investigated 57 women with active pulmonary tuberculosis, attempting to identify evidence of genital tuberculosis involvement. Menstrual blood culture, curettage, and hysterosalpingography were performed. Evidence of genital tuberculosis was found in 12.3% of these women. Endometrial aspirates from cytologic and histopathologic examinations were compared as tools to diagnosing endometrial tuberculosis. Tripathy and Mohanty (1990) found that cytology was reliable in 93% of cases in their series. Polymerase chain reaction (peR) testing of endometrial tissue and menstrual blood culture

Genitourinary Tuberculosis

721

tal tuberculosis. Higher incidence was reported by Agarwal and Gupta who noted that the cervix was involved in 81.5% of patients in their series of 501 women with genital tuberculosis. Primary tuberculous cervicitis without other genital involvement was noted by Chakraborty et al. (1992) in three women of his series of 91 patients with proven genital tuberculosis living in the Darjeeling Hills, an area highly endemic with tuberculosis. Four other women had cervicitis with uterine involvement. Other authors have reported tuberculous cervicitis as an isolated primary site (Vuong et al. 1989). Tuberculous cervicitis is commonly reported in young women but may also occur after menopause (Muechler and Minkowitz 1971). Tuberculous cervicitis has no distinctive clinical or macroscopic features and may simulate malignancy or other granulomatous diseases such as bilharziasis, amebiasis, syphilis, or granuloma inguinale. Koller (1975) from South Africa reported 46 women with granulomatous cervicitis. Tuberculosis was found in 21, bilharziasis in 21, and amoebic cervicitis in four patients. Tuber39.3.3.5 culous cervicitis may initially be mistaken for carciSynechia Uteri: Asherman's Syndrome noma, particularly in nonendemic areas of developed (Features and Investigations) countries (Shobin and SaIl Pellman 1976; Koller 1975; Intrauterine adhesions and fibrosis leading to infer- Vuong et al. 1989; Chahtane et al. 1992; El Mansouri tility, premature labor, miscarriage, placenta previa, 1995). The coexistence of carcinoma and tuberculous or menstrual disorder is also known as Asherman's cervicitis was reported by some authors, yet it is rare syndrome. The most common cause in endemic (Yamabe et al. 1972; Hsu et al. 1985; Bhambhani et al. areas of developing countries is uterine tubercu- 1985). The initial symptoms at presentation include losis. Other causes include Bilharziasis, trauma to vaginal discharge, bleeding after sexual intercourse, pregnant uterus or after curettage or due to other menorrhagia, and weight loss. A past history of infections (Krolikowski et al. 1995). Plain radiogra- extragenital tuberculosis may also be found. Macphy may show calcifications of the uterus (Fig. 39.11). roscopically the cervix is bulky, hypertrophied with Hysterosalpingography may show the classic «glove ulcerations or erosions of the external OS. A necrotic finger appearance." Laparoscopy/laparotomy and or fungating mass that bleeds easily with touch may hysteroscopy, as well as the histopathologic findings be noted. Cytologic examination of cervicovaginal of an endometrial biopsy, can confirm the diagno- smear may be helpful in diagnosing tuberculous sis. Antituberculous treatment with hysteroscopic cervicitis. Granulomatous formation with epithelioid synechialysis may help in restoring fertility on rare cells and Langhans giant cells may be seen (Misch occasions. The prognosis with regard to fertility is et al. 1976; Miller and Herman 1979; Rivasi et al. poor among these women (Bukulmez et al. 1999; 1980; Angrish and Verma 1981; Vuong et al. 1989). Marcus et al. 1994). Histopathologic examination from cervical biopsy sample and tissue culture will confirm the diagnosis. 39.3.3.6 Hysterosalpingography may be difficult to perform Tuberculosis of the Uterine Cervix because of the size of the mass. Intravenous pyelog(Features and Investigations) raphy may depict an associated bilateral kidney and/ or ureteric involvement with calyceal deformities Tuberculous cervicitis is commonly associated with (Shobin and Pellman 1976; Husermeyer 1977). Plain other types of genital tuberculosis but may rarely radiography may show calcifications of the cervix, occur in isolation as the primary site. The incidence uterus, and the tubes (Fig. 39.11). Chest radiography of tuberculous cervicitis reported by most authors may show active pulmonary disease or fibrosis and ranges between 0.4% and 16% of patients with geni- calcifications.

were used by Hasimoto et al. (1994) and Missirliu et al. (1996) and were found to be positive in all cases they studied. PCR became negative 3 months after initiating treatment with antituberculous drugs. Difficulties in diagnosing endometrial sarcoidosis (which may rarely occur) is mainly due to the similarity of its clinical and pathologic features to those of endometrial tuberculosis. Murphy et al. (1992) reported a woman with irregular menses and pulmonary sarcoidosis and a positive family history of sarcoidosis. Endometrial biopsy showed histopathologic changes of granulomas. Endometrial sarcoidosis and difficulties in the diagnosis were similarly noted and reported by Skehan and McKenna (1985). The trophic or atrophic state of the endometrium in patients with tuberculous endometritis will determine the rate of success of pregnancy or IVF as noted before. Hysteroscopic examination of the uterus is a helpful tool of investigation among those presented with infertility, though it is rarely used.

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39.3.3.7 Tuberculosis of the Vagina (Features and Investigations)

Vaginal tuberculosis is rare, and its incidence may range between 0.07% and 0.2% (Nogales-Ortiz 1979; Agarwal and Gupta 1993). Patients with HIV-positive serology may present with tuberculous vaginitis (Arora et al. 1994). Dyspareunia, vaginal discharge, history of urinary dribbling per vagina, or primary infertility may be the presenting clinical features. Pelvic examination may be difficult due to pain or narrowing of the vagina by a circular band of fibrous tissue, and examination under anesthesia may be necessary. Urine may be found to be leaking from the vagina and the orifice of the vesicovaginal fistula may be felt in the anterior wall. Painful ulcer at the posterior fourchette and lower vagina may be seen (Coetzee 1972; Ma et al. 1997). Vesicovaginal fistula may also be depicted by cystogram or intravenous pyelography (Ba-Thike et al. 1992; Singh et al. 1988). Confirmation of tuberculous vaginitis is done by tissue biopsy of vaginal ulcer or other upper genital specimens for histopathologic and microbiologic examinations. Vaginal carcinoma and tuberculosis may coexist and a high index of suspicion is essential (Kutteh and Hatch 1992) to avoid missing this rare coexistence. 39.3.3.8 Tuberculosis of the Vulva (Features and Investigations)

The vulva is the least common site of genital tuberculosis. It is usually associated with tuberculosis in other sites including upper genital organs, chest, or spine (Bhattacharya 1978; Pena et al. 1973; Schaefer 1970; Stewart 1968). Rarely, vulval tuberculosis may be the only primary site, and transmission through intercourse particularly in immunocompromised patients with HIV may occur (Vani et al. 1993; Naika et al. 1987; Millar et al. 1979). The initial symptoms include vulval swelling, ulceration, dyspareunia, or apareunia, vaginal discharge, and weight loss. The most frequent signs are ulcers with irregular outlines and undermined edges affecting the labia. The ulcers are tender, friable, and may bleed when touched. Inguinal lymphadenopathy is a common finding. The second least common signs are those of the swollen hypertrophied type with thickened skin, nodular swellings, multiple wart-like lesions, lupus vulgaris, with or without

M. M. Madkour

ulceration. Multiple discharging sinuses may also be noted. These clinical features are not characteristic and cannot be distinguished from other causes such as carcinoma, bilharziasis, amebiasis, syphilis, or elephantiasis (Heuvet et al. 1979; Gras et al. 1980). Histopathologic examination and culture of biopsy samples of vulval lesions are essential to confirm the diagnosis. Investigations of other genital or respiratory tuberculosis may give associated important clues to the diagnosis. Medical treatment alone may be sufficient, particularly in those who present with ulcers. In the hypertrophic type, surgical excision of the lesion may be necessary. 39.3.3.9 Investigation of Female Genital Tuberculosis

The hemogram and blood biochemistry is usually normal. Plain chest radiography may show features of active tuberculosis or evidence of healed, scarred, old lesions and plain pelvic radiography may depict calcification of both tubes and uterus (Fig. 39.11). A hysterosalpingography, although relatively contraindicated in acute inflammatory pelvic disease, is an essential tool for investigating women presenting with infertility (Siegler and Koutopoulos 1979). Fallopian tube lumen may look like saw teeth with ragged contours and multiple strictures. The ampulla may appear tufted due to occlusion. As fibrosis develops, the tube may appear like a pipe stem in configuration. Filling and spillage of contrast media may not appear in either or both tubes due to obstruction. Tubal diverticulosis or fistula formation in the appendix, cecum, ileum, or colon may occasionally be seen in a hysterosalpingography (Siegler and Koutopoulos 1979; Silva et al. 1988). The uterine cavity may be deformed due to adhesions and endometrial destruction. The endocervical canal may be elongated and dilated. Lymphatic or venous intravasation of contrast media may be noted in endometrial and myometrial tuberculosis. Other imaging modalities playa role in the diagnosis such as transvaginal ultrasound and postenhanced pelvic CT. Axial postenhanced CT of the pelvis may depict cystic masses with ring enhancement in the fallopian tubes, peritoneal thickening, and ascites (Fig. 39.12a, b). MRI may show a tubo-ovarian cyst and peritoneal effusion (Valentini et al. 1998).

723

Genitourinary Tuberculosis

b

a Fig. 39.12a, b. A 23-year-old female married for 4 years presented with primary infertility. She denied any history of fever but had weight loss, and abdominal and pelvic discomfort. On examination, she had a doughy abdomen with ascites but no organomegaly. a Axial postenhanced CT of the pelvis demonstrates peritoneal thickening particularly anteriorly (arrowheads) and ascites (arrow). b Axial CT caudal to (a) demonstrates sizable ascites surrounding the uterus (curved arrows), complex cystic masses with ring enhancement at the fibrillated end of the fallopian tubes (arrow heads). Tuberculous salpingo-oophoritis was diagnosed by laparoscopic biopsy and positive culture

39.3.4 Microbiology and Histopathology Dilatation and curettage of the uterus for histopathology and microbiological examination is important. Positive histopathology and microbiology results from endometrial specimens were present in 79% to 99.5% of those with female genital tuberculosis as reported by sources (Nogales-Ortiz 1979; Agarwal and Gupta 1993). The best time for obtaining endometrial biopsy samples is several days before the expected menstrual period (Schaefer 1970, 1976) at which time the tubercles reach their maximum growth.

39.3.5 Laparoscopy Laparoscopic examination is an important diagnostic procedure in investigating female infertility for those suspected to have female genital tuberculosis without symptoms but with abnormal hysterosalpingography. Abnormal laparoscopic findings were mentioned in "Features and investigations" for female genital tuberculosis.

39.3.6 Treatment of FGTB The chemotherapy regimen for FGTB is similar to that for the genitourinary tract. The role of surgery,

including salpingolysis and fibrinolysis, and tubal anastomosis may be helpful in some patients for restoring fertility. Salpingectomy or salpingo-oophorectomy may rarely be required in some patients (Saracoglu et al. 1992).

39.4 Tuberculosis in Patients with Chronic Renal Failure, on Hemodialysis, or with Renal Transplant Patients with chronic renal failure, renal transplant, and those on hemodialysis are considered as highrisk groups. They have an increased susceptibility to, and high prevalence of, infections with various pathogens including Mycobacterium tuberculosis (AI-Homrany 1997). In these groups of patients, the cell-mediated immune responses are impaired, the cytotoxic activity of natural killer lymphocytic cells CD4+, the migration and responses of activated macrophages, the production of cytokines including interleukins, tumor necrosis factor a, and interferon-g are all suppressed. The development of tuberculosis among these high-risk groups of patients may be a major cause of morbidity and mortality, if not suspected early and treated promptly. The high mortality was reported to range from 11% up to 75% in different series (AI-Homrany 1997). These patients are immunosuppressed by the underlying disease, dialysis,

724

or by use of the immunosuppressive agents used in renal transplants.

39.4.1 Epidemiology There are many case reports on tuberculosis among this high-risk group of patients, yet prevalence for only a few series has been reported. Some authors have even indicated the rarity of tuberculosis among these groups. The prevalence of tuberculosis among these groups is closely related to the prevalence of tuberculosis in the general population in any community. It tends to be several times higher compared with the general population. In Japan, the incidence was reported to be as much as 6 to 16 times higher. In the United States, it was 10-15 times higher, and in Saudi Arabia, 50 times higher than in the general population (Murthy et al. 1997; Wajeh et al. 1990). Wajeh et al. (990) from Saudi Arabia reported 403 renal transplant recipients and found tuberculosis in 14 patients (3.5%). In these patients, tuberculosis was disseminated in 64.3%, pulmonary in 28.6%, and genitourinary in 7.1%. These authors noted nontuberculous mycobacterium in 29% of those with disseminated disease. The mortality was higher among those with disseminated tuberculosis than with other forms (37% and 11%, respectively). The time interval between transplantation and development of tuberculosis ranged from 1 to 84 months, with male predominance and with a mean age of 35.7 years. In another large series from Jeddah, Saudi Arabia, AIShohaib and colleagues (Al-Shohaib 2000) reported 137 patients with chronic renal failure waiting for hemodialysis. Eighty were followed up for a period of 3 years and monitored for the development of tuberculosis. Eight patients did develop tuberculosis (10%) before starting on hemodialysis. Pulmonary tuberculosis was the most common (50%), followed by renal (20%), cervical lymphadenitis 00%), and tuberculous meningitis in 10%. Female predominance was noted in this series (62.5%) and ages ranged between 35 and 55 years. The same authors reported their experience 1 year earlier (Al-Shohaib et al. 1999), with regard to the development of tuberculosis in their patients while on hemodialysis. They found 17 of21O patients (8.1 %) developed tuberculosis, among which they found pulmonary tuberculosis in 10, and lymphadenitis in 8 (one had tuberculosis in the lungs and lymph node sites, while in another patient, pulmonary and peritoneal sites were involved). Male predominance was noted and the mean age was 48 years.

M. M. Madkour

In Riyadh, Saudi Arabia, Al-Homrany et al. (AlHomrany 1997) reported a large series of 250 patients on maintenance hemodialysis seen during 1986 to 1993 inclusive. The authors reported tuberculosis in 13 patients (4.8%), with female predominance (77%) and a mean age of 51 years. The duration of hemodialysis before diagnosis of tuberculosis was 19.23±14.43 months, and the mean duration of symptoms before diagnosis was 4.54±3.38 weeks. More recently, Al-Jondeby et al. (2001) conducted a national review of 5,706 patients on hemodialysis in different regions of Saudi Arabia. These authors reported the incidence of tuberculosis among these patients as ranging from 8% to 10%, with male predominance at a ratio of 2:1 and a mean age of 51.3±1.0 years.

39.4.2 Clinical Features onuberculosis in these Groups The clinical presentations of tuberculosis among these high-risk groups are usually insidious and nonspecific. Symptoms such as fatigue or anorexia are not unusual, but these are not clear indications of the occurrence of tuberculosis. Therefore the diagnosis can be delayed for weeks unless the treating nephrologist has a high index of suspicion that tuberculosis may be the cause of these nonspecific symptoms (AI-Homrany 1997; AI-Shohaib et al. 1999). The most common symptoms are fever, anorexia, fatigue, loss of appetite, weight loss, and cough. Other clinical features at the time of presentation may include hemoptysis, lymphadenopathy, erythema nodosum, or abdominal distension due to tuberculosis peritonitis. Pulmonary tuberculosis is the most common finding in 40% to 70% of patients, followed by disseminated multisystem disease in 30% to 40%, followed by extrapulmonary localizations (Wajeh et al. 1990; Cengiz 1996; AI-Homrany 1997; Al-Shohaib et al. 1999; Al-Shohaib 2000).

39.4.3 Investigations The hemogram may show normocytic normochromic anemia with normal or accelerated sedimentation rate. Biochemical parameters may show findings of chronic renal failure in nondialysed or transplant patients: a PPD test may not be of diagnostic help as it may be positive in only 40% to 60% of patients, which does not necessarily indicate active disease. Positive PPD may be of significance, particularly with recent contact, in

Genitourinary Tuberculosis countries with a low prevalence of tuberculosis among the general population. Plain chest radiography should be done when tuberculosis is suspected. Attempts to identify the organisms from sputum, other body fluids, or tissue should also be carried out. Bacteriologic confirmation of diagnosis among these high-risk groups was achieved at different rates in different series and ranged from 50% to 100% (Wajeh et al. 1990; Mitwalli 1991; Cengiz 1996; AI-Homrany 1997; Murthy and Periera 1997; Al Shohaib 2000). Nontuberculous mycobacterium has been reported among these high-risk groups. These include M. kansasii, M. fortuitum, M. marinum, M. avium, M. abscessus chelonae, M. haemophilum, and M. scrofulaceum (Wajeh et al. 1990).

39.4.4 Treatment of Genitourinary Tuberculosis

The chemotherapy used for the treatment of genitourinary tuberculosis is similar to the regimen given for pulmonary tuberculosis and 6 months duration is sufficient to achieve cure (Garcia-Rodriguez et al. 1994). Antituberculous agents for patients on hemodialysis and fully functioning renal allografts should be the same as in the standard regimens used for immunocompetent patients. There has been no controlled trial with regard to the optimum regimen in these groups of patients. The Committee on Chemotherapy of Tuberculosis in the United States recommended isoniazid and rifampicin, supplemented in the initial phase by either ethambutol, streptomycin, or pyrazinamide in immunosuppressed patients. The duration of treatment is usually 12-24 months. Shorter courses of treatment (6 months) with direct observed therapy (DOT) is also effective in these groups of patients. Streptomycin can be used twice to thrice weekly and with serum level assays to avoid its nephrotoxicity and nerve deafness. Isoniazid, rifampicin, and para-aminosalicyclic acid are generally safe in this group of high-risk patients. AI-Homrany (I997) treated 13 tuberculous patients on hemodialysis using 3 or 4 drug regimens for 6 to 12 months with full recovery and no recurrences on follow-up.

39.4.5 Dose Modification

The efficacy of steroids and cyclosporin used in the management of renal allograft recipients may be diminished in patients that are receiving rifam-

725

picin. Hepatic microsomal enzymes induction by rifampicin may increase the clearance of steroids and cyclosporin, so that the dosage may need to be doubled and adjusted according to cyclosporin serum levels. Streptomycin can be given to hemodialysis patients 6-8 hours before each dialysis, and serum trough level as well as creatinine clearance has to be measured. Chronic renal failure patients who are waiting for hemodialysis may use pyrazinamide three times weekly, however, some authors suggested avoiding its use in those with severe chronic renal failure. Streptomycin can be used in chronic renal failure patients two to three times weekly with close monitoring of serum trough levels as well as urea and creatinine. Ethambutol is excreted unchanged in urine and patients with chronic renal failure are at risk of suffering from its adverse effects (loss of visual acuity, color blindness). It is better avoided in these patients, but if it has to be used, the dose should be reduced to 5 to 10 mg/kg daily.

References Abdel Razic MM, EI-Morsy FE (1990) Genitourinary mycobacteria in infertile Egyptian men. Fertil Steril54:713-717 Adewole IF et al (1997) The value of routine endometrial biopsy in gynaecological practice in Nigeria. West Afr J Med 16:242-245 Agarwal J, Gupta JK (1993) Female genital tuberculosis: a retrospective clinicopathologic study of 501 cases. Indian J Pathol MicrobioI36:389-397 Aka N, Vural EZ (1997) Evaluation of patients with active pulmonary tuberculosis for genital involvement. J Obstet Gynaecol Res 23:336-340 AI-Homrany M (1997) Successful therapy of tuberculosis in hemodialysis Patients. Am J NephroI17:32-35 Al-Jondeby MS et al (2001) Caring for hemodialysis patients in Saudi Arabia, past, present and future. Saudi Med J 22: 199-204 AI-Shohaib S (2000) Tuberculosis in chronic renal failure in Jeddah. J Infect 40:150-153 Al-Shohaib et al (1999) Tuberculosis in active dialysis patients in Jeddah. Am J NephroI19:34-37 Alvarez S, McCabe WR (1984) Extrapulmonary tuberculosis revisited: a review of experience at Boston City and other hospitals. Medicine Anal Rev Gen Med Neurol Dermatol Pediatr 63:25-55 Angrish K, Verma K(1981) Cytologic detection of tuberculosis of the uterine cervix. Acta CytoI25:160-162 Annobil SH,AI-Hilfi Aet al (1990) Primary tuberculosis of the penis in an infant. Tubercle 71:229-230 Arora VK et al (1994) Tuberculosis of the vagina in an HIV seropositive case. Tuberc Lung Dis 75:239-240 Atalay AC, Karaman MI (1997) Distal penile gangrene in a patient with chronic renal failure. Int J Urol 4:431-432

726 Balasubramanian S et al (1999) Congenital tuberculosis. Ind J Pediatr 66:148-150 Balasubramanian V et al (1994) Pathogenesis of tuberculosis: pathway to apical localization. Tuberc Lung Dis 75: 168-178 Ba-Thike K et al (1992) Tuberculosis vesico-vaginal fistula.1nt J Gynaecol Obstet 37:126-130 Baumgartner W et al (1980) Congenital tuberculosis (author's transation). Monatsschr Kinderheilkd 1280:563-566 Beck-Sague C et al (1992) Hospital outbreak of multidrugresistant mycobacterium tuberculosis infections. Factors in transmission to staff and HIV-infected patients. JAMA 268:1280-1286 Berman LB et al (1960) Glomerular abnormalities in tuberculosis. Arch PathoI69:278-285 Bhambhani S et al (1985) Cervical tuberculosis with carcinoma in situ: a cytodiagnosis. Acta CytoI29:87-88 Bhattacharya P (1978) Hypertrophic tuberculosis of the vulva. Obstet Gynaecol1 [Suppl]:21s-22s Birnbaum BA, Friedman JP, Lubat E et al (1990) Extra-renal genitourinary tuberculosis: CT appearance of calcified pipe-stem ureter and seminal vesicle abscess. J Comput Assist Tomogr 14:653-655 Buchholz NP et al (2000) Genitourinary tuberculosis: a profile of 55 in-patients. J Pak Med Assoc 50:265-269 Bukulmez 0 et al (1999) Total corporal synechiae due to tuberculosis carry a varied prognosis following hysteroscopic synechialysis. Hum Reprod 14:1960-1961 Cabral DA, Johnson HW et al (1985) Tuberculous epididymitis as a cause of testicular pseudomalignancy in two young children. Pediatr Infect Dis 4:59-62 Cantwell MF et al (1994) Epidemiology of tuberculosis in the United States, 1985 through 1992. JAMA 272:535-539 Carl P, Stark L (1997) Indications for surgical management of genitourinary tuberculosis. World J Surg 21:505-510 <;:askurlu T et al (1998) Urinary tuberculosis in a two-year-old boy. Int Urol Nephr 30:525-528 Castelo-Branco C et al (1995) Primary adenocarcinoma of the endometrium associated genital tuberculosis: a case report. J Reprod Med 40:673-675 Cengiz K (1996) Increased incidence of tuberculosis in patients undergoing hemodialysis. Nephron 73:421-424 Centers for Disease Control (1985) Drug-resistant tuberculosis among the homeless - Boston. MMWR Morb Mortal Wkly Rep 34:429 Centers for Disease Control (1986) Tuberculosis and acquired immunodeficiency syndrome - Florida. MMWR Morb Mortal Wkly Rep 36:587-590 Centers for Disease Control (1987) Tuberculosis and acquired immunodeficiency syndrome - New York. MMWR Morb Mortal Wkly Rep 36:785-795 Centers for Disease Control (1995) Essential components of a tuberculosis prevention and control program; and screening for tuberculosis and tuberculosis infection in high-risk populations: recommendation from the advisory council for the elimination of tuberculosis. MMWR Morb Mortal Wkly Rep 44:1-34 Chahtane A et al (1992) Hypertrophic tuberculosis of the cervix: three cases. J Gyneacol Obstet BioI Reprod (Paris) 21:424-427 Chakraborty P et al (1992) Tuberculosis cervicitis: a clinicopathological and bacteriological study. J Indian Med Assoc 93:167-168

M. M. Madkour ChangAB et al (1998) Renal tuberculosis in an Australian-born child. J Paediatr Child Health (Australian) 34:293-295 Charghi A (1979) Ureteral replacement using a new variation of the tailored ileal segment. J UroI121:598-601 Chatterjee H et al (1975) Tuberculosis of the penis. J Ind Med Assoc 65:232-234 Chattopadhyay A et al (1997) Genitourinary tuberculosis in pediatric surgical practice. J Pediatr Surg (US) 32:1283-1286 Chattopadhyay SK et al (1986) The pattern of female genital tuberculosis in Riyadh, Saudi Arabia. Br J Obstet Gynaecol 93:367-371 Christensen WI (1974) Genitourinary tuberculosis. Review of 102 cases. Medicine 53:377-390 Chung JJ et al (1997) Sonographic findings in tubreculosis epididymitis and epididymo-orchitis. Eur Radiol 7: 1076-1078 Chung T, Harris RD (1991) Tuberculous epididymo-orchitis: sonographic findings. J Clin Ultrasound 19:367-369 Coetzee LF (1972) Tuberculous vaginitis. S Afr Med 46: 1225-1226 Cohen MS (1986) Granulomatous nephritis. Urol Clin North Am 13:647-657 Cosivi 0, Grange JM et al (1998) Zoonotic tuberculosis due to Mycobacterium bovis in developing countries. Emerging Infect Dis 4:59-70 Cremin BJ (1987) Radiological imaging of urogenital tuberculosis in children with emphasis on ultrasound. Paediatr RadioI17:34-38 Crowley JJ et al (1997) Genital tract tuberculosis with peritoneal involvement: MR appearance. Abdom Imaging 22: 445-447 Dahl DM et al (1996) Penile mass caused by the newly described organism mycobacterium celatum. Urology (US) 47:266 Dankner WM, Waecker NJ et al (1993) Mycobacterium bovis infections in San Diego: a clinicoepidemiologic study of 73 patients and a historical review of a forgotten pathogen. Medicine (Baltimore) 72:11-37 Dhillon 55 et al (1990) Genital tuberculosis: case report and literature review. Wis Med 89:14-17 Drudi FM et al (1991) Tubercular epididymitis and orchitis: US patterns. Eur Radiol 7:1076-1078 Dwyer DE et al (1987) Extrapulmonary tuberculosis - a continuing problem in Australia. Aust NZ J Med 17:507-511 Ellner JJ (1997) Regulation of the human immune response during tuberculosis. J Lab Clin Med 130:469-475 El Mansouri A (1995) Hypertrophic tuberculosis of the cervix. Rev Fr Gynecol Obstet 90:91-93 Emembolu JO (1989) Endometrial flora of infertile women in Zaire, northern Nigeria. Int J Gynaecol Obstet 30:155-159 Engin G et al (2000) Imaging of extrapulmonary tuberculosis. Radiographics (US) 20:471-488 Feeney D, Quesada ET, Sirbasku DM et al (1994) Transitional cell carcinoma in a tuberculous kidney: case report and review of the literature. J UroI151:989-991 Ferrie BG, Rundle JS (1983) Genitourinary tuberculosis in patients under twenty-five years of age. UroI25:576-578 Garcia-Rodriguez JA et al (1994) Genitourinary tuberculosis in Spain: review of 81 cases. Clin Infect Dis (US) 18: 557-561 Goldman SM, Fushman EK, Hartman DS et al (1985) Computed tomography of renal tuberculosis and its pathological correlates. J Comput Assist Tomogr 9:771-776

Genitourinary Tuberculosis Gow JG (1979a) Genitourinary tuberculosis. Br J Hosp Med 6:556-568 Gow JG (1979b) Genitourinary tuberculosis: a 7-year-old review. Br J UroI51:239-244 Gow JG (1992) Genitourinary tuberculosis. In: Walsh PC et al (eds) Campbell's urology, 6th edn. Saunders, Philadelphia, p 961 Gow JG, Barbosa S (1984) Genitourinary tuberculosis. A study of 117 cases over a period of 34 years. Br J Urol 56:449-455 Granados LEA (1998) Testicular abscess: a manifestation of tuberculosis. Aetas Urol Esp 22:381-383 Grange JM et al (1995) Factors determining ethnic differences in the incidence of bacteriologically confirmed genitourinary tuberculosis in southeast England. J Infect 30:37-40 Gras C et al (1980) Schistosomiasis of vulvae (case report and comments) (author's trans!.). Med Trop (Mars) 40:335-338 Hasimoto A et al (1994) A case of endometrial tuberculosis diagnosed by polymerase chain reaction. Kekkaku 69:27-30 Heaton ND, Hogan B et al (1989) Tuberculosis epididymisorchitis: Clinical and ultrasound observations. Br J Urol 64:305 Heaton ND, Hogan B, Michell M et al (1989) Tuberculous epididymo-orchitis: clinical and ultrasound observations. Br J UroI64:305-309 Hemal AK et al (1998) 'Autoprostatectomy': an unusual manifestation in genitourinary tuberculosis. Br J Urol 82: 140-141 Heuvel NVD et al (1979) Lymphagiectases of the vulva in a patient with lymph node tuberculosis. Int Soc Trop Dermatol 18:65-66 Hsu CT et al (1985) The coexistence of carcinoma and tuberculosis in the uterine cervix, report of 2 cases. Asia Oceania J Obstet Gynaecol11:363-369 Husermeyer RP (1977) Postmenopausal tuberculosis of the cervix. Case report and review. Br J Obstet Gynaecol 42: 153-154 Indudhara R, Vaidyanathan S et al (1992) Urethral tuberculosis. Urol Int 48:436-438 Izawa II, Armstrong CE et al (1999) Tuberculous epididymoorchitis: a case report. Can J UroI6:751-756 Jaisankar TJ et al (1994) Penile lupus vulgaris. Int J Dermatol 33:272-274 Kim S, Pollack M, Cho KS et al (1993a) Tuberculous epididymitis and epididymo-orchitis: sonographic findings. J Urol 150:81-84 Kim S et al (1993b) Tuberculous stricture of the urinary tract: antegrade balloon dilation and ureteral stenting. Abdom Imaging 18:186-190 Koller AB (1975) Granulomatous lesions of the cervix uteri in black patients. S Afr Med J 49:1228-1232 Krolikowski A et al (1995) Asherman syndrome caused by schistosomiasis. Obstet Gynaecol 85:898-899 Kumar A et al (1994) Tubercular cavity behind the prostate and bladder: an unusual presentation of genitourinary tuberculosis. J UroI151:1351-1352 Kutteh WH, Hatch KD (1992) Primary vaginal tuberculosis after vaginal carcinoma. Gynecol Oncol 44: 113-115 La Grange JJ (1982) Postmenopausal endometrial tuberculosis: a report of 2 cases and a literature survey. S Afr Med J 59:501-502 Lazarus L, Peraino RA (1984) Reversible uremia due to bilateral urethral obstruction from tuberculosis. Am J Nephrol 4:322-327

727 Leder RA, Low VHS (1995) Tuberculosis of the abdomen. Radiol Clin North Am 33:691-698 Lee HY (1987) A 20-year experience with epididymovasostomy for pathologic epididymal obstruction. Fertil Steril 47:487-491 Lenk S, Schroeder J (2001) Genitourinary tuberculosis. Curr Opin Urol 11:93-98 Lewis EL (1946) Tuberculosis of the penis: a report of 5 cases and a complete review of the literature. J UroI56:737-745 Lueken RP et al (1997) Genital tuberculosis-increased incidence or coincidence. Zentralbl GnakoI119:39-41 Ma YY et al (1997) Vulvovaginal tuberculosis: a case report. Changgeng Yi Xue Za Zhi 20:66-70 Mantovani A et al (1998) Postmenopausal endometrial tuberculosis: a clinical case. Minerva Ginecol 50:93-96 Marcus SF et al (1994) Tuberculous infertility and in vitro fertilization. Am J Obstet Gynecoll71:1593-1596 McGuinness F (2000) Tuberculosis of the genitourinary tract. In: McGuinness F (ed) Clinical imaging of non-pulmonary tuberculosis. Springer, Berlin Heidelberg New York, pp 139-150 McKenna MT et al (1995) The epidemiology of tuberculosis among foreign-born persons in the United States, 19861993. N Engl J Med 332:1071-1076 Medlar EM (1926) Cases of renal infection in pulmonary tuberculosis. Am J PathoI2:401-414 Medlar EM et al (1949) Postmortem compared with clinical diagnosis of genitourinary tuberculosis in adult males. J UroI61:1078-1088 Millar JW et al (1979) Vulval tuberculosis. Tubercle 60:173-176 Miller RE, Herman CJ (1979) Automated cervical cytology screening: performance requirements and instrument evaluation. J Histochem Cytochem 27:512-519 Miranda P et al (1996) Pelvic tuberculosis presenting as an asymptomatic pelvic mass with rising serum CA-125Ievels. A case report. J Reprod Med 41:273-275 Misch KA et al (1976) Tuberculosis of the cervix: Cytology as an aid to diagnosis. J Clin PathoI29:313-316 Missirliu A et al (1996) Genitourinary tuberculosis: rapid diagnosis using the polymerase chain reaction. Eur Urol 30:523-525 Mitwalli A (1991) Tuberculosis in patients on maintenance dialysis. Am J Kidney Dis 18:579-582 Mokhtar A, Salman D (1983) Extrapulmonary tuberculosis. Saudi Med J 4:317-322 Mondal A, Ghosh E et al (1990) The role of transrectal fine needle aspiration cytology in the diagnosis of prostatic nodules suspicious of malignancy-study of 126 cases. Indian J Pathol Microbiol 33:23-29 Moon SY, Kim SH et al (1999) The outcome of sperm retrieval and intracytoplasmic sperm injection in patients with obstructive azoospermia: impact of previous tuberculous epididymitis. J Assist Reprod Genet 16:431-435 Mourad G, Soulillou JP et al (1985) Transmission of Mycobacterium tuberculosis with renal allografts. Nephron 41: 82-85 Moussa OM et al (2000) Rapid diagnosis of genitourinary tuberculosis by polymerase chain reaction and non-radioactive DNA hybridization. J UroI164:584-588 Muechler E, Minkowitz S (1971) Postmenopausal endometrial tuberculosis. Obstet GynecoI38:768-770 Murali TR, Raja NS (1998) Cavernosal cold abscess: a rare cause of impotence. J Urol 82:929-930

728 Murata Y, Yamada I, Sumiya Y et al (1996) Abdominal macronodular tuberculomas: MR findings. J Comput Assist Tomogr 20:643-646 Murphy DM et al (1982) Tuberculous stricture of ureter. Urology 10:382-384 Murphy 0 et al (1992) Endometrial and pulmonary sarcoidosis. Ir J Med Sci 161:14-15 Murthy BVR, Pereira BJG (1997) A 1990 s perspective of hepatitis C, human immunodeficiency virus, and tuberculosis infections in dialysis patients. Semin Nephr 17:346-363 Myers JP et al (1981) Tuberculosis in pregnancy with fatal congenital infection. Pediatrics 67:89-94 Naika RP et al (1987) Esthiomene resulting from cutaneous tuberculosis of external genitalia. Genitourin Med 63: 133-134 Nakamura S, Aoki M et al (1989) Penis tuberculid (papulonecrotic tuberculid of the glans penis): treatment with a combination of rifampicin and an extract from tubercle bacilli (TB vaccine). J Dermatol 16:150-153 Nardell E et al (1986) Exogenous reinfection with tuberculosis in a shelter for the homeless. N Engl J Med 315:1576 National Survey of Tuberculosis Notifications in England and Wales (1983) Characteristics of disease. Report form the Medical Research Council. Tuberculosis and chest disease unit. Tubercle 198768:19-32 Nishigori C, Taniguchi S et al (1986) Penis tuberculosis: papulonecrotic tuberculides on the glans penis. Dermatologica 172:93-97 Nogales-Ortiz F (1979) The pathology of female genital tuberculosis: a 31-year series of 1436 cases. Obstet Gynecol 53: 422-428 Nzerue C et al (2000) Genitourinary tuberculosis in patients with HIV infection clinical features in an inner-city hospital population. Am J Med Sci 320:299-303 O'Flynn D (1970) Surgical treatment of genitourinary tuberculosis. A report of 762 cases. Br J UroI42:667-671 Ormerod LP (1993) Why does genitourinary tuberculosis occur less often than might be expected in the ethnic Indian subcontinent population living in the United Kingdom? J Infect 27:27-32 Otieno LS (1983) Genitourinary tuberculosis at Kenyatta National Hospital 1973-1980. East African Med J 60: 232-236 Paick JS et al (2000) Ejaculator duct obstruction in infertile men. BJU Int 85:720-724 Pal DK (1997) Erectile failure and destruction of glans penis by tuberculosis. Trop Doct 27:178-179 Parikh FR, Nadkarni SG et al (1997) Genital tuberculosis - a major pelvic factor causing infertility in Indian women. Fertil Steril 67:497-500 Pearson et al (1992) Nosocomial transmission of multidrugresistant mycobacterium tuberculosis: a risk to patients and health care workers. Ann Intern Med 117:191-196 Pena G et al (1973) Vulvar tuberculosis. lrev Chil Obstet GynecoI38:67-75 Petersen L et al (1993) Male genitourinary tuberculosis. Report of 12 cases and review of the literature. Scand J Urol Nephr 27:425-428 Pisciolo F, Pusiol T et al (1985) Urinary cytology of tuberculosis of the bladder. Acta CytoI29:125-131 Premkumar A, Lattimer J, Newhouse JH (1987) CT and sonography of advanced urinary tract tuberculosis. AJR Am J Roentgenol 148:65-69

M. M. Madkour Psihramis KE, Donahoe PK (1986) Primary genitourinary tuberculosis: rapid progression and tissue destruction during treatment. J UroI135:1033-1036 Punnonen R et al (1983) Female genital tuberculosis and consequent infertility. Int J Fertil28:235-238 Raghavaiah NV (1979) Tuberculosis of the male urethra. J UroI122:417-418 Rao PS et al (1992) Bacterial flora of the endometrium in infertile women from Manipal. Ind J Pathol MicrobioI35:357-361 Reider HL, Snider DE, Cauthen GM (1990) Extrapulmonary tuberculosis in the United States. Am Rev Respir Dis 141: 347-351 Richards MJ,Angus D (1998) Possible sexual transmission ofgenitourinary tuberculosis (letter). Int J Tuberc Lung Dis 2:439 Rivasi F et al (1980) Diagnosis of cervical tuberculosis by cytology. Report of cases. Quad Sclavo Diagn 16:239-247 Saracoglu OF et al (1992) Pelvic tuberculosis. Int J Gyncol Obstet 37:115-120 Sbihi H et al (1980) Tubo-intestinal fistulae. A report of 4 cases. Ann Radiol (Paris) 23:656-659 Schaefer G (1970) Tuberculosis of the female genital tract. Gynecol Obstet 13:965-998 Schaefer G (1976) Female genital tuberculosis. Clin Obstet GynecoI19:223-239 Selwyn PA et al (1989) A prospective study of the risk of tuberculosis among intravenous drug users with HIV infection. N Engl J Med 320:545-550 Selwyn PA et al (1992) High risk of active tuberculosis in HIV infected drug users with cutaneous anergy. JAMA 268:504-509 Sengupta P, Mukherjee SD (1982) Tuberculosis of the penis. J Indian Med Assoc 78:47-49 Shafer RW et al (1991) Extrapulmonary tuberculosis in patients with human immunodeficiency virus infection. Med 70: 384-397 Shamsa A (1998) Gastric neobladder for treatment of tuberculosis systitis. J Uro1159:202 Shireman PK (1992) Endometrial tuberculosis acquired by a health Care Worker in Clinical laboratory. Arch Pathol Lab Med 116:521-523 Shobin D, Pellman C (1976) Genitourinary tuberculosis simulating cervical carcinoma. J Reprod Med 17:305-308 Siegler AM, Kontopoulos V (1979) Female genital tuberculosis and the role of hysterosalpingography. Semin Roentgenol 14:295-304 Silva PD et al (1988) Diagnosis and management of a tuberculous, tuboappendiceal fistula. Am J Obstet Gynecol 159: 440-441 Simon HB et al (1977) Genitourinary tuberculosis. Clinical features in a general hospital population. Am J Med 63:410 Singh A et al (1988) Tuberculous vesicovaginal fistula in a child. Br J Uro162:615 Skehan M, McKenna P (1985) Sarcoidosis of the endometrium: a case presentation. Ir J Med Sci 154: 114 Soussis I et al (1998) In vitro fertilization treatment in genital tuberculosis. J Assist Reprod Genet 15:378-380 Sporer A, Auerbach 0 (1978) Tuberculosis of Prostate. Urol 11:362-365 Stewart DB (1968) Tropical gynaecology. Ulcerative and hypertrophic lesion the vulva. Proc R Soc Med 61:363-365 Stoller JK (1985) Late recurrence of mycobacterium bovis genitourinary tuberculosis: case report and review of literature. J UroI134:565-566

Genitourinary Tuberculosis Sutherland AM (1982) The changing pattern of tuberculosis of the female genital tract. A thirty-year survey. Arch Gynecol 234:95-101 Sutherland AM (1985) Gynaecological tuberculosis: analysis of a pesonal series 710 cases. Aust NZ J Obstet Gynaecol 25:203-207 Svendsen JH et al (1985) Peritonitis due to genital tuberculosis. Ann Chir Gynecol 74:180-182 Tang LC et al (1984) Atypical presentation of female genital tract tuberculosis. Eur J Obstet Reprod Bioi 17:355-363 Tripathy SN (1990) Place of aspiration cytology in dusfunctional uterine bleeding. J Indian Med Assoc 88:247-248 Tripathy SN, Tripathy SN (1990) Laparoscopic observations of pelvic organs in pulmonary tuberculosis. Int. J Gynecol Obstet 32:129-131 Valentini AL et al (1998) Diagnostic imaging of genitourinary tuberculosis. Rays 23:126-143 Vani R, Kuntal R, Pralhad K (1993) A rare location of extrapulmonary tuberculosis: the vulva. Tuberc Lung Dis 74:64 Vuong PN et al (1989) Pseudotumoral tuberculosis of the uterine cervix. Cytologic presentation. Iacta Cyto 33:305-308 Wajeh et al (1990) Mycobacterial infection after renal transplantation - report of 14 cases and review of the literature. Quart J Med New Ser 77:1039-1060 Wang LJ et al (1997) CT features of genitourinary tuberculosis. J Comput Assisted Tomogr 21:254-258 Wang XY (1989) Female infertility due to tubal obstructionmanagement clinicoopathologic study of 66 cases. Zhonghua Fu Chan Ke Za Zhi 24:201-202, 251 Webster A, Wright DJ (1985) Ziehl-Neelsen staining of urine

729 deposits in the diagnosis of genitourinary tuberculosis. J Clin Pathol 38:236 Wechsler H et al (1960) The earliest signs and symptoms in 127 male patients with genitourinary tuberculosis. JUro183:801 Weir MR, Thornton GF (1985) Extra-pulmonary tuberculosis. Experience of a community hospital and review of literature. Am J Med 79:467-478 Wiskind AK et al (1992) Primary fallopian tube carcinoma with coexistent tuberculosis salpingitis: a case report. J Med Assoc Ga 81:77-81 Wong TW et al (1973) Testicular biopsy in the study of male infertility. Arch PathoI95:160-164 Yamabe T et al (1972) Coincidence of carcinoma and tuberculosis of the uterine cervix. Gan No Rinsho 18:151-153 Yang DM, Chang MS et al (2000) Chronic tuberculous epididymitis: color Doppler US findings with histopathologic correlation. Abdom Imaging 25:559-562 Yang Y et al (1996) Laparoscopic diagnosis of tubal infertility and fallopian tube lesions. Zhonghua Fu Chan Ke Za Zhi 31:327-329 Yates MD, Pozniak A et al (1993) Isolation of mycobacteria from patients seropositive for the human immunodeficiency virus (HIV) in south east England. Thorax 48:990-995 Yip SK et al (1999) Unassisted conception with a normal pregnancy outcome woman with active mycobacterium tuberculosis infection the endometrium. A case report. J Reprod Med 44:474-476 Zamberletti D et al (1981) Scanning electron microscopy of the tubercular fallopian tube. Acta Eur Fertilitatis 12: 213-221

40 Ocular Manifestations of Tuberculosis SHWU-JIUAN SHEU

et al. 1982; Saini et al. 1986; Helm and Holland 1993). Because the treatment of TB is relatively effective and cost efficient (Raviglione and O'Brien 1998; Zumla et al.1999),earlydiagnosis and prompt treatment are key to saving the sight of patients with ocular TB.

CONTENTS 40.1 40.2 40.3 40.3.1 40.3.1.1 40.3.1.2 40.3.1.3 40.3.1.4 40.3.1.5 40.3.2 40.3.2.1 40.3.2.2 40.3.2.3 40.3.2.4

Historical Perspective 731 Pathogenesis 731 Clinical Features 732 External Diseases 732 Eyelid Disease 732 Conjunctival Tuberculosis 732 Phlyctenulosis 733 Corneal Disease 733 Scleral Tuberculos 733 Intraocular Disease~ 733 Uveitis 733 Retinal Tuberculosi~ 735 Endophthalmitis 'i) Eales' Disease and Tuberculin Hypersensitivity 735 40.3.2.5 Optic Neuropathy 735 40.3.3 Orbital Tuberculosis 736 40.4 Diagnosis 736 40.4.1 Clinical Manifestation 736 40.4.2 Smears and Cultures 737 40.4.3 Tuberculin Skin Test 738 40.4.4 Molecular Techniques 738 40.4.5 Isoniazid Diagnostic Trials 738 40.5 Treatment 738 40.5.1 Monitoring of the Response to Treatment 40.5.2 Toxicity of Anti-TB Chemotherapy 739 References 739

40.1 Historical Perspective In 1711, Maitre-Jan reported the earliest description

738

Tuberculosis (TB) is the leading cause of death worldwide due to an infectious agent, the problem being aggravated by the human immunodeficiency virus (HIV) pandemic and the recent increasing incidence of microbial resistance to antibiotics (Brudney and Gob"in 1991; Barnes et al.1991; Berenguer et al.1992). The recurrence of TB as a major public health problem raises the possibility that ophthalmologists may encounter an increasing number of ocular complications. Ocular TB may affect various regions of the eye and cause severe visual loss if not treated properly (Ni

S.-]. SHEU, MD Department of Ophthalmology, Kaohsiung Veterans General Hospital, 386 Ta-Chung, 1st Road, Kaohsiung, Taiwan 813

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

of ocular tuberculosis, an iris lesion that eventually lead to corneal perforation (Maitre-Jan 1711). Gueneau de Mussy recognized the first choroidal tubercle in miliary tuberculosis in 1830 (Wecker 1874) and in 1867, Cohnheim showed that choroidal tubercles seen clinically were identical to tubercles elsewhere in the body. He was able to produce them experimentally in guinea-pigs by injecting tuberculous material (Cohnheim 1867). The tubercle bacillus was discovered by Koch in 1882 (Koch 1882), and the diagnosis of ocular tuberculosis was further proved when von Michel identified tubercle bacilli in the eye one year later (von Michel 1883).

40.2 Pathogenesis Ocular Tuberculosis, caused by M. tuberculosis, presents as a spectrum of ocular diseases. The pathogenesis of ocular TB remains controversial. Ocular manifestations associated with TB are either caused by an active infection, or an immunological reaction in the absence of any infectious agent, which is related to delayed hypersensitivity and an aseptic reaction (Ni et al. 1982; Helm and Holland 1993). Active infection of the eye may be primary, or secondary, in nature. In primary ocular TB, there is no other systemic lesion, whereas secondary ocular TB is defined as an infection resulting from contiguous spread from an

S.-I. Sheu

732

adjacent structure or hematogenous spread. Almost all primary ocular infections are limited to conjunctival and corneal diseases that present as an ulceration, a tumor mass, pWyctenulosis, or interstitial keratitis. However, intraocular TB is usually associated with systemic disease and is therefore considered to represent a secondary infection. The predominant route by which tubercle bacilli reach the eye is through the blood stream, after infecting the lung. The pulmonary foci might not be evident clinically or radiographically. The manner in which tuberculosis may present is determined by several factors, including the amount and virulence of the infecting bacteria, the degree of tissue hypersensitivity already present or which may result from the infection, and the amount of native and acquired resistance possessed by the host.

40.3 Clinical Features TB produces foci of granulomatous inflammation, usually in the lungs, but can involve practically every bodily organ. TB may involve any part of the eye and appear in different clinical forms. The clinical manifestations of ocular TB are non-specific and protean. The most common manifestation of ocular TB in patients with pulmonary TB is choroiditis. Anterior uveitis, choroid tubercles, retinal vasculitis, vascular occlusion, dense vitritis, and papillitis may also occur (Ni et al. 1982; Regillo et al. 1991; Helm and Holland 1993; Bouza et al. 1997). The emergence and rapid development of the HIVIAIDS pandemic has had a devastating impact on the global burden of tuberculosis. The incidence

a

of TB in patients with the acquired immunodeficiency syndrome (AIDS) is almost 500 times the incidence in the general population (Barnes et al. 1991). In this era of the HIV pandemic, TB is becoming more prevalent, and an increasing number of ocular TB cases may eventually be seen. Unfortunately, early diagnosis of TB in HIV-positive persons is not easy as the clinical and radiological features are often atypical and resemble those caused by other HIV-related infections (Festenstein and Grange 1991; Daley 1995).

40.3.1 External Diseases 40.3.7.7 Eyelid Disease

Tuberculosis of the eyelid may present as a tumor or an abscess. The latter may be mistaken for chalazion with erythema and focal, or diffuse swelling of the eyelid. Figure 40.1 shows the histopathology of a painless eyelid mass in a 70-year-old man. Chronic granulomatous inflammation and caseous necrosis as well as acid-fast bacilli proved the diagnosis of ocular TB. 40.3.7.2 Conjunctival Tuberculosis

The first case ofconjunctival tuberculosis was described by Arlt in 1864 (Arlt 1864) and in the review by Eyre in 1912, the conjunctival lesions were classified into five groups based on clinical appearance: ulcerative, miliary tubercle, hypertrophic granulation, lupus, and pedunculated tumor (Eyre 1912). The majority were unilateral and most commonly involved the upper

_ _ _ _..........

Fig. 40.1a, b. A 70-year-old man with a painless tumor in his left lower lid. a Pathology findings of the lid mass showed chronic granulomatous inflammation with caseous necrosis (H&E, x1S0). (Reprinted from Sheu et al. 2001, with permission from Elsevier Science) b Acid-fast stain showed acid-fast bacilli (Kinyoun's crystal Fuchsin acid-fast stain, x198)

b

733

Ocular Manifestations of Tuberculosis

palpebral conjunctiva. Involvement of the lacrimal sac can prevent lacrimal drainage and leads to fistula draining to the skin.

with scleral ulceration (Saini et al. 1988; Nanda et al. 1989).

40.3.1.3 Phlyctenulosis

40.3.2 Intraocular Diseases

Phlyctenulosis are small nodules which arise on the conjunctiva or at the limbus. A small ulcer usually develops at the apex of a phlyctenule several days after its appearance. The lesions may 'wander' across the cornea from their site of origin at the limbus, leaving a narrow vascularized scar to mark its path. An association between phlyctenulosis and tuberculoprotein hypersensitivity is suggested by both epidemiological and experimental evidence (Gibson 1918; Thygeson 1954).

40.3.2.1 Uveitis

40.3.1.4 Corneal Disease

Corneal manifestations of tuberculosis include infiltrates, ulceration, and interstitial keratitis. Interstitial keratitis is rare and it is usually unilateral and painless (Donahue 1967; Thygeson 1974). Figure 40.2 demonstrates a corneal ulcer with descemetocele in a 58-year-old man. Polymerase chain reaction analysis and culture from corneal scraping were both positive for M. tuberculosis. The inflammation resolved after anti-TB medication. 40.3.1.5 Scleral Tuberculosis

TB is a rare, but classic cause of scleritis (which is usually anterior and necrotizing), and is associated

The TB-associated uveitis is usually granulomatous, with mutton-fat keratic precipitates, iris granulomas, and posterior synechiae. Concomitant posterior uveitis is a frequent occurrence, producing focal or diffuse choroiditis. Choroiditis is the most common ocular manifestation during dissemination of the bacillus via the blood stream because of its high level of blood supply and oxygenation. Choroidal tubercles are frequently unilateral, close to the posterior pole and sometimes associated with an inflammatory retinal detachment. The choroidal tubercles range from 1/4 to several disc diameters in size, usually with indistinct margins. The number of lesions ranges from one to as many as 50 or 60, with most eyes having fewer than five lesions. The tubercles may be variously pigmented depending upon the age of the lesion, with older lesions being more hyperpigmented (Massaro et al. 1964; Olazabal 1967; Cangemi et al. 1980; Chung et al. 1989). A case of bilateral choroidal tuberculosis is shown in Fig. 40.3. A 54-year-old woman complained of blurred vision, headache, fever, nausea, vomiting and nuchal rigidity. TB meningitis was diagnosed from her history of pulmonary TB (in her teenage years) and from CSF analysis, (although the culture was found to be negative). The fundus showed multiple

b Fig.40.2a, b. A 58-year-old man presenting with a recurrent corneal ulcer in the right eye. a Slit-lamp biomicroscopy showed a corneal ulcer with descemetocele. b Nested peR from corneal scraping showed a positive result for Mycobacterium tuberculosis (Reprinted from Sheu et al. 2001, with permission from Elsevier Science)

734

S.-T. Sheu

a

b

c

d

e

f Fig.40.3a-f. A 54-year-old woman presenting with bilateral choroidal tuberculosis. a Right eye b Left eye. Fundus montage showed 50 to 60 ill-defined yellowish-white elevated nodules mostly over the posterior pole. Some hemorrhage was noted over the macular area and the optic disc margin was blurred. c Right eye. d Left eye. At the late phase of fluorescein angiography, all the nodular lesions became hyperfluorescent, and mild dye leakage from the disc was also noted. e Right eye. f Left eye. After anti- TB medication, the disc margin cleared and the nodular lesion became more well-defined. Choroidal neovascularization developed in the macula of both eyes

Ocular Manifestations of 'fuberculosis

735

ill-defined yellowish-white elevated nodules mostly who was treated for idiopathic uveitis and was operated over the posterior pole. Some bleeding was noted for a complicated cataract. The ocular inflammation over the macular area and the optic disc margin was execrated after cataract extraction. Pathologic findings blurred. A fluorescein angiogram showed a block of the eyeball showed extensive caseous necrosis with fluorescence in the early phase and leakage in the polymorphonuclear leukocyte infiltration and acid-fast late phase. The meningitis and ocular lesion gradu- bacilli. Pulmonary TB was found in these two cases, ally resolved after anti-TB therapy. Unfortunately, though it was not evident clinically or radiographically choroidal neovascularization in the macula impaired in the initial stage of ocular inflammation. Therapy for the visual outcome. Vitritis can be associated with TB successfully treated the pulmonary TB and ocular choroidal tubercle and obscure the typical fundus inflammation, but it was not possible to save the eyes due to delayed diagnosis and treatment. picture as shown in Fig. 40.4. 40.3.2.2 Retinal Tuberculosis

40.3.2.4 Eales' Disease and Tuberculin Hypersensitivity

Eales' disease occurs predominantly in adult males in their third and fourth decades of life (Eales 1880). The disease presents as recurrent unilateral retinal and vitreous hemorrhaging with involvement of the other eye after a few months. It is usually associated with retinal vasculitis, ischemia and neovascularization with a high risk of intraocular hemorrhage as well. Although an 40.3.2.3 immunologicalmechanism has been postulatedto playa Endophthalmitis role in the pathogenesis of Eales' disease in patients with Some cases of endophthalmitis as· a consequence of tuberculin hypersensitivity, it may be a clinical entity TB infection have been reported (McMoli et al. 1978; with multiple causes. This is because not all patients Grenzebach et al. 1996). Also, endogenous endophthal- have positive tuberculin skin tests (Vine 1992). mitis following intravesicular bacille Calmette-Guerin injection has been confirmed in cultures of the vitreous 40.3.2.5 fluid (Han et al. 1999). Figure 40.5 shows a case of TB Optic Neuropathy panophthalmitis. The pathology of the transbronchial biopsy and eyeball (from enucleation) showed the exis- Optic neuritis has been ascribed to TB. Optic atrophy tence of acid-fast bacilli.Vitreous culture was also posi- can be seen after adhesive arachnoiditis. Optic disc tive for M tuberculosis. Another case of TB endophthal- tubercle, papilledema, and tuberculous neuroretinitis mitis is shown in Fig. 40.6.This shows a68-year-old man have also been reported (Mansour 1998; Stechschulte et TB of the retina is very rare and usually occurs following choroidal involvement. Retinal periphlebitis, vascular occlusion and tumor mass have been reported to be associated with TB (Clever 1980; Saini et al. 1986; Sant 1994).

a

Fig.40.4a, b. A 47-year-old man presenting with a right temporal headache, fever and loss of vision in the left eye. TB meningitis was suggested by his TB history and typical CSF findings, (although the culture was negative). a Fundus examination showed remarkable vitreous opacity. b Fundus examination, one week later, showed several yellowish-white subretinal nodule at posterior pole

S.-J. Sheu

736

a

b

c .........._ .....""""'" Fig.40.5a-d. Panophthalmitis in a 75-year-old woman with pulmonary TB. a Slit-lamp biomicroscopy at presentation showed ciliary congestion and dense anterior chamber reaction (Reprinted from Sheu et aI. 2001, with permission from Elsevier Science). b Acid-fast stain of bronchial biopsy showed acid-fast bacilli (Kinyoun's crystal Fuchsin acid-fast stain, xI000). c Pathologic findings of the eyeball specimen from enucleation showed extensive caseous necrosis of the retinal tissue (H&E, x60). d Pathology findings of the eyeball specimen from an enucleation showed extensive infiltration of acid-fast bacilli (Kinyoun's crystal Fuchsin acid-fast stain, x600) (Reprinted from Sheu et aI. 2001, with permission from Elsevier Science)

al.1999).A case ofpresumed tuberculous neuroretinitis is shown in Figure 40.7. Fundus examination showed disc hyperemia, and swelling, as well as multiple placoid exudative retinal detachment in the posterior pole. Tuberculin skin test resulted in intense reaction with necrosis. The lesion resolved after therapy for TB. 40.3.3 Orbital Tuberculosis

Several cases of orbital tuberculosis have been reported (Baghdassarian et al. 1972; Argrawal et al. 1977; Jain et al. 1979). Orbital tuberculosis occurs by hematogenous spread, or by invasion from adjacent structures (Khalil et al. 1985). The disease is usually slow-growing, chronic, and unilateral. Orbital disease most commonly presents as either proptosis, or as spontaneous fistulization of an orbital abscess. Regional lymph node involvement is common.

40.4

Diagnosis

Ocular TB diagnosis is complicated by the difficulties associated with ocular sampling. A high degree suspicion is essential for the early diagnosis of TB. The past medical history of patients and their families is a major consideration. Confirmation of ocular TB depends on the demonstration of tubercle bacilli in the ocular specimen, but diagnosis remains frequently presumptive for the time being. 40.4.1 Clinical Manifestation

The manifestations of ocular TB are nonspecific and protean. The ocular findings can be seen with other ocular and systemic diseases. The clinical features are not pathognomonic for the diagnosis of ocular TB.

Ocular Manifestations of Tuberculosis

737

a

Fig.40.6a-c. Endophthalmitis in a 68-year-old man with miliary TB. a Slit-lamp biomicroscopy at presentation showed pigmented keratic precipitates, corneal stroma edema, exudate in the anterior chamber. b Pathology findings of the eyeball specimen from an enucleation showed extensive caseous necrosis with polymorphonuclear leukocytes infiltration (H&E, x120). c Acid-fast stain showed acid-fast bacilli in the area of caseous necrosis (Kinyoun's crystal Fuchsin acid-fast stain, x1000) (Reprinted from Sheu et al. 2001, with permission from Elsevier Science)

c

a Fig. 40.7a, b. A 44-year-old woman presenting with presumed tuberculous neuroretinitis. a Fundus showed severe disc swelling and hyperemia as well as multiple placoid exudative retinal detachment in the posterior pole. b Tuberculin skin test resulted in an intense reaction with necrosis

40.4.2 Smears and Cultures A presumptive diagnosis is commonly based on the finding of acid-fast bacilli during microscopic examination (acid-fast bacilli microscopy) of a diagnostic specimen, such as a vitreous aspirate or aque-

ous smear. A definitive diagnosis is dependent on a positive culture of the organism from a diagnostic specimen. Lowenstein-Jensen medium is widely used for the isolation of M tuberculosis. Nevertheless, the culture is difficult and time-consuming. Normally, treatment should be started before the culture results are available.

738

40.4.3 Tuberculin Skin Test This reaction is an immunologic process based on delayed hypersensitivity. A positive skin test result is detectable 3- -8 weeks after the primary infection. An intense skin reaction can become necrotic. There is no specific amount of induration that confirms TB and a negative test result does not exclude the diagnosis. Active disease may be associated with a weak or negative reaction, especially in older patients, the malnourished, immunosuppressed, or those patients undergoing corticosteroid treatment. The tuberculin skin test is of limited value because of its low sensitivity and specificity, especially in countries where the BCG vaccine is used.

40.4.4 Molecular Techniques In recent years, several methods have been developed which shorten the time necessary for specific identification of mycobacteria (Good and Mastro 1989). These methods include the polymerase chain reaction (PCR), which uses a heat-stable DNA polymerase to amplify mycobacterial DNA from clinical samples (Musial et al. 1988). PCR has been used in ocular specimens to diagnose M. tuberculosis infection (Kotake et al. 1994; Gupta et al. 1998). PCR is a rapid diagnostic test with high sensitivity and specificity. Moreover, it is especially useful for diagnosing ocular TB because only a small sample is needed and viable cells are not required.

40.4.5 Isoniazid Diagnostic Trials A two-week therapeutic trial of isoniazid had been recommended in cases of presumed ocular tuberculosis (Abrams and Schlaegel 1982). The diagnostic value of therapeutic trials is diminished by the increasing prevalence of drug-resistant strains of M.

S.-T. Sheu

therapy should always be given as the primary treatment for ocular TB as pulmonary, or other, foci of disease may coexist. Five major drugs are considered to be first-line agents for treating TB: isoniazid, rifampin, pyrazinamide, ethambutol, and streptomycin. They are recommended based on their bactericidal activity (ability to rapidly reduce the number of viable organisms), their sterilizing activity (ability to kill all bacilli and thus sterilize the affected organ, measured in terms of the ability to prevent relapses), and their low rate of induction of drug resistance. A number of second-line drugs (kanamycin, amikacin, capreomycin, ethionamide, cycloserine, PAS, quinolone) are used only to treat patients with TB who are resistant to the first-line drugs. Corticosteroids are sometimes required for the ocular inflammation. Steroids should not be administered in the absence of antimicrobial therapy. Ignoring this rule exposes the patients to a risk of systemic dissemination of TB with a high mortality rate. A multidrug regimen is recommended. Any patient with a disease highly suggestive of ocular TB should be treated from the outset with multiple antituberculous chemotherapeutic drugs because of the increasing incidence of resistance to isoniazid as well as compliance problems. The guidelines of the American Thoracic Society for treatment consist of a 2-month initial phase of isoniazid, rifampin, and pyrazinamide followed by a 4-month continuation phase of isoniazid and rifampin, for a total of 6 months (American Thoracic Society 1992). According to the World Health Organization (WHO) and the International Union Against Tuberculosis and Lung Disease, the resistance to one drug is higher than the combined form (one drug, 9.1%; two or more drugs, 7.7%; multidrug resistance, 4.3%) (World Health Organization 1997). Treatment can be prolonged in immunocompromised patients or those with a disseminated disease. Second-line drugs or other adjuvants are considered in cases of multiple drug resistance or contraindications. Immunotherapy to boost the efficiency of the immune system in infected patients could be a valuable adjunct to anti-TB chemotherapy (Toossi 1998).

tuberculosis. 40.5.1 Monitoring of the Response to Treatment

40.5

Treatment Despite the difficulties in diagnosis, the treatment of TB is relatively effective and cost-efficient. Systemic

Bacteriological evaluation is the preferred method of monitoring the response to treatment for TB. Patients with pulmonary disease should have their sputum examined monthly until cultures are negative, whereas, bacteriological monitoring of patients

739

Ocular Manifestations of Tuberculosis

with ocular TB is more difficult and often not feasible. The response to treatment must be assessed clinically. An initial response usually occurs in two weeks. During treatment, patients should be monitored for drug toxicity.

40.5.2 Toxicity of Anti-TB Chemotherapy The most common adverse reaction of significance is hepatitis. Patients should be carefully educated about the signs and symptoms of drug-induced hepatitis and should be instructed to discontinue medication and seek medical assistance on developing any signs of hepatitis. The drugs can be reintroduced one at a time after liver function has returned to normal. Hypersensitivity reactions usually require discontinuation of all drugs and re-assessment to determine which agent is responsible. Similarly, the occurrence of optic neuritis with ethambutol (and rarely isoniazid), as well as the development of eighth nerve damage with streptomycin require permanent discontinuation of these drugs. Studies that detect subclinical evidence of toxicity before symptoms occur have been sought. In a study by Yiannikas and associates (Yiannikas et al. 1983), pattern-reversal visual-evoked potentials were used to detect a reversible prolongation oflatency and decreased amplitude of the PlOD wave in asymptomatic patients receiving ethambutol. Subclinical impairment of color discrimination was found to be relatively common in patients receiving ethambutol (Joubert et al. 1986). A deuteran type of defect was found to occur early and tritan defect was found to be a later manifestation of toxicity in a group of patients with normal vision who were treated with ethambutol for at least one month. Chronic alcoholics, malnourished individuals, and persons with pre-existing cerebral damage may be at increased risk of developing ocular toxicity. Pyridoxine was advocated for both prophylaxis and treatment of isoniazid-related optic neuritis (Kass et al. 1957). Acute uveitis had also been reported following rifampin administration (Spindler et al.199l). A complete baseline examination prior to treatment and routine test of visual acuity during follow-up is strongly recommended, especially in the unaffected fellow eye. The assistance of an infectious disease specialist, or pulmonologist, is helpful in treating these patients.

References Abrams J, Schlaegel TF Jr (1982) The role of isoniazid therapeutic test in tuberculous uveitis. Am J Ophthalmol 94: 511-515 American Thoracic Society (1992) Control of tuberculosis in the United States. Am Rev Respir Dis 146:1623-1633 Argrawal PK, Nath J, Jain BS (1977) Orbital involvement in tuberculosis. Am J OphthalmoI25:12-16 Arlt CF (1864) Ueber acne rosacea und lupus. Klin Monatsbl Augenheilkd 2:329-330 Baghdassarian SA, Zakharia H, Asdourian KK (1972) Report of a case of bilateral caseous tuberculous dacryoadenitis. Am J Ophthalmol 74:744-746 Barnes PF et al (1991) Tuberculosis in patients with human immunodeficiency virus infection. N Engl J Med 324: 1644-1650 Berenguer J et al (1992) Tuberculous meningitis in patients infected with the human immunodeficiency virus. N Engl J Med 326:668-672 Bouza E et al (1997) Ocular tuberculosis - a prospective study in a general hospital. Medicine 76:53-61 Brudney K, Dobkin J (1991) Resurgent tuberculosis in New York City. Am Rev Respir Dis 144:745-749 Cangemi FE, Friedman AH, Josephberg R (1980) Tuberculoma of the choroid. Ophthalmology 87:252-258 Chung YM et al (1989) Macular subretinal neovascularization in choroidal tuberculosis. Ann OphthalmoI21:225-229 Clever VG (1980) Presumed ocular tuberculosis. Ann Ophthalmol 12:424-426 Cohnheim J (1867) Uber Tuberculose der Choroidea. Virchows Arch Pathol Anat 39:49-69 Daley CL (1995) The typically "atypical" radiographic presentation of tuberculosis in advanced HIV disease. Tuberc Lung Dis 76:475-476 Donahue HC (1967) Ophthalmologic experience in a tuberculosis sanatorium. Am J OphthalmoI64:742-748 Duke-Elder S (1966) System of ophthalmology: disease of the uveal tract, vol 9. Mosby, St Louis, p 248 Eales H (1880) Cases of retinal hemorrhage, associated with epistaxis and constipation. Birmingham Med Rev 9: 262-273 Eyre JWH (1912) Tuberculosis of the conjunctiva: its etiology, pathology, and diagnosis. Lancet 1:1319-1328 Festenstein F, Grange JM (1991) Tuberculosis and the acquired immune deficiency syndrome. J Appl Bacteriol 71:19-30 Gibson WS (1918) The etiology of phlyctenular conjunctivitis. Am J Dis Child 15:81-115 Good RC, Mastro TD (1989) The modern mycobacteriology laboratory. How it can help the clinician. Clin Chest Med 10:315-322 Grenzebach UH et al (1996) Endophthalmitis induced by atypical mycobacterial infection. Ger J Ophthalmol 5:202-206 Gupta V et al (1998) Management of presumed intraocular tuberculosis: possible role of the polymerase chain reaction. Acta Ophthalmol Scand 106:290-294 Han DP et al (1999) Endophthalmitis from mycobacterium bovis bacille Calmette-Guerin after intravesicular bacille Calmette-Guerin injection for baldder carcinoma. Am J OphthalmoI128:648-650 Helm CJ, Holland GN (1993) Ocular tuberculosis. Surv Ophthalmol 38:229-256 Jain MR, Chundawat HS, Batra V (1979) Tuberculosis of the

740 maxillary antrum and of the orbit. Ind J Ophthalmol 1: 18-29 Joubert H et al (1986) Subclinical impairment of colour vision in patients receiving ethambutol. Br J Clin Pharm 21:213-216 Kass I et al (1957) Isoniazid as a cause of optic neuritis and atrophy. JAMA 164:1740-1743 Khalil M, Lindley S, Matouk E (1985) Tuberculosis of the orbit. Ophthalmology 92:1624-1627 Koch R (1882) Die Aetiologie der Tuberculose. Berliner Klin Wochenschr 15:221-230 Kotake S et al (1994) Polymerase chain reaction for the detection of Mycobacterium tuberculosis in ocular tuberculosis. Am J Ophthalmol 117:805-807 Mansour AM (1998) Optic disc tubercle. J Neuroophthalmol 18:201-203 Massaro D, Katz S, Sachs M (1964) Choroidal tubercles: a clue to hematogenous tuberculosis. Ann Intern Med 60: 231-241 McMoli TE et al (1978) Tuberculous panophthalmitis.J Pediatr Ophthalamol Strabis 15:383-385 Musial CE et al (1988) Identification of mycobacteria from culture by using the GenProbe Rapid Diagnostic System for Mycobacterium avium complex and Mycobacterium tuberculosis complex. J Clin MicrobioI26:2120-2123 Nanda M, Pflugfelder SC, Holland S (1989) M tuberculosis scleritis (letter). Am J Ophthalmoll08:736-737 Ni C et al (1982) Uveal tuberculosis. Int Ophthalmol Clin 22: 103-124 Olazabal F Jr (1967) Choroidal tubercles: a neglected sign. JAMA 200:374-377 Raviglione MC, O'Brien RJ (1998) Tuberculosis. In: Frauci AS (ed) Harrison internal medicine, part 7, 14th edn. McGrawHill, New York Regillo CD et al (1991) Ocular tuberculosis. JAMA 266:1490 Saini JS, Mukherjee AK, Nadkarni N (1986) Primary tuberculosis of the retina. Br J Ophthalmol 70:533-535

S.-J. Sheu Saini JS, Sharma A, Pillai P(1988) Scleral tuberculosis. Trop Geogr Med 40:350-352 Sant MS (1994) Ocular tuberculosis masquerading as retinoblastoma. Indian J Pathol Microbiol 37:343-347 Sheu SJ et al (2001) Ocular manifestation of tuberculosis. Elsevier Science, New York, p 1583 (Ophthalmology, vol 108) Spindler E, Deplus S, Flageul B (1991) Acute uveitis in reversal reactions. Acta Leprol 7:331-334 Stechschulte SU, Kim RY, Cunningham ET Jr (1999) Tuberculous neuroretinitis. J NeuroophthalmoI19:201-204 Thygeson P (1954) Observation on nontuberculous phlyctenular keratoconjunctivitis. Trans Am Acad Ophthalmol OtolaryngoI58:128-132 Thygeson P (1974) Nontuberculous phlyctenular keratoconjunctivitis. In: Golden B (ed) Ocular inflammatory disease. Thomas, Springfield, pp SO-52 Toossi Z (1998) Adjunctive immunotherapy of tuberculosis. Cytokines Cell Mol Ther 4:105-112 Vine AK (1992) Severe periphlebitis, peripheral retinal ischemia, and preretinal neovascularization in patients with multiple sclerosis. Am J OphthalmoI118:23-32 Von Michel J (1883) Ober Iris und Iritis. Albrecht v Grafes Arch OphthalmoI27:171-282 Wecker LV (1874) Die Erkrankungen des Uvealtractus und des Glaskorpers. Tuberkeln der Choroidea. Choroiditis tuberculosa. In: Graefe A, Saemich T (eds) Handbuch der gesammten Augenheikunde, vol 4. Engelmann, Leipzig, pp 642-648 World Health Organization (1997) Anti-tuberculosis drug resistance in the world. The WHO/IUATLD project on antituberculosis drug resistance surveillance. World Health Organization Global Tuberculosis Programme, Geneva Yiannikas C, Walsh J, Mcleod JG (1983) Visual evoked potentials in the detection of subclinical optic toxic effects secondary to ethambutol. Arch Neurol 40:645-648 Zumla A et al (1999) The tuberculosis pandemic - which way now? J Infect 38:74-79

41 Otorhinolaryngeal Aspects of Tuberculosis SUJATA MURANJAN

CONTENTS 41.1 41.1.1 41.2 41.2.1 41.2.2 41.3 41.3.1 41.3.1.1 41.3.2 41.3.2.1 41.3.2.2 41.4 41.4.1 41.5 41.5.1 41.6 41.6.1 41.7

41.8 41.9 41.9.1 41.9.2 41.10

Diagnosis 741 Otorhinolaryngeal Manifestations 742 Tubercular Cervical Lymphadenitis 742 Anatomy of Cervical Lymph Nodes 742 Clinical Presentation 742 Tuberculous Neck Abscesses 743 Retropharyngeal Abscess 743 Management 743 Parapharyngeal Space Abscess 743 Investigations 744 Management 744 Tuberculous Laryngitis 745 Clinical Presentation 745 Tubercular Infections of the Oral Cavity and Pharynx 746 Clinical Features 746 Tubercular Infection of the Nose 746 Management 747 Tuberculosis of the Salivary Glands 747 Tuberculosis of the Thyroid Gland 747 Tubercular Infections of the Ear 747 Mode of Infection 747 Signs and Symptoms 747 Medical Management 748 References 749

In the early 18th century Jean Louis Petit accurately described tuberculosis. Almost 100 years later, in 1882, Robert Koch discovered the tubercle bacillus (Plester et al. 1980). Since then millions of deaths have been attributed to tuberculosis. It now affects more than a third of the world population (Sudre et al. 1992). Approximately 1.5xl06 new cases are diagnosed annually in India alone (Mohanty 1999). In the developing countries with poverty, malnutrition, economic recession and overcrowding constantly on the rise, the problem of tuberculosis is acute and continues to exist in spite of extensive tuberculosis eradication campaigns. This rising incidence is, however, S. MURANJAN, MS (ENT), DNB, DORL Consultant in ENT, Suman Appartment, 3rd Floor, 16B Naushir Bharucha Road, Tardeo, Mumbai 400007, India

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

now not confined to the third world countries alone. A 12 per cent increase was noted in the USA between 1986 and 1991 and a greater than 30 per cent increase was noted in Switzerland over the same period. Since 1987, after a declining incidence for decades in England and Wales, the number of cases of tuberculosis has shown a steady increase (Williams and DouglasJones 1995). The resurgence has been attributed to an increase in human migration which has caused rapid mingling of the infected and non-infected communities (Agarwal and Bais 1998). These problems have been compounded by the explosive HIV/AIDS pandemic. The resultant immunosuppression has caused infection of this mycobacterium to spread globally with a vengeance. Thus to quote Williams and Douglas-Jones, the mycobacterium has "truly marched back" (Williams and Douglas-Jones 1995) The bacterium has the propensity to affect virtually any organ in the body. The ear, nose and throat are not excepted. The general symptoms include low-grade fever (with an evening rise), anorexia, weight loss and lassitude. The disease however, can exist even in the absence of these symptoms and is sometimes detected accidentally.

41.1

Diagnosis

The diagnosis may be suspected from the history and a physical examination. A chest radiograph may show the presence of a lesion suggestive of pulmonary tuberculosis. A moderately raised ESR is corroborative. A definitive diagnosis, however, has to be made prior to starting anti-tubercular chemotherapy. This is possible by showing the presence of acid fast bacilli in the sputum, secretions or tissue. Cultures on classical Lowenstein-Jensen slopes may take as long as six to eight weeks. The culture process can be expedited by the use of new technology such as the BACTEC H60 to provide results within three to seven days (Evans et al. 1992). Culture is a necessary

742

pre-requisite for drug sensitivity testing of mycobacteria. Obtaining a drug sensitivity profile is becoming more important as multidrug-resistant strains are being increasingly isolated. Histopathology of the biopsy tissue confirms the diagnosis. The pathognomic features of a tubercular granuloma are central caseating necrosis surrounded by epitheloid cells, giant cells and lymphocytes. Application of modern molecular diagnostic technology provides a rapid and accurate means for identification of M. tuberculosis from sputum and other fresh samples. The technique involves extraction of DNA and amplification of M. tuberculosis specific DNA sequences using the polymerase chain reaction (PCR). However it is important to realize that these PCR techniques can also detect dead non-viable and non-culturable organisms in sputum. This property can therefore aid in retrospective diagnosis (Williams and Douglas-Jones 1995).

41.1.1 Otorhinolaryngeal Manifestations • • • • • •

Cervical Lymphadenitis Deep neck space tubercular abscesses Tubercular laryngitis Tubercular otitis media Tubercular nasal granulomas Lupus vulgaris

Rare cases of tubercular thyroid infection, tonsillopharyngitis, tubercular otitic hydrocephalous, tuberculosis of the petrous apex and tubercular involvement of the salivary glands have been reported. A search has to be made for a primary focus of infection in any diagnosed case of head and neck tuberculosis.

S.Muranjan

central compartment of the neck are the infrahyoid, prelaryngeal and the pretracheal group (Wright and Kenyon 1987) (Fig. 41.1).

41.2.2 Clinical Presentation Lymph node tuberculosis is one of the commonest presentations of extrapulmonary tuberculosis. Approximately five per cent of all patients with tuberculosis develop tuberculous cervicallymphadenitis (Shikhani et al. 1989). Affected lymph nodes may be discreetly enlarged. In 75 per cent of the cases however, the lymph nodes are matted and clinically indistinguishable from a lymphoma (Dandapat et al. 1986). Perilymphadenitis is responsible for the typical matted appearance which is clearly evident on palpation. The initially discreet lymph nodes can caseate subsequently to form abscesses. Tubercular sinuses develop following rupture of these abscesses (Raviglione and O'Brien 1998) (Fig. 41.2). In a case with suspected inflammatory cervical lymphadenopathy a trial of anti-inflammatory drugs and antibiotics has to be given for a period of one week to 10 days. If the lymph node does not regress in size, it has to be subjected to fine needle aspiration cytology (FNAC). When the FNAC shows the pathognomonic appearance of a tubercular granuloma, anti-tubercular therapy has to be promptly initiated. Occasionally in cases of tuberculous lymph nodes, with central caseation, aspiration of caseous material

41.2 Tubercular Cervical Lymphadenitis 41.2.1 Anatomy of Cervical Lymph Nodes Cervical lymph nodes are classified into superficial and deep groups. The superficial nodes include those draining the scalp and face (i.e. the occipital, retro auricular, parotid, facial, submandibular and the submental group). The nodes comprising the deep group are the retropharyngeal, jugulodigastric and jugulo-omohyoid. Lymph nodes of the anterior or

Fig.41.1. Lymph nodes of the neck. 1 Submental; 2 submandibular; 3, 4 jugulodigastric; 5 jugulo-omohyoid; 6 posterior triangle nodes; 7 supraclavicular; 8 pre-laryngeal; 9 parotid; 10 occipital

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Otorhinolaryngeal Aspects of Tuberculosis

way through the various fascial planes in the neck and considerably enlarge in size (Muranjan and Kirtane 2001). An accurate knowledge of the anatomy of the various fascial planes in the neck is essential for drainage of these abscesses.

41.3.1 Retropharyngeal Abscess

Fig. 41.2. Tuberculous cervical lymphadenopathy showing scars and sinuses

may be diagnostic. FNAC can accurately establish a diagnosis in 83% of the cases (Dandapat et al. 1990). If the FNAC is inconclusive and the lymph node does not regress in size, an excision biopsy has to be performed and submitted for histopathology. The fate of the lymph nodes depends on the immunity of the host, resistance of the organism and effectiveness of the anti-tuberculous treatment. Anti tuberculous treatment started at the earliest and taken regularly results in the complete regression of the disease. In up to a quarter of the patients the nodes enlarge when treatment is commenced. This phenomenon is thought to be due to a hypersensitivity reaction to tuberculin released from bacilli that have been killed (Williams and Douglas-Jones 1995). Multiple cervical lymph nodes which do not regress in size despite adequate anti-tubercular medication have to be excised by functional neck dissection. The possibility of drug resistance also has to be considered in cases of cervical lymph nodes which do not regress despite adequate anti-tuberculous treatment.

A retropharyngeal abscess usually arises secondary to tubercular infection of the cervical spine following hematogenous spread. It can also develop subsequent to a suppurated retropharyngeal tuberculous lymph node. Presenting manifestations are low grade fever, odynophagia, drooling and painful neck movements. A large abscess can cause airway obstruction leading to stridor. As the disease progresses, patients often need to support the head with their hands. Irritation of the nerve roots leads to pain referred to the shoulders or arms (Williams and DouglaS-Jones 1995). Oropharyngeal examination generally reveals a fluctuant bulge on the posterior pharyngeal wall. A lateral radiograph of the cervical spine showing destruction of the vertebrae along with an increase in the pre-vertebral soft tissue space is a hallmark of a retropharyngeal tubercular abscess. The normal lordosis of the cervical spine is lost as a result of the spasm of the cervical muscles. 41.3.1.1 Management

The treatment comprises gradual decompression and drainage of the abscess intra-orally over its most prominent part. This is accompanied by the institution of anti-tubercular therapy. Immobilization with neck splints is required in case of severe destruction of the spine (Fig. 41.3). A sudden decompression and mobility can cause collapse of the vertebral column leading to paraplegia. If the patient presents in stridor, an emergency tracheostomy has to be performed prior to embarking on drainage. Anti-tubercular drugs have to be given for at least a year in cases of retropharyngeal abscess due to tuberculosis of the cervical spine.

41.3 Tuberculous Neck Abscesses

41.3.2 Parapharyngeal Space Abscess

Abscesses may originate from suppurating tubercular lymph nodes. These abscesses can dissect their

A retropharyngeal abscess can track laterally in the parapharyngeal space forming a parapharyngeal

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S. Muranjan

Fig.41.3. Lateral plain radiograph of the neck showing a splinted cervical spine following drainage of a tuberculous retropharyngeal abscess

FigA1.4. Left sided diffuse neck swelling due to an underlying tuberculous parapharyngeal abscess

space abscess. This can also occur secondary to suppuration of tubercular lymph nodes along the internal jugular vein. These patients then present with torticollis, tenderness and swelling in the lateral aspect of the neck (Fig. 41.4).

lations from walls of the abscess cavity have to be sent for histopathological examination. Complications encountered in cases of parapharyngeal abscesses include encroachment on the airway causing respiratory obstruction, sloughing off of the carotid artery and internal jugular vein as a result of the infection and spread to the mediastinum (Fig. 41.5). Spread of the abscess superiorly towards the base skull can lead to paralysis of the 9th, 10th, lith and 12th cranial nerves. It is not normal for a tubercular laryngeal abscess to develop after suppuration of a pre-laryngeal lymph node. In a previously reported case an abscess had tracked along the anterior visceral space, inferior

41.3.2.1 Investigations

An ultrasound of the neck helps in identifying the approximate size of the abscess. A computed tomography (CT) scan can establish its exact size and extent. 41.3.2.2 Management

If the parapharyngeal abscess communicates with a retropharyngeal component it can be drained intraorally (as mentioned above) so that drainage of the retropharyngeal part itself will enable the parapharyngeal component to drain. In case the abscess is only restricted to the parapharyngeal space, it has to be drained externally. Following a skin incision at the level of the upper border of the thyroid cartilage, the sternocleidomastoid muscle needs to be retracted laterally. The carotid sheath has to be identified and retracted following which the abscess cavity can be approached and drained. The pus obtained from any abscess drainage has to be sent for smear and culture sensitivity tests. Granu-

Fig. 41.5. An axial CT scan showing a left tuberculous parapharyngeal space abscess tracking inferiorly into the superior mediastinum

Otorhinolaryngeal Aspects of Tuberculosis

745

to the lamina of the thyroid cartilage, through the cricothyroid membrane to extend intra-laryngeally. The left true vocal fold was pushed medially, thus encroaching upon the airway and leading to stridor {Fig. 41.6). The abscess was drained externally. Prompt institution of anti-tubercular treatment lead to complete regression of the disease with restoration of a normal airway (Muranjan and Kirtane 2001) {Fig. 41.7).

41.4

Tuberculous Laryngitis At the turn of the century tuberculosis was the commonest condition to affect the larynx (Williams and Douglas-Jones 1995). Prior to the chemotherapeutic era there was an associated morbidity of 70 per cent with laryngeal disease (Ormerod 1951). The pathogenesis of laryngeal tuberculosis is either primary or secondary. Primary infection occurs in the absence of pulmonary disease where the bacillus is transmitted by aerosolized particles. The laryngeal mucosa is thus directly infected. Secondary infection of the larynx generally occurs in patients with pulmonary tuberculosis. The infected sputum laden with the acid-fast tubercular bacilli is expectorated and then swallowed, thereby inoculating the larynx. Seeding of the bacilli can also occur by the hematogenous and lymphatic routes (Richter et al. 2001; Soda et al. 1989). The posterior part of the larynx was identified as being the most frequently affected in early descriptions of laryngeal tuberculosis (Thompson 1924). This may have been due to its association with florid pulmonary disease in bed-ridden patients in whom the infected sputum accumulated over the interarytenoid region. Recent evidence indicates that the lesions are located in the anterior part of the larynx. This is thought to be related to the ambulatory treatment regimens now instituted which prevent pooling of saliva in the posterior larynx (Soda et al. 1989).

41.4.1 Clinical Presentation The patient presents with hoarseness of insidious onset, cough with occasional blood streaked sputum, odynophagia, dysphagia, dyspnea, and sore throat (Richter et al. 2001). Occasionally the patient may complain of referred otalgia. There may be a history of pulmonary tuberculosis. The clinical

Fig. 41.6. An axial CT scan at the level of the vocal cords showing an abscess lateral to the left true vocal cord pushing it medially and compromising the airway

Fig. 41.7. A post-operative CT scan of the same patient done two months after incision and drainage showing complete resolution of the disease and a normal airway

manifestations mimic those of a laryngeal carcinoma. A distinguishing feature is the presence of painful dysphagia which is a common symptom of tuberculous laryngitis (Bull 1966). Tuberculosis should therefore be considered in the differential diagnosis of malignancy of the larynx and hypopharynx. This is especially important in the perspective of resurgence of tuberculosis in all parts of the world (Goyal et al. 1998). The other differential diagnoses, though less common but which should nevertheless be borne in mind include leprosy, sarcoidosis, fungal infections, Wegener's granulomatosis and cat-scratch disease. Systemic diseases like systemic lupus erythematosus, rheumatoid arthritis, relapsing polychondritis and amyloidosis are also included in the differential diagnosis (Richter et al. 2001).

746

The vocal folds are the sites most commonly affected by tuberculosis, closely followed by the ventricular folds (Soda et al. 1989). The other sites affected in approximately 10% to 15% of cases are the aryepiglottic folds, arytenoids, posterior commissure, subglottis and epiglottis (Richter et al. 2001). Contrary to the earlier descriptions the anterior half of the larynx is affected twice as often as the posterior half (Bailey and Windle-Taylor 1981). A laryngoscopy will show the characteristic features of granulations and irregularity of the vocal cords termed as a "moth eaten appearance". The posterior commissure and arytenoids may be covered with granulations. Infiltration of the lax mucosa around the arytenoids produces a pale, fleshy swelling that may appear tense and shiny as if full of fluid, but is in fact solid. In the past this has been referred to as pseudo-edema. When the lesions heal by fibrosis, the epiglottis assumes a typical 'turban shaped' appearance and the arytenoids appear pyramidal. Fibrosis at the crico-arytenoid joint can impair vocal cord mobility. Stridor in tubercular laryngitis can result from granulations which occlude the glottis in the active phase of the disease, vocal fold paralysis secondary to mediastinal disease (Shah and Ramakantan 1990) or stenosis or fibrosis of the larynx. A tracheostomy may be required in such cases. Smear and culture tests of the sputum may show presence of the acid fast bacilli. Acid fast bacilli are detected in the sputum in 70 per cent of patients (Bailey and Windle-Taylor 1981). A microlaryngoscopy with biopsy of the granular lesions will show the characteristic tubercular granuloma on histopathology thus distinguishing it from a malignancy. Laryngeal tuberculosis responds rapidly to anti-tubercular treatment. Symptoms resolve within two weeks of instituting chemotherapy and the sputum becomes negative for mycobacteria. The persistence of a suspicious lesion after treatment may be due to non-compliance, a resistant organism or a concomitant carcinoma which should be excluded by a repeat biopsy (Hunter et al.1981).

41.5 Tubercular Infections of the Oral Cavity and Pharynx Though oral and pharyngeal involvement in this disease is quite rare, there have been reports of the pyriform fossa, tonsils and oropharynx being affected by tuberculosis (Goyal et al. 1998; Gupta et al. 2001). Tonsillar tuberculosis could be demonstrated in over

S.Muranjan

one third of patients with cervical lymphadenitis at the beginning of the century. The tonsils were usually infected with M. bovis by ingestion of infected cow's milk. With pasteurization of milk, tonsillar tuberculosis is now a rare entity. Primary infection of the oral cavity can occur following mucosal damage but as a rule the infection is secondary to pulmonary disease.

41.5.1 Clinical Features The lesion manifests itself as a painless ulcer which has an undermined edge. More often than not there is an associated regional lymphadenopathy. The sites affected are gums, tongue, palate and floor of mouth (Prabhu et al. 1978; Haddad et al. 1987). The appearance is indistinguishable from carcinoma and biopsy is therefore mandatory. The differential diagnosis includes ulcers due to trauma, hematological disorders, actinomycosis, syphilis, midline granulomas, Wegener's granuloma and aphthous ulcers (Gupta et al. 2001). Sarcoidosis, deep mycotic infections and malignancy must also be borne in mind. Tubercular ulcers usually regress completely following institution of anti-tubercular drugs.

41.6 Tubercular Infection of the Nose Tuberculosis of the nose is a rare entity which presents either in the nodular or the ulcerative form. It generally occurs secondary to pulmonary tuberculosis. Lupus vulgaris is an indolent and chronic form of tuberculosis affecting the skin of the face and mucous membrane of the nose (Weir 1987). In the nasal cavity the muco-cutaneous junction is the commonest site of inoculation. The nasal lesions are frequently associated with precursor nodules on the face. The disease course is slow with periods of remission and exacerbations. The early appearance is typical. There is mucosal pallor with minute 'apple jelly nodules. Application of topical adrenaline fails to blanch these nodules which in turn are rendered more obvious against the surrounding mucosa. As these nodules coalesce the mucosa becomes granular and the septum may perforate. The edge of the perforation is irregular and surrounded by pale mucosa (Williams and Douglas-Jones 1995). Ulceration may be followed by healing with fibrosis and contraction with distortion of the alae nasi.

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Otorhinolaryngeal Aspects of Tuberculosis

The disease may spread from the muco-cutaneous junction to the floor of the nasal cavity, turbinates, and posteriorly towards the choanae. The patient then presents with mucopurulent and occasionally blood stained nasal discharge and obstruction. Anterior rhinoscopy and diagnostic nasal endoscopy reveals a reddish nodule. Occasionally the disease may also present as a nasal polyp (AI Serhani 2001). The diagnosis is confirmed by visualization of the acid fast tubercular bacilli in the nasal discharge and a biopsy of the nodule will show the classical tubercular granuloma. Complications like dacryocystitis, corneal ulceration and nasopharyngeal lupus can occur and atrophic rhinitis may be a sequel.

41.6.1 Management

Treatment comprises anti-tuberculous drugs which are given for 6-9 months. When the disease is completely arrested, surgical repair of the nasal deformity may be required.

41.7 Tuberculosis of the Salivary Glands The parotid gland is the commonest gland to be affected, followed by the submandibular and the sublingual gland. Infection within the parotid most often arises in the intraparotid lymph nodes and is often the only site affected. The bacilli presumably reach the gland either via the duct or through lymphatic channels. The focus of entry is either in the pharynx or the tonsils (Batsakis 1974). Pain is a late manifestation and facial palsy is a rare complication. Fine needle aspiration is generally diagnostic and conventional anti-tuberculous chemotherapy commenced early can avoid unnecessary surgery.

41.8 Tuberculosis of the Thyroid Gland Tuberculous thyroiditis is an extremely rare condition. It arises secondary to other tubercular foci of infection through hematogenous spread. The two types of tuberculosis of the thyroid gland are the diffuse miliary form and the caseous type. The miliary form is usually less common and asymptomatic while the focal form

is more common. This usually presents as a painless solitary nodular goiter in a euthyroid patient (Patankar et al. 1999). Occasionally abscess formation may occur. Fine needle aspiration cytology is a sensitive, specific and reliable method for diagnosing tuberculous thyroiditis (Mondal and Patra 1995). Prompt institution of anti-tubercular drugs is required to control the infection. In cases of multiple tubercular abscesses of the gland, a thyroidectomy may be indicated.

41.9 Tubercular Infections of the Ear Tuberculous otitis media was first reported over 100 years ago (OdetoyinboI988). The incidence of tuberculosis of the middle ear cleft is reportedly low in the developed countries. However this varies from country to country depending on a number of factors like the socio-economic status, under-diagnosis and underreporting. Achieving an early diagnosis is difficult due to several factors. Significant amongst these are low index of suspicion, false negative cultures due to the presence of other bacteria in the specimen which interfere with the isolation of the bacillus and change in the histopathology of the middle ear because ofwidespread use of antibiotic ear drops such as neomycin and gentamycin with weak anti-tubercular activity (Yaniv 1987; Grewal et al. 2000). In addition to the above factors, ear swabs have a poor sensitivity for AFB on microscopy as the yield of mycobacteria from clinical specimen other than sputa is very low (Lee and Drysdale 1993).

41.9.1 Mode of Infection

Bacilli from the infected sputum in case of pulmonary tuberculosis can gain access to the middle ear via the Eustachian tube. In regions where unpasteurized milk is consumed, spread of Mycobacterium bovis can occur directly via the Eustachian tube. Hematogenous dissemination is also an important route of spread of infection.

41.9.2 Signs and Symptoms

The disease is of an insidious onset. Classically the patient presents with painless profuse otorrhoea and profound hearing loss. The otorrhoea fails to respond

748

to standard antibiotics. Occasionally mild deep-seated pain may be present possibly due to granulations within the mastoid under pressure (Plester et al. 1980). On otoscopic examination classical multiple perforations can be seen on the tympanic membrane. These multiple perforations are caused by a number of tubercles involving the tympanic membrane. Though these were initially thought to be a hallmark of the disease, they are rarely encountered today. A central, or a total, perforation is more commonly encountered (Farrugia 1997). Occasionally pale granulations or polyps may be seen. The disease can cause extensive destruction of the ossicular chain. Osteomyelitis of the labyrinthine bone and the lateral sinus lead to sequestra formation (WindleTaylor and Bailey 1980). The resulting deafness is generally out of proportion to the otoscopic findings and it may be of a conductive nature. In case of labyrinthine involvement deafness may be of a mixed or sensorineural type and is accompanied by symptoms of giddiness and vomiting. Involvement of the fallopian canal by the disease can give rise to a lower motor neuron type of facial paralysis. Tuberculosis must be the prime suspect in patients with facial paralysis in chronic middle ear disease, without cholesteatoma, (Plester et al. 1980). Spread of the disease can also occur along the petrous apex where in addition to the otorrhoea, the patient also presents with a lateral rectus palsy, diplopia and pain along the distribution of the trigeminal nerve. This symptom complex is classically termed as Gradenigo's syndrome. A tympanomastoidectomy has to be performed. All the granulations and bony sequestra have to be cleared from the middle ear and mastoid cavity. While exploring the ear, the possibilities of erosion of the bony facial nerve canal and fistulae over the lateral semi circular canal and promontory have to be borne in mind. The granulations and bone have to be sent for biopsy and antitubercular drugs must be started at the earliest and administered for about 9-12 months. In a previously operated mastoid cavity, tuberculous otitis media must be considered if there is a recurrence of granulation tissue, slow wound healing, persistent otorrhoea and formation of bone sequestra. Hence during any aural surgery if granulation tissue is encountered, it should always be sent, with the bone, for biopsy.

S.Muranjan

chapter. A combination of drugs is used for the treatment of tuberculosis to reduce the probability of emergence of drug-resistant mutants. Factors such as monotherapy, poor compliance, omission of some drugs, suboptimal dosage, poor drug absorption or an insufficient number of active agents in a drug regimen contribute to the emergence of resistance to multiple drugs within a matter of months (Gostin 1993). The usual standard drug regimen for head and neck tuberculosis include a four drug therapy comprising rifampicin, isoniazid, pyrazinamide and ethambutol given over a period of 2 months followed by a combination of rifampicin and isoniazid for another 4-7 months. Following administration of anti-tubercular drugs, the patient's local as well systemic symptoms along with the ESR have to be monitored. After 3-4 weeks of therapy in a completely compliant patient, if the symptoms do not improve or if the ESR remains persistently high, drug resistance has to be suspected. Quinolones such as ciprofloxacin or ofloxacin, aminoglycosides likes streptomycin or kanamycin, or other drugs like ethionamide, PAS, clofazimine, and cycloserine may have to be added to the regimen. Culture-sensitivity tests have to be performed to confirm the sensitivity of the bacilli to these drugs. Any anti-tuberculous treatment has to be preferably started following consultation with a chest physician. Poor compliance is thought to be the primary cause for emergence of drug resistance. To increase compliance many centers employ a combination of strategies such as incentives and directly observed therapy (DOT) in which a health worker actually witnesses the patient taking the medicines. This ensures complete compliance on part of the patient. Thus maintaining a high index of suspicion, early diagnosis and prompt treatment at an early stage can lead to complete cure. However the dictum, "prevention is better than cure" cannot be more adequately stressed especially in case of tuberculosis. Strengthening the patient education and awareness programs, easy accessibility to the health centers and prompt and regular use of the antituberculous drugs are crucial in bringing this dreaded disease under control.

Acknowledgements. I am thankful to Dr. Renuka 41.10 Medical Management Discussion of the entire medical management of tuberculosis would be beyond the scope of this

Bradoo, Professor and Head, Department of ENT, Lokmanya Tilak Municipal Medical College and General Hospital, Mumbai, India for the constant encouragement given by her and Dr. Surendra Lele, Consultant ENT Surgeon, Seven Hills Hospital, Visakhapatnam, India for the valuable suggestions given by him.

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References Agarwal P, Bais AS (1998) A clinical and videostroboscopic evaluation of laryngeal tuberculosis. J Laryngol Otol 112: 45-48 Al Serhani AM (2001) Mycobacterial infection of the head and neck: presentation and diagnosis. Laryngoscope 111: 2012-2016 Bailey CM, Windle-Taylor PC (1981) Tuberculous laryngitis. Laryngoscope 91 :93-100 Batsakis JG (1974) Non neoplastic diseases of the salivary glands. In: Tumours of the head and neck. Williams and Wilkins, Baltimore, pp 54-55 Bull TR (1966) Tuberculosis of the larynx. Br Med J 2:991-992 Dandapat M, Mishra B, Dash SP, Car PK (1990) Peripheral lymph node tuberculosis: a review of 80 cases. Br J Surg 77:911-912 Dandapat M, Padhi N, Nanda BP (1986) Peripheral lymph node tuberculosis - a comparison of various methods of management. Indian J Tuberc 33:20-23 Evans KD, Nakasone AS, Sutherland PA, de la Maza LM, Peterson EM (1992) Identification of Mycobacterium tuberculosis and Mycobacterium intracellulare directly from primary BACTEC cultures by using acridinium-ester-Iabelled DNA probes. J Clin MicrobioI30:2427-2431 Farrugia EJ (1997) Tuberculous otitis media- a case report. J LaryngoIOtollll:58-59 Gostin LO (1993) Controlling the resurgent tuberculosis epidemic. J Am Med Assoc 269:255-260 Goyal A, Nagarkar NM, Uppal KS, Mohan H, Daas A (1998) Tuberculosis of the pyriform fossa - a rare entity. J LaryngoIOtoI112:782-783 Grewal DS, Hathiram BT, Agarwal R, Dwivedi A, Walvekar R (2000) Otitic hydrocephalus of tubercular origin: a rare cause. J Laryngol OtoI114:874-877 Gupta K.B, Tandon S, Jaswal TS, Singh S (2001) Tuberculosis of tonsil with unusual presentation. Indian J Tuberc 48: 223-224 Haddad N, Zaytoun G, Hadi U (1987) Tuberculosis of the soft palate: an unusual presentation of oral tuberculosis. Otolaryngol Head Neck Surg 97:91-99 Hunter AM, Millar JW, Wightman AJA, Horne NW (1981) The changing pattern oflaryngeal tuberculosis. J Laryngol Otol 95:393-398 Lee PYC, Drysdale AJ (1993) Tuberculous otitis media - a difficult diagnosis. J Laryngol Otoll07:339-341 Mohanty KC (1999) Tuberculosis and atypical mycobacteria. In: Sainani GS (ed) API textbook of medicine, 6th edn. Association of Physicians of India, Mumbai, pp SO-55 Mondal A, Patra DK (1995) Efficacy of fine needle aspiration

cytology in the diagnosis of tuberculosis of the thyroid gland: a study of 18 cases. J Laryngol Otol109:36-38 Muranjan SN, Kirtane MV (2001) Tubercular laryngeal abscess. J Laryngol OtoI115:660-662 Odetoyinbo 0 (1988) Early diagnosis of tuberculous otitis media. J Laryngol Otol102:133-135 Ormerod F (1951) A review of tuberculosis of the upper air passages during the past thirty years and its treatment by streptomycin. J Laryngol OtoI65:461-471 Patankar T, Prasad S, Chowdhary S, James P (1999) Plunging goitre due to tuberculous thyroiditis. J Assoc Physicians India 47:347 Plester D, Pusalkar A, Steinbach E (1980) Middle ear tuberculosis. J Laryngol OtoI94:1415-1421 Prabhu S, Daftary D, Pholakia HM (1978) Tuberculosis ulcer of the tongue: report of case. J Oral Surg 36:384-386 Raviglione MC, O'Brien RJ (1998) Tuberculosis. In: Fauci AS, Braunwald E, Isselbacher KJ (eds) Harison's principles of internal medicine, vol 1, 14th edn. McGraw-Hill, New York, pp 1004-1014 Richter B, Fradis M, Kohler G, Ridder GJ (2001) Epiglottic tuberculosis: differential diagnosis and treatment. Ann Otol Rhinol Laryngolll0:197-201 Shah P, Ramakantan R (1990) Hoarseness of the voice due to recurrent laryngeal nerve palsy in tuberculous mediastinits (letter). Arch Otolaryngol Head Neck Surg 116(1):108 Shikhani AH, Hadi UM, Mufarrij AA, Zaytoun GM (1989) Mycobacterial cervical lymphadenitis. Ear Nose Throat J 68:660-672 Soda A, Rubio H, Salazar M, Ganem J, Berlanga D, Sanchez A (1989) Tuberculosis of the larynx: clinical aspects in 19 patients. Laryngoscope 99:1147-1150 Sudre P, Dam G, Kochi A (1992) Tuberculosis: a global overview of the situation today. Bull WHO 70:149-159 Thompson St Clair (1924) Tuberculosis of the larynx - its significance to the physician. Br Med J 2:841-844 Weir N (1987) Acute and chronic inflammations of the nose. In: Mackay IS, Bull TR (eds) Scott-Brown's otolaryngology, vol 4. Rhinology. Jaypee, New Delhi, pp 115-141 Williams RG, Douglas-Jones T (1995) Mycobacterium marches back. J Laryngol Otol 109:5-13 Windle-Taylor PC, Bailey CM (1980) Tuberculous otitis media a- a series of 22 patients. Laryngoscope 90:1039-1044 Wright D, Kenyon G (1987) Cancer of the neck. In: Stell PM (ed) Scott-Brown's otolaryngology, vol 5. Laryngology. Jaypee, New Delhi, pp 315-339 Yaniv E (1987) Tuberculous otitis media: a clinical record. Laryngoscope 97:1303-1306

42 Endocrine and Metabolic Manifestations of Tuberculosis SOHAIL INAM and MONA AL-SHAHED

in active tuberculosis results from either a direct affliction of the organs with the disease (endocrine tuberculosis) or more commonly as an abnormality of circulating hormones as a consequence of systemic disease. The latter results from the effects of malnutrition, cytokines and other inflammatory mediators on the hypothalamic-pituitary axis, hormone binding proteins and peripheral metabolism of hormones.

CONTENTS Introduction 751 Endocrine Tuberculosis 751 Adrenal Tuberculosis 751 CT Features of Adrenals Tuberculosis 752 Illustrative Case Report 754 Subclinical Tuberculous Adrenalitis and Related Controversies 755 42.2.2 Thyroid Tuberculosis 756 42.2.2.1 Illustrative Case Report 757 42.2.3 Pituitary Tuberculosis 758 42.2.3.1 Illustrative Case Report 760 42.2.4 Parathyroid Tuberculosis 760 Endocrine Perturbations Related 42.3 to Systemic Tuberculosis 761 42.3.1 Hypercalcemia 761 42.3.2 Water and Sodium Balance in Tuberculosis 42.3.3 Effect of Tuberculosis on Circulating Hormones 764 Tuberculosis and Diabetes Mellitus 765 42.4 Endocrine and Metabolic Effects 42.5 of Anti-Tuberculous Drugs 766 References 766

42.1 42.2 42.2.1 42.2.1.1 42.2.1.2 42.2.1.3

42.2 Endocrine Tuberculosis 762

42.1 Introduction Tuberculosis (TB) is often termed 'a great mimicker', as it can affect almost any organ in the human body and present in a variety of ways. The endocrine system is no exception, though the incidence of clinical disease is very low. The occurrence of extrapulmonary tuberculosis appears to be increasing in the developed world and is probably a reflection of the impact of mv infection. Endocrine dysfunction

S. INAM, MBBS, FRCP (Edin), FRCP Head of Endocrinology Division, Department of Medicine, Riyadh Armed Forces Hospital, P.O. Box 7897, Riyadh 11159, Saudi Arabia M. AL-SHAHED, MBBS, FRCR Consultant Radiologist, Department of Radiology, Riyadh Armed Forces Hospital, P.O. Box 7897, Riyadh 11159, Saudi Arabia

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

Endocrine tuberculosis is uncommon. It may affect any endocrine organ and is the result of organ seeding following hematogenous spread or contiguous spread from a nearby-afflicted structure. Hematogenous dissemination of virulent tubercle bacilli can occur during the course of primary infection or long after the initial infection. Its clinical manifestation may be part of the systemic disease or may be the sole manifestation of the condition. This chapter deals with tuberculosis affecting the adrenal, thyroid and pituitary glands. Tuberculosis of the gonads is covered elsewhere (chapter 39). Direct tuberculous involvement of the parathyroid glands and the pancreatic islets is extremely rare.

42.2.1 Adrenal Tuberculosis Primary adrenal insufficiency (PAl) secondary to bilateral adrenal destruction by tuberculosis, was originally described by Addison in 1855. In a review of his eleven patients with adrenal insufficiency seven had tuberculosis. In the past when the disease was rampant and untreatable, tuberculosis was the commonest cause of PAl accounting for 70-80% of the cases (Guttman 1930). With the development of effective chemotherapy and early treatment, tubercu-

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losis has increasingly become less common as a cause of PAl and presently contributes from 7-20% of the cases (Nomura et al. 1994; Oelkers 1996). Tuberculous PAl is still thought to be a major cause of PAl in countries like Saudi Arabia where the disease is common. However, in a series of 15 new adult patients diagnosed with PAl since 1982 at the Riyadh Armed Forces Hospital tuberculosis could only be established in three as a cause. Adrenal involvement occurs from hematogenous seeding. The adrenal glands are especially vulnerable because of their rich blood supply and immunosuppressive effects of high local production of corticosteroids. In an autopsy series of patients with late generalized tuberculosis, adrenal seeding was seen in 53% of patients (Slavin et al. 1980). This is not necessarily associated with clinical disease. Both adrenal glands are involved, though they may not be equally affected. Seeding is followed by an inflammatory reaction which if unchecked causes gradual destruction of the glands. About 90% destruction of both adrenal glands is required before the onset of clinical adrenal insufficiency. Destruction of the adrenal medulla is more common than that of the adrenal cortex (Guttman 1930). The clinical manifestations, however, are related to the deficiency of adrenal cortical hormones. All the layers of the adrenal cortex are affected but as the zona glomerulosa consists of scattered cell groups rather than being a distinct layer, it may be initially only partly destroyed, so that the clinical manifestations may be solely those of glucocorticoid deficiency. The histology of adrenal TB is no different from any other organ affliction (see Chapter 10 on Pathology for details). Earlier in the course of disease there is inflammatory cell infiltration followed by granuloma formation resulting in adrenal gland enlargement. As the disease progresses micro-abscess formation and tissue necrosis occurs. Mass lesions may develop secondary to cold abscesses. With progressive destruction, the glands are gradually replaced by caseous nodules and fibrosis so that after about two years they become normal, or small, in size and ultimately over time they become fibrosed and calcified (Vita et al. 1985). The clinical features of adrenal TB are similar to those of any other cause of primary adrenal insufficiency. These include weakness, fatigue, weight loss, abdominal pain, diarrhea, hyperpigmentation and orthostatic hypotension. There may be associated fever and abnormal mental activity. The laboratory tests show hyponatremia, hyperkalemia, azotemia, anemia and eosinophilia. The clinical syndrome may

S. Inam and M. Al-Shahed

accompany active systemic disease such as acute pulmonary, miliary or other extra-pulmonary tuberculosis (Alvarez and McCabe 1984). More commonly as adrenal destruction is a slow process the clinical presentation occurs as an isolated entity years after the initial infection (Nomura et al. 1994; Sanford and Favour 1956; Vita et al. 1985). Rarely the presentation is that of an adrenal mass (unilateral or bilateral) seen on CT of the abdomen (Jayakar et al. 1998). Whereas the presentation is insidous, patients may occasionally present with an acute adrenal crisis following the use of rifampicin (Elansary and Earis 1983). The diagnosis of adrenal insufficiency is confirmed by demonstrating a decreased, or absent, cortisol response to exogenous ACTH (synacthen stimulation test). Elevated ACTH levels and associated mineralocorticoid deficiency confirm that the adrenal insufficiency is due to adrenal destruction. Mineralocorticoid deficiency is characterized by hyponatremia and hyperkalemia and confirmed by findings of high renin and low aldosterone levels. Once a hormonal diagnosis of PAl is made the next step is to determine its cause. A supportive CT scan, or MRI of the adrenal glands, absence of adrenal antibodies and other causes of this disease are required to support TB as the cause of PAI.(Laureti et al. 1998). The presence of extra-adrenal TB is highly supportive. A final diagnosis requires either histological proof or positive tissue cultures. Although not performed routinely a CT-guided needle biopsy of the adrenals can provide diagnostic material and is useful in doubtful cases. It is of great value during investigation of unilateral or bilateral adrenal masses (Yee et al. 1986). 42.2.1.1 CT Features of Adrenals Tuberculosis

CT plays a major role in diagnosis of established tuberculous adrenal disease (Hauser and Gurret 1986; Villabona et al. 1993;Wang et al. 1998; Wilms et al. 1983). The appearance of the adrenals on CT will vary depending on the stage of disease. Adrenal enlargement has been commonly documented during routine screening in pulmonary tuberculosis. It is more likely to occur with acute pulmonary TB, rather than chronic pulmonary disease (Kelestimur et al. 1994). An enlargement of the adrenals seen in patients with pulmonary tuberculosis during routine CT probably represents stress related hyperplasia or adrenalitis and not clinical disease (Gulmez et al. 1996; Kelestimur et al.1994). The following presentations are well recognized in tuberculous adrenalitis.

Endocrine and Metabolic Manifestations of Tuberculosis

a. Bilateral adrenal enlargement: The enlargement is smooth, has sharp margins and diffuse enhancement post contrast. This appearance is non-specific and may represent direct tuberculous involvement of the glands or simply hyperplastic adrenals as a part of stimulatory response to systemic illness (Fig. 42.1). b. A unilateral mass: Rarely the disease manifests as a unilateral mass making it difficult to differentiate it from an adrenal tumor (Fig. 42.2). c. Irregularly enlarged adrenals with multiple ring enhancements: This would be a classical appearance and mimics that seen in other organs. The appearances are due to multiple areas of caseation necrosis or abscess formation (Fig. 42.3). d. Small fibrotic glands with multiple calcifications. This can also be seen on a plain abdominal radiograph (Fig. 42.4).

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An MRI of the adrenal glands shows features similar to that of CT and offers no major advantage. Ultrasound can also detect enlarged adrenals, adrenal masses and calcification. The appearances are again not specific. Abdominal calcification can also be seen on plain film radiographs of the abdomen in the late stages of the disease. This occurs in about 50% of cases and is not specific since it can be seen in other types of infectious adrenalitis and following adrenal hemorrhage (Vita et al. 1985). The treatment of adrenal tuberculosis consists of standard anti-TB therapy in a similar manner to other forms of extra-pulmonary TB, along with adrenal hormone replacement. Duration of six months of anti-TB therapy using first line medications is sufficient. Glucocorticoids are replaced with hydrocortisone (20-30 mg per day in divided doses) or prednisolone (4-7.5 mg/day) or dexamethasone

a

c

Fig.42.1. a Post-enhanced CT of the upper abdomen demonstrating bilateral suprarenal gland enlargement showing homogeneous enhancement (arrowheads). L. liver, S. spleen. b Magnetic resonance image (MRI), of the same patient, Tlweighted image (TR 516, TE 14): The enlarged suprarenal glands appear as low signal intensity with well defined margins (arrow). c MRI post-enhanced (gadolinium), TI (TR 516, TE 14), image showing diffuse homogeneous enhancement of both suprarenal glands (arrows)

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Fig.42.2. Post-enhanced CT of the upper abdomen demonstrates unilateral adrenal gland enlargement. The right adrenal gland is enlarged and is diffusely enhancing (large arrow). Note multiple shotty lymph nodes in the para-aortic region (small arrows). L Liver; S spleen

Fig.42.3. Post-enhanced CT of the upper abdomen showing enlargement of both adrenal glands with multiple ring enhancement consistent with abscess formation (arrows)

S. Inam and M. Al-Shahed

(0.25-0.75 mg/day). Mineralocorticoids are replaced using fludrocortisone in a dose of 50-200 Jlg/day. As rifampicin is an enzyme inducer and increases the metabolism of steroid hormones the dose of glucocorticoids should be increased (Edwards et al. 1974). Mineralocorticoids on the other hand are less likely to be affected (Schulte et al. 1987). During rifampicin therapy the dose of glucocorticoids is increased to two to three times the replacement dose initially and then slowly titrated down to the lowest possible dose achieving adequate replacement. The treatment is adjusted based on clinical response, serum electrolytes,ACTH levels and measurement of plasma renin. ACTH levels are usually maintained between two to three times the upper limits of normal. Initial presentation with an acute adrenal crisis is rare and may follow a physical stress or the initiation of therapy with rifampicin. This is a medical emergency. The goal of therapy is treatment of hypotension, reversal of electrolyte abnormalities and glucocorticoid deficiency. Hypotension is treated with liberal infusion of 0.9% saline. Hydrocortisone 100 mg or dexamethasone 4 mg intravenously is started immediately after drawing blood for cortisol and ACTH analysis. Dexamethasone therapy is preferred initially as it does not interfere with the measurement of cortisol and it does not interfere with the synacthen stimulation test (for confirmation of the diagnosis). Intravenous fluids are maintained for 24-48 hours and hydrocortisone 100 mg is given every eight hours for the first 24 hours. The latter is then tapered to a replacement dose over the next 24-48 hours and fludrocortisone replacement started. Once adrenal damage manifests as a clinically diagnosed adrenal insufficiency, a 90% destruction of both adrenal glands has occurred and this is usually irreversible (Bhatia et al. 1998). However case reports do document recovery, even after a prolonged period indicating that, it may be appropriate to re-evaluate adrenal function after therapy (Penrice and Nussey 1992). Although rifampicin therapy is known to unmask underlying adrenal insufficiency (Elansary and Earis 1983) it has no deleterious effects in the outcome of treatment (Barnes et al. 1989).

42.2.7.2 Illustrative Case Report

Fig. 42.4. Abdominal plain radiograph demonstrating bilateral suprarenal gland calcification (arrowheads)

A 50 year-old female presented with several months history of productive cough, fever and weight loss. A diagnosis of pulmonary IB was made based on a representative chest radiograph, sputum smear positive for acid-fast bacilli (AFB) and positive culture.

Endocrine and Metabolic Manifestations of Tuberculosis

Her biochemistry at that time was unremarkable. She was started on a four-drug regimen with isoniazid (INH), rifampicin, pyrazinamide and ethambutol. A few days later she developed a generalized skin rash. All medications were stopped and later introduced individually in low dosage. She redeveloped rash with both pyrazinamide and ethambutol. She was thus treated with INH and rifampicin. Six months later she presented to the emergency room with altered consciousness. She had been experiencing poor appetite, increasing pigmentation, general fatigue and dizzy spells for the past several weeks. She was hypotensive and pigmented. Her glucose on arrival was 1.6 mmolll, serum Na+ 116 mmolll, K+ 6.7 mmolll. Her basal cortisol was 87 nmolll and failed to respond to IV 250 flg of synacthen (30 and 60 minute samples 75 and 84 nmolll respectively). The CT of her adrenals is shown in Fig. 42.3, which is classical of multiple abscesses. Adrenal auto-antibodies were negative. She responded well to IV hydrocortisone and hydration with 0.9% saline. She has since been maintained on hydrocortisone and fludrocortisone. Her follow-up CT scans showed progressive shrinkage with no calcification. She has permanent primary adrenal insufficiency. 42.2.1.3

Subclinical Tuberculous Adrenalitis and Related Controversies Whereas PAl secondary to tuberculosis is an established entity, debate rages on the existence and significance of subclinical adrenal disease during screening of patients with active tuberculosis. Certain caveats, however, need to be addressed to understand this controversy. In systemic tuberculosis, as in other systemic illnesses, there is adrenal stimulation as a result of increased activation of the hypothalamic-pituitary axis. Mycobacterium cell-wall components cause a release of cytokines such as Ill, IL6 and TNF alpha, all of which stimulate the release of CRH/ACTH resulting in an increase in serum cortisol levels (Habib et al. 2001; Fukata et al. 1993; Spangelo 1994; Zhang et al. 1993). This stimulation can result in hyperplasia of the adrenal glands to the extent that they may appear enlarged on CT scans (Gulmez et al. 1996). The levels of serum cortisol and adrenal response to exogenous ACTH vary depending upon the degree of stress, chronicity of illness, malnutrition, drug therapy and adaptation to stress. Basal cortisol levels are higher and often elevated (Barnes et al.1989; Chan et al.1993). There may be loss of the diurnal variation ofserum cortisol concentration (Sarma et al. 1990; York et al. 1992) and the cortisol

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levels are higher in acute and miliary disease than in chronic TB (Barnes et al. 1989). Adrenal inflammation in tuberculosis if significant, is associated with abnormal hormonal reserve with varying degrees of dysfunction. The most commonly applied test to assess adrenal reserve has been the measurement of cortisol response to 250 flg of synacthen (a synthetic form of ACTH). Application of this test in screening for the presence of subclinical disease in patients admitted with active pulmonary or extrapulmonary tuberculosis is a major source of this debate. The abnormal response rate has varied from 0-55% (Barnes et al. 1989; Ellis and Tayoub 1986; Kelestimur et al. 1994; Keven et al. 1998; Post et al. 1994; Prasad et al. 2000; Sarma et al. 1990; Siddiqi et al. 1997). The major reason for this difference is the diagnostic criteria used in these studies. The criteria used after synacthen stimulation have been either a peak cortisol response of 200-300 nmolll above baseline or an absolute value of 550 nmolll at any time during the test. Using the first criterion the frequency of abnormality has been between 30-55% (Ellis and Tayoub 1986; Prasad et al. 2000; Sarma et al. 1990; Siddiqi et al. 1997). However if basal values are already high then the absolute increase post ACTH is likely to be lower because of an already near maximal endogenous stimulation of the adrenals (Chan et al. 1993; Patel et al.1991). Thus studies using a threshold value of 550 nmolll during the test, which is presently favored, show a frequency of 0% (Chan et al. 1993; Kelestimur et al. 1994; Post et al. 1994). Other confounding factors in these studies are the duration and extent of disease, which may also have a bearing on the adrenal response to ACTH stimulation (Barnes et al. 1989; Sarma et al. 1990). Rifampicin an inducer of cytochrome P450 microsomal enzymes increases cortisol catabolism, some reports suggest a reduced response to Synacthen with the use of rifampicin further complicating the issue (Ellis and Tayoub 1986). Alternatively ACTH levels have been used as a measure of detecting early adrenal dysfunction. Reduction in adrenal reserve causes a decrease in circulating free cortisol levels, which by interrupting the negative feedback on the hypothalamic-pituitary unit results in a rise in ACTH levels. Whereas this test has been shown to be very sensitive in picking up both subclinical and established adrenal insufficiency, its application has been unable to clarify the controversy. This is due to the fact that systemic illness itself alters ACTH levels. The study by Post et al. (1994) clearly shows the limitation of this test in systemic tuberculosis. It is possible that the difference in the prevalence of abnormal adrenal reserve following stimulation with

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Synacthen, could be solely explained by the use of different diagnostic criteria, yet some patients do show abnormal responses even when using more stringent criteria (Barnes et al. 1989; Prasad et al. 2000). This could represent a subtle adrenalitis or a functional defect in cortisol secretion related to the effect of illness. The latter has been demonstrated in septic shock (Rothwell et al. 1991). Improvement of the cortisol response after treatment using the same criteria tends to support these possibilities (Barnes et al. 1989; Chan et al. 1993). The fact that subtle tuberculous adrenalitis does occur has been shown histologically. In the autopsy series by Slavin adrenal seeding was seen in 53% of their cases whereas only one patient had clinical adrenal insufficiency (Slavin et al. 1980). In a recent report by Chan et al., none of three patients who died of active pulmonary TB with bilateral adrenal granulomata at autopsy (and who had also had a synacthen stimulation test available), had cortisol deficiency (Chan et al. 1993). Thus at least in acute pulmonary TB, tuberculous adrenalitis may occur but is usually not associated with PAL The blunted increase poststimulation with synacthen is related to an already maximally stimulated adrenal gland with high basal cortisol levels. Things may be different in chronic disease as PAl usually presents years later. In order to address this controversy Kelestimur has recently reported on the assessment of adrenal reserve using the Imcg synacthen test in active pulmonary tuberculosis (Kelestimur et al. 2000). This test uses a low dose of ACTH, which causes a submaximal stimulation and more suited to pick up subtle abnormalities in adrenal hormonal reserve. They showed normal adrenal reserve in all their patients and no advantage over the standard 250 mcg synacthen test. Thus the diagnosis of PAl due to tuberculous requires a clearly abnormal response to synacthen. Subtle adrenalitis does occur but it may not be of clinical significance when treated early. Although a high level of suspicion for this life threatening complication should be maintained, routine screening for abnormal adrenal reserve is not recommended. If such screening is attempted it should be only done as a part of clinical studies using more stringent and uniform criteria. The implications of subtle abnormalities of adrenal reserve in tuberculosis remain unclear.

42.2.2 Thyroid Tuberculosis The first report of tuberculous thyroid involvement was by Lebert in 1862. Clinical thyroid tuberculosis

S. Inam and M. Al-Shahed

(TT) is very rare. In thyroid surgical specimens Rankin reported tuberculous thyroiditis in 0.1% of 20,758 specimens examined at the Mayo clinic (Rankin and Graham 1932) and Levitt reported two cases amongst 2114 consecutive thyroidectomy specimens (Levitt 1952). Slavin reported a 14% seeding of the thyroid gland in an autopsy series of selected patients in the pre- and post-antibiotic eras (Slavin et al. 1980). In the largest single clinical series of 18 cases diagnosed by fine needle aspiration (FNA) with demonstrable AFB, Mondal reported an incidence of 1.15% amongst 1565 thyroid FNAs (Mondal and Patra 1995). Tuberculous involvement of the thyroid gland can occur from hematogenous seeding or from contagious spread from an adjacent afflicted lymph node. TT secondary to congenital transmission in infants of mothers with untreated tuberculosis has also been reported (Kang and Chi 1990). The thyroid gland has an extensive blood supply and hematogenous spread would not be unusual, yet clinical tuberculosis of the thyroid gland is rare. Tuberculosis causes the formation of epitheloid granulomas with central caseation necrosis, Langhans' giant cells and peripherallymphocyte cuffing (Kapoor et al. 1985). TT can present in two forms. 1) As part of miliary tuberculosis, which rarely gives rise to clinical disease or 2) As a goiter due to caseous tuberculosis (Barnes and Weatherstone 1979). The commonest clinical presentation is that of a thyroid nodule or mass often mimicking a carcinoma (Khan et al. 1993; Tan 1993; Takami and Kozakai 1994). Less commonly the patient presents as a cold abscess (Surer et al. 2000) or a diffuse goiter (Barnes and Weatherstone 1979). In a review of the literature of TT in Japan in 63.6% of 44 cases the clinical diagnosis was that of a thyroid tumor (Takami and Kozakai 1994). Pressure on the adjacent structures may cause symptoms of dysphagia, dysphonia, dyspnea and at times laryngeal nerve palsy (Berger et al. 1983). Patients may also present with symptoms mimicking subacute thyroiditis (Berger et al. 1983; Sachs et al. 1988). However in TT pain, tenderness and fever are less common than in patients with bacterial thyroiditis and the presentation more indolent (Berger et al. 1983). TT is usually associated with TB elsewhere, occasionally though it may be the sole manifestation of the disease (Mondal and Patra 1995) and occasionally the disease is found incidentally in a surgical specimen (Kapoor et al. 1985). Most patients with TT are euthyroid. Infrequently the patient may present because of abnormal thyroid hormone function. Both primary hypothyroidism secondary to extensive damage (Barnes and Weather-

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stone 1979) and thyrotoxicosis due to a subacute thyroiditis (Berger et al. 1983; Nieuwland et al.1992) have been described. Abnormalities in circulating thyroid hormones in TB are more commonly due to the effect of systemic disease - the sick euthyroid syndrome. This is characterized by a normal or low free T4 (FT4), reduced levels of T3, increase in RT3 (reverse T3) and a normal or low TSH. These abnormalities reverse with treatment ofTB (Chow et al.1995). The diagnosis ofTT can be made if there is a strong clinical suspicion especially in the presence of extrathyroidal TB. Ultrasound of the thyroid is imprecise. It may show a thyroid mass, heterogeneous thyroid texture, abscess formation or fibrocalcific disease (Kang et al. 2000). CT of the thyroid may be highly suggestive if it shows nodules with centrallow-attenuation and peripheral ring enhancement (Moon et al. 1997; Kang et al. 2000). Thickening due to inflammation of the neighboring muscles, subcutaneous tissue and skin may also be seen and is termed the 'dermal sign'. Cervical lymphadenopathy is commonly present. Radionuclide thyroid scans show focal, or diffuse, diminished uptake in the affected tissue (Mondal and Patra 1995). Histological diagnosis is required for final confirmation. Recent reports document the efficacy of FNA of the thyroid in the diagnosis of TT. The presence of caseating granulomas is highly suggestive and surgery can be avoided. Additionally thyroid aspiration may also yield AFB on smear or culture (Das et al. 1992; Mondal and Patra 1995). Mondal reported positive AFB on smear in 12 cases and positive cultures in 14 of 18 cases diagnosed using FNA. This high yield may relate to the rich blood supply and consequent higher oxygen concentration available in thyroid tissue. Other granulomatous disorders such as subacute granulomatous thyroiditis (de Quervain's thyroiditis), sarcoidosis and syphilis need to be considered in the differential diagnosis. The type of granulomas and presence of caseation necrosis help in differentiation. Demonstration of AFB and positive culture of course confirm the diagnosis. TT is rare, however it should be considered in the evaluation of a cold nodule in endemic areas especially in the presence of cervical lymphadenopathy. Radiology is of limited value except where a CT scan shows an area of central necrosis with ring enhancement. FNA of the thyroid is the diagnostic tool of choice. If the cytology shows caseation necrosis, or pus, then smears should be stained for AFB and aspirate sent for appropriate culture. FNA of associated enlarged lymph nodes is likely to greatly increase the diagnostic yield. A surgical biopsy should be limited only to doubtful cases.

The optimal treatment of this rare condition remains undetermined. Anti-TB therapy alone, surgical excision or drainage with anti-TB therapy have all been advocated. Although the literature often recommends a combination of surgery and anti-tuberculous chemotherapy (Berger et al. 1983), this is because some form of surgery has often been required for diagnosis (Khan et al. 1993; Sachs et al. 1988; Takami and Kozakai 1994; Tan 1993). In the absence of an abscess anti-TB therapy alone should suffice (Kang et al. 2000; Mondal and Patra 1995). The duration of therapy should be six months using standard drug regimens. The associated abnormality of thyroid function when present needs additional therapy. Hypothyroidism appears to be permanent and requires long-term replacement therapy with thyroxine, except when it occurs as a part of subacute thyroiditis (Barnes and Weatherstone 1979). On the other hand, the treatment of thyrotoxicosis is less well established and would follow that of other causes of subacute thyroiditis, i.e. beta-blockers, pain relief and treating the underlying condition (Berger et al. 1983; Nieuwland et al. 1992). Corticosteroids could be used in severe cases after starting anti-TB therapy. Anti-tuberculous chemotherapy may also affect the thyroid. Treatment with para-aminosalicylic acid and ethionamide has been associated with goiter as they have actions similar to propylthiouracil; these drugs are rarely used in modern practice. Rifampicin may enhance extrathyroidal metabolism of thyroid hormones (Christensen et al. 1989), this does not seem to be of clinical importance. 42.2.2.1 Illustrative Case Report

A 17 year-old male presented with a two month history of fever, weight loss, headache and a painful neck swelling. He had clinical signs of thyrotoxicosis and a diffuse non-tender firm goiter on examination. Another smaller swelling was palpable in the left supraclavicular fossa. His FT4 50 pmolll (N 11-23), TSH <0.02 mUll, thyroglobulin 262 Ilgl1 (N 0-55), ESR 60 mmllst hour and thyroid antibodies were negative. An ultrasound of the neck revealed an enlarged thyroid with non-homogeneous architecture and several enlarged cervical lymph nodes with necrotic centers. An isotopic thyroid scan showed a very low thyroidal uptake suggestive of subacute thyroiditis. An FNA of the lymph node showed granulomatous inflammation whereas the thyroid aspirate was consistent with acute inflammation. AFB smears were negative but the aspirates from both the lymph

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node and thyroid grew Mycobacterium tuberculosis on culture, fully sensitive to first line anti-tuberculous drugs. The patient was commenced on rifampicin, INH, pyrazinamide and pyridoxine. Thyrotoxicosis was treated with beta-blockers. His sequential thyroid function tests showed a classical picture of recovery from thyroiditis with the TSH rising to 60 mUll before gradually returning to normal. He has put on 4 Kg in weight and is doing well.

42.2.3 Pituitary Tuberculosis Intracranial tuberculomas constitute 0.15-4% of intracranial space occupying lesions (DeAngelis 1981; Mauruce-Williams 1972). In the developing countries with poor socio-economic conditions they may still account for 15-30% of neurosurgical cases (Basaria et al. 2000; Esposito et al. 1987). Pituitary tuberculosis is extremely rare. Coleman and Meredith reported the first case of intrasellar tuberculoma in the English literature in 1940. Since, there have been 36 cases reported in the English literature. The disease is more common in females, which account for over 70% of the cases (Ashkan et al. 1977; Ranjan and Chandy 1994; Sharma et al. 2000). An autopsy series of 14,160 specimens in the pre-antibiotic era over 11 years yielded only two cases (Kirshbaum and Levy 1941) and Slavin reported a 4% incidence of pituitary involvement in a select group of patients with late generalized tuberculosis (Slavin et al.I980). The largest clinical series is that by Sharma et al. of 18 cases collected over a IS-year period (Sharma et al. 2000). Intrasellar tuberculomas have also been reported along with another pituitary tumor (Gazioglu et al. 1999; Sharma et al. 2000, 2001). Pituitary involvement results from either seeding during initial hematogenous dissemination with subsequent activation or direct extension from adjacent structures such as the sphenoid sinus, brain and meninges. Any part of the pituitary gland (anterior, posterior, and stalk) or the hypothalamus may be involved. The presentation often occurs in isolation although it can occur in association with tuberculous meningitis, or as part of miliary TB. The clinical presentation is that of a non-functioning pituitary tumor with headache being the most prominent and commonest manifestation. Vomiting and fever may be present. Compression of the pituitary and its stalk leads to varying degrees of hypopituitarism, hyperprolactinemia and diabetes insipidus. Reduced growth hormone and gonadotropins are the common-

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est hormone deficiencies. Pressure on the optic chiasm can lead to visual field disturbances and extension into the cavernous sinus causes cranial nerve (oculomotor and abducent) palsies. However there may be no endocrine abnormality present at diagnosis (Sharma et al. 2000). Sinha reported absence of endocrine dysfunction in 71.4% of the cases they reviewed (Sinha et al. 2000). Systemic features are usually absent though a raised ESR has been described in several reports (Patankar et al. 2000; Petrossians et al. 1998). The diagnosis is based on suggestive radiology, surgical findings and demonstration of granulomas consistent with TB at histology. Demonstration of TB bacilli in pituitary tissue or culture is confirmatory. The presence of active TB at another site especially the CSF would be highly suggestive although, abnormal CSF alone can be seen in other types of granulomatous hypophysitis and even in lymphocytic hypophysitis (Cheung et al. 2001). Concomitant active TB has been reported in only two cases (one lymph node, one CSF) where as a history of previously treated TB is described in nine cases. Thus in the vast majority intrasellar tuberculoma is the only manifestation of TB. The radiological features help in pointing to the nature of the lesion (Ashkan et al. 1977; Patankar et al. 2000; Ranjan and Chandy 1994; Sharma et al. 2000; Sinha et al. 2000). This is important as differentiating these lesions from those due to pituitary adenomas can avoid surgery. Plain film skull radiographs may show sellar or suprasellar calcification. Typically CT scan shows an isointense lesion with diffuse, intense enhancement with contrast. The latter can be so marked that the appearance is similar to that of an aneurysm. Less commonly the lesion is hypointense with enhancement of the margins. MRI is the modality of choice. MRI shows a mass which is isointenselhypointense compared to the brain on Tl weighted images (Tl WI), variably hyperintense on T2 weighted images (T2WI) (which enhances with gadolinium contrast). The enhancement pattern may be diffuse or show areas of low intensity within (Fig. 42.5). Thickening of the pituitary stalk when present is highly suggestive (Pereira et al. 1995; Sinha et al. 2000). However these features are shared with other forms of granulomatous and lymphocytic hypophysitis (Buxton and Robertson 2001; Cheung et al. 2001). Recently a report by Shimizu et al. has suggested that Gallium-67 scanning may help to differentiate these inflammatory lesions from adenomatous pituitary tumors (Shimizu et al. 1998). The surgical findings always show dural thickening, intrapituitary fibrosis, and yellow-gray tissue

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Endocrine and Metabolic Manifestations of Tuberculosis

b

a

Fig. 42.5a, b. MRI of the pituitary gland. a T1 weighted coronal image demonstrates enlargement of the pituitary gland (straight arrow). The enlarged gland appears hypointense to the adjacent brain tissue. b Post-enhanced (gadolinium) coronal T1 image shows diffuse and intense enhancement of the pituitary gland

(curved arrow)

that is difficult to remove. The tissue is usually avascular (Ashkan et al. 1977; Ranjan and Chandy 1994; Sharma et al. 2000; Sinha et al. 2000). Histological findings are those of epitheloid granulomas with central caseation necrosis, Langhans' giant cells and peripheral lymphocyte cuffing. There is varying degree of inflammation, destruction and fibrosis of the normal pituitary tissue. The definitive diagnosis requires demonstration of AFB in the specimen or on culture. This is exceedingly rare and only one case has had positive TB culture from pituitary tissue (Patankar et al. 2000) and another two had demonstrable AFB in the surgical specimen (Basaria et al. 2000; Sinha et al. 2000). Whereas Ziehl Neelsen stain for AFB has been reported in most series the tissue has been rarely sent for culture due to an initial diagnosis of pituitary tumor. In a recently reported case a positive PCR for TB from the pituitary tissue was used for diagnosis (Petrossians et al. 1998). The differential diagnosis is that of granulomatous hypophysitis which is an increasingly described entity (Buxton and Robertson 2001; Cheung et al. 2001). The granulomatous inflammation in this condition can be primary (idiopathic/autoimmune) or secondary to conditions such as TB, fungal infections, sarcoidosis, Wagner's granulomatosis, syphilis, histiocytosis and Crohn's disease. Thus the presence of granuloma alone on histology is not diagnostic of TB. The presence of caseating necrosis along with epitheloid cells and Langhans giant cells is highly

suggestive of TB in the absence of other causes of a necrotising granulomatous inflammation. Of the 36 cases reported in the English literature only 18 have documented the presence of caseation necrosis. Other reports have either documented no caseation or failed to describe it casting some uncertainty about the diagnosis. The diagnosis of pituitary tuberculoma should be suspected in young females presenting with a nonfunctioning pituitary mass in which the radiology is suggestive and confirmed by trans-sphenoidal biopsy unless there is active TB elsewhere. The transsphenoidal surgical approach is preferred as it avoids opening the CSF space and bacterial seeding of the meninges. Caseation necrosis with epitheloid granulomas and Langhans giant cells are highly suggestive of tuberculosis. Demonstration of TB bacilli on staining or culture would be diagnostic. The role of PCR in the diagnosis of pituitary TB remains unclear. The treatment consists of anti-tuberculous therapy. It should be started soon after surgery to avoid TB meningitis. The exact duration of therapy remains unproven, based on the recommendation for intracranial tuberculomas therapy duration of 9-18 months has been used in the cases reported (Ashkan et al. 1977; Ranjan and Chandy 1994; Sharma et al. 2000; Sinha et al. 2000). A 12 month course of therapy based on the recommendations for meningeal and disseminated TB however would suffice (Horsburgh et al. 2000). Resolution of the lesion is usually seen at six months. Use of addi-

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tional corticosteroids does not seem to give any extra advantage over anti-tuberculous therapy alone in most cases. Primary granulomatous hypophysitis results in resolution of the pituitary mass with time, whether spontaneous or in response to steroids, thus resolution with anti-TB therapy alone should not be considered diagnostic. Recovery of pituitary function in tuberculous hypophysitis appears to be common (Sinha et al. 2000), this is in contrast to that of tuberculous adrenal involvement. Such recovery may be complete or partial. Persistent hypopituitarism however may result (Ranjan and Chandy 1994). Hypopituitarism has also been described as a sequel to TB meningitis in childhood (Haslam et al. 1969; Lam et al. 1993; Sherman et al. 1971). This is most probably a result of hypothalamic damage. Lam et al. (1993) reported in a subset of 49 patients with TB meningitis in childhood that 20% had some abnormality of pituitary function on stimulation testing. The study was compromised by its retrospective nature and by the fact that only 49 of 246 patients were available for evaluation. Growth hormone deficiency was the most common sequel followed by gonadotropin deficiency. MRI performed in 10 affected patients showed a normal pituitary in seven. Pituitary atrophy, enhanceable tissue in the suprasellar cistern, hypothalamus or pituitary stalk and dilatation of the third ventricle were the abnormalities seen. Central precocious puberty has also been described in patients with a history of tuberculous meningitis. Desai et al. have reported a history of tuberculous meningitis in 37% of girls and 27% of boys with central precocious puberty (Desai et al. 1993).

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chiasm. The lesion was isointense on T1 WI, variably hyperintense on T2WI with diffuse enhancement following gadolinium contrast (Fig. 42.5). There was no other abnormality seen in the brain or meninges. Trans-sphenoidal surgery was performed which showed a very thickened dura, a firm fibrous yellow-gray lesion that was difficult to excise. Histopathology confirmed granulomatous inflammation with caseation necrosis (Fig. 42.6). Stains for AFB and fungi (PAS) were negative. No tissue was sent for TB culture. CSF examination and CT scan of the chest were normal. ESR 41, CRP 20 (0-6), ACE 39 (11-127). The patient has been treated with a standard four-drug regimen for TB, with a plan to continue for 12 months. Three months after commencing treatment her FT4, TSH, PRL returned to normal and a repeat MRI showed marked regression of the pituitary lesion.

42.2.4 Parathyroid Tuberculosis Involvement of the parathyroid glands can occur through hematogenous spread or from an adjacent affected structure. Clinical disease is extremely rare. In a recent case report, Kar et al. documented the presence of epitheloid granulomas in a parathyroid adenoma. Whereas AFB smear and culture were negative, a PCR for Mycobacterium tuberculosis from the parathyroid tumor homogenate was positive. The patient also had granulomatous lymphadenitis (Kar et al. 2001).

42.2.3.1

Illustrative Case Report A 29 year mother of three presented with progressive headache of six months duration. The headache was like pressure deep and behind the eyes. Two weeks prior to presentation the headaches became worse and were associated with diplopia. She had a long history of irregular periods. Her first two pregnancies required bromocriptine therapy. Following the delivery of her last child she had taken four injections of medroxyprogesterone and remained amenorrheic for 18 months. On presentation she had a partial left third nerve palsy. FT4 6.1 pmolll (N 10-25), TSH 0.119 mUll, PRL 830, LH 0.4, Estradiol 76. An MRI showed a 1.6 cm pituitary tumor extending into the left cavernous sinus and the suprasellar cistern almost touching the optic

Fig.42.6. Histological section showing necrotizing granulomatous hypophysitis. Note the frequent multinucleated giant cells (arrowheads) and central necrosis (arrow). Residual acini of adenohypophysis are seen on the far left. (Hematoxylin and eosin, original magnification _40).

Endocrine and Metabolic Manifestations of Tuberculosis

42.3 Endocrine Perturbations Related to Systemic Tuberculosis 42.3.1 Hypercalcemia

Active TB has been well documented as a cause of hypercalcemia and hypercalciuria. It has been reported both in adults and children. The incidence of hypercalcemia varies from 0-50% in the literature (Abbasi et al. 1979; Fuss et al. 1988; Kelestimur et al. 1996; Roussos et al. 2001; Sharma 1981; Shek et al. 1990). The wide variation in the incidence of hypercalcemia between countries results from the difference in the intake of vitamin D and calcium and the variable amount of sun exposure (Chan 1997). Countries like the UK, Belgium and Saudi Arabia with low levels of vitamin D have a very low incidence of hypercalcemia (Anonymous 1981; Fuss et al. 1988; Taha et al. 1984). Similarly a report from Turkey failed to show an increase in calcium in patients with TB (Kelestimur et al. 1996). On the other hand the prevalence may be as high as 25% in Sweden and 50% in Australia (Chan 1997). In Hong Kong tuberculosis is the second commonest cause of hypercalcemia in hospitalized patients after malignancy (Shek et al. 1990). Other reasons for the differences in reporting relate to analytical methods, cut-off values used and failure to correct for protein binding, (hypoalbuminemia is especially common in these patients at presentation) (Morris et al. 1989; Roussos et al. 200!). The ionized calcium (free calcium) is more likely to be elevated since it is independent of protein binding. However in a recent report measurement of ionized calcium did not give added information over total calcium corrected for serum albumin (Roussos et al. 200!). Most patients with hypercalcemia have pulmonary tuberculosis, it has been less frequently associated with miliary infection, peritonitis and osteomyelitis (Chan et al. 1994; Lim et al. 1994). The mechanism of hypercalcemia is similar to that of other granulomatous disorders and results from increased production of 1,25 dihydroxycholecalciferol (1,25 (OHh D3 or calcitriol), the active form of vitamin D. Calcitriol levels are elevated in patients with tuberculosis compared to controls (Epstein et al. 1984; Peces and Alvarez 1987; Pouchot et al. 1993; Sharma 2000; Yang et al. 2000). Normally calcitriol is produced in the kidney and tightly regulated by PTH and phosphate levels. In granulomatous disorders there is an increased extra-renal production by mononuclear cells. This has been documented

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in vivo in anephric patients (Peces and Alvarez 1987; Pouchot et al. 1993; Gkonos et al. 1984) and in vitro from macrophages and T cells obtained from patients with tuberculosis (Cadranel et al. 1990). The major sites of production are the lung and lymph nodes. Elevated free calcitriol levels have also been documented in pleural fluid in patients with tuberculosis (Barnes et al. 1989). Macrophages possess the 1 alpha-hydroxylase enzyme which converts 25 OH D3 to its active form 1,25 (OHh D3. The local production of this metabolite enhances the ability of macrophages and monocytes to inhibit growth of mycobacteria and influences the granulomatous reaction (Cadranel et al. 1994; Crowle at al. 1989; Rook 1988; Sharma 2000). The antibacterial efficacy of pyrazinamide is also enhanced by vitamin D and its active metabolites (Crowle et al. 1989). Normally production of calcitriol by mononuclear cells is locally regulated, increasing levels of 1,25 (OHh D3 inhibit further production and increases its own degradation. If this process becomes unregulated then a systemic spill over of the active vitamin D metabolite occurs resulting in hypercalcemia. It has been shown that gamma interferon may be responsible for both induction of increased 1 alpha hydroxylase activity and inhibition of the negative feed back response to calcitriol. It may be one of the stimuli responsible for allowing continued production and decreased degradation of calcitriol (Dusso et al. 1997). Calcitriol causes hypercalcemia mainly from increased intestinal absorption of calcium. It also causes bone resorption. The parathyroid hormone levels are suppressed. Other mechanisms contributing to hypercalcemia in tuberculosis include an increased production of parathyroid hormone related peptide (PTHrP) at inflammatory sites and bone involvement in extensive tuberculosis (Roussos et al. 2001; Braman et al. 1973). The hypercalcemia may become more evident on exposure to vitamin D supplements, sunlight, increased calcium intake or if there is associated renal impairment (Abbasi et al. 1979; Fuss et al. 1988; Sharma 198!). The ability of the kidney to excrete large amounts of calcium is protective and may explain the mild degree of calcium elevation in tuberculosis. Thus renal impairment can contribute significantly to increase in serum calcium and result in severe hypercalcemia (Carroll 1987). As in sarcoidosis, hypercalciuria is more common than hypercalcemia and being vitamin D-related is seen mainly in the postabsorptive state (Martinez et al. 1993). The degree of hypercalcemia is usually mild, though severe hypercalcemia has been reported especially in association with miliary disease (Isaacs

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et al. 1987; Yang et al. 2000). Typically hypercalcemia is seen at presentation. However this may be masked by the associated hypoalbuminemia. Some reports have first noticed the condition one week to several months after start of therapy. This may relate to improved albumin levels, antigen stimulation by release of bacterial products, more sun exposure and improved nutrition. The latter could increase vitamin D and calcium in diet (Fuss et al. 1988; Sharma 1981). Renal impairment due to rifampicin-induced interstitial nephritis was responsible in one patient (Carroll 1987). Hypercalcemia is usually mild and asymptomatic. It is detected on routine biochemical tests. When levels are over 2.9 mmolll the patient may experience lethargy, anorexia, abdominal pain and vomiting. It may also contribute to impaired mental status in elderly individuals. The latter is especially likely to occur with levels in excess of 3.2 mmolll. Laboratory findings in addition to hypercalcemia show an elevated inorganic phosphate, suppressed PTH levels and high normal or high 1,25 (OHh D3 levels. The 24-hour urine calcium is elevated. Treatment of hypercalcemia usually consists of adequate hydration, reduced intake of calcium and vitamin D and anti-TB therapy. Vitamin D supplements should be avoided in these patients. If calcium intake is reduced then oxalate intake should also be lowered, to avoid increased oxalate absorption and renal stones. Anti-tuberculous therapy is associated with a drop in levels of calcitriol and serum calcium (Roussos et al. 2001; Yang et al. 2000). Rifampicin induces hepatic microsomal enzyme induction and increases catabolism of vitamin D, whereas isoniazid (INH) inhibits 1 alpha hydroxylase activity and reduces synthesis of calcitriol (Brodie et al. 1982; Davies et al. 1987; Fuss et al. 1988). Both these actions lead to a decrease in the levels of calcitriol and calcium and a consequent rise in PTH. In countries with low stores of vitamin D, anti-tuberculous therapy may not only prevent the development of hypercalcemia but may induce osteomalacia (Chan 1996; Shah et al. 1981). The above measures usually suffice in the management of this condition. Hypercalciuria also responds to anti-tuberculous therapy (Martinez et al. 1996). The activation of vitamin D is also inhibited by glucocorticoids, which can be used in more symptomatic or severe cases. A dose of 10-30 mg of prednisolone is sufficient in inhibiting this process and treat hypercalcemia (Sharma 2000). Alternatively ketoconazole (a cytochrome P450 inhibitor), which affects the I-alpha hydroxylase enzyme, can be effective in the management of this

S. lnam and M. Al-Shahed

condition (Saggese et al.1993).As in sarcoidosis both chloroquine and hydroxychloroquine are also effective in lowering calcium levels by inhibiting vitamin D activation (Sharma 2000). Bisphosphonates such as pamidronate, which act predominantly by inhibiting osteoclastic bone resorption are also effective as in other causes of vitamin D toxicity, substantiating the contribution of bone resorption in causing hypercalcemia (Isaacs et al. 1987). Severe hypercalcemia is rare and when it happens the therapy consists of aggressive fluid replacement, use of loop diuretics after adequate hydration, intravenous hydrocortisone and if required pamidronate or calcitonin may be used. Dialysis using a low calcium solution may be required if there is severe renal impairment or inability to control hypercalcemia.

42.3.2 Water and Sodium Balance in Tuberculosis Hyponatremia is a well-known manifestation of TB. It occurs in 10-60% of patients with active pulmonary TB (Chung and Hubbard 1969; Post et al. 1994; Morris et al. 1989). The condition occurs with a greater frequency in those with miliary disease and TB meningitis (Karandanis and Shulman 1976; Singh et al. 1994) and has also been described in tuberculous epididymo-orchitis (Motiwala et al. 1991). It is usually mild and related to systemic illness. Less frequently it is due to associated adrenal or pituitary insufficiency. Two processes are involved in its pathogenesis. The first and major mechanism of hyponatremia is altered excretion of water by the kidney due to release of arginine vasopressin (AVP). The levels of AVP when measured are usually elevated or inappropriately high to the degree of hypo-osmolality (Cotton et al. 1991, 1993; Hill et al. 1990; Rose and Post 2001; Usalan et al. 1998). Several mechanisms may be responsible for this. Some patients are intravascular volume depleted as a result of fever, poor intake, increased diaphoresis and increased GI loss causing appropriate secretion of AVP. The majority of patients however are euvolemic and the levels of AVP are inappropriate to the hypo-osmolality, consistent with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). SIADH in tuberculosis is due to the following pathogenetic mechanisms: (i) Excessive production of AVP or similar peptides from the hypothalamus or inflammatory tissue in response to pulmonary infection. The usual source of AVP is the hypothalamus

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and is most probably cytokine-induced, although Urine osmolality is inappropriately high for the other factors such as hypoxia and nausea may also serum osmolality and urine sodium is >40 mmol/l. playa part (Dreyfuss et al. 1988; Hill et al. 1990). Pro- To fulfill the diagnostic criteria for SIADH the patient duction in the involved tissue was shown by Vorherr should be euvolemic and there should be no adrenal, et al. (1970). They isolated bio-assayable AVP from pituitary or renal disease. In states of renal salt wastthe affected lung but not from the normal lung in ing there is volume depletion, urine sodium usually a patient with fatal pulmonary tuberculosis. (ii) A exceeds 100 mmolll and the plasma urea level is high. more common cause of the inappropriately elevated Elevated serum potassium should raise the possibillevels of AVP is altered osmoregulation because of ity of mineralocorticoid deficiency. a reset osmostat. Normally as the serum osmolalThe treatment of hyponatremia will depend on ity drops below 280-282 mosmollK AVP secretion its degree, symptoms and its cause. In the category is turned off, thus hypo-osmolality should result associated with impaired water excretion the degree in undetectable levels of AVP. In this condition the of hyponatremia is usually mild, self limiting and osmostat is set to switch of at an even lower level of asymptomatic. The hyponatremia corrects with osmolality, as a consequence AVP release continues treatment of the infection. Replacing volume in in spite of hypo-osmolality. This secretion can be depleted patients or restricting fluid in euvolemic turned off by further lowering the serum osmolality patients usually suffices. The aim being slow cor(such as by a water load), suggesting that osmo-regu- rection «10 mmol124 hours). In more severe cases lation is intact but set at a lower point. This explains of symptomatic SIADH with CNS dysfunction the the modest degree of hyponatremia in these patients, use of hypertonic saline or urea may be warranted which is usually stable. The cause for the lower reset (Decaux et al. 1980). In adults 3% saline 500 ml is of the osmostat is not well understood and is prob- given over 6-8 h. The aim is to raise the serum sodium ably mediated through cytokines, vagal stimulation by 6-10 mmolll as this is enough to reduce cerebral or other yet undefined mechanisms (Dreyfuss et al. edema and alleviate symptoms. This should be fol1988,1991; Hill et al.1990). lowed by fluid restriction. In this situation one should The second mechanism of hyponatremia is renal avoid increasing serum sodium by >12-15 mmol124 salt wasting. This occurs in the following settings: h or reaching an absolute value> 125 mmolll to avoid a) Mineralocorticoid deficiency secondary to tuber- osmotic demyelination. In renal salt wasting replacement with fluids and culous destruction of the adrenals. This can cause significant hyponatremia and should always be con- salt is necessary. Addition of mineralocorticoids sidered as a possibility in these patients (O'Rahilly is necessary in tuberculous Addison's disease (see 1985). b) Cerebral salt wasting (CSW) which can be above section on adrenal tuberculosis). In tubercuseen in TB meningitis. CSW occurs due to the pro- lous meningitis the situation is more complex. The duction of natriuretic substances and/or stimuli as a hyponatremia may be related to SIADH or CSw. Since result of cerebral injury and can cause severe hypo- the treatment of these two conditions is diametrically natremia. The natriuretic substances responsible are opposite extreme vigilance is required. In CSW there ANP (atrial natriuretic peptide) and other similar is volume depletion related to renal salt wasting and peptides of cerebral origin (Narotam et al. 1994; Ti et fluid restriction is deleterious. CSW should always al. 1998). The rennin-angiotensin system is usually be suspected if there is evidence of volume deplesuppressed. c) TB renal involvement can cause an tion, high urine output with a raised osmolality interstitial nephritis with impaired tubular function and urinary sodium in excess of 100 mmol/l. This and consequent renal salt wasting. is treated by aggressive fluid and salt replacement. A Most patients are asymptomatic as the hyponatre- central line is recommended to gauge fluid replacemia is usually mild and slow in onset. Serum sodium ment. Hypertonic saline (1.8%) may be necessary to levels <125 mmol/l may be associated with lethargy, replace the large amount of sodium loss. In severe anorexia and vomiting. Severe hyponatremia with cases fludrocortisone, a mineralocorticoid may be levels <120 mmolll especially if develops rapidly can required to reduce natriuresis (Sakarcan and Boclead to an impaired state of consciousness. However chini 1998). Fludrocortisone is started at a dose of 50 CNS disturbance is more likely to be related to intra- Jlg/day and titrated up to 200Jlg/day based on 24-h cranial infection. urine sodium and serum sodium values. The laboratory finding will depend on the pathoHypernatremia can also occur in tuberculosis genesis. In SIADH there is hyponatremia, hypo- though it is uncommon. It is due to excessive free water osmolality and normal to low urea in the plasma. loss from the kidneys secondary to diabetes insipidus

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(DI). DI may be central or nephrogenic. Central DI occurs in tuberculous meningitis due to hypothalamic injury with consequent AVP deficiency. Nephrogenic DI is secondary to tubulo-interstitial renal damage and is characterized by high AVP levels. The treatment for these conditions is similar to other causes of Dr. The initial therapy is directed towards the volume deficit. 0.9% saline is preferred initially in patients with significant volume depletion. Once adequate volume is achieved or in those who are not significantly volume depleted 0.45% saline can be used to replenish the remaining water deficit and slowly lower serum sodium towards normal. In central DI the hormone deficiency is replaced by DDAVP. In the nephrogenic form a thiazide diuretic or non-steroidal anti-inflammatory drug such as indomethacin may be effective.

42.3.3 Effect ofTuberculosis on Circulating Hormones The most common reason for an abnormality of circulating hormones in tuberculosis is the effect of systemic disease. These effects are mediated through malnutrition, changes in hormone binding proteins, altered peripheral metabolism of hormones and the effects of cytokines and other inflammatory mediators on the hypothalamic-pituitary axis. The adaptive response to illness is stereotypic and is characterized by provision of energy to essential organs, postponement of anabolism and activation of the immune response while protecting the host against the latter's deleterious biological effects. The hypothalamus regulates endocrine function, autonomic functions, temperature, appetite and weight to name a few. It is in turn influenced by impulses from higher centers, the autonomic nervous system, environmental factors and altered homeostasis. It plays a key role in the adaptive process to stress. It is thus no surprise that almost any significant systemic disease can alter its functions. These effects are mediated through inflammatory mediators related to infection, and injury, or neurotransmitters released by impulses from the higher centers. Considered teleologically the aim is to channel resources away from catabolic and non-essential functions. Systemic illness causes activation of the hypothalamic-pituitary-adrenal axis, suppression of the thyroid and gonadal axis and initially in increased growth hormone and prolactin secretion (Chorousos and Gold 1992; van den Berghe et al.1998). This results in minimal to marked alteration in hormonal secretion and target organ effect depending on the severity of illness.

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Tuberculosis is associated with hypogonadism in both males and females. Menstrual abnormalities are not uncommon. Typically levels of testosterone and estrogen are low and accompanied by inappropriate levels of LH, a picture of hypogonadotropic hypogonadism. In the report by Post et al. (l994) 73% of their male patients with active pulmonary tuberculosis had hypogonadotropic hypogonadism. The decrease in circulating hormones is not due to changes in sex hormone-binding globulin, as it is not significantly affected by critical illness (Luppa et al. 1991; Woolf et al.1985). The inflammatory cytokines release beta-endorphin, corticotropin releasing hormone (CRH) and cortisol, which cause reduced pulsatility and decreased secretion of gonadotropins (Chrousos and Gold 1992; Elenkov et al. 1999; Habib et al. 2001). Additionally there may also be alteration in the biological activity of gonadotropins (Semple et al. 1987). Similar abnormalities have been reported in other systemic illnesses and relate to their severity (Spratt et al. 1993). This type of functional hypothalamic disorder is reversible and has to be distinguished from that due to direct tuberculous damage of the hypothalamus or pituitary. Elevated levels of cortisol also interfere with the action of LH on the gonads, this occurs early in illness and results in reduced secretion of hormones from the gonads (Chrousos and Gold 1992). Rarely tuberculosis can cause direct damage to the gonads causing primary gonadal failure, this is characterized by high levels of gonadotropins. Alteration of thyroid function tests in systemic illness is termed the 'sick euthyroid' syndrome. This is characterized by normal to low levels of T4, reduced levels ofT3 and increase in levels of reverse T3 (RT3). Plasma levels of T4 are influenced by both a reduction in binding proteins (TBG, transthyretin and albumin) and an alteration in their ability to bind the hormone. The latter results from an alteration in the structure of TBG and the presence of circulating inhibitors of thyroid hormone binding such as free-fatty acids and bilirubin (Docter et al. 1993). These alterations interfere with most commercially available methods for FT4. In contrast measurement of FT4 by equilibrium dialysis gives normal or even elevated levels (Chopra et al. 1998). Levels of T3 are more likely to be reduced since 80% of T3 is produced peripherally from T4. Decreased peripheral production of this hormone results from the inhibition of the enzyme 5' -monodeiodonase. Inhibition of this enzyme is caused by decreased caloric intake, the effects of systemic illness through increased cortisol levels, elevated non-esterified free fatty acids, cyto-

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kines (TNF-alpha, Ill, IL6) related to inflammation and reduced transport of T4 across cell membranes (Utiger 1995). RT3 on the other hand is degraded by the same enzyme, which explains its elevation. In addition to peripheral events, another reason for reduced thyroid hormones is a form of transient central hypothyroidism secondary to hypothalamic effects of systemic illness. There is reduced TSH secretion and in severe illness there is loss of the nocturnal rise. Additionally there may be a decrease in the biological activity of TSH due to abnormal glycosylation (van den Berghe et al. 1998). The result is decreased stimulation of the thyroid and reduced production of thyroid hormones. The TSH levels are either normal or low and thus inappropriate for the level of T4. This form of central hypothyroidism is mediated by increased secretion of cortisol, CRH and dopamine (Habib et al. 2001; van den Berghe et al. 1998). The incidence of the sick euthyroid syndrome in tuberculosis ranges from 63-92% (Chow et al. 1995; Hill et al. 1995; Post et al. 1994). These alterations may serve as an indicator of severity of disease and predict mortality. The hormone levels return to normal in survivors within one month of therapy (Chow et al. 1995). Anti-tuberculous therapy is associated with an increase in TBG levels, an effect probably related to the hepatic effects of rifampicin (Hill et al. 1995). The pituitary-adrenal axis as discussed earlier is activated. Basal cortisol and 24-hour urine cortisol levels may be elevated. Like other causes of stress, nocturnal levels are high and there may be loss of diurnal variation. This is often associated with decreased suppression with dexamethasone. Mycobacterium tuberculosis cell-wall components cause release of cytokines such as Ill, IL6 and TNF alpha, which stimulate the release of CRH/ACTH resulting in "the above changes (Fukata et al. 1993; Spangelo 1994). Elevation of CRH and cortisol may be responsible for decreased secretion of gonadotropins, TSH and growth hormone as well as reduced responsiveness of their target organs during illness (Habib et a1.2001). Acute illness causes hypersecretion of growth hormone (GH) but in chronic illness GH levels are inhibited. This is presumably through increase in somatostatin, CRH and cortisol levels (Chrousos and Gold 1992; van den Berghe et al. 1998). The IGFI (Insulin-like growth factor 1) levels are reduced early in illness. The latter is produced by peripheral tissue in response to GH stimulation. Peripheral effects of cytokines, altered nutrition, excess cortisol and other effects of systemic infection are responsible for its

decreased production. In chronic illness inhibition of GH levels further contribute to decreased production ofIGFl. This accounts for reduced growth in children with active tuberculosis and contributes to the negative nitrogen balance. Prolactin is elevated in acute physical and psychological stress (van den Berghe et al. 1998). The elevations are usually modest and mediated by the vasoactive intestinal polypeptide, oxytocin and dopaminergic pathways (Reichlin 1993). There is likely to be an adaptation in chronic illness with a reduction in levels back to normal and a decrease in the pulsatile fraction. There has been no systemic study of prolactin in human tuberculosis in the English literature. Elevated prolactin levels are often seen in pituitary and hypothalamic tuberculosis and return to normal after adequate therapy (Sharma et al. 2000).

42.4 Tuberculosis and Diabetes Mellitus See chapter 7 on tuberculosis in special groups for more details. In brief the prevalence of tuberculosis amongst diabetics is 2-5 times higher than in the non-diabetic population (Kim et al. 1995; Opsald et al. 1961). The increase in risk is related to abnormalities of the immune cell function, impaired cytokine production, pulmonary microangiopathy and effects of non-enzymatic protein glycation on alveolar membrane and the pulmonary basal lamina (Koziel and Koziel 1995). These abnormalities are more pronounced in uncontrolled patients making them more susceptible. There is evidence in the literature to suggest that patients with TB have a higher prevalence of diabetes (Mugusi et al.1990). This may be partly related to the fact that in diabetic screening programs almost 50% of patients are found to be undiagnosed. There also appears to be an increased occurrence of impaired glucose tolerance in patients with TB based on the systematic use of the oral glucose tolerance test (Jawad et al. 1995; Mugusi et al. 1990). This has been shown to improve with therapy suggesting that it may represent infection-related stress though other factors such as poor carbohydrate intake and malnutrition may playa role. The clinical presentation is similar to non-diabetics. Involvement of the lower lobes, cavitary disease, multilobar involvement and pleural effusions are thought to be more common (Morris et al.1992; Perez-Guzman

766

et al.2000). This has not been borne out by more recent controlled studies (Bacakoglu et al. 2001). The treatment is similar to non-diabetics and the relapse rates are comparable. There is no major dissimilarity amongst different types of diabetics and the degree of control as regards treatment outcome. There is a report of an increased likelihood of drugresistant strains during relapse in these patients (Kameda et al. 1990).

42.5 Endocrine and Metabolic Effects of Anti-Tuberculous Drugs Rifampicin is a potent inducer of cytochrome P450 hepatic microsomal enzymes. This has a significant effect on steroid hormone metabolism. Cortisol metabolism is enhanced resulting in increased requirements, which has major clinical implications. In patients with subclinical adrenal insufficiency, the introduction of rifampicin can result in an acute adrenal crisis as the damaged adrenal is unable to meet the increased demand (Elansary and Earis 1983; Wilkins et al. 1989). This is seen within 2 weeks after starting therapy (Wilkins et al. 1989). In patients with established adrenal insufficiency an adrenal crisis can be precipitated unless the dose of glucocorticoids is increased (Edwards et al. 1974). (See section 42.2.1.1 above on the treatment of adrenal tuberculosis for details.) The effect on mineralocorticoids is less pronounced and there is no need to alter their dose (Schulte et al. 1987). It may also impair cortisol response to synacthen (Ellis and Tayoub 1986). Rifampicin increases catabolism of vitamin D to inactive metabolites, decreasing levels of both 25(OH)D3 and 1,25(OHhD3 (Brodie et al. 1982; Davies et al. 1987). This can cause a significant rise in PTH levels (Brodie et al. 1982) and in the presence of low vitamin D reserves lead to hypocalcaemia and even osteomalacia (Chan 1996; Shah et al. 1981). Rifampicin does increase extrathyroidal metabolism of thyroid hormones but this seems to be of no clinical significance (Christensen et al. 1989). It has also been reported to increase insulin requirements in type 1 diabetes mellitus. This was shown to be related to augmented intestinal absorption of glucose (Atkin et al. 1993). The major effect ofINH is on vitamin D metabolism. It inhibits 1 alpha hydroxylase activity and reduces synthesis of calcitriol (Brodie et al. 1982; Davies et al. 1987). In combination with rifampicin there are substantial decreases in the levels of both 25(OH)D3 and 1,25(OHhD3. PTH levels may rise by 57% (Brodie et al.

S. Inam and M. AI-Shahed

1982). Hypocalcaemia and osteomalacia may develop in the presence of marginal vitamin D stores (Chan 1996; Shah et al.198l).As vitamin D deficiency reduces the effect of PTH, anti-TB therapy can mask primary hyperparathyroidism (Kovacs et al.1994). Para-aminosalicylic acid (PAS) and ethionamide have effects similar to propylthiouracil on the thyroid. They inhibit synthesis of thyroid hormones and can lead to goiter and hypothyroidism (Munkner 1969). PAS has also been implicated as causing hypoglycemia (Dandona et al. 1980). Both these drugs are seldom used in modern day practice.

Acknowledgements. We would like to express our gratitude to Emeritus Professor David Price Evans for reviewing the manuscript and his valuable comments. We are also very grateful to Drs Fahd AISabaan and Fahd AI-Rabiah for allowing us to use their cases as illustrative case reports.

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767 Crowle AJ, Ross EJ, May MH (1987) Inhibition by 1,25 (OH)2 vitamin D3 of the multiplication of virulent tubercle bacilli in cultured human macrophage. Infect Immun 55:2945-2950 Crowle AJ, Salfinger M, May MH (1989) 1,25 (OH)2 vitamin D3 synergises with pyrazinamide to kill tubercle bacilli in cultured human macrophages. Am Rev Respir Dis 139: 549-52 Dandona P, Greenbury E, Beckett AG (1980) Para-aminosalicylic acid-induced hypoglycaemia in a patient with diabetic nephropathy. Postgrad Med J 56:135-136 Das DK, Pant CS, Chachra KL et aI (1992) Fine needle aspiration cytology diagnosis of tuberculous thyroiditis: a report of eight cases. Acta Cytol 36:517-522 Davies PD, Brown RC, Church HA et al (1987) The effect of antituberculous chemotherapy on vitamin D and calcium metabolism. Tubercle 38:261-266 DeAngelis LM (1981) Intracranial tuberculoma: case report and review of the literature. Neurology 31:1133-1136 Decaux G, Unger J, Mockel J (1980) Urea therapy for inappropriate antidiuretic hormone secretion from tuberculous meningitis. J Am Med Assoc 244:589-590 Desai M, Colaco MP, Choksi CS et al (1993) Isosexual precocity: the clinical and etiologic profile. Indian Pediatr 30: 607-623 Docter R, Krenning EP, de Jong M et aI (1993) The sick euthyroid syndrome: change in thyroid hormone serum parameters and hormone metabolism. Clin Endocrinol 39:499-518 Dreyfuss D, Leviel F, Paillard M et aI (1988) Acute infectious pneumonia is accompanied by latent vasopressin-dependent impairment of renal water excretion. Am Rev Respir Dis 138:583-589 Dreyfuss D, Leviel F, Paillard M et aI (1991) Resetting of the vasopressin osmostat during infectious pneumonia. Am J Med 90:407-408 Dusso AS, Kamimura S, Gollieni M et aI (1997) Gamma interferon induced resistance to 1,25 (OH)2 D3 in human monocytes and macrophages: a mechanism for the hypercalcemia of various granulomatoses. J Clin Endocrinol Metab 82:2222-2232 Edwards OM, Courtenay-Evans RJ, Galley JM et al (1974) Changes in cortisol metabolism following rifampicin therapy. Lancet 2:549-551 Elansary RH, Earis JE (1983) Rifampicin and adrenal crisis. Br Med J 286:1861-1862 Elenkov IJ, Webster EL, Torpy DJ et aI (1999) Stress, corticotropin-releasing hormone, glucocorticoids, and the immune/ inflammatory response: acute and chronic effects. Ann NY Acad Sci 876:1-11 Ellis ME, Tayoub F (1986) Adrenal function in tuberculosis. Br J Dis Chest 80:7-12 Epstein S, Stein PH, Bell NH et aI (1984) Evidence for abnormal regulation of circulating 1 alpha, 25 dihydroxy vitamin D in patients with pulmonary tuberculosis and normal serum calcium metabolism. Calcif Tissue Int 36:541-544 Esposito V, Fraioli B, Ferrante L et aI (1987) Intrasellar tuberculoma: case report. Neurosurgery 21;721-723 Fukata J, Imura H, Nakao K (1993) Cytokines as mediators in the regulation of the hypothalamic-pituitary-adrenocortical function. J Endocrinol Invest 16:141-155 Fuss M, Karmali R, Pepersack T et al (1988) Are tuberculous patients at a great risk from hypercalcemia? Quart J Med 69:869-878

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S. Inam and M. Al-Shahed Kelestimur F, Goktas Z, Gulmez I et al (2000) Low dose (1 mcg) adrenocorticotropin stimulation test in the evaluation of hypothalamo-pituitary-adrenal axis in patients with active pulmonary tuberculosis. J Endocrinol Invest 23:235-239 Keven K, Uysal AR, Erdogan G (1998) Adrenal function during tuberculous infection and effects of antituberculous treatment on endogenous and exogenous steroids. Int J Tuberc Lung Dis 2:419-424 Khan EM, Haque I, Pandey R et al (1993) Tuberculosis of the thyroid gland: a clinicopathological profile of four cases and review of the literature. Austr NZ J Surg 63:807-810 Kim SJ, Hong YP, Lew WJ et al (1995) Incidence of pulmonary tuberculosis among diabetics. Tuberc Lung Dis 76: 529-533 Kirshbaum JD, Levy HA (1941) Tuberculoma of hypophysis with insufficiency of anterior lobe: a clinical and pathological study of two cases. Arch Intern Med 68:1095-1104 Kovacs CS, Jones G, Yendt ER (1994) Primary hyperparathyroidism masked by antituberculous therapy-induced vitamin D deficiency. Clin EndocrinoI41:831-836 Koziel H, Koziel MJ (1995) Pulmonary complications of diabetes mellitus: pneumonia. Infect Dis Clin North Am 9: 65-96 Lam KSL, Sham MMK, Tam SCF et al (1993) Hypopituitarism after tuberculous meningitis in childhood. Ann Intern Med 118:701-706 Laureti S, Aubourg P, CalcinaroF et al (1998) Etiological diagnosis of primary adrenal insufficiency using an original flowchart of immune and biochemical markers. J Clin Endocrinol Metab 83:3163-3168 Levitt T (1952) The status oflymphadenoid goitre, Hashimoto's and Riedel's diseases. Ann R CoIl Surgeons 10:369-404 Lim SM, Tsai SL, Chan CS (1994) Hypercalcemia in tuberculous peritonitis without active pulmonary tuberculosis. Am J GastroenteroI89:2249-2250 Luppa P, Munker R, Nigel D et al (1991) Serum androgens in intensive-care patients: correlations with clinical findings. Clin EndocrinoI34:305-31O Martinez ME, Gonzalez J, Sanchez-Ceabezudo MJ et al (1993) Evidence of absorptive hypercalciuria in tuberculous patients. Calcif Tissue Int 53:384-387 Martinez ME, Gonzalez J, Sanchez Cabezulo MJ et al (1996) Remission of hypercalciuria in patients with tuberculosis after treatment. Calcif Tissue Int 59:17- 20 Mauruce-Williams RS (1972) Tuberculomas of the brain in Britain. J Postgrad Med 48:679-681 Mondal A, Patra MS (1995) Efficacy of fine needle aspiration cytology in the diagnosis of tuberculosis of the thyroid gland: a study of 18 cases. J Laryngol Otoll09:36-38 Moon WK, Han MH, Chang KH et al (1997) CT and MR imaging of head and neck tuberculosis. Radiographics 17:391-402 Morris CDW, Bird AR, Nell H (1989) The haematological and biochemical changes in severe pulmonary tuberculosis. Quart J Med 73:1151-1159 Morris JT, Seaworth BJ, McAllister CK (1992) Pulmonary tuberculosis in diabetics. Chest 102:539-541 Motiwala HG, Sanghvi NP, Barjatiya MK et al (1991) Syndrome of inappropriate antidiuretic hormone following tuberculous epididymo-orchitis in renal transplant recipient: case report. J Urol 146: 1366-1367 Mugusi F, Swai AB, Alberti KG et al (1990) Increased preva-

Endocrine and Metabolic Manifestations of Tuberculosis lence of diabetes mellitus in patients with pulmonary tuberculosis in Tanzania. Tubercle 71:271-276 Munkner T (1969) Studies on goitre due to para-aminosalicylic acid. Scand J Respir Dis 50:212-226 Narotam PK, Kemp M, Buck R et al (1994) Hyponatremic natriuretic syndrome in tuberculous meningitis: the probable role of atrial natriuretic peptide. Neurosurgery 34: 982-988 Nieuwland Y, Tan KY, Elte JW (1992) Miliary tuberculosis presenting with thyrotoxicosis. Postgrad Med J 68:677-679 Nomura K, Demura H, Saruta T (1994) Addison's disease in Japan: characteristics and changes revealed in a nationwide survey. Intern Med 33:602-606 O'Rahilly S (1985) Secretion of antidiuretic hormone in hyponatremia: not always "inappropriate". Br Med J 290: 1803-1804 Oelkers W (1996) Adrenal insufficiency. N Engl J Med 335: 1206-1212 Opsald R, Riddervald HO, Aas TW (1961) Pulmonary tuberculosis in mitral stenosis and diabetes. Acta Tuberc Scand 4:290 Patankar T, Patkar D, Bunting T et al (2000) Imaging in pituitary tuberculosis. J Clin Imaging 24:89-92 Patel SR, Selby C, Jeffcoate WJ (1991) The short synacthen test in acute hospital admissions. Clin Endocrinol 35:259-261 Peces R, Alvarez J (1987) Hypercalcemia and elevated 1,25(OH)zD3 levels in a dialysis patient with disseminated tuberculosis. Nephron 46:377-379 Penrice J, Nussey SS (1992) Recovery of adrenal function following treatment of tuberculous Addisons's disease. Postgrad Med J 68:204-205 Pereira J, Vaz R, Carvalho D et al (1995) Thickening of the pituitary stalk: a finding suggestive of intrasellar tuberculoma? Case report. Neurosurgery 36:1015-1015; discussion 1015-1016 Perez-Guzman C, Torres-Cruz A, Villarreal-Velarde H et al (2000) Progressive age-related changes in pulmonary tuberculosis images and the effect of diabetes. Am J Respir Crit Care Med 162:1738-1740 Petrossians P, Delvenne P, Flandroy P et al (1998) An unusual pituitary pathology. J Clin Endocrinol Metab 83:34543458 Post FA, Soule SG, Wilcox PA et al (1994) The spectrum of endocrine dysfunction in active pulmonary tuberculosis. Clin Endocrinol40:367-371 Pouchot J, Dreyfuss D, Gardin JP et al (1993) Ectopic production of 1,25-dihydroxyvitamin D3 in tuberculosis. Nephrol Dial Transplant 8:560-562 Prasad GA, Sharma SK, Mohan A et al (2000) Adrenocortical reserve and morphology in tuberculosis. Indian J Chest Dis Allied Sci 42:83-93 Ranjan A, Chandy M (1994) Intrasellar tuberculoma. Br J Neurosurg 8:179-185 Rankin FW, Graham AS (1932) Tuberculosis of the thyroid gland. Ann Surg 96:625-648 Rook GA (1988) The role of vitamin D in tuberculosis. Am Rev Respir Dis 138:768-770 Reichlin S (1993) Neuroendocrine-immune interactions. N Engl J Med 329:1246-1253 Rose BD, Post TW (2001) Clinical physiology of acid-base and electrolyte disorders, 5th edn. McGraw-Hill, New York, pp 729-733 Rothwell PM, Udwadia ZF, Lawler PG (1991) Cortisol response

769 to corticotrophin and survival in septic shock. Lancet 337: 582-583 Roussos A, Lagogianni I, Gonis A et al (2001) Hypercalcemia in Greek patients with tuberculosis before the initiation of anti-tuberculosis treatment. Respir Med 95: 187-190 Sachs MK, Dickinson G, Amazon K (1988) Tuberculosis adenitis of the thyroid mimicking subacute thyroiditis. Am J Med 85:573-575 Saggese G, Bertelloni S, Baroncelli GI et al (1993) Ketoconazole decreases the serum ionised calcium and 1,25-dihydroxyvitamin D levels in tuberculous-associated hypercalcemia. Am J Dis Child 147:270-273 Sakarcan A, Bocchini J (1998) The role of fiudrocortisone in a child with cerebral salt wasting. Pediatr Nephrol 12: 769-771 Sanford JP, Favour CB (1956) The interrelationships between Addison's disease and active tuberculosis: a review of 125 cases of Addison's disease. Ann Intern Med 45:56-72 Sarma GR, Immanuel C, Ramachandaran G et al (1990) Adrenal function in patients with pulmonary tuberculosis. Tubercle 71:277-282 Schulte HM, Monig H, Benker G et al (1987) Pharmacokinetics of aldosterone in patients with Addison's disease: effect of rifampicin treatment on glucocorticoid and mineralocorticoid metabolism. Clin Endocrinol 27:655-662 Semple CG, Gray CE, Beastall GH (1987) Male hypogonadism-a non-specific consequence of illness. Quart J Med 64:601-607 Shah SC, Sharma RK, Hemangini et al (1981) Rifampicin induced osteomalacia. Tubercle 62:207-209 Sharma MC, Arora R, Mahapatra AK et al (2000) Intrasellar tuberculoma - an enigmatic pituitary infection: a series of 18 cases. Clin Neurol Neurosurg 102:72-77 Sharma MC, Vaish S, Arora R et al (2001) Composite pituitary adenoma and intrasellar tuberculoma: report of a rare case. Pathol Oncol Res 7:74-76 Sharma OP (2000) Hypercalcemia in granulomatous disorders: a clinical review. Curr Opin Pulmon Med 6:442-447 Sharma SC (1981) Serum calcium in pulmonary tuberculosis. Postgrad Med J 57:694-696 Shek CC, Natkunam A, Tsang Vet al (1990) Incidence, causes and mechanism of hypercalcemia in a hospital population in Hong Kong. Quart J Med 77:1277-1285 Sherman BM, Gorden P, di Chiro G (1971) Postmeningitic selective hypopituitarism with suprasellar calcification. Arch Intern Med 128:600-604 Shimizu C, Kubo M, Kijima H et al (1998) Giant cell granulomatous hypophysitis with remarkable uptake on Gallium67 scintigraphy. Clin EndocrinoI49:131-134 Siddiqi S, Elahi HA, Hussain M et al (1997) Evaluation of adrenal function in long standing pulmonary tuberculosis: a study of 100 cases. J Pakistan Med Assoc 47:132-134 Singh BS; Patwari AK, Deb M (1994) Serum sodium and osmolal changes in tuberculous meningitis. Indian Pediatr 31:1345-1350 Sinha S, Singh AK, Tatke M (2000) Hypophyseal tuberculoma: Direct radiosurgery is contraindicated for a lesion with a thickened pituitary stalk: case report. Neurosurgery 46: 735-739 Slavin RE, Walsh TJ,PollackAD (1980) Late generalized tuberculosis: a clinical pathologic analysis and comparison of 100 cases in the preantibiotic and antibiotic eras. Medicine 59:352-366

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43 Tuberculous Vasculitis and Mycotic Aneurysms M. MONIR MADKOUR

CONTENTS 43.1 43.2 43.3 43.4 43.5 43.5.1 43.5.2 43.5.3 43.6 43.7

Introduction 771 Historical Aspects 771 Epidemiology 771 Pathogenesis 772 Clinical Features 773 Our Own Case Report 773 Surgical Findings (June 20, 1982) Successful Outcome of Surgery and Follow-up for 20 Years 776 Investigation 776 Treatment 776 References 777

774

come, complications (including relapses and fatalities) still occur (Atnip 1989; Chan 1989; Chiba et al. 1996; Hollier 1993; Ikezawa et al. 1996; Strand et al. 2001). The recent resurgence of tuberculosis that followed the HIV epidemic was associated with increasing reports of patients with tuberculous aneurysms and co-existing HIV (Bojar et al. 1998; Boggian et al. 1994; Gouny et al. 1992; Seelig et al. 1999). The use of BCG in recent years for adjuvant immunotherapy of bladder carcinoma has been reported to cause tuberculous aneurysms (Hakim et al. 1993; Seelig et al. 1999; Wolf et al.1995; Rozenblit et al. 1996).

43.1 Introduction

43.2 Historical Aspects

Mycotic aneurysms (or more properly 'infected aneurysms') are rare. They were first described by Sir William Osler, an Oxford physician born in 1849. The word 'mycotic' that he used came from their resemblance to fungal growth. Osler described a patient with multiple beadlike aneurysms caused by a supportive infection of the vessel wall. Despite its rarity, the greatest incidence of mycotic aneurysms is found in patients with infective endocarditis due to Staphylococcus aureus and Streptococcus viridans. Other organisms are also capable of inducing mycotic aneurysms including M. tuberculosis and Brucella melitensis (Madkour 2001). Tuberculous mycotic aneurysms are rare but carry a high mortality rate due to perforation, or rupture, with massive hemorrhage and shock (Golzarian et al. 1999; de Kruijf et al. 2000; Ito et al. 1992; Yo et al. 1993; Zhang et al. 1994). The diagnosis may only be found when an autopsy is carried out. Despite the recent advances in diagnostic techniques, potent anti-tuberculous agents and successful surgical-treatment out-

In the pre-antibiotic era, with limited imaging capabilities, the diagnosis of tuberculous aneurysms was made as an autopsy finding. Tuberculous aneurysm of the aorta was first reported by Kamen in 1895 and femoral artery tuberculous aneurysms were first reported in 1933 by Baumgarten and Cantor (Baumgarten et al. 1933). Surgical attempts to repair tuberculous aneurysms of the abdominal aorta was first reported by Herndon and colleagues in 1952. It was not successful and the patient died six days after the operation from massive gastrointestinal bleeding. The first successful excision of tuberculous aneurysms of the abdominal aorta was reported by Rob and Eastcott in 1955. Four years later successful resection of a tuberculous aneurysm in the thoracic aorta was reported by de Prophetis and colleagues in 1959. The association between tuberculous aortitis and military tuberculosis was first described by Weigert in 1882.

M. M. MADKOUR, MD, DM, FRCP Consultant, Department of Medicine, Riyadh Armed Forces Hospital, P.O. Box 7897, C-119, Riyadh 11159, Saudi Arabia

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

43.3 Epidemiology Before antibiotics became available the incidence of tuberculous mycotic aneurysms was estimated to be 0.3% from more than 22,000 autopsies reported

772

by Parkhurst and Deckerin in 1955 (Parkhurst et al. 1955). Slavin and colleagues (1990) reported a series of 100 autopsies with confirmed late-generalized tuberculosis, only one instance of tuberculous aortitis was found. Few authors have reviewed the literature in an attempt to identify special clinical, or diagnostic, patterns that could help in predicting its occurrence in patients before its diagnosis at autopsy. In 1913 and 1933 reviews concluded that tuberculous mycotic aneurysms of the aorta had been recognized but were rare. In a recent review from the English literature, only 39 cases were found over a period of 53 years (1945-1998) (Long et al.1999). The authors also described two patients of their own and concluded that the prevalence has remained relatively constant. The recent resurgence of tuberculosis that followed the HIV epidemic was expected to be associated with more reports of tuberculous and mycotic aneurysms. There are four reports of single cases each from USA, Germany and France of young males in their early thirties with HIV and tuberculous mycotic aneurysms of the aorta (Bojar et al. 1998; Boggian et al. 1994; Gouny et al. 1992; Seelig et al. 1999). In a review of the literature in just over 7 years from 1990 to mid-2002 I found a total of 59 cases. Males were more affected than females (55% vs. 45%, respectively. Tuberculous arteritis with mycotic aneurysms were more frequent in the age group 3050 years (range 9-91 years). The aorta was affected in 38 cases (75%) (20 in the thoracic aorta, 17 in the abdominal aorta and one thoraco-abdominal). Twenty-one reported cases involved other arteries with mycotic aneurysms including; middle cerebral, left posterior inferior cerebella, internal carotid, bronchial, Rasmussen's aneurysms, internal mammary, hepatic, renal, superior mesenteric, inferior mesenteric, inferior gluteal, femoral and popliteal (Cross et al. 1995; Ito et al. 1992; Hildebrandt et al. 1998; Jebara et al. 1998; Kao et al. 1999; Sanyik et al. 1999; Patankar et al. 2000; Deshmukh et al. 2000; Tsurutani et al. 2000; Oran et al. 2001; Beeresha et al. 2000). Most reported cases in the literature came from developed, industrialized countries particularly from the USA and Japan. In developing countries most of the reported cases came from India.

43.4 Pathogenesis M. tuberculosis bacilli are the most common cause of tuberculous aneurysms and followed by M. bovis

M. M. Madkour

(BCG) (Seelig et al.1999; Rozenblit et al.1996; Wolf et al. 1995; Hakim et al. 1993; Woods et al. 1988). At least three distinct mechanisms have been implicated in the seeding of arteries. 1. The most common mode of transmission is direct extension of infection from a contiguous focus in the lung parenchyma, empyema, periaortic lymphadenitis, pericarditis, spondylitis or paravertebral abscesses of the thoracic aorta (Ishibataku and Onizuka 1998; Tsurutani et al. 2000; Long et al. 1999; Yo et al. 1993; Wetteland et al. 1956). Direct spread of infection to the abdominal aorta may occur from a nearby retroperitoneal lymphadenitis, intestinal tuberculosis, spondylitis, psoas abscess or the prostate (Ghosh 1954; Hagino et al. 1996). 2. Hematogenous spread to the arterial intima is difficult unless pre-existing damage by atherosclerotic plague is present. 3. Septic embolization of the arterial wall via the vasa vasorum, or the lymphatics, will result in seeding in the adventitia, or media, in patients with miliary or disseminated tuberculosis (Ishibataku and Onizuka 1998; Tsurutani et al. 2000). Iatrogenic or exogenous introduction of live attenuated M. bovis bacilli (BCG) may occur. BCG, an attenuated live strain of M. bovis, has been used to correct defects in cell-mediated immunity that occur in patients with malignant tumors. Intravesical administration of BCG to treat patients with urinary bladder carcinoma has been reported. Experimental evidence of systemic absorption of M. bovis after intravesical administration of BCG has been reported (Schellhammer et al. 1975). In humans, acid-fast bacilli may persist in the genitourinary tract up to 3 years or more after BCG therapy for bladder carcinoma (Hurle et al. 1998). In Italy, Hurle and Colleagues reported a 67-yearold man with Benign Prostatic Hypertrophy (BPH) and superficial urinary bladder cancer underwent intravesical BCG therapy in 1992. Three years later he developed hematuria. At cystoscopy there was no tumor recurrence but bladder ulcers with inflammation were noted. Acid-fast bacilli were detected in the urine by Ziehl-Neelsen staining. Histopathology of bladder ulcers biopsy showed granulomatous necrotizing inflammation with numerous acid-fast bacilli. Prostatic tissue biopsy also showed similar histopathological changes with acid-fast bacilli. At least six reports have appeared describing tuberculous mycotic aneurysms of the abdominal aorta following intravesical BCG therapy (Woods et al.1988; La Berge et al.1999; Hakim et al.1993; Wolf et al.1995;

773

Tuberculosis Vasculitis and Mycotic Aneurysms

Rozenblit et al.1996; Seelig et al.1999). The mechanism of transmission of the bacilli from the bladder to the aorta is not clear. After seeding of the bacilli into the arterial wall, an inflammatory granulomatous process with caseating necrosis and with fibrosis occurs. The entire thickness of the arterial wall and surrounding tissue are involved. Perforation may occur with contained encapsulated leakage to form a perivascular hematoma (Peyton 1965; Hatakeyama et al.1997; Girard et al. 1997) (False or pseudo-aneurysm) or it may lead to massive hemorrhage. Single saccular true aneurismal dilatation is the most common but extensive multiple tuberculous aneurysms of the entire abdominal aorta and its major branches may be affected (See our own case illustration below). Infection may spread longitudinally leading to a true aneurysm and may involve the entire abdominal aorta leading to an irregular aortic lumen, stenosis due to fibrosis or even occlusion (See below). Tuberculous pulmonary artery stenosis is extremely rare and may occur secondary to adjacent mediastinal tuberculous lymphadenitis (Beaconsfield et al. 1998). Small, or medium size, arteries located in the lung parenchymal cavity due to active tuberculosis, may undergo local dilatation (Rasmussen aneurysm). Intracranial carotid artery, or basilar arteries, tuberculous arteritis may occur. Rupture of the aneurysm (pseudo or true) may occur into the lung with massive hemoptysis, or into the esophagus (or bowel) leading to massive bleeding.

43.5 Clinical Features The clinical features of tuberculous aneurysm at presentation may be dominated by disseminated or miliary tuberculosis or other extrapulmonary disease. However, presentation may be related to the aneurysm with persistent pain mostly related to the location of the aneurysm. Patients may present with a palpable pulsating abdominal mass, a para-aortic mass found on imaging, aneurismal leakage or rupture (Ogawa et al. 1990; Takahashi et al. 1986; Quaini et al.1985; Oran et al.2001; Muller-Wening et al.1982; O'Leary et al. 1977). Felson and colleagues (l997) reported three patients with tuberculous aneurysms of thoracic aorta. Two patients had constitutional symptoms and miliary tuberculosis. The third patient presented with hemoptysis without any physical or laboratory findings. The diagnosis was initially suspected from chest radiographs in these three patients. The operation was

successful in one patient who survived, while the other two died post-operatively. Constitutional symptoms, fever, sweating, loss of appetite, weight loss and weakness may be present in over 50% of patients. Long and colleagues (l999) reviewed the clinical presentation of 39 patients published by other authors in a literature review. Evidence of pulmonary or extrapulmonary tuberculosis were found in 63% of reported cases with tuberculous aneurysms. They proposed a clinical presentation scenario as follows: 1. Persistent chest, abdominal or back pain in 64%. 2. Hypovolemic shock or other major bleeding in 38%. 3. Palpable or radiologically visible paraaortic mass in 64%. Fever was reported in 35% and hypertension in only four patients (Long et al. 1999). Kao and colleagues (l999) reviewed the literature on tuberculous pseudoaneurysm of the femoral artery and found 6 cases and add one of their own. Three patients had pulmonary tuberculosis and two had spine and bursa disease.

43.5.1 Our Own Case Report This extremely rare case report of one of my patients with multiple tuberculous mycotic aneurysms and irregular arterial lumen including: a. Abdominal aorta b. Right hepatic artery c. Left renal artery d. Celiac artery e. Inferior mesenteric artery f. Both iliac arteries g. Occlusion of the superior mesenteric artery Detailed operative findings are including which indicate the difficulties that the surgeon faced in such complex case. A 25-year-old female patient was referred from the Arabian Oil Company in Al-Khafji (Saudi town on the border with Kuwait) on April 1, 1981. She presented with dizziness, weakness, headaches, hypotension and bradycardia. She was on atenolol prescribed for her in Kuwait two years earlier for hypertension that was investigated with no apparent cause. The atenolol was stopped and her blood pressure ranged between 140/100 to 150/110 mmHg. The hemogram showed hemoglobin 9.0 G/dl, normal

774

M. M. Madkour

white cell count but ESR was 92 mm/h. The biochemi- arteries were found. There was an occlusion of the cal parameters and urine culture were normal. superior mesenteric artery 1 cm distal to its origin She delivered in February 1981 and developed par- (Fig. 43.1a,b). The most likely diagnosis was tuberoxysmal attacks of bilateral loin pain that was radiat- culous aneurysms based on: clinical features, normal ing to both inguinal areas. This was thought to be a and equal pulses, no discrepancies in blood pressure, urinary tract infection and treated with antibiotics. chest radiography, strongly positive tuberculin test, She had IVU, which did not show any abnormalities. predilection for abdominal aorta. She was examined by a gynecologist who found no Anti-tuberculous treatment with rifampicin abnormalities. 600 mg, isoniazid 300 mg, ethambutol 600 mg and At presentation, April 1, 1981, she was ill-looking, pyridoxine 20 mg daily was given. Surgical manageweak, with low blood pressure 90/70 and pulse of ment was not possible at our hospital and arrangeonly 40/min. There were no other clinical findings. ments were made for her transfer to the USA. She was referred to our hospital for the investigation The patient was admitted to Georgetown Uniof her recurrent abdominal pain, headaches, hyper- versity Hospital, Washington, D.C. She was fully tension and raised ESR. She came to our hospital on assessed by clinicians from internal medicine, gasApril 6, 1981 and gave a history of abdominal pain troenterology, rheumatology, infectious diseases since February 1981. It was paroxysmal and associ- and vascular surgery to assist in the work up of this ated with vomiting, night fever, sweating, loss of complex problem. She was admitted on May 25,1981. appetite and weight loss. She gave a history of being Her anti-tuberculous medications were temporarily investigated in Kuwait for headaches and found to stopped on admission. Detailed clinical history and have hypertension in 1980. physical examination were carried out by these conNo cause was found to explain her hypertension at sultants. Extensive laboratory tests were performed this age and she was treated with atenololl 00 mg daily. in addition to bone marrow biopsy, lumbar puncture, Other systems enquiries were non-contributory. On all were similar to ours. Aortic arteriography was not examination, she looked ill, pale and in pain. The pulse repeated as the films and medical report were given was 80/min regular and the peripheral pulse could be to the patient before leaving to USA. felt and were normal. Her temperature was 38.1°C and Their initial pre-operative discharge diagnosis blood pressure 200/140 and there were no discrep- was: Abnormal aneurysms? Tuberculous arteritis. ancies in blood pressure. There were no lymphade- Anemia and hypertension. nopathy or cardiac murmurs and the chest was clear. Abdominal examination showed a soft abdomen and a pulsatile central abdominal mass, slightly lateral to the 43.5.2 umbilicus measuring 3x3 cm was felt. There was no Surgical Findings (June 20, 1981) organomegaly, no bruit over the mass and the bowel sounds were normal. The hemogram showed hemo- The patient was assessed operatively on June 20, 1981. globin 10.0 gldl, normal white cells and ESR 94 mm/h. The operative findings from a report include: "The Biochemical parameters, tests for syphilis, brucella midline was incised and the abdomen somewhat non-adhesive. Immediately upon opening of the and salmonella all were normal. Chest radiography showed left pleural thicken- abdomen a very large marginal artery was prominent ing with small fibrocalcific changes most likely coursing through the entire large colon mesentery. It due to old tuberculosis. The Mantoux skin test was came out from an inferior portion of the aneurysm. strongly positive with induration of 34 mm after 48 The superior mesenteric artery was obliterated. hours. Morning urine for three days was sent for The aneurismal dilatation at the end of the aorta cytology for AFB smear staining and cultures for M. was approximately 4x4 cm. The retro peritoneum tuberculosis were negative. Abdominal ultrasound was then opened and investigation around the aorta showed a tortuous, irregular and dilated abdominal revealed much lymphoid tissue, hyperplasia and reacaorta, celiac trunk and left iliac arteries. Complete tive nodes. The nodes were sent for frozen section and aortic arteriography found no abnormalities in the came back as granuloma. It is significant to note that thoracic aorta. The abdominal aorta was grossly there is much reaction over the entire aorta, particuirregular with multiple areas of aneurismal dilata- larly in the areas of the aneurismal dilatation. At this tion and aneurysms. Also, aneurysmal dilatations point before resecting the aneurysm consideration for the left common iliac, left renal, right hepatic, over to the left renal artery was delivered. There was gastroduodenal, splenic and the inferior mesenteric a small rent in the renal vein, which was over sewn

Tuberculosis Vasculitis and Mycotic Aneurysms

775

b

a

c

Fig. 43.1. a TB vasculitis and aneurysmal formation. A 25-year-old female presented with fever, abdominal pain, headaches and hypertension. There is extensive irregularity of the aortic wall and its branches (arrows). There are multiple aneurysms of the hepatic, splenic and renal arteries (arrowheads). The superior mesenteric artery was occluded. b Post-operative angiogram-the patient had a graft (arrow) at the site of the aneurysm, but developed a large aneurysm of her right renal artery (arrowheads). c Selective right renal angiogram showing the aneurysm to a better extent (arrowheads)

with a 5-0 Ethibond suture. The left renal artery as it came off the aorta was aneurysmal and the dilatation was for approximately 1.5 cm. It then followed a very tortuous course with two further aneurysms, the last one measured 3x2 cm and was deep within the pelvis of the left kidney. This probably was a contraindication to resection since nothing could be sewn into the renal artery distally and it was wrapped with material to prevent any further expansion. There was much fibrosis in this area and Surgicel was placed into the wound around the area of the left renal artery aneurysm.

Next, the iliac vessels were surrounded and cleared of the surrounding tissue. The aorta and iliac vessels were cross-clamped and the aneurismal dilatation was resected down to the area past the bifurcation of the iliac vessels. A 16x8 bifurcation Dacron graft (Dacron velour graft) was brought onto the field. The cross clamp time for the large inferior mesenteric artery was approximately 40 minutes. Woven Dacron wide graft was inserted into the aorta and into both iliac vessels. Frozen biopsy of the artery in the iliac region revealed granulomatous inflammation. The graft was sewn

776

into place. The inferior mesenteric artery was anastomosed into the aorta at the level above the area of the bifurcation. There was a clot in the inferior mesenteric artery, briefly anastomosed and the artery was incised and the clot was removed. No blood oozing and the abdomen was irrigated and was closed. The operative blood loss was approximately 3,500 cc and the patient was brought to the intensive care uniC'

43.S.3 Successful Outcome of Surgery and Follow-up for 20 Years Before the patient had returned to Saudi Arabia she had been put back on her anti-tuberculous chemotherapy (post-operatively). As tuberculosis was confirmed by histopathological evidence of granulomatous lesions found in the resected aneurysms as well as the extensive tuberculous lymphadenitis all over the abdomen. Her raised blood pressure remained high and she was placed on atenolol in the USA. Her constitutional symptoms, fever, weight loss and abdominal pain all resolved. The hemoglobin and ESR have returned back to normal values. She has been followed up at our hospital regularly every 3 months up until the present time. She had no recurrences of her abdominal aortic aneurysms, as we are performing post-operative complete aortic angiography once every years for the initial five years and every four years after that. Her blood pressure, however, failed to normalize with atenolol two years post-operatively. Anti-hypertensive medication was changed and she is currently on amlodipine 10 mg once daily oral and is controlling her hypertension well. Her kidney functions are regularly assessed with biochemical parameters and creatinine clearance tests and remained normal. The follow-up aortic angiography performed last year is shown in Fig. 43.1b,c. In conclusion, this young lady initially presented with headaches and hypertension that was initially investigated and no cause was found in Kuwait. Only one year later, her constitutional symptoms were fever, weight loss, anemia, abdominal pain and high ESR, and she was referred to our hospital. The physical finding of palpable pulsating aneurismal mass in the abdomen, the presence of plain chest radiography of lung parenchymal scarring and calcified hilar lymphadenopathy, high ESR and strongly positive tuberculin test made us suspect tuberculosis as the cause of the multiple aneurysms depicted on the ultrasound and aortic angiography. She was placed on anti-tuberculous chemotherapy and atenolol. Because of the mul-

M. M. Madkour

tiplicity of the aneurysms and the close proximity of the renal artery aneurysm to the renal pelvis she was referred to Washington, USA. During surgery, the diagnosis of tuberculosis was confirmed by tissue biopsies obtained from the massively extensive abdominal lymphadenopathy as well as from the tissues of the resected aneurysms with granulomatous lesions seen on histopathological examination. The patient was already on anti-tuberculous chemotherapy for two months before surgery and tissue cultures were, as expected, negative. She resumed antituberculous treatment after surgery and completed a 18 months regimen. Her hypertension did not settle and she required continuous anti-hypertensive treatment till present. Her abdominal symptoms, anemia, raised ESR and weight loss all resolved. Follow-up for 20 years showed no evidence of recurrence of the disease, or further expansion of the aneurysms that could not be resected.

43.6

Investigation

Imaging modalities plays an important role in the diagnosis of arterial mycotic aneurysms. Chest radiography may depict miliary tuberculosis, severe lung parenchymal damage due to tuberculosis. Sputum smear, cultures for M . tuberculosis, serological tests for brucella should be done in countries where these two diseases are endemic. Serology testing for HIV is required in individuals at high risk. Abdominal ultrasounds are useful in depicting abdominal aortic mycotic aneurysm or in its major branches. It may also depict mesenteric or para-aortic lymph adenopathy. Complete aortic arteriography is essential in the diagnosis for establishing the site of aneurysm, its multiplicity in other arteries and the state of the arterial wall irregularity and lumen narrowing or occlusion. Magnetic resonance angiography is a noninvasive diagnostic modality. It is more sensitive than contrast arteriography for the detection of distal runoff vessel patency (Kao et al. 1999).

43.7

Treatment Patients may have surgery for the tuberculous aneurysms before the true cause is discovered and receive

Tuberculosis Vasculitis and Mycotic Aneurysms

the anti-tuberculous chemotherapy after surgery. The treatment of tuberculous aneurysms is the combination of anti-tuberculous medication and surgery. The choice of anti-tuberculous drugs is dependent on local incidence of drug resistance as well as the immune status of the patient. Treatment should be extended for at least 9-12 months or longer (Allins et al.1999; Penn et al.I996).Allins and colleagues (1999) from California reviewed the English language literature and found 26 patients who were operated for tuberculous aneurysms of the descending thoracic or abdominal aorta. Six patients had emergency operations for massive hemoptysis, aortoduodenal fistula or abdominal rupture of the aneurysm with a mortality rate at 30 days of 50%. Twenty patients had elective or semi-elective aneurismal repair and 19 survived for more than 30 days. The outcome of surgery for tuberculous aneurysm was also reported by Long and colleagues (1999) of published reports in the literature. A total of 22 patients had surgery for tuberculous aneurysms of the thoracic and abdominal aorta and 19 patients (86%) survived one month or more after surgery while the other three died shortly after surgery. In India, Choudhary et al. (2001) reported the surgical outcome of five young patients with tuberculous pseudo aneurysms seen over a 3-year period. Sites of involvements were: ascending aorta, distal aortic arch, proximal descending thoracic aorta, distal descending thoracic aorta, infra-renal abdominal aorta. All had the infection caused by a contiguous focus of tuberculous tissue, or from an organ close to the location of the tuberculous pseudo-aneurysm. All five patients were known to have tuberculosis before the operations. The reasons for the operations were rapid clinical deterioration. Surgery was successful in all five patients, with one patient developing recurrence at the same site of the previous aneurysm 8 months later.

References Allins AD et al (1999) Tuberculous infection of the descending thoracic and abdominal aorta: Case report and literature review. Am Vasc Surg 13:439-444 Atnip RG (1989) Mycotic aneurysms of the suprarenal abdominal aorta: prolonged survival after in situ aortic and viscera! reconstruction. J Vasc Surg 10:635-641 Baumgarten EC et al (1933) Tuberculous mesaarteritis with aneurysm of the femoral artery: report of a case. JAMA 100:1918-1920 Beaconsfield T et al (1998) Case report: tuberculous pulmonary arteritis - an unusual cause of light pulmonary artery stenosis. Clin RadioI53:229-231

777 Beeresha GLH et al (2000) Hepatic artery mycotic aneurysm of tubercular aetiology. J Assoc Physicians India 48:247-248 Boggian K et al (1994) True aneurysm of the ascending aorta in HIV disease. Schweiz Med Wochenschr 124:2083-2087 Bojar RM, Turner MT, Valdez S et al (1998) Homograft repair of a tuberculous pseudoaneurysm of the ascending order. Chest 114:1774-1776 Chan FY (1989) In situ prosthetic graft replacement for mycotic aneurysm of the aorta. Ann Thorac Surg 47:193-203 Chiba Yet al (1996) Surgical treatment of infected thoracic and abdominal aortic aneurysms. Cardiovas Surg 4:476-479 Choudhary SK et a! (2001) Tubercular pseudoaneurysms of aorta. Ann Thorac Surg 72:1239-1244 Cross DT et al (1995) Endovascular treatment of epistaxis in a patient with tuberculosis and a giant petrous carotid pseudoaneurysm. AMJ NeuroradioI16:1084-1086 De KruijfEJF et al (2000) Tuberculous aortitis with aortodudenal fistula presenting as recurrent gastrointestinal bleeding. Clin Infect Dis 31:841-842 De Prophetis N et al (1959) Rupture of tuberculous aortic aneurysm into lung. Ann Surg 150:1046-1051 Deshmukh H et al (2000) Endovascular management of an inferior gluteal artery pseudo aneurysm secondary to tuberculous cold abscess. Cardiovasc Intervent Radiol 23: 80-82 Felson B et al (1977) Mycotic tuberculous aneurysm of the thoracic aorta. JAMA 237:1104-1108 Ghosh H (1954) Tuberculous lymphadenitis: report of a case with perforation of aorta into duodenum. Am J Clin Pathol 24:1044-1049 Girard P et al (1997) An unusual cause of aorto-bronchial fistula: tuberculosis-aortitis. Rev Mal Respir 14:221-222 Glozarian J et al (1999) Tuberculous pseudoaneurysm of the descending thoracic aorta. Tex Heart Inst J 26:232-235 Gouny P et al (1992) Human immunodeficiency virus and infected aneurysm of the abdominal aorta: report of three cases. Ann Vasc Surg 6:239-243 Hagino RT et al (1996) A case of Pott's disease of the spine eroding into the paraspinal aorta. J Vasc Surg 24:482-486 Hakim S et al (1993) Psoas abscess following intravesical bacillus calmette-Guerin for bladder cancer: a case report. J UroI150:188-189 Hatakeyama S et al (1997) Massive hemoptysis in a patient with a tuberculous thoracic aneurysm. Nihon Kyobu Shikkan Gakkhai Zasshi 35:106-110 Herndon JH et a! (1952) Ruptured tuberculous false aneurysm of the abdominal aorta: report of a case with resection of the aneurysm and survival for six days. Tex State J Med 48:336-338 Hildebrandt JW et al (1998) Diagnostic case study: Rasmussen aneurysm. Semin Respir Infect 13:160-162 Hollier LH et al (1993) Direct replacement of mycotic thoracoabdominal aneuryms. J Vasc Surg 18:477-485 Hude R et al (1998) Acid-fast bacilli in the genitourinary tract 3 years after intravesical Bacilli Calmette-Guerin therapy for bladder carcinoma. Br J UroI81:496-497 Ikezawa T et al (1996) Tuberculous pseudoaneurysm of the descending thoracic aorta: a case report and literature review of surgically treated cases. J Vasc Surg 24:693-697 Ishibatake H, Onizuka R (1998) A successfully treated case of miliary tuberculosis with adult respiratory distress syndrome and tuberculous aneurysm of abdominal aorta. Kakkakuy 73:403-411

778 Ito K et al (1992) A case of extra-anatomic bypass for ruptured thoraco-abdominal aneurysm with tuberculosis. Kyobu Geka 45:640-643 Jebara VA et al (1998) Mycotic aneurysm of the popliteal artery secondary to tuberculosis. A case report and review of the literature. Tex Heart Inst J 25: 136-139 Kamen L (1895) Aortenruptur auf tuberkuloser Grundlage. Beitr Pathol Anat Allg Patho117:416 Kao CL et al (1999) Tuberculous pseudoaneurysm of the femoral artery: a case report. J Vasc Surg 30:561-564 Long R et al (1999) Tuberculous mycotic aneurysm of the Aorta. Review of published medical and surgical experience. Chest 115:522-531 Madkour MM (2001) Cardiovascular localizations - Brucella Mycotic Aneurysms. In: Madkour MM (ed) Madkour's Brucellosis, 2nd edn. Springer, Berlin Heidelberg New York, pp 139-141 Muller-Wening D et al (1982) Tuberculous aneurysm of the descending aorta with aorta-bronchial fistula (in German). Prax Klin Pneumol 36:22-26 O'Leary M et al (1977) Rupture of a tuberculous pseudoaneurysm of the innominate artery into the trachea and esophagus: report of a case and review of the literature. Hum Pathol 8:458-467 Ogawa J et al (1990) A tuberculous pseudoaneurysm of the thoracic aorta presenting as massive hemoptysis - a case of successful surgical treatment. Jpn J Surg 20:107-110 Oran I et al (2001) Mesenteric artery aneurysm in intestinal tuberculosis as a cause of lower gastrointestinal bleeding. Abdom Imaging 26:131-133 Parkhurst GF et al (1955) Bacterial aortitis and mycotic aneurysm of the aorta: a report of twelve cases. Am J Pathol 31:821-835 Patankar T et al (2000) Fatal hemoptysis caused by ruptured giant Rasmussen's aneurysm. AJR Am J Roetgenol 174: 262-263 Penn RL et al (1996) Lower respiratory tract infections. In: Reese RE, Betts RF (eds) A practical approach to infectious diseases, 4th edn. Little Brown, Boston, pp 258-349 Peyton RW (1965) Surgical correction of tuberculous pseudoaneurysm of upper abdominal aorta: first reported case. Ann Surg 162:1069-1074 Quaini E et al (1985) Mycotic tuberculous aneurysm of the descending thoracic aorta. Tex Heart Inst J 12:257-260 Rob CG, Eastcott HHG (1955) Aortic aneurysm due to tuberculous lymphadenitis. BMJ 1:378-379

M. M. Madkour Rozenblit A et al (1996) Infected aortic aneurysm and vertebral osteomyelitis after intravesical bacillus calmetteGuerin therapy. AJR Am J RoetgenoI167:711-713 Sanyika C et al (1999) Pulmonary angiography and embolization for severe hemoptysis due to cavitary pulmonary tuberculosis. Cardiovasc Intervent RadioI22:457-460 Schellhammer PF et al (1975) Study of local and systemic effects of intravesical BCG. Urology 6:562-567 Seelig MH et al (1999) Mycotic vascular infections of large arteries with Mycobacterium bovis after introvesical bacillus calmette-guerin therapy: Case report. J Vasc Surg 29: 377-381 Slavin RE et al (1990) Late generalized tuberculosis: a clinical pathologic analysis and comparison of 100 cases in the preantibiotic eras. Medicine 59:352-366 Strand BT et al (2001) Tuberculous aneurysm of the aorta presenting with uncontrolled hypertension. J Vasc Interv RadioI12:521-523 Takahashi et al (1986) A case of tuberculous abdominal aortic aneurysm which ruptured and perforated the sigmoid (in Japanese). Nippon Geka Gakkai Zasshi 87:99-104 Tsurutani H et al (2000) Hepatic artery pseudoaneurysms in a patient treated for miliary tuberculosis. Intern Med 39: 994-998 Volini FI et al (1962) Tuberculosis of the aorta. JAMA 181: 78-83 Weigert C (1882) O'ber Venetuberkel und ihre Beziehungen zur Tuberculosen Blutinfection. Vircow Arch Pathol Anat 88:307-379 Wetteland P et al (1956) Tuberculous aortic perforations. Tubercle 37:177-182 WolfYG et al (1995) Infection of a ruptured aortic aneurysm and an aortic graft with bacilli calmette-Guerin after intravesical administration for bladder cancer. J Vasc Surg 22: 80-84 Woods JM et al (1988) Mycotic abdominal aortic aneurysm induced by immunotherapy with bacilli Calmette-Guerin vaccine for malignancy. J Vasc Surg 7:808-810 Yo Y et al (1993) Case report of miliary TB, with mediastinal TB, involving the aorta, trachea and esophages with death due to hemorrhage from perforation of aorta into the esophagus during treatment. Nihon Koyobu Skikkan Gakkai Zasshi 31:738-743 Zhang JS et al (1994) Bronchial arteriography and transcatheter embolization in the management of hemoptysis. Cardiovasc Intervent RadioI17:276-279

Treatment

44 Treatment of Tuberculosis DEAN

E. SCHRAUFNAGEL

CONTENTS 44.1 44.2 44.3 44.4 44.4.1

Introduction 781 Evolution of the Treatment of Tuberculosis 781 The Problem of Drug Resistance 782 Latent and Paucibacillary Tuberculosis 783 Which Therapy for Latent Tuberculosis Is Best? 785 44.5 Extrapulmonary Tuberculosis 786 44.6 Children 786 44.7 Pregnancy 787 44.8 Liver Disease 787 44.8.1 Patients Who Start with Normal Livers 788 44.8.2 Treating Patients with Liver Disease 789 44.9 Renal Failure 789 44.10 Individual Drugs 790 44.10.1 Isoniazid 790 44.10.2 Rifampin 791 44.10.3 Pyrazinamide 791 44.10.4 Ethambutol 792 44.10.5 Streptomycin and Other Aminoglycosides 792 44.10.6 Rifabutin 792 44.10.7 Rifapentine 793 44.10.8 Fluoroquinolones 793 44.10.9 Capreomycin 794 44.10.10 Ethionamide 794 44.1 0.11 Cycloserine 794 44.10.12 Para-aminosalicylic Acid (PAS) 794 44.10.13 Linezolid 794 44.10.14 Other Treatments 795 References 795

44.1 Introduction Excellent statements of recommendation for the treatment of tuberculosis have been produced by the American Thoracic Society-Centers for Disease Control and Prevention (American Thoracic Society et al., 2003), World Health Organization (1997), and other organizations. These statements are written by committees of experts and set the standard for D. E. SCHRAUFNAGEL, MD Department of Medicine M/C 719, University of Illinois at Chicago, 840 S. Wood St, Chicago, IL 606127323, USA

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

treatment. They are more authoritative than any single authored work and should be consulted for the treatment and management of tuberculosis. This chapter generally keeps within these standards, but occasionally goes beyond, or aside of, them especially when clinical trial data is unavailable or unreliable. Anecdotal information, although less authoritative, is often additive and helpful in dealing with clinical problems and practice.

44.2 Evolution of the Treatment of Tuberculosis Koch's demonstration that tuberculosis was caused by a bacillus (Koch 1882) opened the way for treatment and cure, but his early attempts at treatment through immunomodulation failed (Roullion 1981). Between the 1890s and 1940s claims for cures of tuberculosis included a variety of diets, drugs, and surgeries. Patients with tuberculosis often improve spontaneously and this improvement confused both the patient and investigator. The problem for the investigator was that only about half of sputum positive patients would die of tuberculosis in five years. About a fourth would be 'cured' and about a fourth would become 'chronic'. The cures were attributed to an intervention, but the 'cures' would often relapse. When 'galloping consumption' set in with its 'hectic fevers' and wasting, progression and death were more certain. The false hopes for cures lead to the first controlled clinical trial of streptomycin for the treatment of tuberculosis (Hill 1948). Even though this study showed that streptomycin 'cured' tuberculosis (Hinshaw and Feldman 1945; Schatz and Waksman 1944), after only a few months the disease often returned and was then incurable as the organisms had developed resistance to it. It was not until Lehmann discovered that paraaminosalicylic acid (PAS) had anti-tubercular activity (Lehmann 1946) that a combination of this relatively weak drug and streptomycin could really

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cure tuberculosis. The idea of combination therapy was born. PAS was difficult to take and toxic. Fortunately, isoniazid was soon discovered. During much of the 1950s different combinations of doses and durations of these three drugs were studied. Isoniazid was at first thought to be without side effects and its advent heralded a new optimism for reducing the burden and possibly eliminating tuberculosis. The late 1950s and 1960s saw the introduction of pyrazinamide (Yeager et al. 1952), ethambutol, thiacetazone, ethionamide, cycloserine, capreomycin, and aminoglycosides. By the end of the 1960s, ethambutol was deemed to be safe and the next most effective drug. The standard treatment for tuberculosis was two years of isoniazid and ethambutol, which was later shortened to 18 months. PAS, streptomycin, and the others were reserved for resistant disease, difficult cases, and special situations such as meningitis. Rifampin was discovered in 1966 (Maggi et al. 1966) and came into popular use in the late 1970s. A series of well performed trials by the British Thoracic Society established a lower dose of pyrazinamide (-25 mg/kg) as a first line agent. Earlier studies showed that higher doses (50 mg/kg) were too toxic for use as a first line drug. Additional British Thoracic Society trials, and subsequently others, showed that pyrazinamide, rifampin and isoniazid for 6 months was adequate (Aquinas 1978; Chan et al. 1994; Cohn et al. 1990; Hong Kong Chest Service and British Medical Research Council 1991; Hong Kong Chest Service/British Medical Research Council 1987; Hong Kong Chest Service/Tuberculosis Research Centre and Madras/British Medical Research Council 1989; Hong Kong Chest Service/Tuberculosis Research Centre and Madras/British Medical Research Counci11991; Snider et al. 1984a,b). Experience and other studies established these three drugs as the core of the current treatment for tuberculosis. A fourth drug, ethambutol, was added until the resistance patterns were known. See Tables 44.1 and 44.2 for the doses of the first and second line agents.

44.3 The Problem of Drug Resistance The number of bacilli living in a person with tuberculosis is great. A single cavity may have 109 organisms. Organisms found in nature or 'wild type' organisms have rare, naturally occurring resistance to the antibiotics in use at a frequency of about 106 3 to 10- depending on the drug being considered

D. E. Schraufnagel

(David 1970). This means that a cavity may have 10 3 to 106 organisms that are resistant to a given antibiotic before the antibiotic is first given. Resistance to different classes of antibiotics is independent of each other so that the chances of a wild type organism being resistant to two different antibiotics would be, using our same range, (10- 3_10- 6 ) X (10- 3_10- 6) which would be 10-6 _10- 12 • Using two to three antibiotics would assure the killing of virtually all wild type organisms. When streptomycin was first given, most of the organisms were killed. The progeny of the remaining bacilli that were not killed, and thus resistant to streptomycin, multiplied. It appeared to the clinician that a recurrence had occurred about three months later, which was an appropriate time for these slow growing bacteria to repopulate. Combination therapy prevents the development of resistance but only if at least two effective drugs are given. Problems arise with ineffective medication and poor compliance. Giving anti-tuberculous agents one by one, with adequate time for repopulation, promotes resistance. Unfortunately drug resistance is common and found in all countries. The main reasons for this are patient non-adherence to a standard therapeutic regimen, errors in prescribing and delivering medication, failure to teach and emphasize the importance of taking the medication until completion, monotherapy for unrecognized tuberculosis, and unsuspected primary resistance. Patient non-adherence to a regimen may result from drug side-effects. Fortunately for populations where drug resistance is high, good national tuberculosis control should eventually reduce the resistance in the population. This is because evolutionary principles decree that wild type organisms are the fittest for survival under the stable environmental conditions in which they live. As selective pressures change, because incomplete anti-tuberculous therapy kills sensitive bacteria, native organisms are supplanted by resistant strains. Using an overwhelming force of antibiotics destroys all bacilli and does not allow the resistance to develop. If the selective pressure from partial or weak drug application is removed, there is a return to the native state in which the wild type again becomes the dominant strain in a region (Hong et al. 1998; Schraufnagel and Abubaker 2000; Weiss et al. 1994). To discover resistance early, health care workers following patients on anti-tuberculous drugs must check culture and sensitivities and follow the sputum, although the latter is often difficult because most patients stop producing sputum as they improve. Radiographs should be taken until improvement is

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Table 44.1. Doses of standard (first line) anti-tuberculous drugs for adults Drug

Daily (Maximal)

Twice weekly (Maximal)

Thrice weekly (Maximal)

5mg/kg (300 mg) Rifampin 10 mg/kg (600 mg) Ethambutol 15 mg/kg (1600 mg) Pyrazinamide 25 mg/kg (2000 mg) Rifabutin 5 mg/kg (300 mg)

15 mg/kg (900 mg) 10 mg/kg (600 mg) 45-50 mg/kg (4000 mg) 40-50 mg/kg (4000 mg) 5 mg/kg (300 mg)

15 mg/kg (900 mg) 10 mg/kg (600 mg) 25-35 mg/kg (2400 mg) 35 mg/kg (3000 mg) 5 mg/kg (300 mg)

Isoniazid

For further information consult the American Thoracic Society statements (http://www.thoracic.org) or Centers for Disease Control website (http://www.cdc.govl)

Table 44.2. Doses of secondary anti-tuberculous drugs for adults Drug

Daily (Maximal)

Twice weekly Thrice weekly (Maximal) (Maximal)

Streptomycin" 15 mg/kg 15 mg/kg (1000 mg) (1000 mg) Levofloxacin b (500 mg) Moxifloxacinb (400 mg) Gatifloxacin b (400mg) Capreomycin" 15 mg/kg 15 mg/kg (1000 mg) (1000 mg) Rifapentine 10 mg/kg once or twice weekly (600 mg) Amikacin" 15 mg/kg 15 mg/kg (1000 mg) (1000 mg) Kanamycin" 15 mg/kg 15 mg/kg (1000 mg) (1000 mg) Ethionamideb 15-20 mg/kg (500-750 mg) PAS b (8-12 g in 3 doses)

15 mg/kg (1000 mg)

15 mg/kg (1000 mg)

15 mg/kg (1000 mg) 15 mg/kg (1000 mg)

" Dose and interval depends on efficacy of companion drugs and mycobacterial burden. Reduce dose to 750 or 500 mg for the elderly. Start or move to twice or thrice weekly soon. b Intermittent dose not established.

clear and the lesions are either resolved or stable. Radiographic signs of active tuberculosis include cavities, alveolar shadows, pleural effusions and changing lesions with time. If radiographic signs of activity are present when the course is scheduled for completion, consideration should be given to continue treatment. This is especially true if the patient has cavitary disease or prolonged sputum positivity. On the follow-up visits, weight loss, new symptoms, and deterioration in general health may be important clues to treatment failure or the appearance of a new disease, such as coincident lung cancer.

Any of these features should prompt a search for a pathological process. To counter problems of drug resistance and to assure a continuous strong drug presence, directly observed therapy (DOT) is now recommended throughout the world. DOT means that a designated person watches the patient swallow each dose of the prescribed drugs (Bayer and Wilkinson 1995). DOT increases the cure rate and reduces the prevalence of tuberculosis (Weiss et al. 1994). Education is an important part therapy. Discussing how patients obtained the disease and how to prevent its spread may help in decreasing its transmission in the community. Showing patients their chest radiograph can engage them in their treatment and point out the progress they are making. Praising them for adherence to the regimen and being available for questions are part of a good therapeutic plan. When drug sensitivities are available the medication should be changed to take advantage of the sensitivities. With resistance to any single drug, the chance for cure is nearly the same as for tuberculosis resulting from a fully sensitive organism, although the time of treatment may be longer. Even with using the same standard four-drug regimen, the survival with isoniazid resistance is about the same (Perries et al. 1995). However, any drug resistance means a smaller margin of safety. Resistance in vitro may not always translate into failure for that drug but susceptibility tests are the best predictors of whether a drug will be valuable. Ethambutol resistance in vitro can be artifactual because it tends to degenerate in the media with time and allow growth. Isolated ethambutol resistance should be rechecked by another laboratory. Developing drug resistance is not important when dealing with latent tuberculosis because it is estimated that these patients have only a small number of organisms, perhaps 10 2_10 4; this is readily treated by a single drug.

44.4 Latent and Paucibacillary Tuberculosis Latent tuberculosis is defined as a tuberculous infection in a person who has no symptom of disease and the signs are limited to a positive tuberculin skin test and a chronic stable chest radiograph with only granulomata, adenopathy, apical capping, or pleural thickening. Infected persons harbor bacilli and have a rate activation that can be estimated in large part

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from the comorbid factors affecting the immune system and the duration of infection. Almost a third of the world has latent tuberculosis attesting to the prowess of M. tuberculosis as a human pathogen. In deciding whether to treat these individuals, one must weigh the risk and benefit between the chance of the tuberculous infection becoming active versus the side effects of the required medication. Identifying the risk of activation is summarized periodically by the American Thoracic Society and other organizations (American Thoracic Society and Center for Disease Control and Prevention 2000). The recommendations to treat latent tuberculosis were based on the risk benefit of using isoniazid for a year, which has been well studied and had been the standard for a least two decades (American Thoracic Society and Center for Disease Control and Prevention 2000). In 1994, the ATS recommendations were to go for 6-12 months (Bass et al. 1994). In 2000, the recommendations were changed to treat latent tuberculosis with isoniazid for nine months, rifampin for four months, pyrazinamide and rifampin for two months, or isoniazid for six months (American Thoracic Society and Center for Disease Control and Prevention 2000) but these recommendations were based on much less data. If these, or other new, regimens prove to be safer, the risk benefit of treating more or all persons with latent tuberculosis should be reconsidered. Latent syphilis, a disease with potential for harm similar to tuberculosis, is virtually always treated because of the safety and ease of using penicillin. A comparable anti-tuberculous regimen may dictate its use for all infected persons, but currently this is not the case. The treatment of latent tuberculosis has resulted in a great reduction of the community prevalence of tuberculosis (Comstock et al. 1967). Treating tuberculosis prevents further transmission, which means the treatment of latent tuberculosis has a greater implication than merely aiding the infected individual. Paucibacillary tuberculosis is the presence of symptoms and signs characteristic of tuberculosis but an inability to find organisms on sputum smear. For abacillary tuberculosis, sputum cultures are also negative. The symptoms and signs improve with antituberculous treatment. The Hong Kong Chest Service reported that 57% of patients who were thought to have tuberculosis but had five negative sputa went on to develop active tuberculosis within five years (Hong Kong Chest Service/Tuberculosis Research Centre and Madras/British Medical Research Council 1989). A South African study reported similar

D. E. Schraufnagel

findings (Cowie et al.1985). These studies tell us that patients presenting with symptoms and signs of typical tuberculosis should be treated even if the organism is not identified. The failure to find bacilli should not be a deterrent from treating a person who presents with typical findings. In general the treatment should start with four drugs, rifampin, isoniazid, pyrazinamide, and ethambutol and continue for four months with 2-4 drugs depending on the resistance pattern in the area. The two drug follow-up regimen, of isoniazid and rifampin, is permissible if the case comes from a community whose drug resistance is less than 4%. The 4-month course has been shown to be sufficient for paucibacillary disease (Dutt and Stead 1994; Hong Kong Chest Service/Tuberculosis Research Centre and Madras/British Medical Research Council 1989). If the person does not improve with treatment, continuing the treatment and searching for another diagnosis is often warranted. 'Treating only until cultures come back' is not recommended in patients with characteristic symptoms, or signs, of tuberculosis and a positive skin test, especially if they would qualify for treatment of latent disease. A 4-month isoniazid and rifampin treatment will treat abacillary and latent tuberculosis. The treatment may help make another diagnosis. For example, a patient has one or more lung nodules and is at high risk for surgery. The differential diagnosis includes tuberculosis and cancer. If anti-tuberculous treatment is started and the lesion continues to grow the diagnosis of tuberculosis is unlikely. If the drugs were stopped with negative cultures, the diagnosis of the growing lesion at a later date could still be tuberculosis or cancer. Furthermore, the difference in side effects between treating active and latent tuberculosis is small. Frequently, treatment for latent disease is still required and the initial therapy has already begun. The first days of any drug therapy are the most common time for side effects to occur. Of course, if latent tuberculosis is not a consideration and another diagnosis has been made, it may be appropriate to stop the anti-tuberculous therapy. There are two fundamental rules for the treatment of latent tuberculosis: First, rule out active disease. This is especially true if only a single agent is used. Ruling out active disease is often difficult when other lung disease is present and the subtle symptoms of tuberculosis may be overshadowed by chronic respiratory symptoms and the radiograph is abnormal. Subtle radiographic changes may be missed. It is possible that undetected active, or 'smoldering', tuberculosis may account for the failure of the 'prophylactic

Treatment of Tuberculosis

tuberculosis treatment' reported in silicosis. The hazard of treating active disease as latent is causing the development of drug resistance. The second basic rule is: 'Do not harm the patient'. The lifetime risk of developing active tuberculosis for a tuberculin positive individual and no other risk factor is probably only about 10%. In treating latent tuberculosis, the harm is caused by side effects of the medications. To reduce the chance of serious harm, detailed education and careful follow-up must be given. Patients should be told that this medicine, like all drugs, can cause side effects. The warning about hepatitis should be explicit. On each follow up clinic visit the health care worker should specifically ask about symptoms of hepatitis and compliance. If a side effect occurs, the patient must stop taking the medication and call the physician or nurse. The patients should be warned that if they continue taking the medication, the side effect may worsen and could cause death. If the drugs are promptly stopped, the problem will resolve. Patients should report any new symptom to the health care worker who must see beyond a patient's attribution of symptoms to the cause. For example, a patient may attribute a lack of appetite to a change in smoking or work schedule, but the symptom may be the first sign of hepatitis. Health care workers must be alert to clinic 'no-shows' and be especially concerned if there is a language or cultural difference. The importance of treating latent tuberculosis increases for a recent conversion and factors that decrease the host defense against tuberculosis. A person with a recent conversion has the greatest chance of developing tuberculosis in the first two years after the conversion. If a recent converter has HIV, the risk of developing active disease may increase to 41 % in 60 days (Di Perri et al. 1989).

44.4.1 Which Therapy for Latent Tuberculosis Is Best? The ATS now recommends four choices of treatments for latent tuberculosis: isoniazid for nine months, rifampin for four months, pyrazinamide and rifampin for two months, or isoniazid for six months (American Thoracic Society and Center for Disease Control and Prevention 2000). A study of the International Union Against Tuberculosis showed that taking isoniazid for 12 months reduced tuberculosis in compliant patients by 93% compared to placebo controls; six months of treatment reduced it by 69% and three months by 31% (International Union

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Against Tuberculosis and Lung Disease 1982). The chance of developing a liver reaction from isoniazid is about 0.1 % per month. A physician choosing conservative treatment who wants substantial data would probably select 9-12 months of treatment with isoniazid as the regimen of choice to treat latent tuberculosis. The data on 12 months of isoniazid is substantial and convincing. That for nine months of isoniazid is scarce but reasonable. It comes largely from post hoc analysis of longer trials but has convinced many experts to pick this regimen as their first choice. The regimen of isoniazid alone may be best for patients on medicine that might interact with rifampin. Its biggest drawbacks are that non-adherence is correlated to length of therapy and the additional cost of monthly follow-up visits. The course that most departments of health chose after the 1994 ATS recommendation was six months of therapy. This is still an ATS recommended choice, but when I presented the six-month versus twelvemonth choice to more than 200 mostly health care workers who were beginning treatment for latent tuberculosis between 1994 and 1999, more than 95% choose the 12-month course despite the inconvenience and greater risk of toxicity of longer therapy. Choosing the rifampin-based treatments depends on how comfortable one is with less data. After the ATS-CDC recommendations appeared in the year 2000, many health departments switched to the two-month course of rifampin and pyrazinamide, which resulted in financial and manpower savings, but additional reports of fatalities (American Thoracic Society and Center for Disease Control and Prevention 2001) have caused the enthusiasm for this regimen to diminish. The two-month rifampin and pyrazinamide regimen is supported by an open, controlled study (Gordin et al. 2000) that showed no difference in efficacy and toxicity between it and isoniazid for 12 months. Other reports have found it is more toxic (American Thoracic Society and Center for Disease Control and Prevention 2001) which has led to the retraction of this general recommentation. Nevertheless, the 2-month rifampin-pyrazinamide regimen might be applicable for those who cannot be followed for a longer period, or do not wish to take medication for the longer period. It may be appropriate for those who have already started four- drug therapy and has the advantage that a two drug combination avoids monotherapy, if active disease is inadvertently treated. It has been shown to be effective in patients with HIV and it may be useful to complete the course quickly and resume antiretroviral therapy

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that may have been stopped because of rifampin drug interactions. Rifampin alone for four months has advocates who point out that it may be the single-most effective agent against tuberculosis. It is thought to be the safest of the regimens, although comparative trials have not found differences between these regimens. It is convenient, but the data from clinical trials in limited (Villarino et al. 1997). In Hong Kong, silicotics with latent tuberculosis given three months of rifampin did as well as three months of isoniazid and rifampin and six months of isoniazid and much better than placebo (Hong Kong Chest Service/ Tuberculosis Research Centre and Madras/British Medical Research Council 1992).

44.5 Extrapulmonary Tuberculosis and Corticosteroids Although some authorities recommend that miliary, meningeal, bone, and joint tuberculosis should receive up to 12 months of treatment (American Academy of Pediatrics 2000; American Thoracic Society et al. 2003), clinical studies generally show that the six-month treatment courses are effective for treating extrapulmonary disease. However, antibiotic therapy beyond six months should be considered for any tuberculosis if the number of infecting organisms is great, the antibiotics may fail to reach the target in adequate strength, or there is a wish to broaden the margins of safety. Tuberculous cavities are teeming with bacilli and cavitary disease is characteristic of pulmonary tuberculosis. Extrapulmonary disease usually does not have cavities, or has far fewer cavities, resulting in a lower bacillary burden than pulmonary disease. The argument for a longer therapy for meningeal, bone, and joint tuberculosis is that tissue penetration of the antibiotics is less. Several studies have found that the standard sixmonth therapy does not result in a worse outcome than longer treatment for meningitis (Alarcon et al. 1990; Biddulph 1990; Chotmongkol 1991; Doganay et al. 1995; Donald et al. 1998; Jacobs et al. 1992; van Loenhout-Rooyackers et al. 2001). A British Thoracic Society trial comparing six months versus nine months of therapy for tuberculous adenopathy showed that the six-month regimen was as good (British Thoracic Society Research Committee 1992).

D. E. Schraufnagel

There have been many papers on the use of corticosteroids as an adjunct in the treatment of tuberculosis (Dooley et al. 1997; Hosoglu et al. 1998,2002; Schoeman et al. 1997). The main damage done by tuberculosis results from the body's response rather than the bacteria themselves. The shadows on the chest film do not result from bacilli but rather the exudation elicited by inflammatory cytokines and the leukocytes themselves. Advanced AIDS and neutropenic patients usually do not have cavitary disease and necrosis despite lesions containing many bacilli. This concept also explains the 'paradoxical' response seen with treating tuberculosis. There is no paradox, if the damage is attributed to the host's reaction, and bacterial products elicit the host's response (Afghani and Lieberman 1994; Dastur et al. 1995). A damage analogy might be opening a fire hose in a finely furnished home. The smoking toaster is extinguished but the water damage may be great. Steroids control the water damage. Many studies have shown no harm from corticosteroids if the tuberculosis is being treated with appropriate antibiotics. Steroids reduce inflammation that may cause scarring and its long-term effects. Corticosteroids are recommended in meningitis because small amounts of scarring can impede the flow of cerebral spinal fluid. Steroids may reduce the scarring seen with endobronchial tuberculosis (Alzeer and FitzGerald 1993; Chan and Pang 1989; Park et al. 1997), and may improve the outcome in tuberculous pericarditis (Long et al. 1989; Trautner and Darouiche 2001) and brain tuberculoma (Garg 1999; Gavazzi et aI.1998). They also reduce the inflammation in tuberculous pleurisy (Dooley et al. 1997; Galarza et al. 1995; Grewal et al. 1969; Habibullah 1968; Lee et al. 1988; Wyser et al.I996).

44.6 Children The treatment of tuberculosis in children is essentially the same as adults, although the Academy of Pediatrics recommends not using ethambutol if children cannot tell you if they have visual problems (American Academy of Pediatrics 2000). At the dose of 15 mg/kg and in the absence of renal disease, ethambutol rarely causes eye or any other side effects, but the benefit of ethambutol is also low in children who usually have a low mycobacterial load. Ethambutol does not shorten the course or add significantly to the treatment of tuberculosis caused by fully sensitive bacilli. The American Academy of Pediatrics

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Treatment of Tuberculosis

also recommends that duration of anti-tuberculous therapy should be at least nine months for children and at least 12 months for children with miliary, bone, joint and meningeal tuberculosis but there is no evidence from clinical trials to support this. The difficulty in diagnosing tuberculosis in children may translate into difficulty in treating it. Children usually do not have cavitary disease and do not expectorate. The inability to isolate M. tuberculosis makes drug susceptibility testing impossible. The antibiotics given should cover the organism from the presumed source. Quinolones are not recommended in children (see below: Pregnancy).

44.7 Pregnancy Work up and treatment of tuberculosis should not be delayed in pregnant women. All pregnant women with active tuberculosis should be treated. The risk to the fetus is much higher from maternal tuberculosis than it is from potential harm from the anti-tuberculous drugs. No drug has been approved by the FDA for use in pregnancy but there is experience with almost all of them. Isoniazid, rifampin, and ethambutol are routinely given in pregnancy. The duration of treatment should be for nine months if pyrazinamide is not given. The lack of literature on the use of pyrazinamide in pregnancy is a major drawback and the reason why it has not been recommended (ATS et al. 2003). Streptomycin was used extensively in pregnancy as a lifesaving measure when it was first available; it has been associated with congenital deafness (Conway and Birt 1965; Robinson and Cambon 1964) and is no longer used in pregnancy. The other aminoglycosides and capreomycin have a similar side-effect profile and are also not used. Although there is a report that seven out of 23 mothers taking ethionamide had children with congenital anomalies (Potworowska et al. 1966), careful examination of the cases show that the link is not convincing; two received ethionamide only in the last month of pregnancy and two had finished their course months before the onset of pregnancy. Of the three who took it throughout the pregnancy, two had Down's Syndrome and one had an ill-defined abnormality. Several other small series found no abnormality with ethionamide. PAS has been considered safe in pregnancy (Hamadeh and Glassroth 1992; Heinonen et al. 1977; Scheinhorn and Angelillo 1977; Wilson et al. 1973). The quinolones have been associated with cartilage and joint defects in animals and have interdicted for

use in pregnancy (ATS et al. 2003), but several good studies have failed to uncover fetal harm (Anonymous 1999; Berkovitch et al.1994; Larsen et al. 2001; Loebstein et al. 1998; Schaefer et al. 1996). As with several areas in tuberculosis treatment, when the experience is incomplete it is necessary to weigh the potential risks, benefits, and choices. The argument for their use in pediatrics is similar to their use in pregnancy. The management of latent tuberculosis in pregnancy depends on several factors. As with all medical treatments, the benefits must be weighed against the risks. The risk for someone with latent disease converting to active disease varies with comorbid factors and timing of the exposure. For persons with long-standing latent tuberculosis and no additional risk factors, the risk of developing active tuberculosis is about 10% in a lifetime or about 0.1-0.2% per year. The risk of maternal serious side effects from the drugs is probably about 1%. The risk to the fetus is unknown but low because no study has shown the anti-tuberculous drugs used cause any adverse effect on the fetus. A report suggesting that an increased risk of isoniazid toxicity during pregnancy based on cross-sectional data (Franks et al. 1989) is not convincing. Treating latent tuberculosis is favored for those with an increased immediate risk, as seen with recent converters, and those with high risk such as HIY. Waiting until after the pregnancy, or at least until after the first trimester, is favored in those with no other risk factor. For those with other risk factors, the risk-benefit considerations lie somewhere in between. A problem with postponing therapy is that many times this is the only contact with the health care system for these young women. If they are not treated, it is a missed opportunity and active tuberculosis may be discovered when the children develop disease. Breast feeding can be permitted despite the passage of medications into the milk (Tran and MontakantikuI1998). The concentrations in milk are small and not sufficient to treat the infant. Information on the use of drugs such as pyrazinamide, ethionamide, and capreomycin during breast feeding is limited (Tran and MontakantikulI998).

44.8 Liver Disease Liver disease in the treatment of tuberculosis can be perplexing because both tuberculosis and its treatment can cause and exacerbate liver disease. Detect-

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ing a liver reaction early may be challenging, but if the treatment is not promptly stopped, the side effect can be fatal. A fatality from hepatotoxicity is particularly tragic when treating a patient for latent tuberculosis. Virtually all patients with drug-induced liver disease have abnormal transaminase levels. Yet, enzyme levels are a poor predictor of significant toxicity. It is best to consider this as two problems: 1) patients with normal livers who develop liver disease from the anti-tuberculous medications and 2) the treatment of tuberculosis in patients with pre-existing liver disease. A third problem is tuberculosis of the liver that is generally treated by the standard regimen.

44.8.1 Patients Who Start with Normal Livers Probably all anti-tuberculous agents can cause hepatitis in normal individuals, although it is rare with the aminoglycosides, capreomycin, and ethambutol. The first question to ask is what constitutes liver disease? The definitions of liver reactions range from an elevation of transaminases to fatal fulminate hepatitis. There is no controversy about two issues: 1. Anti-tuberculous drugs can cause fatal hepatitis. 2. When patients without previous liver disease develop symptoms of liver toxicity and have elevated liver enzymes, the drugs must be stopped immediately. Restarting the offending drug after an episode of clinical liver disease carries a substantial risk of recurrent hepatotoxicity. On the other hand, asymptomatic liver function test elevations often revert to normal despite continuing the same drug regimen. In the absence of symptoms, the offending drug, especially if it is isoniazid, can be restarted. About 20% of patients who take isoniazid develop serologic liver-test abnormalities and only about 1% of these patients have serious hepatitis. Most tests with such low specificity would not be considered useful clinically, but the occurrence and gravity of the delay in diagnosis of liver reactions, the subtlety of the symptoms, and the lack of better tests are the basis of the recommendations for serological testing. Serological testing may be beneficial in getting patients back to the clinic regularly to talk with a health care worker about possible side effects. Serological testing should not be a substitute for careful instruction to the patient about tuberculosis and its treatment and careful clinical follow-up. After the initial visit all patients should be warned specifically with words such as, "At the first sign of symptoms of hepatitis, which are loss

D. E. Schraufnagel

of appetite, fatigue, nausea, vomiting, abdominal pain, dark urine and jaundice, you should stop the medicine and call this number. You should not restart the medicine until told to do so by a health care professional." At every visit, the patients should be asked questions about these symptoms. If patients have symptoms, even non-specific fatigue or decreased appetite, liver enzymes should be drawn. If the enzyme levels are normal, it is unlikely that the symptoms result from hepatotoxicity and the drugs can be continued. If the liver enzymes are abnormal, especially if symptoms are more than trivial, generally all drugs should be stopped. Generally, the physician should wait until the symptoms have disappeared and the liver function tests have returned to normal before restarting any medicine. One should judge the activity and severity of the tuberculosis and the likelihood that the different drugs may be involved. If hepatotoxicity occurs with treatment of latent tuberculosis, especially late in the course of therapy, it may appropriate to simply stop the medication permanently. If a patient is sick with tuberculosis, or the liver disease is severe, switching to ethambutol, streptomycin, and a quinolone may be a reasonable choice. Although liver enzymes are not as useful as one would like for following asymptomatic patients, they are good indicators of liver damage for the symptomatic patient. Many patients with isoniazid hepatotoxicity have a relatively abrupt onset of symptoms (a few days) and improve in about the same time span, but the enzyme levels do not return to normal for several weeks. If one is uncertain of the offending agent, especially if the reaction has not been life threatening, it is common practice to reintroduce the drugs starting with the least likely to be the cause. On reintroducing the drugs, a rise in liver enzyme levels without symptoms is usually sufficient to permanently stop the drug. In patients with symptomatic reactions, re-introducing a known offending drug is likely to cause recurrence of the liver reaction and is not recommended. Re-introducing the drugs should be followed by frequent open communication and measurement of the enzyme levels on a weekly basis. A major problem is that the symptoms of hepatitis may be subtle. Fatigue or anorexia may be the only symptom for days to weeks. The patient may not understand the seriousness of informing the medical team about the symptoms. The health care team may not be situated to respond to the patient's call.

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Treatment of Tuberculosis

44.8.2 Treating Patients with Liver Disease The rifampicins, isoniazid, pyrazinamide, ethionamide, and PAS are all metabolized in the liver and liver disease affects their metabolism. Not only does the liver disease affect the drugs but the drugs affect the measurements ofliver function and can cause liver dysfunction. The drugs can alter the metabolism of other drugs that can cause other side effects. Finally, patients with chronic liver disease have fluctuations in their liver function as determined by the serologic tests, which makes evaluation more difficult. With severe liver disease, beginning therapy with ethambutol, streptomycin, and a quinolone is usually recommended, although these agents are clearly not as good as the first line drugs. I will not forget treating a young woman with a liver transplantation, liver failure, and tuberculosis with these drugs in our intensive care unit for about six weeks. She died from and had extensive disseminated tuberculosis at autopsy. The extensive disease is almost never seen in patients treated with rifampin, isoniazid, and pyrazinamide for this time. As the liver failure improves, it is usually possible to add isoniazid and rifampin. This may be done sequentially while monitoring the liver enzymes. A more common problem is how to treat tuberculosis in an alcoholic or patient with viral hepatitis. If the liver dysfunction is mild, the standard regimen is usually tolerated. If the patient is symptomatic or the liver enzymes are elevated, the first consideration is to withhold pyrazinamide, which appears to be the most hepatotoxic (Liu et al. 1991). If the treatment does not include pyrazinamide, the rifampin and isoniazid should be continued for nine months. Adding or beginning with ethambutol, streptomycin, and a quinolone if the mycobacteriological burden is high, may also be helpful in moderate liver disease. For patients with liver disease, transaminase levels are used to follow the liver disease, but again there are caveats, and serologic testing does not replace close clinical follow-up. One alcoholic cirrhotic had a tripling of his already abnormal enzymes for which I was about to stop the drugs, when a medical resident pointed out to me that the enzyme levels were substantially higher than the current level on other occasions in the past, before the treatment was begun. We continued the patient on the same course and his liver enzyme levels reduced at the next clinic visit. Elevated liver enzymes in patients with chronic liver disease does not have the same meaning as those with a normal liver at the start of therapy. For example, if the transaminases rise 3-5 fold after starting treat-

ment for tuberculosis, most authorities recommend stopping treatment, but many experts in tuberculosis would begin treatment tuberculosis with isoniazid and rifampin in a cirrhotic whose transaminases were 3-5 times normal. In the former, the assumption is that the anti-tuberculous drugs are causing the problem; in the latter it is that the patient's liver disease was the cause. The reason for serological liver function testing before beginning tuberculosis medications is to detect occult pre-existing liver disease. Liver transplantation and tuberculosis are an increasing problem. The immunosuppression that goes with liver transplantation substantially increases the risk of developing active tuberculosis and cannot be ignored. Liver failure, rejection and drug interactions can make treatment difficult (Meyers et al. 2000). A reasonable approach is to test all transplant candidates with tuberculin but to withhold treatment for latent disease until the new liver is in place and functioning well, usually about three months after transplantation. The patients then should be treated with isoniazid because rifampin interacts with the immunosuppressive agents. On the other end of the spectrum is Gilbert's syndrome, which can be treated with the standard four-drug regimen. Isoniazid and rifampin metabolism appears to be unchanged (Adachi et al. 1975; Pereira-Filho et al. 1985).

44.9 Renal Failure Treating tuberculosis in patients with renal failure can be a problem because the drug dosages are not well established. For patients on hemodialysis, all drugs should be given by directly observed therapy immediately after dialysis. Thrice-weekly intermittent therapy fits well with dialysis and medical personnel can administer the medications after dialysis with ease. Dosing medication after dialysis avoids the early inadvertent reduction of the levels by dialysis. Ethionamide, clofazimine, rifampin and PAS are not significantly dialyzed (Malone et al. 1999). Treating patients with renal failure who are not on dialysis is more difficult. The rifamycins can be given at their usual doses. Isoniazid is generally given at its usual dose, but its metabolism is changed and clearance is decreased (Bowersox et al. 1973; Cheung et al. 1993; Gold et a1.1976; Kim et al. 1993). Pyrazinamide is metabolized by the liver but its main metabolite, pyrazinoic acid, is excreted by the kidneys. Etham-

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butol can become dangerous in renal failure. Consideration should be given to avoiding these agents or giving them twice or thrice weekly at their daily dose. Cycloserine and the aminoglycosides should probably only used if no other agents are available and blood levels are monitored. Regular checking of vision in patients on ethambutol is important.

44.10 Individual Drugs 44.10.1 Isoniazid Isoniazid has been the most used anti-tuberculous drug through the years. It has excellent bactericidal activity that is largely limited to M. tuberculosis and to a lesser extent to other members of the mycobacterial family. It appears to interfere with the mycolic acid synthesis (Winder and Collins 1970). Resistance to isoniazid was associated with less virulence in vitro and decreased catalase activity (Cohn et al. 1954). This has been attributed to mutations of the KatG gene, which encodes a catalase-peroxidase required to activate isoniazid (Zhang et al. 1992). Mutations of the regulatory region of the ahpC gene cause overproduction of alkyl hydroperoxide reductase but do not confer virulence (Heym et al.1993). Mutations in these two genes appear to account for most of the isoniazid resistance. The daily dose is 5 mg/kg for adults and 10-15 mgt kg for children to 300 mg daily. For intermittent therapy, 15 mg/kg up to 900 mg is given twice or thrice weekly. See Table 44.1 for dosage. Suspension and parenteral preparations are available. The major problems with isoniazid are asymptomatic elevation of liver enzymes and potentially fatal hepatitis, which have been discussed, and additionally, rash, neuropathy, lupus reaction, fever, and a variety of minor symptoms also can occur. The rash, in my experience, usually has a small macular or acneiform pattern on the chest, abdomen, and arms. It may be pruritic and may respond to diphenhydramine and calamine lotion and diphenhydramine by mouth. The rash may abate despite continuation of the medication, however, with attractive alternatives to isoniazid for the treatment of latent tuberculosis, a rash should generally prompt a change in medication. Stopping and restarting the drug may not be associated with return of the rash and the rash is not necessarily a contraindication to using or restarting isoniazid.

D. E. Schraufnagel

Isoniazid neuropathy usually occurs in patients with underlying nerve disease, diabetes, pregnancy, alcoholism, and poor nutrition, but is occasionally seen in otherwise healthy patients. The symptoms are often distal paresthesia. The usual treatment, when isoniazid must be continued, is pyridoxine or increasing the pyridoxine if it is already being given. There is no trial that shows the routine use of pyridoxine is indicated in patients receiving isoniazid, but it is recommended for those at higher risk to develop neural symptoms. It is given in doses between 10 and 50 mg daily. With the onset of symptoms of neuropathy, 100-200 mg are usually given. If the symptoms do not respond to the pyridoxine, the isoniazid should be stopped. Isoniazid-associated lupus occurs infrequently. It usually presents with arthralgias. The serum antinuclear antibodies are positive and the syndrome usually progresses until the medication is stopped. The lupus reaction may be preceded by a rash. Isoniazid associated fever may be characteristic. The fever may begin about six hours after ingestion of the isoniazid, rise to a high level, be accompanied by a chill, and last only a short time. Hours later the patient may feel completely normal. The fever may return the next day with clock-like regularity but it becomes more intense and lasts longer if the medicine is continued. With each day, the fevers become more hectic, last longer, and the timing breaks down. In other patients, the course may be less characteristic but it is usually debilitating and require that the medicine be stopped. The fever usually recurs if the drug is restarted. The fever may be preceded by a rash. If patients are educated and told to report any abnormal sensation, it is common to get mild and unexpected complaints. Frequent ones include flushing especially with alcohol, decreased energy, sleepiness, headache, light-headedness, and an inability to concentrate. Most often they respond to reassurance and go away without changing the medication. Isoniazid interacts with phenytoin and carbamazepine. The phenytoin concentrations predictably go up and the patient becomes phenytoin toxic. The phenytoin dose should be reduced and the serum concentrations of it monitored. The question of whether isoniazid should be used despite low level resistance has never been solved (Victor et al. 1997). Two types of drug resistance are commonly seen with isoniazid. One is complete resistance at all concentrations and the other is resistance at low levels only. The latter is associated with resistance to ethionamide. Older studies indicated that isoniazid was not effective if any resistance was pres-

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ent (Bignall et al. 1969; Stewart and Crofton 1964). The high-level resistance may be associated with katG gene mutations, which are also associated with lower virulence (Heym et al. 1995). The inhA gene isolated from M. smegmatis was thought at first to be associated with the low-level resistance but the effect of the gene is less clear in M. tuberculosis (Mdluli et al.1996). Isoniazid is not given when drug sensitivity testing indicate complete resistance.

44.10.2 Rifampin

Rifampin may be the most important drug for the treatment of all forms of tuberculosis. Short course chemotherapy can not be accomplished without it. The time to the reduction of almost all symptoms and signs, radiographic improvement, and sputum negativity are lower when rifampin is used in tuberculosis and other mycobacterial disease (Schraufnagel et al. 1984). Rifampin inhibits a DNA-dependent RNA polymerase. This enzyme appears to be a complex oligomer that is made up of different subunits encoded by the rpo genes. Most rifampin resistance comes from modification in the rpoB genes (Telenti et al. 1993). Rifampin is usually given at a dose of 10 mglkg in adults and 10-20 mglkg in children up to 600 mg daily. See Table 44.1 for dosage. It is an integral part of intermittent therapy but is given at the same dose twice or thrice weekly. It can be given orally or parenterally. The main problems with rifampin include the expected reactions, such as the orange discoloration of body fluids and drug interactions. Nausea, rash, flu-like symptoms, and liver, renal, and hematologic toxicity are uncommon. Patients should be warned that rifampin and its metabolites are red-orange and the urine will turn that color as the drug is excreted. Oral contraceptives may no longer be effective after rifampin is started. Antiretrovirals, cyclosporine, tacrolimus and warfarin are some commonly used drugs that may have markedly changed serum levels after rifampin is started. Rifampin may cause intractable nausea that resolves only with stopping the medication. A flu-like syndrome can occur with intermittent therapy and is the main reason why rifampin cannot easily be given once weekly. The symptoms are sometimes subtle and can also be seen in twice-weekly therapy. For self-administered therapy, these symptoms suggest that the patient is taking the medicine irregularly.

The hepatitis of rifampin may be more subtle and slower to develop than that resulting from isoniazid, but there is overlap and it is not easy to establish which drug causes the hepatic reaction without stopping and reintroducing them. Rifampin may cause an isolated elevation of serum bilirubin. As with isoniazid, the rash may be self-limited, but switching to another regimen is recommended for treatment of latent disease with other good alternatives. Renal and hematological toxicity are uncommon but can be fatal and are contraindications to restarting the medication. Thrombocytopenia, hemolytic anemia, and renal failure may occur separately or together.

44.10.3 Pyrazinamide

Pyrazinamide is the number three drug for the treatment of tuberculosis. Its antituberculous activity was not recognized until the 1950s and it was considered to be too hepatotoxic at its earlier doses of up to 50 mgl kg. The British Thoracic Society trials in the 1970s established its place among the best agents for tuberculosis. Many studies have shown that it decreases the time of culture positivity and allows a shorter course of treatment. Reducing the dose to 25 mglkg allowed its common use. However, it is still associated with substantial hepatotoxicity and lower doses are being studied. (See Table 44.1 for dosage.) Pyrazinamide is interesting in that it only works at low pH. Pyrazinamide may be converted to pyrazinoic acid in the secondary lysosome. In this location it lowers the pH, which increases the killing of the mycobacteria harbored there. The pyrazinoic acid may be trapped in the macrophage and its accumulation may add to its toxicity for the mycobacteria (Salfinger et al. 1990). However, sensitivity to pyrazinamide is not correlated with pyrazinamidase which metabolizes pyrazinamide to pyrazinoic acid. Most pyrazinamide resistance occurs with mutated pncA genes (Sreevatsan et al. 1997a). The drug is now used in children and can be used for intermittent therapy. The drug is usually given for the first two months of therapy when the mycobacterial burden is greatest. In addition to hepatotoxicity, nausea, anorexia, and gastric intolerance are common. The main metabolite of pyrazinamide is pyrazinoic acid which competes with uric acid metabolism and causes a rise in serum uric acid. In persons with gout, the pyrazinamide may trigger an attack. In the absence of pre-existing gout, the arthralgias are different from gout and do

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not respond to the treatment of gout. The symptoms usually occur after about 6-8 weeks of therapy and are usually mild. Fortunately, therapy with pyrazinamide usually goes for only 8 weeks, so patients can usually be persuaded to continue therapy for the last few days. Aspirin may give symptomatic relief. Gastrointestinal symptoms can be a major deterrent to taking pyrazinamide. The first approach to nausea from any anti-tuberculous medications is to take them with food, or before bed, and to split the dose.

44.10.4 Ethambutol Ethambutol is the fourth major drug for the treatment of tuberculosis. It can be given for all forms of tuberculosis and may be synergistic with most medications. Soon after it was discovered ethambutol was shown to decrease the development of resistance to isoniazid and streptomycin. It is the least likely of the four major drugs to cause side effects and this favorable side effect profile also adds to its value. The dose is usually 1525 mg/kg daily. The dose for intermittent therapy is 25 to 50 mg/kg. (See Table 44.1 for dosage.) Ethambutol inhibits mycobacterial arabinosyl transferase and the synthesis of arabinogalactan, a component of the polymer core of the mycobacterial cell wall (Takayama and Kilburn 1989). Etharnbutolresistant mycobacteria have variant arabinosyl transferases and truncated lipoarabinomannans (Khoo et al. 1996). Most ethambutol resistance results from alteration of embAB gene products (Belanger et al. 1996b; Sreevatsan et al. 1997b) that cause an overproduction of arabinosyl transferase (Belanger et al.1996a). A rare but worrisome side effect of ethambutol is optic neuritis that can cause blindness. It generally occurs with doses higher than 15 mg/kg, or with renal failure. Occasionally the renal failure is unknown or develops after therapy is started. Patients at increased risk for this side effect should have their visual acuity and color vision tested. The 25 mg/kg dosage has not been shown to be more effective than the 15 mg/kg. The drug must be stopped and not restarted if visual toxicity occurs. Rash and peripheral neuropathy are also rare.

44.10.5 Streptomycin and Other Aminoglycosides Although streptomycin is still considered the fifth drug for tuberculosis, it is being supplanted by the quinolones. It was the first effective drug to be used

D. E. Schraufnagel

against tuberculosis so there is extensive experience with it. It is effective but must be given intramuscularly or intravenously. Giving it intravenously reduces the muscular discomfort and gives a higher peak level. Its broad use throughout the world has resulted in many areas developing strains resistant to it. The aminoglycosides penetrate the inner and outer membranes probably through porin channels and exert their influence by binding to bacterial ribosomes. This reduces bacterial protein synthesis and induces misreading of mRNA. There appears to be several mechanisms of streptomycin resistance (Douglass and Steyn 1993), but most arise from altered genes, e.g. rpsL, which encodes the ribosomal protein S12, and rrs, a 16S rRNA gene (Finken et al. 1993; Nair et al. 1993). These stabilize the structure formed by the 16S rRNA and confer resistance. Resistance is not uniform among the aminoglycosides and resistance to one member of the family does not necessarily mean that the organism is resistance to another. Caution should be used in renal failure, although giving after dialysis works satisfactorily. The recommended dose of streptomycin is 15 mg/ kg up to 0.5 g to 1 g daily or intermittently. The higher dose daily therapy is often restricted to the first 1-2 weeks when the mycobacterial burden is greatest. Beginning with or making an early shift to intermittent therapy reduces toxicity and may allow its use for a longer duration. A lower dose should be used for older patients especially if the companion drugs are good and the mycobacterial burden is not high. Its main problems are patients' non-acceptance because of the painful injections and the eighth nerve toxicity and to a lesser extent nephrotoxicity. Other common problems include rash, eosinophilia, and neurotoxicity. Amikacin and kanamycin are more toxic and less effective and should be used only for tuberculosis caused by organisms that are resistant to the first line anti-tuberculous drugs and sensitive to these drugs. However, these agents are less commonly used and are likely to have less resistance than streptomycin. All patients on any aminoglycoside must be followed closely with regular hearing tests. A report of balance disturbance should prompt pause or cessation of therapy.

44.10.6 Rifabutin Rifabutin is the second member of the rifamycin family. It was discovered in about 1980 (Sanfilippo et

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al. 1980) and entered the United States formulary for the treatment of M. avium in 1993. Most human studies show that it is equal to, or better, than rifampin for tuberculosis (Chan et al. 1992; Grassi and Peona 1996; Hong Kong Chest Service/British Medical Research Council 1992; McGregor et al. 1996). In a Ugandan trial of patients with tuberculosis and AIDS, patients on rifabutin had better sputum conversion at two months than those in the rifampin group (81 % compared to 48%) (Schwander et al. 1995). Rifabutin is usually not effective against tuberculosis that is resistant to rifampin. The side-effects of rifabutin are different from rifampin and patients intolerant to rifampin may take rifabutin or rifapentine. Uveitis (Tseng and Walmsley 1995) and leukopenia are common with rifabutin. Patients on rifabutin who develop new fever must have the medicine stopped at once and have an urgent complete blood count. This may be accompanied by gastrointestinal symptoms. The symptoms usually respond within a few days to withdrawal of the medication. I do not re-challenge patients with this reaction to rifabutin. The rifamycins are effective against M. avium (Nightingale et al. 1993; Sullam et al. 1994) and they should be used if it is unclear whether a patient has disease from an environmental mycobacteria rather than tuberculosis. Rifabutin is used to prevent mycobacteriosis avium in patients with AIDS (Gordin and Masur 1994) and may be used for treatment of latent tuberculosis (McGregor et al. 1996). As discussed, the rifamycins enhance the metabolism of the protease inhibitors, cyclosporine and many other drugs. The drugs that interact with the rifamycins must be carefully selected and the patients must be monitored for side effects (Center for Disease Control and Prevention 2000). Rifabutin has a lower enzyme-inducing effect than rifampin. The mechanism of action and resistance for the rifamycins is similar but the dosing is different. The standard dose of rifabutin is 300 mg daily but using half of this has been successful (Gonzalez Montane et al. 1994).

44.10.7 Rifapentine

Rifapentine is a newer rifamycin with a long half-life of about 14 hours, which makes it a candidate for twice and once weekly therapy. Trials have tested the once weekly dosing after a two-month daily course of the standard 4 drugs, isoniazid, rifampin, pyrazinamide and ethambutol. A Chinese study found daily

and twice weekly rifampin comparable to twice and once weekly rifapentine along with isoniazid, ethambutol, and pyrazinamide for eight months (Biya et al. 1992). A Hong Kong study found that the continuation rifampin and isoniazid thrice weekly was better than rifapentine and isoniazid once weekly, but the failure of the rifapentine group may have been because of decreased bioavailability of this compound that was not manufactured by the original developer (Tam et al.I997).A US Public Health Service study found continuation rifapentine and isoniazid once weekly fell short of rifampin and isoniazid twice weekly for four months in patients with AIDS. It is recognized that spacing isoniazid to once weekly may make the regimen ineffective even though rifapentine is effective for this time span. Coupling rifapentine with another effective long-acting agent might improve its efficacy. Rifapentine might be ideal for the treatment of latent tuberculosis (Chapuis et al.1994).

44.10.8 Fluoroquinolones

The quinolone family has good activity against mycobacteria. Sparfloxacin and levofloxacin appear to be superior to the older agents, ciprofloxacin and ofloxacin, in vitro (Berlin et al. 1987). Levofloxacin is less likely to cause phototoxicity than sparfloxacin but is slightly less effective in vitro and in mice Oi et al. 1995; Lounis et al. 1997; Rastogi and Goh 1991). Gatifloxacin (Alvirez-Freites et al. 2002), grepafloxacin (Mizutani 1996) and moxifloxacin (Gillespie and Billington 1999; Ii et al. 1998; Miyazaki et al. 1999; Yoshimatsu et al. 2002) also have good antituberculous activity. The quinolones act by interfering with a variety of DNA-related processes primarily through their actions on DNA gyrase, the enzyme that promotes supercoiling in bacterial DNA. Many activities of DNA including replication, transcription, and transposition are sensitive to supercoiling. DNA gyrase is a topoisomerase composed of two A and two B subunits that are encoded by gyrA and gyrB. Mutations of these genes has been shown to confer resistance in many bacterial species (Musser 1995). Although the data is limited, it appears that the quinolones are at least equal to the second line antituberculous drugs and have much fewer side-effects (Kennedy et al. 1993; Suo et al.I996).

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44.10.9 Capreomycin Capreomycin is a polypeptide antibiotic isolated from s. capreolus that is made up of four microbiologically active components. It is closely allied with the aminoglycosides in that it localized to ribosomes (Yamada et al. 1976) and can have cross resistance with kanamycin. Its dosage and side effects are similar to the aminoglycosides. Capreomycin should be used only for tuberculosis that is resistant to the first-line antituberculous drugs and known to be sensitive to it. It usually is not cross resistant with streptomycin.

44.10.10 Ethionamide Ethionamide is a thioamide derivative of isonicotinic acid and an analog of isoniazid. Similar to isoniazid, it inhibits the mycolic acid biosynthetic pathway (Schroeder et al. 2002). It is an effective agent against tuberculosis (Lees 1963), but its side effects limit is usefulness. Ethionamide is metabolized to an active product that is similar in structure to that formed by the activation of isoniazid by the catalase-peroxidase KatG. Overproduction of Rv3855 (EtaR), a regulatory protein from M. tuberculosis confers resistance to ethionamide (DeBarber et al. 2000). Ethionamide is commonly associated with nausea, vomiting, and weight loss. This may be profound. It is common and dose related. It is generally used against mycobacteria with resistance to the first-line anti-tuberculous drugs and sensitivity to it. The dose is usually 500-750 mg per day (15-20 mg/kg). There may be cross resistance with isoniazid.

44.10.11 Cycloserine Cycloserine is a structural analog of D-alanine and exerts in influence by competitively blocking the enzymes alanine racemase and D-alanyl-D-alanine synthetase (Aranda 1996). The dipeptide D-alanyl-Dalanine is essential for the synthesis of the mycobacterial wall. It is relatively weak agent with significant side effects. Its problems include psychosis, which can be subtle or severe. Paranoia, depression, delusions, and seizures are common. Blood levels may be helpful in avoiding side effects. The peak should be

D. E. Schraufnagel

between 20 and 35 f.Lglml (ATS et al. 2003). Pyridoxine (100-200 mg) should be given to reduce neural toxicity. If pyridoxine is given at a dose greater than 300 mg it may reduce the potency of the drug. Serum phenytoin level should be monitored. Cycloserine should only be used against mycobacteria that are resistant to first-line drugs and sensitive to it. It may be of value for patients with hepatitis because like the ethambutol, arninoglycosides and quinolones, it can be used in hepatic failure. The usual dose is 250 mg twice or thrice daily (10-15 mglkg).

44.10.12 Para-aminosalicylic Acid (PAS) PAS is a structural analog of para-aminobenzoic acid. Its bacteriostatic affect on M. tuberculosis results from its ability to block the conversion of para-aminobenzoic acid to folic acid. Folic acid, which is essential to purine and DNA synthesis, is made in bacterial cells from para-aminobenzoic acid (Aranda 1996). PAS is a drug of great historical significance in that it allowed the cure of most cases of tuberculosis by being the second effective agent to be discovered (Lehmann 1946). Now, it should be used only for treating drug-resistant tuberculosis. The usual dose is 8-12 g daily in divided doses. It comes as a granular form in 4 g packets that is usually mixed with juice. The unpleasant taste and nausea have caused at least one of my patients to vow never to drink orange juice again. Other side effects include bloating, anorexia, vomiting, diarrhea, weight loss, fever, rash, fluid retention, arthralgia, and eosinophilia with radiographic lung shadows.

44.10.13 Linezolid Linezolid is an oxazolidinone, a class of antibiotics that inhibit early bacterial protein synthesis. It has good anti-tuberculous activity in several models (Barbachyn et al.1996; Cynamon et al.1999a,b). I have used linezolid in a patient with multi-drug resistant tuberculosis and multi-drug intolerance and found it effective in eliminating his tuberculosis despite an inadequate intake of his all other agents. The problem with linezolid is its effect on peripheral blood cells. The agent must be stopped if unexplained leukopenia, thrombocytopenia, or anemia develops. This side effect has occurred with longer therapy, which makes its use for tuberculosis problematic. This drug should

Treatment of Tuberculosis

only be used against tuberculous organisms that are resistance to first and second-line anti-tuberculous drugs and the bacilli are known to be sensitive to it. Blood cell counts must be monitored carefully and the drug should not be given for a prolonged period. The dose is usually 400-600 mg twice daily.

44.10.14 Other Treatments Many new drugs are on the horizon (Schraufnagel 1999), but until more information is available they should be tried only when first and second line drugs have been exhausted and sensitivity in vitro has been demonstrated. Other approaches, such as immunomodulation, hold hope but are still insufficiently studied to be recommended.

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798 Mdluli K, Sherman DR, Hickey MJ, Kreiswirth BN, Morris S, Stover CK, Barry CE III (1996) Biochemical and genetic data suggest that InhA is not the primary target for activated isoniazid in Mycobacterium tuberculosis. J Infect Dis 174:1085-1090 Meyers BR, Papanicolaou GA, Sheiner P, Emre S, Miller C (2000) Tuberculosis in orthotopic liver transplant patients: increased toxicity of recommended agents; cure of disseminated infection with nonconventional regimens. Transplantation 69:64-69 Miyazaki E, Miyazaki M, Chen JM, Chaisson RE, Bishai WR (1999) Moxifloxacin (BAY12-8039), a new 8-methoxyquinolone, is active in a mouse model of tuberculosis. Antimicrob Agents Chemother 43:85-89 Mizutani S (1996) Chemotherapy of pulmonary Mycobacterium kansasii infection. Kekkaku 71:527-531 Musser JM (1995) Antimicrobial agent resistance in mycobacteria: molecular genetic insights. Clin Microbiol Rev 8:496-514 Nair J, Rouse DA, Bai GH, Morris SL (1993) The rpsL gene and streptomycin resistance in single and multiple drug resistant strains of Mycobacterium tuberculosis. Mol Microbiol 10:521-527 Nightingale SO, Cameron W, Gordin FM, Sullam PM, Cohn DL, Chaisson RE, Eron LJ, Sparti PO, Bihari B, Kaufman DL, Stern JJ, Pearce DD, Weinberg WG, LaMarta A, Siegal FP (1993) Two controlled trials of rifabutin prophylaxis against Mycobacterium avium complex infections in AIDS. N Engl J Med 329:828-833 Park IW, Choi BW, Hue SH (1997) Prospective study of corticosteroid as an adjunct in the treatment of endobronchial tuberculosis in adults. Respirology 2:275-281 Pereira-Filho RA, Seva-Pereira A, de Magalhaes AF (1985) A acetilacao da isoniazida na sindrome de Gilbert. Arq Gastroenterol 22: 172-175 Perriens JH, St.Louis ME, Mukadi YB, Brown C, Prignot J, Pouthier F, Portaels F, Willame JC, Mandala JK, Kaboto M, Ryder RW, Roscigno G, Piot P (1995) Pulmonary tuberculosis in HIV-infected patients in Zaire. A controlled trial of treatment for either 6 or 12 months. N Engl J Med 23: 779-784 Potworowska M, Sianozecka E, Szufladowicz R (1966) Ethionamide treatment and pregnancy. Polish Med J 5: 1152-1158 Rastogi N, Goh KS (1991) In vitro activity of the new difluorinated quinolone sparfloxacin (AT-4140) against Mycobacterium tuberculosis compared with activities of ofloxacin and ciprofloxacin. Antimicrob Agents Chemother 35: 1933-1936 Robinson GF, Cambon KG (1964) Hearing loss in infants of tuberculous mothers treated with streptomycin during pregnancy. N Engl J Med 271:949-951 Roullion A (1981) Centenary of the discovery of the tubercule bacillus by Robert Koch 1882-1982. Introduction. Bull Int Union Tuberc 56:83-85 Salfinger M, Crowle AJ, Reller LB (1990) Pyrazinamide and pyrazinoic acid activity against tubercle bacilli in cultured human macrophages and in the BACTEC system. J Infect Dis 162:201-207 Sanfilippo A, Della Bruna C, Marsili L, Morvillo E, Pasqualucci CR, Schioppacassi G, Ungheri 0 (1980) Biological activity of a new class of rifamycins, spiropiperdyl-rifamycins. J Antibiot 33:1193-1198

D. E. Schraufnagel Schaefer C, Amoura-Elefant E, Vial T, Ornoy A, Garbis H, Robert E, Rodriguez-Pinilla E, Pexieder T, Prapas N, Merlob P (1996) Pregnancy outcome after prenatal quinolone exposure. Evaluation of a case registry of the European Network of Teratology Information Services (ENTIS). Eur J Obstet Gynecol Reprod Bioi 69:83-89 Schatz A, Waksman SA (1944) Effect of streptomycin and other antibiotic substances on Mycobacterium tuberculosis and related organisms. Proc Soc Exp Bioi Med 57:244-248 Scheinhorn OJ, Angelillo VA (1977) Antituberculosis therapy in pregnancy. Risk to the fetus. West J Med 127:195-198 Schoeman JF, van Zyl LE, Laubscher JA, Donald PR (1997) Effect of corticosteroids on intracranial pressure, computed tomographic findings, and clinical outcome in young children with tuberculous meningitis. Pediatrics 99:226-231 Schraufnagel DE (1999) Tuberculosis treatment for the beginning of the next century. Int J Tuberc Lung Dis 3:651-662 Schraufnagel DE, Abubaker J (2000) Global action against multidrug-resistant tuberculosis. JAMA 283:54-55 Schraufnagel DE, Leech JA, Schraufnagel MEN, Pollak B (1984) Short-course chemotherapy for mycobacteriosis kansasii. Can Med Assoc J 130:34-38 Schroeder EK, de Souza N, Santos OS, Blanchard JS, Basso LA (2002) Drugs that inhibit mycolic acid biosynthesis in Mycobacterium tuberculosis. Curr Pharm Biotechnol 3:197-225 Schwander S, Rusch-Gerdes S, Mateega A, Lutalo T, Tugume S, Kityo C, Rubaramira R, Mugyenyi P, Okwere A, Mugerwa R,Aisu T, Moser R, Ochen K, M'Bonye B, Dietrich M (1995) A pilot study of antituberculosis combinations comparing rifabutin with rifampicin in the treatment of HIV-l associated tuberculosis. Tuberc Lung Dis 76:210-218 Snider DE, Graczyk J, Bek E, Rogowski J (1984a) Supervised six-months treatment of newly diagnosed pulmonary tuberculosis using isoniazid, rifampin, and pyrazinamide with and without streptomycin. Am Rev Respir Dis 130: 1091-1094 Snider DE, Jr., Long MW, Cross FS, Farer LS (1984b) Sixmonths isoniazid-rifampin therapy for pulmonary tuberculosis. Report of a United States Public Health Service Cooperative Trial. Am Rev Respir Dis 129:573-579 Sreevatsan S, Pan X, Zhang Y, Kreiswirth BN, Musser JM (1997a) Mutations associated with pyrazinamide resistance in pncA of Mycobacterium tuberculosis. Antimicrob Agents Chemother 41 :636-640 Sreevatsan S, Stockbauer KE, Pan X, Kreiswirth BN, Moghazeh SL, Jacobs WR Jr, Telenti A, Musser JM (1997b) Ethambutol resistance in Mycobacterium tuberculosis: critical role of embB mutations. Antimicrob Agents Chemother 41: 1677-1681 Stewart SM, Crofton JW (1964) The clinical significance oflow degrees of drug resistance in pulmonary tuberculosis. Am Rev Respir Dis 89:811-829 Sullam PM, Gordin FM, Wynne BA (1994) Efficacy of rifabutin in the treatment of disseminated infection due to Mycobacterium avium complex. The Rifabutin Treatment Group. Clin Infect Dis 19:84-86 SUO J, Lin TP, Chiang CY, Lee CN, Yu MC (1996) Treatment of multidrug-resistant tuberculosis in Taiwan. Chemotherapy 42 [SuppI3):20-23 Takayama K, Kilburn JO (1989) Inhibition of synthesis of arabinogalactan by ethambutol in Mycobacterium smegmatis. Antimicrob Agents Chemother 33: 1493-1499

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799 Weiss SE, Slomm PC, Blais FY, King B, Nunn M, Matney GB, Gomez E, Foresman BH (1994) The effect of directly observed therapy on the rates of drug resistance on relapse in tuberculosis. N Engl J Med 330:1179-1184 Wilson EA, Thelin TJ, Ditts PV (1973) Tuberculosis complicated by pregnancy. Am J Obstet Gynecol 115:526-529 Winder FG, Collins PB (1970) Inhibition by isoniazid of synthesis of mycolic acids in Mycobacteium tuberculosis. J Gen MicrobioI63:41-48 World Health Organization (1997) Treatment of tuberculosis: guidelines for national programmes, 2nd edn. World Health Organization, Geneva Wyser C, Walzl G, Smedema JP, Swart F, van Schalkwyk EM, van de Wal BW (1996) Corticosteroids in the treatment of tuberculous pleurisy. A double-blind, placebo-controlled, randomized study. Chest 110:333-338 Yamada T, Mizuguchi Y, Suga K (1976) Localization of coresistance to streptomycin, kanamycin, capreomycin, and tuberactinomycin in core particles derived from ribosomes of viomycin-resistant Mycobacterium smegmatis. J Antibiot (Tokyo) 29:1124-1126 Yeager RL, Monroe WE, Dessau FI (1952) Pyrazinamide in the treatment of tuberculosis. Am Rev Tuberc 65:523-546 Yoshimatsu T, Nuermberger E, Tyagi S, Chaisson R, Bishai W, Grosset J (2002) Bactericidal activity of increasing daily and weekly doses of moxiftoxacin in murine tuberculosis. Antimicrob Agents Chemother 46:1875-1879 Zhang Y, Heym B, Allen B, Young D, Cole S (1992) The catalaseperoxidase gene and isoniazid resistance of Mycobacterium tuberculosis. Nature 358:591-593

4S Directly Observed Treatment for Tuberculosis Control ZHANG LI-XING

CONTENTS 45.1 45.2 45.3 45.4 45.5 45.6

Introduction 801 Current Status of DOTS Implementation 801 Impact and Advantages of DOTS 802 Main Principles of Implementation of DOTS 805 Approaches to DOTS Implementation 806 Limitations of DOTS Strategy 808 References 808

45.1 Introduction The goals of tuberculosis control are to control infection from Mycobacterium tuberculosis, reduce morbidity of the disease and finally to eliminate tuberculosis in the community. To achieve this, the first and foremost intervention is to break the chain of transmission of M. tuberculosis by identifying the sources of infection and rendering them noninfectious by use of chemotherapy. Providing chemotherapy to infectious cases of tuberculosis is the most efficient way to interrupt transmission of M. tuberculosis (Kamat et al. 1966; Enarson et al. 2001; IUATLD 2000; Enarson 2000). More than 50 years after the introduction of chemotherapy for tuberculosis, many developing countries and areas continue to have a low cure rate, high relapse rate, development of multi-drug-resistant tuberculosis, and chronic tuberculosis excretors. Such poor treatment outcomes are mainly due to poor adherence of new smear-positive cases to treatment, which in turn is due to a poorly organized treatment program. In addition, these failures have enhanced the transmission of M. tuberculosis and worsened the tuberculosis epidemic. Improving adherence to treatment is a priority issue for tuberculosis con-

Z. LI-XING, MD President,Chinese Anti-Tuberculosis Association, 5,Dong Gang Hu-Tong, Beijing 100035, China

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

trol program. In the early 1960s, the British Medical Research Council (BMRC) successfully researched, and developed, fully supervised chemotherapy to the patient adherence to the prescribed treatment regimen (Fox 1963). In the 1980s, the International Union Against Tuberculosis and Lung Disease (IUATLD) gradually implemented this fully supervised chemotherapy in Tanzania and other African countries (Enarson 1991). In the 1990s, building on the pioneering experiences of BMRC and IUATLD, the World Health Organization (WHO) developed the directly observed treatment (DOTS) strategy (IUATLD 2000; WHO 1993). As a package, the DOTS strategy has five key components (WHO 1993): ilII Strong government commitment to sustain tuberculosis control effort; ~ Case-detection using sputum smear microscopy among symptomatic patients; " Standardized short-course chemotherapy for at least all confirmed sputum smear-positive cases, with direct observation of drug intake for at least the initial two months; • A regular uninterrupted supply of all essential anti-tuberculosis drugs; and • Standardized recording and reporting system that allows assessment of treatment results for each patient and of the overall tuberculosis control program.

45.2

Current Status of DOTS Implementation Although the DOTS strategy is widely accepted and its use has expanded from 10 countries in 1990 to 127 countries in 1999, only about 23% of the estimated smear-positive tuberculosis cases in the world was reported by programs using the DOTS strategy in 1999; this percentage is nearly the same as the 22% in 1998 (WHO 2001a,b). lWenty-two countries, with a combined population of 3.74 billion persons, have 80% of the global tuberculosis burden. In 1999, these

802

Z. Li-Xing

22 high tuberculosis burden countries had an estimated 6,621,000 new tuberculosis cases, of which 2,936,000 were new smear-positive pulmonary tuberculosis cases, and only about one-fourth cases of smear positive treated with DOTS (WHO 2001a). Today, DOTS is the most effective strategy available for tuberculosis control at the global level (Enarson 2000; Fox 1963; WHO 1993; Zhang et al. 1985, 1989, 1995, 2000a,b; Zhang and Kan 1992; China Tuberculosis Control Collaboration 1996). Expansion of DOTS should be the top priority for tuberculosis control in the world.

Cure Rate Greatly Increased: The most important benefit from implementing DOTS is the greatly increased cure rate, which is due to improved patient adherence to treatment. The cure rate of new smear-positive cases is about 50% in non-DOTS area, compared to a cure rate of 85-96% in Beijing or other areas where DOTS has been implemented (Table 45.1, Fig. 45.1) (Enarson et al. 2001; IUATLD 2000; Enarson 2000; Fox 1963; Zhang et al. 2000a; Zhang and Kan 1992). The two-year relapse rate for 4037 patients treated under DOTS in China was only 3.2% (China Tuberculosis Control Collaboration 1996). Decline in Tuberculosis Mortality Accelerated: Prior

45.3 Impact and Advantages of DOTS The epidemiology of tuberculosis is influenced by a number of factors. One is the relatively recent introduction of the DOTS strategy. Another is the introduction of the AIDS epidemic in some areas. In Beijing, the DOTS strategy has successfully operated for two decades; (Zhang et al. 1985, 1989, 1995, 2000a,b; Zhang and Kan 1992) however, the prevalence of human immunodeficiency virus (HIV) infection is still very low. Therefore, the steady improvement in tuberculosis epidemiology over the past two decades can be used to illustrate the impact of DOTS on the tuberculosis epidemic.

to the introduction of DOTS in Beijing, the annual reduction in tuberculosis mortality averaged less than 3% between 1965 and 1975. Following the introduction of DOTS in 1978, tuberculosis mortality declined more rapidly, averaging more than 7% per year (Table 45.2).

II e-cl~.s%

o.~_I.2llo _ poolM o.n. o OloclI.2llo • DeIIuIoocl

Fig.45.1. Cohort analysis of results of new smear-positive cases in China, 1991-2000

Table 45.1. Cohort analysis of treatment results among new smear-positive cases in Beijing,1985-2000 Year 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000

z

Successfully Treatment treated* % failure %

Died %

Defaulted % Transferred %

1945 1823 1808 1473 1210 1346 1219 923 764 785 819 746 786 802 764 733

85.4 87.7 89.9 92.4 90.0 89.1 94.1 93.2 95.8 92.7 91.0 96.6 90.2 90.0 92.0 91.7

4.4 8.7 5.5 3.6 4.4 3.6 2.5 2.7 0.7 1.9 0.7 1.6 3.9 2.9 2.9 3.8

3.4 2.9 3.0 2.6 3.2 5.9 2.8 3.7 2.4 3.6 4.6 0.0 4.2 5.7 4.2 2.7

5.5 0.1 0.7 0.7 1.5 0.4 0.2 0.1 0.8 1.0 2.2 0.7

1.3 0.6 0.9 0.5 0.9 1.0 0.4 0.3 0.3 0.8 1.5

1.1

0.9 0.9 1.0

0.5 0.6 0.0 0.8

17946

90.7

3.9

3.4

1.3

0.7

Total no.

0."

C OIhoto.s-.

1.1

*Includes those completing treatment with or without final sputum smear examination

803

Directly Observed Treatment for Tuberculosis Control Table 45.2. Trend in tuberculosis mortality in Beijing, 1965-2000 Year

Mortality/ Trend (%) 100,000

1965 24.9 1975 17.6 11.2 1980 1985 6.6 1990 4.2 1995 2.6 2000 1.8 1965-2000

(-29.3) (-36.4) (-41.1) (-36.4) (-38.1) (-30.0) (-92.8)

Mean trend DOT coverage % %/year -2.9 -7.3 -8.2 -7.3 -7.6 -7.1 -7.2

(45) (63) (93) (96) (92)

Rapid Decline in Tuberculosis Prevalence: Following the introduction of DOTS, the prevalence of smearpositive pulmonary tuberculosis in Beijing fell from 127 cases/l00 000 persons in 1979 to 16 cases/lOO 000 persons in 1990 - a total reduction of 87.4% and an annual reduction rate of 17.2% (Fig. 45.2) (Zhang et al. 2000a). In the World Bank-supported DOTS project in China, which covered 13 provinces half of China's population from 1991-2002, the decline in smear-positive tuberculosis prevalence was 5.7% annually between 1990 and 2000. By contrast, over the same period of time, the other half of China without this project had an annual reduction of only 1.3% in smear-positive tuberculosis prevalence (Table 45.3) (National Technic Steering Group 2002).

in 1988 in Shun-yi County, a rural county of Beijing Municipality. In 1995, all 14,420 first grade pupils (aged 6-7 years old) in all 181 primary schools in Shun-yi county were registered for standardized tuberculin testing with PPD RT23 + Tween 80. The prevalence of infection in this group of children was 1.4%. This translated to an estimated ART! of only 0.19% between 1988 and 1995 (Zhang et al. 2000b). The effective implementation and comprehensive coverage of DOTS appears to be the most likely explanation for the low risk of tuberculous infection. Additional evidence of reduced transmission of M. tuberculosis following DOTS implementation include a decline in the number of tuberculosis meningitis among children from 0-4 years-old, especially in an area without BCG vaccination for newborns (Table 45.4, Fig. 45.2). The decline in rate of tuberculosis in children, which paralleled the decline in rate of meningitis in young children, further confirms a reduction in the transmission of M. tuberculosis, especially to the younger generation (Fig. 45.3).

Reduction in Risk of Drug Resistant Tuberculosis: The aim of the modern tuberculosis control program is a rapid reduction in the transmission of M. tuberculosis and permanent cure for infectious cases through the effective application of chemotherapy. 1000

Reduction in Chronic Cases: The high prevalence of chronic infectious cases in many developing countries is one of the most difficult problems to solve in tuberculosis control. The best way to begin is to start with a well-organized and effective treatment program for new smear-positive cases in order to halt the production of new chronic cases. This is then followed by the re-treatment of previously treated cases (Zhang et al. 2000a). Following the introduction of DOTS and re-treatment for chronic cases in Beijing, the prevalence of chronic smear positive cases notified in the program decreased rapidly from 28.9 cases/lOOOOO persons in 1979 to 2.6 cases/IOOOOO persons in 1990 - an annual reduction rate of 19.7% (Fig. 45.2).

Reduction in Tuberculosis Infection Rate: The annual risk of tuberculous infection (ART!), estimated using on age-specific prevalence of tuberculous infection, is a reliable means to assess the overall epidemiological situation and can be used to evaluate the impact of DOTS. In countries with a high coverage of Bacillus Calmette-Guerin (BCG) vaccination at birth, it is very difficult to monitor the ART!. To estimate the ART! in Beijing, BCG vaccination was discontinued

..

,

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--ClvonIca

--McnIly --loIoI*lgiIII

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Fig.45.2. The association of tuberculosis indices in Beijing, 1978-1996 Table 45.3. National wide sampling survey of prevalence of smear positive pulmonary tuberculosis in China,1990-2000 Region

Standardized prevalence 1/100,000 1990

DOTS project region 142 Non-project region 130

Reduction rate(%)

Annual reduction rate(%)

44.4 12.3

5.7

2000 79 114

1.3

804

Z. Li-Xing

Table 45.4. Cases of tuberculosis meningitis in children aged 0-4 years, 1981-2000 in Beijing (other than Shun-Yi County) and Shun-Yi County Year

Beijing (other than Shun-yi county)

Shun-yi county

Meningitis cases

Meningitis cases

BCG coverage(%)

BCG+ BCG1981 1982 1983 1984 1985 1986 1987 1988* 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000

2 6 3 7 2 8 0 2 2 3 3 2 1 0 2 0 3 0 0 0

8 4 6 5 4 5 6 2 0 0 0 1 0 0 0 0 0 0 0 0

Total

46

41

BCG coverage (%)

BCG+ BCG98.5 98.1 98.6 98.7 99.3 99.1 99.1 98.9 99.3 99.7 99.1 99.5 99.9 99.9 99.9 99.2 99.1 98.9 98.4 98.5

0 0 0 1 1 1 3 1 0 0 1 0 0 0 0 0 0 0 0 0

1 0 0 0 0 0 0 0 0 1 0 1 0 0 0 0 0 0 0 0

8

3

99.0 99.6 99.2 99.7 99.9 99.9 99.9 BCG BCG BCG BCG BCG BCG BCG BCG BCG BCG BCG BCG BCG

discontinued discontinued discontinued discontinued discontinued discontinued discontinued discontinued discontinued discontinued discontinued discontinued discontinued

Abbreviations: BCG =bacillus Calmette-Guerin *BCG discontinued in Shun-yi county on July 15, 1988 u

in Beijing, the levels of initial resistance to isoniazid and streptomycin gradually decreased from 13.9% and 12.3% in 1978-1979 to 4.2% and 5.8% in 1996. Furthermore, the level of initial resistance to rifam-------.ua picin and to both isoniazid and rifampicin (MDR) ..• '"0 -I"' remained low. (Table 45.5) (Zhang et al. 1995)

.-

.0

§2I @.o

1.. CD

~10

Improvement in Case-finding: The aim of case-find-

oL---

o

--' 15

'0

Age group

U

10

Fig. 45.3. Trends in the notification of newly diagnosed sputum smear-positive tuberculosis in Beijing by age group,1980-1997

At the same time, the program aims to minimize the development of resistance to anti-tuberculosis drugs, which is a consequence of inappropriate use of these drugs in the community (National Technic Steering Group 2002). Drug-resistant tuberculosis, and multidrug-resistant tuberculosis (MDR-TB) in particular, is clearly a man-made disease and remains one of the main obstacles to tuberculosis control. It can be avoided by the effective implementation of the DOTS strategy (Zhang et al. 1995; Kimerling 2000; Fujiwara and Fine Sherman 1997). After implementing DOTS

ing is to discover the most potent sources of infection, namely those with smear-positive pulmonary tuberculosis. Passive case-finding now applied is the active search for patients with smear positive among patients with suspicious symptoms who seek health care. Case-finding is of no value by itself unless a good treatment program is available to ensure that all new smear-positive cases discovered are appropriately treated. The DOTS strategy integrates both case-finding and treatment into a single entity. When well-organized and effectively implemented, DOTS should increase the case-notification rate. Through the World Bank's Infectious and Endemic Disease Control Project, DOTS expanded rapidly to cover half of China's population in 13 municipalities, provinces and autonomous regions. The case-finding rate of new smear-positive cases notified in the proj-

Directly Observed Treatment for Tuberculosis Control Table 45.5. Trends of initially resistant anti-tuberculosis drugs (0/0) in Beijing, 1978-1996 Period

INH

SM

RMP

EMB

INH+RMP

1978-1979 1981-1982 1983-1984 1985-1986 1987-1988 1989-1990 1991-1992 1995 1996

13.9 7.8 11.6 10.0 8.1 3.9 6.8 5.4 4.2

12.3 10.8 11.3 12.7 7.3 5.8 4.2 6.0 5.8

0.4 0.3 1.2 2.4 1.9 1.7 2.7 2.5

0.4 0.7 0.4 1.6 0.6 1.7 1.3 0.8

0.4 0.3 0.0 1.6 0.0 0.0 0.7 0.8

805

Treatment costs under DOTS were a tenth to a twentieth the cost with traditional (including in-patient) care. According to one study, the rate of relapse or acquired resistance with DOTS occurred in only 1.2% of patients and accounted for 6.0% of cost. In comparison, relapse or acquired resistance occurred in 10.9% of patients and accounted for 35.7% of cost with traditional care (Weis et al.1999). With DOTS, $5.5 could save one disability-adjusted life year (DALY) whereas $57.5 is needed to save one DALY in a program without DOTS (Xu Qun et al. 2000).

INH=isoniazid; SM=streptomycin; RMP=rifampicin; EMB=ethambutol

ect increased from 9.1 cases/100,000 persons in 1992 to 28.5 cases/lOO,OOO persons in 2000. In comparison, the case rate in the other half of China that lacked a comprehensive DOTS program increased from 7.1 cases/100 000 person in 1992 to 9.8 cases/100 000 persons in 2000 (Fig. 45.4). There are a number of reasons for much higher case-finding in the above DOTS program. First, free diagnosis and treatment was provided to all patients with smear-positive pulmonary tuberculosis. Second, the project cured a high percentage of its patients. Third, the program was easily accessible to patients and good services attracted patients with symptoms to seek health care in the project. Fourth, comprehensive training was provided to health personnel working at various levels. Fifth, the project raised the health care workers' awareness of tuberculosis and its related symptoms. Sixth, health promotion on tuberculosis and its treatment was provided to the public.

45.4 Main Principles of Implementation of DOTS To achieve the impact of DOTS on tuberculosis control and to reach global tuberculosis control targets - ensure at least 70% of estimated smear-positive pulmonary cases are detected and 85% of smearpositive pulmonary cases are cured - the following key principles of DOTS implementation should be implemented:

Government Commitment: Governments should give high priority in order to intensify tuberculosis control effort; the national tuberculosis program (NTP) should be provided with sufficient financial support to sustain the implementation of DOTS; it should formulate and implement laws and regulations related to tuberculosis control, and build the capacity to implement DOTS at different levels. Nationwide Coverage: The DOTS strategy should

Cost Effective Approach to Tuberculosis Control: Several studies have clearly demonstrated that DOTS is the most cost effective approach to control tuberculosis (Murray et al. 1991; Xu Qun 2000; Weis et al. 1999).

••

21.0'1

n."

U.M

cover and be implemented in the entire country, especially the rural area.

National Tuberculosis Program (NTP): Implementation of DOTS nationwide can only be conducted successfully within the context of a NTP. This serves to ensure a permanent and sustainable tuberculosis control program.

11.51

.OOTS_ ._OOTS_

Emphasis Place on Smear-positive Pulmonary Tuberculosis: The control of the most potent sources of transmission of M. tuberculosis, namely smear-positive pulmonary tuberculosis, should be the highest priority.

Year

Fig.45.4. The rate of new smear-positive cases registered by the DOTs project in China,1992-2000

Ambulatory Chemotherapy: The control program should fully utilize the powerful weapon of directly observed treatment with short-course ambulatory

806

Z. ii-Xing

chemotherapy. At the very least, this should be provided free of charge to every smear-positive case of pulmonary tuberculosis.

Primary Health Care: It is essential to have a wellfunctioning primary health care system to effectively implement DOTS. DOTS can be integrated with primary health care or community health care.

45.5 Approaches to DOTS Implementation Organizational Structure: A good nationwide system of health services is essential for the effective implementation of DOTS. DOTS should be incorporated into and should fully utilize the existing health care system. DOTS implementation should enhance health sector development, and vice-versa. The functions of DOTS at different levels of the health sector are shown in Table 45.6. Demonstration Area: At the start of DOTS implementation, it is useful to establish a demonstration area to pilot various aspects of DOTS. A country can be chosen to obtain first-hand experience in DOTS implementation. Thereafter, DOTS can be carefully expanded. Although the main principles of DOTS are the same everywhere, approaches in implementation can be adapted to local conditions. A carefully selected program manager should be responsible for the demonstration project. The objectives of this pilot project include the following: establish a well-functioning health section system for DOTS implementation; determine the acceptability, feasibility and practicality of DOTS; and to determine the effective of treatment under local conditions.

Training Course: The DOTS strategy is whole new approach to tuberculosis control for many health

care personnel. To implement DOTS, it is essential for health care personnel at all levels to have a thorough knowledge and a clear understanding of the principles and elements of DOTS. This is especially important to convince senior level doctors that DOTS is an advance in tuberculosis control and has a sound scientific basis. In addition, it is important to orient health care workers to the public health approach to tuberculosis control. Proper training courses should contain the following: Government commitment to tuberculosis control; smear-positive pulmonary tuberculosis cases are the most infectious cases; passive case-finding in tuberculosis; standardized treatment regimens for tuberculosis; sputum examination for the diagnosis of tuberculosis; and how to implement DOTS.

Patient Education Prior to the Start of Treatment: Whenever a patient has symptoms suggestive of pulmonary tuberculosis, sputum specimens should be collected and examined by microscopy to look for acid-fast bacilli (AFB). If AFB is detected, the patient is confirmed to have smear-positive pulmonary tuberculosis. Prior to the start of treatment, it is important for the patient and his, or her, family members to be educated on the following issues: IJ Tuberculosis is an infectious disease and is spread through the air 1II Purposes of chemotherapy for tuberculosis are to cure the disease, to reduce relapse after treatment completion, and to prevent transmission of M.

tuberculosis llII

~ (\I

Main reasons for treatment failure Effectiveness of DOTS How DOTS is performed in detail How to receive directly observed therapy and cooperate with health personnel

At the same time, the health care personnel, frequentlya nurse, should try to understand the following issues:

Table 45.6. DOTS function at different level of health sector Level

Function in DOTS

National

Policymaking, NTP Planning, Budget, Manual of program, Training, Reference laboratory Quality control smear Supervision Supplies of drugs and Materials, Center registration, microscopy, Culture and susceptibility for TB Manual of DOTS

State or provinces

Training, supervision, Supplies of drugs and materials, Center registration, Quality control, Pilot study

District or Determine regimen, Implementing DOTS Maintaining supplies of drugs, Supervision, Training, Registration county PHC

Directly observed treatment, Make up with treatment, Registration

Reference laboratory Quality control of smear microscopy, culture and susceptibility for TB Smear microscopy Collect sputum specimen

Directly Observed Treatment for Tuberculosis Control

• Any obstacles for the patient to receive DOTS • How to solve any problems that patient may have during treatment On average, about 20 minutes is needed to educate the patient and family members. By spending the time, the health care worker gains the trust of the patient and treatment is more likely to be successful.

Standardized Regimen of Chemotherapy: Standardized chemotherapeutic regimens, as recommended by WHO and IUATLD, are based on rigorous, multicenter, scientific studies conducted under various settings. These regimens have high efficacy, low toxicity, good tolerability, and low cost. The following standardized regimens of chemotherapy are used in the DOTS program in China: For new smear positive pulmonary tuberculosis, 2H3R3Z3E3/4H3R3: Isoniazid (H): 600 mg,Rifampicin (R) 600 mg,Pyrazinamide(Z) 2000 mg and Ethambutol (E) 1250 mg or Streptomycin (S) 750 mg given every other day for two months and followed by four months of Hand R given every other day. For smear-positive relapsing cases and others re-treatment cases, 2H 3 R3 Z3 S3 E3/6H 3R3E3. Supervised Chemotherapy: To ensure that DOTS is provided conveniently to patients, a health care worker should address the following issues with each patient: • Chose the supervisor who will supervise the intake of medication; this is usually a health care personnel working in the primary health center. • If the supervisor is not a health care personnel, special training should be provided to this supervisor. • Decide on the time and venue for supervision of drug intake. This should be based on what is convenient for the patient, e.g. at a primary health center, home or work site. The supervisor is responsible for observing the intake of every dose of drugs. Every supervised dose should be recorded on the treatment card. If a patient fails to attend a supervised dose, the supervisor should take immediate action, including calling the patient or going to the patient's home to find out the reason for the missed dose, then make up the treatment on the same day. To avoid re-sale of drugs by patients, drugs should be kept by the supervisor and the amount of drugs remaining should be compared with the treatment card.

Full DOTSfor Entire Duration ofShort-course Treatment: During the initial phase of treatment, patient adherence may be good because patients are still symptomatic.

807

However, by the end of the second month of treatment, the rate of patient non-adherence often increases as symptoms are resolving. Because the completion of the entire 6-8 months of short-course chemotherapy will significantly improve cure and reduce relapse rate, every smear-positive case should be encouraged to complete the full course of treatment. In many areas, a patient's home may be far from the primary health care center or the area may not even have a health care center. This is especially common in remote rural and mountainous areas. In these areas, DOTS can only to given for the first two months (intensive phase) of treatment and then the patient can self-administer their TB drugs during the remaining months of treatment.

Quality Control of DOTS: To ensure that patients are really complying with DOTS and that they are completing the full course of treatment, supervision at different levels should be carried out on a regular basis. To maintain the quality of DOTS, a team from the state or province level should makes random visits to patients, to the village health posts, and to the district tuberculosis centers to check the treatment cards, the amount of remaining drugs and collect urine specimen from patients to test for the metabolites of anti-tuberculosis drugs.

Advocacy: Effective advocacy and social mobilization is necessary for successful DOTS implementation.

Assessing Results ofDOTS: Evaluation of DOTS implementation is very important to maintain and improve the program. The use of independent experts and the collection and analysis of program data is the best way to evaluate DOTS. The following data are important to analysis: • DOTS detection rate: The percentage of estimated new smear-positive cases detected in a DOTS program is an important indicator to evaluate the NTP. • Sputum conversion: All initial sputum smearpositive cases have to submit sputum specimens for repeat smear examination at end of the second month of treatment. The percentage of patients with no AFB found on smear examination is another important indicator. • Cohort Analysis: A cohort analysis is conducted at end of each year to evaluate treatment outcome for all smear-positive cases, including those treated under DOTS and on self-administered therapy. For the cohort analysis, treatment outcomes include cure, treatment completion, treatment failure, death, transfers and treatment default. The percentage of

808

treatment failure, which should be less 5%, provides an indication of the efficacy of the regimen and the level of resistance to anti-tuberculosis drugs.

Logistic Supply: High quality anti-tuberculous drugs, microscopes, and transportation tools should be available in a timely manner.

45.6 Limitations of DOTS Strategy In Beijing, results from the prevalence survey conducted between 1979 and 1990 showed a consistent decline in the prevalence of smear-positive tuberculosis (Fig. 45.1). However, the trend in notified rate of new smear-positive pulmonary tuberculosis is different. The notified rate showed a slight increase in the early years after the introduction of DOTS. After 1987, the rate began to decline but then leveled off and did not change between 1993 and 2000. This likely reflects that the fact that the majority of new cases are the result of endogenous reactivation of old tuberculous infections. A consistent decline in tuberculosis incidence will require a sustained effort to implement DOTS. Over the long term, the implementation of DOTS can be influenced by many factors including political change, social-economic reform, health sector reform, health personnel or program director change, and other unpredictable events. It is not easy to implement DOTS strategy for a sustained period. It is also difficult to cover and reach all populations and areas in large countries with a DOTS program because of socio-cultural, religious, geographical, and people-related barriers. From a technical perspective, there are some disadvantages and limitations to the current DOTS strategy. For instance, it does not deal with those with tuberculous infection, treatment duration is too long, and it does not adequately address MDR-TB and the HIV-TB co-epidemic. For these and other new challenges, new diagnostic tests, new drugs and new vaccines are needed in the fight against tuberculosis.

References China Tuberculosis Control Collaboration (1996) Results of directly observed short-course chemotherapy in 112 842 Chinese patients with smear-positive tuberculosis. Lancet 348:358-362 Enarson DA (1991) Principles of IUATLD collaborative tuberculosis programmes. Bulllnt Union Tuberc Lung Dis 66:195-199 Enarson DA (2000) World tuberculosis control: how far have we to go? Int J Tuberc Lung Dis 4:s219-s223

Z. Li-Xing Enarson DA, Beyers N, Zhang LX (2001) The tuberculosis pandemic today: routes of transmission and new target groups. Scand J Infect Dis 33:9-12 Fox W (1963) Ambulatory chemotherapy in a developing country: Clinical and epidemiological studies. Adv Tuberc Res 12:28-149 Fujiwara PI, Fine Sherman L (1997) Multidrug-resistant tuberculosis: many paths, same truth (editorial). Int J Tuberc Lung Dis 1:297-298 IUATLD (2000) Management of tuberculosis: a guide for low income countries, 5th edn. International Against Tuberculosis and Lung Disease Kamat SR et al (1966) A controlled study of the influence of segregation of tuberculosis patients for one year on the attack rate of tuberculosis in a 5-year period in close family contacts in South India. Bull WHO 34:517-532 Kimerling ME (2000) The Russian equation : an evolving paradigm in tuberculosis control. Int J Tuberc Lung Dis 4:S160-S167 Murray CJL et al (1991) Cost effectiveness of chemotherapy for pulmonary tuberculosis in three sub-Saharan African countries. Lancet 338: 1305-1308 National Technic Steering Group of the Epidemiological Sampling Survey for Tuberculosis (2002) Report on fourth national epidemiological sampling survey of tuberculosis. Chin JTuberc Respir Dis 25:3-7 Weis SE, Foresman B, Matty KJ et al (1999) Treatment costs of directly observed therapy and traditional therapy for Mycobacterium tuberculosis: a comparative analysis. Int J Tuberc Lung Dis 3:976-984 WHO (1993) Treatment of tuberculosis: guidelines for national programmes. World Health Organization, Geneva WHO (2001a) Global tuberculosis control, WHO report 2001 (WHO/CDS/TB/2001.287). World Health Organization, Geneva WHO (2001b) The global DOTS expansion plan. Communicable Disease Information Resource Center. World Health Organization, Geneva World Health Organization! International Union Against tuberculosis and Lung Disease (1997) Anti-tuberculosis drug resistance in the world. WHO/TB/97.229, Geneva, p 227 Xu Qun, Jin Shuigao, Zhang Lixing (2000) Cost-effectiveness of DOTS and non-DOTS strategy for smear-positive pulmonary tuberculosis. Bull Chin Antituberc Assoc 22:60-62 Zhang LX, Kan GQ (1992) Tuberculosis control program in Beijing. Tubercle Lung Dis 73:162-166 Zhang LX et al (1985) Supervised intermittent chemotherapy for pulmonary tuberculosis in a rural area of China. Tubercle 66: 1-7 Zhang LX, Kan GQ, Liu CW (1989) A model of fully supervised chemotherapy for pulmonary tuberculosis in the tuberculosis control program in a rural area of China. Bull Int Union Tuberc Lung Dis 64:20-21 Zhang LX et al (1995) Trend of initial resistance of tubercle bacilli isolated from new patients with pulmonary tuberculosis and its correlation with tuberculosis program in Beijing. Tubercle Lung Dis 76:100-103 Zhang LX et al (2000a) Risk of tuberculosis infection and tuberculous meningitis after discontinuation of Bacillus CalmetteGuerin in Beijing. Am J Respir Crit Care Med 162:1314-1317 Zhang LX, Tu DH, Enarson DA (2000b) The impact of directly observed treatment on the epidemiology of tuberculosis in Beijing. Int J Tuberc Lung Dis 4:904-910

46 Multi-Drug-Resistant Tuberculosis PETER D.

O. DAVIES

CONTENTS 46.1 46.1.1 46.1.2 46.1.3 46.2 46.2.1 46.2.1.1 46.2.1.2 46.2.2 46.3 46.4 46.4.1 46.4.2 46.4.3 46.4.4

46.4.4.1 46.4.4.2 46.4.4.3 46.5 46.5.1 46.5.2 46.5.2.1 46.5.3 46.5.3.1 46.5.3.2 46.6 46.6.1 46.6.2 46.6.3 46.6.4 46.6.5 46.6.6 46.6.7 46.6.8 46.6.9 46.6.10

The Epidemiology of Multi-Drug-Resistant Tuberculosis 809 Definitions and Causation 809 Global Epidemiology of Drug-resistant TB 810 Impact of SCC on the Treatment of Drug-resistant TB 811 Examples of Important Areas of MDR-TB 812 India 812 DOTS and its Impact in India 813 Practical Problems DOTS Faces In India 813 MDR-TB in Africa 814 Drug Resistance in Prisons 816 The Microbiology of Drug-Resistant Tuberculosis 816 Molecular Diagnostic Techniques 816 Molecular Testing for Drug Resistance 817 Rapid Tests in Routine Use 819 How the Sequencing of the Mycobacterial Genome Will Help the Development of New Drugs in the Treatment of Tuberculosis 819 Breaching the Wall of "Fortress Mycobacterium" 819 In Vivo Phenotypes: Targeting Persistent Organisms 820 Latent Tuberculosis 821 The Treatment of MDR-TB 821 Introduction 821 Management of Non-MDR Resistance 822 Isolated Resistances 822 Multi-Drug-Resistant Tuberculosis 822 Infection Control 823 Clinical Management 823 Tuberculosis and HIV Infection 824 Introduction 824 HIV and TB 824 MDR-TB Outbreaks 824 Treatment 825 Alternative Therapies 825 Contacts 825 Prognosis and Predictors 825 Sporadic MDR-TB in HIV 826 The Financial Challenges of MDR-TB 827 Different Countries, Different Problems, Different Expectations 827

P. D. O. DAVIES, DM, FRCP Director, Tuberculosis Research Unit, Cardiothoracic Centre, Liverpool Ll4 3PE, UK

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

46.6.11 The Individual Patient with MDR-TB 828 46.6.12 The Consequences for Others 829 46.6.13 Implications for Public Health and the Wider Economy 829 46.6.14 Is There One World Message After All? 830 46.6.15 Transmission of MDR-TB 831 46.7 Conclusions 832 References 833

46.1 The Epidemiology of Multi-Drug-Resistant Tuberculosis 46.1.1 Definitions and Causation Drug-resistant tuberculosis and, particularly, multidrug-resistant tuberculosis (MDR-TB; defined as strains of M. tuberculosis resistant to at least isoniazid and rifampicin, the two most powerful anti-TB drugs), have recently received heightened attention in the media. This has not only helped advancement within the field of MDR-TB, but it has also brought TB to the forefront of discussions in public health. Drug resistance in TB is primarily created by two man-made mechanisms. The first is erroneous prescribing practices combined with the inability to implement systems of patient adherence to treatment. This is often seen when private practitioners are not fully aware of TB control procedures (Mahmoudi and Iseman 1993). For instance, one study in India revealed 80 different treatment regimens were being recommended for difficultto-trace patients in a single slum in Bombay (Uplekar and Shepard 1991). The second is patient-related, as they fail to follow the prescribed regimen, or are affected by other diseases (such as co-infection with HIV) that interfere with the mechanisms of anti-TB drugs (Kochi et al. 1993). These factors place selective pressure upon the bacilli in a patient, thereby increasing the growth of resistant bacilli (Pablos-Mendez and Lessnau 2000). However, these two factors simply reflect the principle that drug resistance tends to

810

arise when national TB programmes do not adhere to international recommendations for TB control (World Health Organization 1997).

46.1.2 Global Epidemiology of Drug-Resistant TB Since 1994, the World Health Organization (WHO) and the International Union Against Tuberculosis and Lung Disease (IUATLD) have conducted a global project on drug resistance surveillance. The project builds upon international recommended methods for drug resistance surveillance and drug susceptibility testing to four first-line anti-TB drugs: isoniazid, rifampicin, ethambutol, and streptomycin (World Health Organization 1997a,c). The project distinguishes between drug resistance among new cases (the presence of resistant strains of M. tuberculosis in a newly diagnosed patient who has never received TB drugs or has received them for less than one month of treatment) and drug resistance among previously treated cases (presence of resistant strains of M. tuberculosis in a patient who has previously received treatment for at least one month) (World Health Organization 2000a). Data from the two surveys conducted in 1994-1997 and 1997-2000, respectively, confirm the existence of drug resistance among new cases in all countries surveyed. Data also show that MDR-TB is present in 58 of 67 sites surveyed {Pablos-Mendez et al. 1998; Espinal et al. 200l}. In the most recent survey (l9972000) the median prevalence of drug resistance among previously treated cases was 10.7% (range 1.7-36.9%), and the median prevalence of MDRTB among new cases was 1.0% (range 0-14.1%). The median prevalence of resistance to each drug was as follows: isoniazid - 6.2%, rifampicin - 1.2%, ethambutol - 0.6%, streptomycin - 5.2%. Surveys in countries such as Botswana, Cuba, Chile, Slovenia, Uruguay, Venezuela showed low prevalence of drug resistance among new cases. This was expected, as these countries are also known for the high quality of their TB control programmes. However, surveys in other countries demonstrated higher levels of drug resistance among new cases. These countries include those of the former Soviet Union (Russia, Estonia, and Latvia) Bolivia, Thailand, Sierra Leone, and some settings in China and India. The WHO/IUATLD Global Project has revealed the existence of several 'hot spots' for MDR-TB (defined conventionally as those where the prevalence of MDR-TB among new cases was 3% or above) including Dominican Repub-

P. D. O. Davies

lie, Estonia, Iran, Ivory Coast, Latvia, Mozambique, and selected areas in China, India, and the Russian Federation {Table 46.l}. Trends analysis from those countries that had more than one survey done over the years clearly outlines the importance of sound TB control practices in preventing the emergence of drug resistance. For instance, Cuba and Chile have successfully implemented the DOTS strategy for more than 20 years (World Health Organization 2001). As a result, Cuba had a prevalence of MDR-TB among all TB cases varying from 0 to 1% between 1995-1998, and Chile maintained a prevalence of MDR-TB of less than 1% from 1980-1998. However, Ivanovo Oblast in the Russian Federation reported a prevalence of MDRTB of 6% in 1995, reaching 9% in 1998. In the case of Estonia, an even more alarming situation has been described where MDR-TB among new cases gradually increased from 10% in 1994 to 14% in 1998. Given the recent trend of international migration and the potential spread of MDR-TB across continents (Becerra et al. 1999) industrialised countries have begun to examine national policies ofTB control in foreign-born populations (Talbot et al. 2000). The WHO/IUATLD project also attempted to determine if foreign-born populations, generally immigrating from high TB prevalence areas, have a higher or lower level of MDR-TB than indigenous populations. Not surprisingly, all industrialised countries examined showed a higher prevalence of drug-resistance among foreign-born new cases. A similar trend was observed with MDR-TB among foreign-born new cases (Gilad et al. 2000). Previously treated cases have a much higher likelihood of being infected with drug- resistant strains, mostly due to acquiring resistance during improper treatment in the past (World Health Organization 1997d). In the most recent survey (l997-2000) the median prevalence of resistance among previously treated cases was 23.3% (range 0-93.8%), and that of MDR-TB was 9.3% (range 0 - 48.2%) (Espinal et al. 2001). However, recognising that some of these cases were infected with drug-resistant TB or MDR-TB at the outset, the term 'acquired resistance' was abandoned after the first survey and replaced with 'resistance among previously treated cases'. The use of 'acquired resistance' should be limited to settings that possess the capability (technically and financially) to perform drug-susceptibility testing and DNA fingerprinting on all new TB cases. This is in order to determine if a resistant strain, once isolated in a case for re-treatment, is the same one that produced the disease in the previous episode and acquired drug

811

Multi-Drug-Resistant Tuberculosis Table 46.1. Drug resistance in patients with no history of prior treatment expressed as a percentage of cases Country

Year

Sample Overall

Resistance to 1 drug

Benin Botswana Botswana Cameroon Central African Republic Ethiopia Ghana Guinea Ivory Coast Kenya Lesotho Mozambique Sierra Leone Sierra Leone South Africa (Hlabisa) South Africa (Mpumalanga) Swaziland Uganda Zimbabwe

94-97 94-97 1998 1995 1999

333 407 638

1995

167

1998 94-97 94-99 94-97 1999 94-97 1997 1996

539 320 445 330 1028 463 117

1997

661

94-97 1997 94-96

224 374 676

464

poly-resistance

2 drugs 3 drugs 4 drugs

any

MDR

6.0 3.4 5.3

2.1 0.2 0.8

0.3 0.0 0.2

0.0 0.0 0.00

2.4 0.2 0.9

0.3 0.2 0.5

10.8

3.7

1.7

0.2

5.6

1.1

9.8 5.3 5.4 6.1 12.2 16.6 17.9

4.3 6.3 0.9 2.4 5.8 10.2 6.0

0.6 1.6 0.0 0.3 2.3 1.1 0.9

0.0 0.3 0.0 0.0 0.5 0.2 0.0

4.8 8.1 0.9 2.7 8.7 11.4 6.8

0.6 5.3 0.0 0.9 3.5 1.1 0.9

8.0

5.9

1.2

0.5

0.5

2.1

1.5

11.7 19.8 3.3

12.8 1.3

6.7 1.2

0.3 0.1

0.0 0.6

7.0 1.9

0.5 1.9

8.4 3.7 6.3 31.8 16.4 15.6 54.5 14.7 13.4 6.3 8.8 20.8 28.1 24.8 8.9

resistance during treatment, or whether it is a new strain that re-infected the patient after the first episode was diagnosed and tested.

46.1.3 Impact of see on the Treatment of Drug-ResistantTB SCC recommended as part of the DOTS strategy can generate treatment success rates as high as 98% in new cases (Fox 1981). However, this high level of cure was observed in settings with minimal levels of primary drug resistance. Among cases resistant to a single drug, SCC may achieve cure rates as high as those in pan-susceptible cases. Evidence also suggests that for new cases of TB resistant to one or more anti-TB drugs, including isoniazid, ethambutol, or streptomycin, rates of failure are comparable to those of new drug-susceptible cases. However, new cases of TB resistant to rifampicin experience significantly higher failure rates than drug-susceptible cases (Mitchison and Nunn 1986; Espinal et al. 2000). For patients with MDR-TB, SCC is not appropriate for treatment (Table 46.2) (Espinal et al. 2000). In settings where effective DOTS is implemented (Korea, Peru, Hong Kong), the cure rate achieved with SCC is no greater than

59% in new MDR-TB cases as compared to 85-89% among new drug-susceptible cases and 76-87% among new isoniazid resistant (non-MDR) cases. For regions and countries with generally poorer TB control programmes (Ivanovo Oblast of the Russian Federation and the Dominican Republic) cure rates in MDR-TB cases range from 10 to 20% (Espinal et al. 2000). As expected, increasing levels of resistance correlate directly with decreasing rates of treatment success (Coninx et al. 1999). For MDR-TB cases, failure rates to SCC have reached up to 40% in some settings (Espinal et al. 2000). Not only do these cases continue to remain infectious, but also such cases may undergo amplification of resistance to the drugs to which they were exposed in the regimen on which they failed (Farmer 1999). This 'amplification' phenomenon is simply the well-described mechanism of acquired drug-resistance. In conclusion, these data indicate that alternative strategies for the management of MDR-TB cases, including use of regimens containing second-line anti-TB drugs, should be considered in those settings where MDRTB is frequent and where there is need to treat cases at a programmatic level (Espinal et al. 1999). WHO and its partners are currently piloting a strategy called 'DOTS-Plus' that aims to develop global policy recommendations for the management of MDR-TB with second-line anti-TB drugs (World

812

P. D. O. Davies

Table 46.2. Levels of drug resistance to each drug in selected African countries Country

Benin Botswana Botswana Cameroon CAR Ethiopia Ghana Guinea Ivory Coast Kenya Lesotho Mozambique Sierra Leone Sierra Leone South Africa (Hlabisa) South Africa (Mpumalanga) Swaziland Uganda Zimbabwe

Year

Sample size

INH

RMP

EMB

SM

mono any

mono any

mono any

mono any

1999

333 407 638

3.3 1.2 3.6

5.4 1.5 4.4

0.0 0.7 0.2

0.3 1.0 0.6

0.0 0.0 0

0.6 0.0 0.2

2.7 1.5 1.6

4.8 4.5 2.2

1998

464

4.1

9.5

0.2

1.3

0.0

2.4

6.5

11.0

1998

1997

539 320 445 330 1028 463 117

4.5 3.1 5.4 5.2 7.9 2.6 3.4

9.3 11.3 6.3 7.9 16.5 13.0 10.3

0.2 0.0 0.0 0.0 1.8 0.2 0.0

0.7 5.3 0.0 0.9 5.3 1.3 0.9

0.0 0.0 0.0 0.0 0.0 0.6 0.0

0.6 0.3 0.0 0.0 0.5 2.4 0.0

5.2 2.2 0.0 0.9 2.5 13.0 14.5

9.5 6.9 0.9 0.3 10.5 24.0 21.4

1997

661

3.5

5.6

0.2

1.7

0.0

0.5

2.3

3.8

1997

334 374 676

3.9 6.2 6.7

9.0 12.5 20.0

0.0 2.0 1.1

0.9 5.8 3.6

0.3 3.0 0.2

0.9 8.0 1.1

2.4 5.6 11.1

7.2 11.2 24.1

1999

Health Organization 2000b). This strategy must be based on the existence of an effective DOTS programme. (See below)

46.2 Examples of Important Areas of MDR-T8 46.2.1 India

The epidemiology of tuberculosis in India is bedevilled by a number of confounding factors. Notification is seldom if ever performed, few laboratories in the country reliably perform sensitivity testing, laboratory techniques are not standardised, and most existing Indian studies fail to reliably distinguish primary from secondary drug resistance. Indeed, India's TB data recording is woeful. In a study by Raviglione, India was the only one of eight world regions with less than 2% of its population covered (in 1997) by WHO control strategy (Raviglione et al. 1997). It was also the region with the worst kept data on case holding, cure, and outcome rates. These provisos must be kept in mind when the epidemiology of MDR-TB is discussed. India fared poorly in the two global studies on MDR-TB conducted by the WHO/ IUATLD Global

Surveillance Project. In the first conducted by Cohn et aI., Indian MDR-TB rates in the four Indian studies included in this Medline search, varied from 0.9% in Jaipur to 33.8% in Gujarat (Cohn et al. 1978). These rates were the second highest worldwide after Nepal. However this study can be criticised for including only 7939 isolates from four laboratories of widely varying standards. Besides, primary resistance was not reliably distinguished from secondary resistance in any of these samples. The second study, conducted by Pablos-Mendez was a major global co-ordinated effort including data as it did from 35 countries between 1994 and 1997. Here too, India emerged with the second highest MDR rates globally after Latvia (Pablos-Mendez et al. 1998). The combined MDR-TB rate from India was 13.3%. This study too can be criticised for including small numbers of isolates (2240) from only one region in the country (New Delhi). Again, as in Cohn's study, primary resistance could not be reliably distinguished from acquired resistance. Both these global studies probably under-estimate the extent of the MDR-TB problem in India. A closer search reveals several other Indian MDR prevalence studies, with primary prevalence rates varying from 0.9% to 36.6% and acquired resistance rates varying from 6.3 to 56.6% (Gothi and Sen 1996). The highest prevalence rates ever reported have been from centre at the Hinduja hospital in Bombay (Udwadia et al.

813

Multi-Drug-Resistant Tuberculosis

1996). Here, Level 2 mycobacterial laboratory, which serves as a reference lab for the teeming metropolis of Bombay, currently reports around 60% of all isolates it receives as MDR. 46.2.1.1 DOTS and its Impact in India

Most DOTS principles originated in Indian studies that emerged from research arising from the Tuberculosis Research Centre in Madras and the National Tuberculosis Institute in Bangalore (Bayer and Wilkinson 1995). These two centres contributed truly pioneering research in the 1950s and 1960s that helped shape not only India's TB control programmes but also those of many developed nations. It was in 1993 that DOTS began in India, starting with pilot studies covering 2.35 million people in five states. The numbers covered have steadily increased so that 250 million were covered by the end of 2000, and further cover of 100 million people each year is planned, until the entire population is eventually covered. This makes the Indian DOTS programme the second largest in the world after China. Case detection rates are higher than those reported from China and Bangladesh and success rates are comparable to those from South East Asia and Africa. Where DOTS is used in India, TB patients are twice as likely to be cured. Where DOTS is not used patients are seven times more likely to die of TB. A recent report by reveals that detection rates in all Indian states have steadily increased over time with treatment outcomes also steadily improving from 72% in 1993 to 90% in 2000. Overall failure rates run at an impressive 3.5%, default rates at 9% and death rates at 4% (Khatri and Frieden). Thus the initial gains made by DOTS in India have undoubtedly been impressive but it is doubtful if the success of DOTS can be sustained to cover the entire country. In the words of Mukund Uplekar, noted TB health researcher; "DOTS will be as good and as effective as the general health services in the country:' Thomas Frieden, while WHO director S.E. Asia, is cautiously optimistic about DOTS but admits; "The key challenge is to balance the urgent need for rapid expansion with the paramount importance of ensuring quality of implementation:' 46.2.1.2 Practical Problems DOTS Faces In India 1. A verifiable address is mandatory before an Indian

patient can be registered at an Indian DOTS centre.

Where does that leave the homeless, the slum dweller, the pavement dwellers and the migrants that form up to 50% of the population of some big Indian cities like Bombay? 2. Women are more hesitant to attend DOTS centres in India finding them too obtrusive. Indeed tuberculosis in India robs Indian women of the little respect and standing they have in society. Visiting a DOTS clinic is something Indian women are reluctant to do for fear of being stigmatised further. It is less conspicuous for them to visit a private doctor and as a consequence many Indian DOTS clinics have skewed male to female ratios of 3:1.

3. 'Difficult' patients seem to be deliberately weeded out in an attempt to make results appear more impressive. Thus, the alcoholics, the drug addicts and the marginalized whom DOTS centres should be striving to incorporate find themselves being excluded. 4. Patients complain that DOTS clinic hours are too rigid and inflexible. A daily-wage labourer often ends up going without pay, and his family therefore without food on the days they visit a DOTS clinic. Travelling large distances across harsh terrain in a country as vast as India is a real problem in DOTS clinics located in more remote parts of the country. This becomes particularly difficult for the old, the sick, the invalid and the poor. The incentives, which are an important component of DOTS programmes in the developed world, are an unaffordable luxury in India. 5. Private patients are outside the purview of DOTS. Private practitioners rarely refer their patients to DOTS centres, as this would mean loss of control. Since at least 50% of TB patients would choose to first visit a private practitioner over attending a government clinic a large segment of the population is excluded. 6. The extra workload imposed by DOTS may overwhelm the system. The pre-DOTS system struggled to cope with the large numbers of patients it faced. Each patient registered at a DOTS clinic needs 40 episodes of supervision over the course of his or her six-month SCC. This may prove an unmanageable additional load that under-staffed and under-funded DOT centres may eventually buckle under the strain. Successful implementation of DOTS would need much more in terms of staff, infrastructure and funds than can be presently afforded. This is currently estimated to run into an incremental recurrent cost of $100 million a year.

814

46.2.2 MDR-T8 in Africa A total of 80 % of all the reported incident cases were said to have occurred in 22 countries and eight of the ten countries with the highest incidence were found in Africa. This increased burden of disease from tuberculosis globally, in an era where there is effective drug treatment, has been ascribed to factors such as poor control in areas such as Southeast Asia, eastern Europe and sub-Saharan Africa and co-infection with HIV in some African countries (Dye et al. 1999). Though Southeast Asia and the Western Pacific regions had the highest number of reported cases of TB, Africa had the highest incidence rate per capita with an average of 259/100,000. This region also has the highest rate of HIV infection in TB patients, with an average of 32% (Dye et al. 1999) though this figure varies from 17.8% in countries such as Cameroon (Bercion and Kuaban 1997) to as high as 70% in countries such as Botswana, Zambia (Elliott et al. 1995) and Zimbabwe. The case fatality rate for tuberculosis in Africa is high, exceeding 50% in some African countries, compared to a global figure of 23% (World Health Organization 2000a). The high rate of HIV co-infection has contributed to this high case fatality rate. The available data on the rates of drug resistance in Africa is not extensive as many countries have not conducted nationwide surveillance of the levels of drug resistance. The available reports generally cover a small area of the country or the sample size is usually small and hence cannot be considered to be representative of the country as a whole. In collaboration with the International Union Against Tuberculosis and Lung Disease (IUATLD), WHO has conducted a major surveillance of the global rates of drug resistance between 1994 and 1996 (World Health Organization 1997a) and this exercise was repeated between 1997 and 1999 (World Health Organization 2001). During the surveillance 16% of the countries were sampled. In the first round eight countries from the AFRO region (sub-Saharan Africa) were included - these were Benin, Botswana, Ivory Coast, Kenya, Lesotho, Sierra Leone, Swaziland and Zimbabwe. In the second surveillance seven African countries were included (Botswana, Central African Republic, Guinea, Mozambique, Sierra Leone, South Africa and Uganda). Thus only Botswana and Sierra Leone were assessed in both surveys. The levels of primary drug resistance in Africa vary according to the country assessed. The presence of drug resistance is an indicator of the treatment deliv-

P. D. O. Davies

ery process and resistance occurring in patients with no prior history of treatment reflects poor treatment in the past. The rate of drug resistance in patients with a previous history of treatment for tuberculosis is always much higher than in patients with no history of previous treatment for tuberculosis. In general the levels of drug resistance in Africa are low when compared to other parts of the world. This is despite the HIV associated increase in TB cases and political strife and wars. This is probably a reflection of the presence of relatively well functioning control programmes, 61 % of the countries in the African Region of WHO were covered by the DOTS strategy compared to the global average of 42.6%. The more recent introduction of rifampicin may also contribute to this lower incidence of drug resistance. In the first survey conducted by WHO and IUATLD the overall level of resistance among new cases for the African countries were as follows; Zimbabwe 3.3%, Botswana 3.7%, Kenya 6.3%, Benin 8.4%, Lesotho 8.8%, Swaziland 11.7%, Ivory Coast 13.4% and Sierra Leone 28.1% (Table 46. 1)(World Health Organization 2000a). In this survey, the Dominican Republic had the highest level of resistance to any drug, with a rate of 40.6%. Overall drug resistance to any drug in the second survey conducted between 1996 and 1999 in the African countries were as follows; Botswana 6.3%, South Africa (Mpumalanga Province) 8.0%, Guinea 14.7%, Central African Republic 16.4%, Uganda 19.8%,Mozambique 20.8% and Sierra Leone 24.8%. Between the two surveys, the level of resistance in Botswana increased from 3.7% to 6.3%, while for Sierra Leone the rate reduced from 28.1 % to 24.8%. The rate of resistance in other countries not included in the WHO survey vary widely from country to country. The available figures are as follows; Malawi 11.8%, Cameroon 31.8% (2), Ghana 54.5%, Ethiopia 15.6% and Tanzania 2.8%, Senegal 37% (Demissie et al. 1997; Range et al. 2000). The levels of resistance to isoniazid in new patients or primary resistance varied from 1.2% in Ivory Coast to 12.4% in Cameroon. Resistance to streptomycin ranges from 0% in Kenya to 20.5% in Cameroon. Levels of mono-resistance to rifampicin are low, being less than 1% in most countries where it has been reported (Botswana, Benin, Sierra Leone, Central African Republic, Guinea, Cameroon) and only Mozambique (1.8%) and Ethiopia (1.8%) had higher rates. Only Sierra Leone (0.6%), Swaziland (0.3%), Cameroon (0.4%) and Uganda (2.4%) have reported any mono-resistance to Ethambutol. The low levels of mono-resistance to rifampicin reflect

815

Multi-Drug-Resistant Tuberculosis

the recent introduction of rifampicin containing regimens as well as the tendency to use rifampicin as a combined tablet with isoniazid. Available data on drug resistance indicates that the rates of resistance are higher to one drug than to two or more drugs. The level of multi-drug resistance in Africa is relatively low with the highest level reported for Ivory Coast (5.3%) (Dosso et al. 1999), Mozambique (3.5%), Zimbabwe (1.9%), South Africa Mpumalanga Province (1.5%), Sierra Leone (1.1 %) (Range et al. 2000) and other countries reporting less than 1% of MDR (Botswana, Benin, Lesotho, Swaziland, Guinea, Uganda and Tanzania)(Table 46.2). In Kenya there was no multi-drug resistance reported in the WHO survey conducted between 1994 and 1997, though in the refugee population the level of MDR was 2.9% (Githui et al.I999). It should be noted however, that the countries included in the WHO surveys are countries, which have reasonably functioning programmes. In countries where there is a lack of a well-functioning programme the levels of MDR-TB may be much higher. In a survey conducted in Cameroon without a functioning control programme, among patients with a previous history of treatment, multi-drug resistance was observed in 27.6% of the cases (Kuaban et al. 2000).

The level of drug resistance is substantially higher in patients with a history of prior treatment with antituberculosis drugs than in patients with no previous treatment for tuberculosis. This fact supports the impression that the development of drug resistance is primarily associated with irregular medication and poor control of tuberculosis. In Durban, South Africa, the strongest predictor of drug resistance was a history of prior treatment with anti-tuberculosis therapy (Table 46.3) (ATT.) (Anastasis et al. 1997). In Hlabisa, Kwa Zulu-Natal, South Africa, resistance to isoniazid was 6.4% in cases with no prior history of treatment compared to 13.6% in cases with a history of prior treatment (Davies et al.). In Uganda, resistance to isoniazid in cases with no history of prior treatment was 6.7% compared to 37.8% in those cases with prior treatment. Rates of MDR are similarly higher in cases with prior treatment (4.4%) compared to those with no prior treatment (0.5%) (Bertzel et al.1999). No significant association has been observed between the level of resistance to TB drugs and HIV serostatus in several studies (Bercion and Kuaban 1997; Anastasis et al. 1997; Churchyard et al. 2000; Braun et al. 1992). However the presence of the increased rates of infection due to co-infection with HIV has placed a strain on the existing control mea-

Table 46.3. Levels of drug resistance on patients with a history of prior treatment Country

Benin Botswana Botswana Cameroon CAR Ethiopia Ghana Guinea Ivory Coast Kenya Lesotho Mozambique Sierra Leone Sierra Leone South Africa (Hlabisa) South Africa (Mpumalanga) Swaziland Uganda Zimbabwe

Sample

Overall

Resistance to

poly-resistance

1 drug

any

MDR

2 drugs 3 drugs 4 drugs

114 145

14.91 22.8

7.0 12.4

2.6 6.2

0.9 4.1

4.4 0.0

7.9 10.3

6.1 9.0

33

36.4

12.1

6.1

15.2

3.0

24.2

18.2

32

50.0

9.4

12.5

15.6

12.5

40.6

28.1

46 53 122 172 13

37.0 34.0 45.1 52.9 61.5

30.4 20.8 22.1 16.3 30.8

6.5 5.7 21.3 24.4 7.7

0.0 5.7 0.8 5.2 23.1

0.0 1.9 0.8 7.0 0.0

6.5 13.2 23.0 36.6 30.8

0.0 5.7 3.3 12.8 23.1

100

22.0

11.0

11.0

0.0

0.0

11.0

8.0

44 45 36

20.5 51.1 13.9

9.1 28.9 5.6

4.5 20.0 5.6

2.3 2.2 2.8

4.5 0.0 0.0

11.4 22.2 8.3

9.1 4.4 8.3

N.B. Table 1-3 are adapted from the WHO/IUATLD Global Project on Anti-tuberculosis Drug Resistance Surveillance and other available data

P. D. O. Davies

816

sures for tuberculosis and the ensuring falling quality of control can lead to an increase in the overall levels of drug resistance and in particular for MDR-TB. Due to high levels of HIV infection, the health system has been over-burdened. In some countries up to 75% of the hospital admissions are due to HIV related infections, hospitals are over-crowded, bed-occupancy rates are very high and isolation of infectious cases may not be possible. Hence the situation where a patient with open TB may be next to a patient with HIV related complications. The possibility of nosocomial infections are therefore high. Thus there is the possibility that drug resistant strains will easily spread within the community. Though the levels of drug resistance in Africa are relatively low compared to other countries such as Russia and Estonia, it is vitally important that every effort is made to maintain a low incidence. Currently many African countries with high levels of tuberculosis are unable to adequately fund tuberculosis control efforts without external support from cooperating partners. Though the cost of treatment for tuberculosis is one of the most cost effective strategy, in some countries this figure is more than the per capita expenditure available for the whole health budget. It therefore follows that treatment of multi-drug resistance tuberculosis will be beyond the reach of most countries (Schlunger 2000). Thus prevention of the development of resistance should be viewed as a major priority for these countries.

46.3 Drug Resistance in Prisons The world's prisons, jails, police cells and detention centres are inherently unhealthy because people with a number of diseases including HIV and tuberculosis are concentrated. Rates of tuberculosis in prisons are very high sometimes as much as 100 times as common as in the community (World Health Organization 1997b). The International Committee of the Red Cross (ICRC) found that the rate of TB in prison was 60 times higher than in the community and was a major cause of death (ICRC 1998). In Kazakhstan in 1997, 1034 of the 1491 (63%) prisoner deaths that year were from tuberculosis (Tuberculosis in Prisons Roundtable 2000). If the treatment of TB in such an environment is not well organised, MDR-TB can result. Information on the extent of MDR in prisons is limited but recent figures from WHO suggest that they may be as high as 24% (Stern 1999).

Countries of the former Soviet Union are particularly at risk. An ICRe study found that 69% of patients with tuberculosis had resistance to at least one drug (Amnesty International 1999).

46.4 The Microbiology of Drug-Resistant Tuberculosis The principal aims of TB microbiology are, first, the detection of mycobacteria, either by microscopy or molecular techniques, secondly, the isolation and identification by culture, using solid or liquid media and thirdly, the susceptibility testing of cultures and the identification of drug resistant, particularly multiple drug resistant (MDR TB) isolates. The laboratory is at the core of our understanding of the epidemiology of TB transmission and surveillance of drug resistance patterns. Since the development of acid-fast staining techniques in 1882 by Robert Koch, the principles of TB microscopic diagnosis have changed little and the acid-fast smear is still the most rapid method for the detection of M. tuberculosis. The sensitivity is only around 5_103 per ml and microscopy must be supplemented with culture, which while sensitive, is slow, taking 4-6 weeks to produce a positive result on most solid culture media, such as L- J slopes. The recent development of automated liquid culture systems such as the Mycobacterial Growth Indicator Tubes, (MGIT Bactec 960, Becton Dickinson, Franklin Lakes, USA) and the MB BacT Alert systems (Organon Teknika, Boxtel, Netherlands) have improved time to detection to 12-18 days and reduced hands-on time compared to their semi-automated predecessor, the Bactec 460 TB. For optimal results these systems should be used in conjunction with solid-media based culture. Safety of liquid culture systems is an important issue, as handling of liquid cultures carries an increased risk of potential microbial contamination of the laboratories from culture vials.

46.4.1 Molecular Diagnostic Techniques The advent of molecular technology has led to the development and implementation of tests, which are both rapid and sensitive for the detection, and identification of mycobacteria. They can be used in several ways: for the detection of mycobacteria, for

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Multi-Drug-Resistant Tuberculosis

the specific detection of M. tuberculosis complex, for the differentiation of M. tuberculosis complex and MOTT (mycobacteria other than tuberculosis), and for the detection of drug resistance. Molecular detection methods utilise a series of common steps, starting with the amplification of nucleic acid sequences, which can be achieved using several techniques. The best known and most widely employed is the polymerase chain reaction (PCR). Other techniques include transcription mediated amplification (Amplified MTD-2, Gen-probe, SanDiego, USA) (Miller et al. 1994), strand displacement amplification (Probe-Tec ET, Becton Dickinson, Franklin Lakes, USA), (Bergmann et al. 2000) ligase chain reaction (LCX MTB, Abbott, Illinois, USA) (Piersimoni et al. 1998) and QB replicase Galileo system (Gene-TraklVysis, Illinois, USA) (Smith et al. 1997; Della-Latta 1999). These alternative techniques have shown comparable performance to PCR. While some have been withdrawn at the clinical trial stage (Vitros, Johnson & Johnson, Rochester, USA & QB Replicase Galileo System, Gene-TraklVysis, Illinois, USA) many are now on the market with sensitivity and specificity consistently evaluated at over 90%. Detection systems can be colorimetric, such as in the Line probe assay, or LiPA, (Innogenetics, Zwijndrecht, Belgium) and Amplicor TB (Roche Diagnostics, Indianapolis, USA) or through chemiluminescent, or fluorescent, tagging of probes (Drobniewski et al. 2000a). A major problem for these molecular techniques is cost. While it is relatively easy to scale-up production of kits of molecular detection methods, once they have been developed, their execution requires skilled laboratory personnel, the concurrent performance of multiple controls, several dedicated laboratory areas and the use of relatively expensive consumable reagents. All of these factors make the costs prohibitive for laboratories in developing nations. Furthermore, in developing nations, where perhaps 95% of mycobacterial disease is due to MTB complex, the use of molecular techniques to differentiate MOTT is of little benefit as appropriate therapy for MOTT disease is usually unattainable. Therefore kits such as the Accuprobe system for the identification of a small number of pathogenic mycobacteria, which was introduced commercially on a wide-scale in 1987 (Gen-Probe, San-Diego) would be of questionable value in these settings. A similar argument applies to molecular amplification based methods.

46.4.2 Molecular Testing for Drug Resistance Mycobacteria spontaneously develop drug resistance and the rates of mutation are different for each drug. For M. tuberculosis these have been shown to be approximately 108 to 109 for isoniazid and streptomycin, 10 10 for rifampicin, 107 for ethambutol and 109 for cycloserine (Gangadharam 1984). It has been known almost since the inception ofTB chemotherapy, when the first relapses following streptomycin monotherapy were seen, that therapy with any single TB drug leads to the selection of a drug resistant population. For example mono-therapy with streptomycin led to a rise from 1 in 88,750 drug resistant mutant bacteria in sputum to 1 in 367 after 15 weeks of treatment (Herbert et al. 1999). Combination therapy must be used, therefore, to reduce the probability of drugresistant strains emerging. Multiple drug resistant TB (MDR TB) is defined as resistance to at least isoniazid and rifampicin. In the UK, drug resistance has been monitored by the laboratory-based system MYCOBNET since 1994. MDR-TB prevalence in initial isolates for the UK rose from 0.6% to 1.7% between 1993 and 1996, and then fell to 1.1% in 1999. In 1999,6.3% of initial TB cases were resistant to one or more first-line TB drugs: 5.9% resistant to isoniazid, 0.9% resistant to rifampicin, 0.5% to ethambutol, 0.4% to pyrazinamide, and 1.1% were MDR-TB (Telenti et al. 1993). The traditional determination of drug-resistance is by resistance ratio, minimum inhibitory concentration (MIC) or the proportion methods. These can be done in liquid media such as Middlebrook 7H9, solid media such as LowensteinJensen slopes, or Middlebrook 7H10 agar. As with isolation techniques, faster susceptibility testing methods have been developed using the semi-automated Bactec system or automated systems such as MBBacT, MGIT and Bactec. The first stage in the development of molecular detection methods for drug resistance is the identification of the relevant genes and mutations involved in drug resistance. The simplest drug to analyse has been found to be rifampicin, where approximately 95% of all clinical isolates resistant to rifampicin have a mutation in a 81 base pair region (codons 507-533) of the rpoft gene encoding the beta chain of the DNA dependent RNA polymerase (Zhang et al. 1992). This has made the development of genotypic methods for the detection of rifampicin resistance relatively straightforward. As approximately 90% of all rifampicin resistant isolates in the UK are also resistant to isoniazid, a positive result for rifampicin resistance can be taken as a strong indica-

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tor of MDR TE. However, isoniazid resistance is much more complex, as at least four genes are known to be important. These are the katG gene, which encodes the catalase-peroxidase enzyme, inhAimabA, which has a role in fatty acid elongation (Quemard et al. 1995) ahpC, which encodes the alkyl hydroperoxide reductase C (Sreevatsan et al. 1997) and oxyR which is the oxidative stress regulator (Alcaide et al. 1997). Two genes have been identified which are important in streptomycin resistance, the rrs gene, which codes for the 16S rRNA, and rpsL which codes for ribosomal protein S12. Similarly, Ethambutol- resistance involves mutations in the embA, B, and C, genes (Sreevatsan et al. 1997, ) encoding enzymes involved in lipoarabinomannan and arabinogalactan synthesis. Ciprofloxin resistance is conferred principally by mutations in gyrA, gyrB and nor genes, encoding DNA gyrase subunits A and B and an efflux protein, respectively. Pyrazinamide resistance is conferred by mutations in the pncA gene, which encodes pyrazinamidase. In a study by Sreevatsan et al. (1997; Telenti et al. 1993). Although 72% of pyrazinamide resistant isolates carried mutations in this region there were many mutation sites throughout this gene, which makes the development of tests for pyrazinamide resistance far more complex than rifampicin. Once genes such as these have been sequenced and the specific mutations identified, there are several options for the genotypic detection of drug resistance. The gold standard is DNA sequencing, but this is impractical in routine clinical use, due to the expense, skill and time demands of the technique, although systems have become increasingly userfriendly. Alternative techniques which have been employed include PCR single-strand conformation polymorphism (PCR-SSCP) (Telenti et al. 1993c) analysis, heteroduplex analysis, mutation specific priming, restriction enzyme analysis (Rossau et al. 1997) and solid-phase hybridisation methods (Carrier et al.I997). PCR-SSCP relies on the difference in tertiary structure between two single strands of DNA, which differ by single mutations or more. The conformational change of the tertiary structure can be detected by a change in mobility when analysed on a polyacrylamide gel. Heteroduplex analysis involves mixing amplified DNA from the sample with that of reference drug-sensitive strains. The DNA is then denatured and cooled again to allow the DNA to hybridise into hybrid double-stranded DNA. The DNA is then analysed on a denaturing electrophoresis gel. Where the sample DNA carries a drug-resistant mutation there

P. D. O. Davies

will be a mismatch in the complimentary base-pairing and the heteroduplex will have a different mobility to the homoduplex. Solid-phase hybridisation analysis involves the immobilisation of DNA probes complementary to the most common mutations and to drug sensitive patterns. Amplified DNA can then be hybridised to the probes and detected through fluorescence, radiolabel or colorimetric reaction in the normal way. One such assay, which is commercially available is the line-probe assay (LiPA, Innogenetics, Zwijndrecht, Belgium) for the detection of rifampicin resistance. One possible disadvantage of genotypic detection methods is that they give no indication of the susceptible:resistant ratio of organisms in a population and therefore may lead to the withdrawal of drugs from a regime when their therapeutic value is still high. Other rapid detection systems have recently been developed based on phenotypic methods, which can be adapted for use as susceptibility tests. One such technique utilises mycobacteriophage such as phAE40 or phG518. Jacobs et al. (Jacobs 1993; Riska et al.1999) inserted the lux gene, which codes for luciferase, into the phage genome. This enzyme catalyses the reaction of luciferin with ATP and emits light, which can then be detected. If the mycobacteria are grown in the presence of a drug, where the organism is susceptible the mycobacteria will die and therefore the phage will fail to replicate and no light will be emitted. While this technique allows all types of resistant organism to be detected, regardless of genotype, it requires expensive equipment and therefore unsuitable for the developing world where rapid detection systems for drug resistance are most urgently required. The same group has addressed this problem by developing a simpler microtitre plate format with a film detection system (Wilson et al. 1997). A more economical approach is the PhaB (phage amplified biologically) assay (Eltringham et al. 1999). Mycobacteriophage are added to the test sample which then infect any mycobacteria present where they are protected from the subsequent addition of viricide, which kills all external phage. The viricide is then removed through wash steps and the sample incubated until lysis of the bacteria releases the phage. The phage progeny are detected by plating onto a lawn of rapidly growing Mycobacterium smegmatis in which, following overnight incubation, they form plaques. The system has been adapted to allow susceptibility testing and showed 100% correlation with resistance ratio testing for rifampicin (Eltringham et al. 1999b), 94% for isoniazid, 96% for streptomycin, 100% for ciprofloxacin, 88% for ethambutol and

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Multi-Drug-Resistant Tuberculosis

87% for pyrazinamide (Kirk et al. 1998). This system is also relatively simple, and cheap to perform. However, stringent precautions must be taken in a diagnostic or reference laboratory to avoid the contamination of reference strains and archive samples with mycobacteriophage. Other rapid phenotypic methods which have been investigated include flow cytometry (Cangelosi et al. 1996), which requires the provision of prohibitively expensive equipment, and reverse transcriptase PCR (RT-PCR). One such RT-PCR assay which measured a reduction in inducible heat shock protein dnaK mRNA levels in susceptible isolates exposed to rifampicin showed a 96% (46/48) correlation in susceptible isolates and 97% (35/36) correlation in resistant isolates (Eltringham et aI.1999). Alternative RNA based approaches have included measuring levels of pre16S rRNA stem sequences through hybridisation to specific radiolabelled probes for rifampicin and ciprofloxacin (Hellyer et al. 1999) and quantitative analysis of 85B mRNA for rifampicin and isoniazid (Watterson et al.).

46.4.3 Rapid Tests in Routine Use The Public Health Laboratory Mycobacterium Reference Unit (PHLS MRU) offers a Fastrack diagnostic service for the detection of rifampicin resistance, using the LiPA (Innogenics, Zwijndrecht, UK) commercially available kit (Drobniewski et al. 2000). Correlation with standard methods has been over 90%. Where Fastrack was performed on cultures the correlation was 33/36 (91.7%), on primary specimens,55/61 (90.2%) and on smear positive sputum, 44/48 (91.7%). This rapid detection system allowed drug resistance to be detected on average 27.6 days earlier (n=56) for smear positive sputum specimens, 27.7 days earlier (n=61) for all primary specimens, and 19.1 days (n=36) when used for cultures (Raviglione et al. 1997).

46.4.4 How the Sequencing of the Mycobacterial Genome Will Help the Development of New Drugs in the Treatment of Tuberculosis Elucidation of the complete genome sequence of M. tuberculosis provides access to an immense reservoir of fundamental information about the evolution and constitution of the organism (Cole et al. 1998). Use

of this information to enhance understanding of the biology of tuberculosis is the driving force for research in the post-genomic era (Young 2001). In principle, the genome sequence includes information about all of the possible targets to which new antimycobacterial agents might be directed. At the most direct level, structural and functional information about a particular protein target can be deduced from the sequence of its encoding gene. Further analysis of interactions between individual gene products provides information about the biosynthesis of more complex molecular structures, and about the flux of metabolites essential for bacterial viability. How can we use this new information resource to accelerate development of reagents for improved tuberculosis control? 46.4.4.1

Breaching the Wall of "Fortress Mycobacterium" The outer coat is commonly viewed as the defining characteristic of a mycobacterium, determining its microbiological staining properties and its relationships with external reality (Brennan and Nikaido 1995). Many current anti-mycobacterials (isoniazid, ethambutol, ethionamide and pyrazinamide) affect the processes involved in cell-wall biosynthesis, and there is every likelihood that novel reagents targeted against similar processes will have comparable efficacy. Many of these biosynthetic pathways are now understood at a genetic level. Knowledge built up through decades of traditional biochemistry allows identification of the genes encoding enzymes that make up the pathways, and recombinant DNA techniques have opened a new era of detailed structurefunction analysis. One approach to exploiting this information in drug discovery programmes is to clone and express genes encoding selected biosynthesis enzymes. The recombinant proteins can be used in functional assays to screen for inhibitors, and at the same time provide the opportunity to generate structural information for optimised drug design (Dessen et al. 1995). Following an alternative approach, changes induced in the bacteria as a result of the action of an existing drug - characteristic transcriptional signals, for example (Slayden et al. 2000) - can be used to screen for novel compounds that exert an analogous inhibitory mechanism. Both of these strategies are suitable for use in high-throughput screen formats, allowing testing of millions of novel compounds. Compounds for such screens are typically derived by combinatorial chemistry techniques, which use simple building block strategies

820

to facilitate rapid generation of extensive libraries of structurally diverse small molecules. The principles and practice of modern high-throughput screening, and potential applications to tuberculosis, are comprehensively described in the Scientific Blueprint recently developed by the Global Alliance for TB Drug Development (Global Alliance for TB Drug Development 2001). Drug discovery programmes focused on cell-wall targets have a strong scientific foundation and a well-defined rationale; there are excellent prospects for identification of novel inhibitory compounds. This approach has the limitation, however, that new compounds are likely to have properties broadly similar to those of current drugs. It may be possible to selectively improve the pharmacokinetic properties and avoid established resistance mechanisms, but it is hard to envisage new cell-wall inhibitors driving major changes in the overall design of treatment regimens. They would clearly be drugs of choice for treatment of resistant disease, but cost factors are likely to argue against their routine replacement of existing drugs. In this particular case, would a pharmaceutical company be able to recoup the considerable costs involved in taking a novel compound through the complex process of developing a promising 'hit' into a clinically useful drug? This would seem to represent a significant economic risk, particularly in light of strong public opposition to the practice of marketing drugs in low-income countries at prices, which reflect research and development costs. The economic risk will have to be borne by the public sector; either by funding a guaranteed market for new drugs to treat multi-drug-resistant tuberculosis, or by carrying out at least parts of the development process within public or charitable institutions. The cost of development of a new drug is generally estimated to be of the order of half a billion dollars. Given the magnitude of the effect of tuberculosis on the global health and economy, this figure is well within the budget of institutions such as the World Bank, and mobilisation of public-private financing to promote development of new cell-wall inhibitors warrants high priority in the battle to control tuberculosis. 46.4.4.2 In Vivo Phenotypes: Targeting Persistent Organisms

The economic case for drug development is much stronger for a compound, which would significantly improve current therapy. A drug which reduced current treatment regimens from six months to six weeks is likely to be adopted as standard therapy,

P. D. O. Davies

for example, and would have widespread application even if unit costs were higher than existing drugs. The biological factors dictating the requirement for prolonged therapy in tuberculosis are the subject of extensive speculation (McKinney 2000).A reasonable hypothesis is that a proportion of the bacteria persist in a form in which they are relatively resistant to the action of the drug. For example, in the case of a drug, which acts by inhibition of cell-wall biosynthesis, bacteria will be immune to its effects if they don't happen to be engaged in the construction of new cell-wall components. The presence of the drug must therefore be maintained until the persisting bacteria enter a renewed phase of cell division. Can this period be reduced by targeting some metabolic process, which is essential even in non-dividing bacteria? It is widely recognised that all bacterial pathogens adapt to the environmental conditions they experience within the infected host, and that the resulting biological properties of the organism - the phenotype - are therefore different from those seen in the microbiology laboratory. Many investigators are applying post-genomic tools to study the in vivo phenotype of M. tuberculosis; monitoring patterns of gene and protein expression, and constructing mutants with defects at individual genetic loci. An example of this approach in the context of potential drug discovery is the case of isocitrate lyase. McKinney and colleagues (2000) demonstrated that this particular enzyme is essential if M. tuberculosis is to set up a chronic infection in mice. In contrast to enzymes required for cellwall biosynthesis, isocitrate lyase is dispensable during the initial phase of active replication; it is thought to playa role in the lipid-based metabolism that prevails during the persistent phase of the infection. Inhibition of isocitrate lyase activity might therefore be a particularly effective route by which to attack persistent bacteria. The isocitrate lyase gene has been cloned and expressed, providing the basis for a novel drug discovery programme (Sharma et al. 2000). The targeting of in vivo phenotypes generates scientific excitement, but the corresponding drugscreens present important practical problems. It can be anticipated that inhibitors of isocitrate lyase will have little or no effect on mycobacterial growth in vitro, for example, introducing a requirement for costly screening in animal models at an early stage in the drug discovery programme. In an attempt to reproduce in vivo phenotypes in a simpler experimental system, we have developed an 'ex vivo' screen. This involves infecting mice with luminescent reporter strains of M. tuberculosis (Snewin et al. 1999), sacrificing animals after sev-

Multi-Drug-Resistant Tuberculosis

eral days or weeks, and establishing cell cultures from spleen or lung cells. Mycobacteria maintained in these cultures resemble those in intact animals in being held under the control of the host immune response, and display a drug-susceptibility profile resembling that seen in vivo. Establishment of cultures in 24- or 96well plate formats permits testing of dose-response relationships for multiple compounds from only a small number of animals. 46.4.4.3

Latent Tuberculosis

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described above - was defective in the chronic phase that develops subsequent to immune recognition. One possible explanation for these observations is that the higher level of antigen expression attracts a stronger immune response, stimulating a greater effort to clear the infection. Induction of antigen expression during latent infection might similarly trigger enhanced immune activity against the persisting organisms. An intervention of this type - a drug acting in synergy with the immune response - would be complementary to the current control strategies based on antibacterial therapy of active disease and prophylactic vaccination prior to infection.

Elimination of latent tuberculosis presents a third target for drug action. It is well-established that conventional drug treatment can reduce the risk of development of clinical disease in individuals 46.5 recently infected with M. tuberculosis; can we imag- The Treatment of MDR-T8 ine expanding this approach to prevent tuberculosis in the one third of the global population estimated to 46.5.1 be harbouring latent infection? For 90% of infected Introduction individuals the immune response provides a level of protection sufficient to avoid the development of The specific management of drug-resistant patients the active disease, and it is attractive to consider the is only possible where facilities exist for both mycodevelopment of drugs or vaccination protocols that bacterial culture and for drug susceptibility testmight add to this protection. In contrast to the cell- ing, which excludes most of the developing world. wall targets discussed above, the scientific platform Treatment guidelines in the United Kingdom, and for a rational drug discovery programme in this elsewhere, are predicated on the drug-resistance area has yet to be established. Latent infection is data prevailing in the circumstances of their use. dependent on the presence of an effective immune In developed countries the inclusion of the fourth response, but could be explained as an equilibrium drug (ethambutol but occasionally streptomycin) reached by actively replicating mycobacteria together depends on the level of isoniazid resistance expected with coincident immune killing, the existence of a or known in a given patient group. non-replicating 'dormant' form of mycobacteria (perIn the United Kingdom, the British Thoracic haps analogous to the persistent phenotype invoked Society's Guideline (Joint Tuberculosis Committee of above), or some intermediate between these two the British Thoracic Society 1998), recommends the extremes. Understanding how a pathogen can be so omission of ethambutol in the initial phase only if the aggressive during active disease and yet can main- patient meets all the following criteria, based on the tain a stable and apparently harmless interaction for drug resistance data held (Tuberculosis Update 1999; years, or decades, within the infected host remains a Hayward et al. 1996): fundamental challenge for tuberculosis research. • White ethnic origin In a recent study, we have investigated the effect of • Previous untreated for tuberculosis manipulation of the antigen expression on M. tubercu- • Known, or thought likely to be on risk assessment, HIV-negative losis infection in a murine model (Stewart et al. 2001). By interfering with regulatory circuits involved in the • Not a known contact of drug resistant disease. control of gene expression, we constructed a mutant The European Respiratory Society (Migliori et al. strain of mycobacteria characterised by constitutive over-expression of a set of heat shock proteins. These 1999) recommend the inclusion of ethambutol in the proteins protect cells during exposure to harsh envi- initial phase for those in WHO Treatment Group I, ronments, but also provide an important signal by that is:- new sputum smear-positive tuberculosis, which the immune system recognises the presence new smear-negative tuberculosis with extensive of an infection. The mutant strain was able to initi- parenchymal involvement, new cases of severe extraate an infection but - like the isocitrate lyase mutant pulmonary tuberculosis (not defined). A three drug

822

initial phase is recommended for those in WHO Category III :- new smear-negative pulmonary tuberculosis (except in Category I) and new less severe forms of extra-pulmonary tuberculosis. The American Thoracic Society (American Thoracic Society 1994) advise the inclusion of ethambutol or streptomycin in the initial phase of a daily regimen at an isoniazid resistance prevalence of 4% . Most parts of the world do not have mycobacterial culture and drug susceptibility testing capabilities and in these regions the standard advised regimen has to cover the possibility of the commoner drug resistances. Studies in Hong Kong used regimens of rifampicin, isoniazid and pyrazinamide, with streptomycin or ethambutol, and both streptomycin and Ethambutol (Hong Kong Chest Services 1981, 1982, 1987) and using rifampicin and isoniazid throughout with pyrazinamide for 2, 4 or 6 months Hong Kong Chest Service/British Medical Research Council. Results at 30 months (Hong Kong Chest Service 1991) showed that all the regimens were effective in patients with initial isoniazid and/or streptomycin resistance. Treatment failures and relapse rates were low. If routine drug susceptibility tests are not available, these regimens can be assumed to be highly effective if such resistances are present. The results of these studies (Hong Kong Chest Services 1981,1982, 1987) provide the rationale for using four drugs in the initial phase, with rifampicin and isoniazid in the continuation phase, in areas or in population subgroups with significant incidences of isoniazid and/or streptomycin resistance. An analysis of the influence of initial drug resistance on response to short-course regimens in the Medical Research Council (MRC) collaborative trials in Hong Kong, Singapore and Africa was reported in 1986 (Mitchison and Nunn 1986). In those trials, patients with initial isoniazid and/or streptomycin resistance had a failure rate of 17% when given a six-month rifampicin and isoniazid regimen, and a failure rate of 12% in those given rifampicin in the two-month initial phase. As the number of drugs given in the regimen and the duration of rifampicin treatment increased, the failure rate fell, reaching only 2% of those receiving 4-5 drugs including rifampicin throughout a six-month regimen. Relapse rates after chemotherapy were only slightly increased with initially resistant organisms. The key exception was that of rifampicin resistance, where the outcome was much poorer. Although this data applies to countries without drug susceptibility testing, the view taken in the United Kingdom is that where drug susceptibility

P. D. O. Davies

tests are available, they should be followed, and the treatment modified (Joint Tuberculosis Committee of the British Thoracic Society 1998). The strength of the scientific evidence to support various recommendations (Petrie et al. 1995) is also given in the 1998 BTS treatment guidelines (Joint Tuberculosis Committee of the British Thoracic Society 1998).

46.5.2 Management of Non-MDR Resistance 46.5.2.1

Isolated Resistances 1) Streptomycin resistance. Some of the drug resistance reported, particularly in ethnic minority groups, is to streptomycin alone. This is not clinically important since streptomycin is not often used as a first line drug in developed countries, and the efficacy of the regimen recommended for both respiratory and non-respiratory tuberculosis is not affected. 2) Streptomycin and isoniazid resistance. Combined streptomycin and isoniazid resistance is the commonest dual resistance in the United Kingdom. Management should be the same as for isoniazid resistance found after treatment is commenced but with treatment fully supervised throughout. 3) Other combinations. Other combinations of non-MDR-TB resistance are uncommon. Treatment needs to be individualised depending on the combination involved and is best determined after discussion with a highly experienced clinician and mycobacterial services. Patients with drug resistance (excluding isolated streptomycin resistance) should be followed up for 12 months after cessation of therapy.

46.5.3 Multi-Drug-Resistant Tuberculosis The risk factors for MDR-TB are those for ordinary drug resistance but are even more exaggerated. The United Kingdom data shows that the odds ratios for risk factors were, previous treatment 11.7 (95% confidence interval 5.5-20), HIV-positivity 8.9 (2.1-30.7), birth in India 4.6 (1.2-6.1), residence in London 4.0 (1.7-9.3) and male sex 2.2 (1.1-4.3). In countries without drug susceptibility testing a patient having treatment failure should be considered to be at risk of MDR-TB, and anyone failing a supervised Retreat-

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ment with a WHO category II Retreatment regimen, should be assumed to have MDR-TB. 46.5.3.1 Infection Control

Patients with suspected MDR-TB, should have molecular testing of samples with Rifampicin resistance probes where possible. Those with clinical or microbiological suspicion/proof of MDR-TB should be isolated in a negative pressure room, and have infection control and HIV assessments made (The Inter Departmental Working Group on Tuberculosis 1998; Joint Tuberculosis Committee of the British Thoracic Society 2000). Criteria for the removal from strict respiratory isolation are also given (Joint Tuberculosis Committee of the British Thoracic Society 1998, Tuberculosis Update 1999). 46.5.3.2 Clinical Management

The drug treatment of MDR-TB is time consuming and demanding on both patient and physician. In the United Kingdom the advice is that treatment should only be carried out by: A) Physicians with substantial experience in managing complex resistant cases, and B) Only in hospitals with appropriate isolation facilities, and C) In very close liaison with Mycobacteriology Reference Centres.

This may require the transfer of patients to an appropriate unit where both criteria (A) and (B) above are met. Treatment of such patients has to be planned on an individual basis (Goble et al. 1993; Iseman 1993) and needs to include reserve drugs (see Table 46.4). Such treatments must be closely monitored because of the increased toxicity but, more importantly, full compliance is essential to prevent the emergence of further drug resistance, so that all such treatment must be directly observed throughout, both as an inpatient and as an outpatient [B]. Treatment should start with five, or more, drugs to which the organism is, or is likely to be, susceptible and continued until sputum cultures become negative [B]. Drug treatment then has to be continued with at least three drugs to which the organism is susceptible on in vitro testing for a minimum of nine further months, and perhaps up to, or beyond, 24 months, depending on the in vitro drug resistance profile, the available drugs (Farmer 1999) and the patients HIV status. Consideration may also have to be given to resection of pulmonary lesions under drug cover (Iseman 1993). The outcome in MDR-TB depends on how rapidly the diagnosis is made, what treatment and facilities are available, and the patient's HIV status. Results in patients who are HIV-positive have been poor with high mortalities often because of late diagnosis (Drobniewski 1997; Small et al. 1993), but the outcome in those who are HIV-negative can be much better where appropriate facilities exist 100 and where the drug resistance profile is less extensive (Telzak

Table 46.4. Reserve drugs: dosages and side-effects Drug

Children

Streptomycin

15 mg/kg

Adults

Amikacin Kanamycin Capreomycin Ethionamide or Prothionamide Cycloserine Ofloxacin Ciprofloxacin Azithromycin Clarithromycin Rifabutin

15 mglkg (max dose 1 gm) 15mg/kg 15mg/kg 15 mg/kg 15 mg/kg 15-20mg/kg <50 kg 375 mg bd >50 kg 500 mg bd 250-500 mgbd 400mgbd 750 mg bd 500 mg od 500mgbd 300-450mg

Thiacetazone

4mg/kg

Clofazimine PAS sodium

300 mg/kg

Main side-effects Tinnitus, ataxia, vertigo renal impairment

As for streptomycin As for streptomycin As for streptomycin Gastrointestinal, hepatitis avoid in pregnancy Depression: fits Abdominal distress, headache Tremulousness As ofloxacin plus drug interactions Gastrointestinal upset as azithromycin as for rifampicin: uveitis can occur with drug interactions e.g. macrolides. Often cross resistance with rifampicin. 150 mg od Gastrointestinal, vertigo, rash Conjunctivitis. AVOID if HIV-Positive (Stevens-Johnson syndrome) 300 mg od Headache, diarrhoea, red skin discolouration 10 gm od or 5 gm bd Gastrointestinal, hepatitis, rash, fever

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P. D. O. Davies

et al. 1995). After treatment all MDR-TB patients require long-term follow-up. Michael Iseman has ,Ten Commandments' for the treatment of tuberculosis. The first is ,Thou shalt not add a single drug to a failing regimen'; the second to tenth commandments repeat the first commandment nine times to make sure the message has been received. It can therefore be argued that to give a WHO re-treatment regimen (World Health Organization Tuberculosis Unit 1991). (Category II), which adds only a single drug to the combination that has failed (Category I) regimen, breaks the commandments and may actually be adding to the incidence of MDR-TB, and this needs debating.

The reason that HIV is strongly associated with MDR-TB is through outbreaks. These occur because HIV positive patients have an increased risk of developing active tuberculous disease once infected with Mycobacterium tuberculosis. In HIV non-infected people for every ten people who are exposed and infected with TB (whether drug sensitive or resistant,) only one will develop the disease during their lifetime. For those with HIV infection this risk of around 10% in a whole lifetime is telescoped down to only one to two years. Highly active antiretroviral therapy does have an impact on rates of developing tuberculosis however and may reduce the rates of tuberculosis in countries where patients are offered anti HIV treatment.

46.6 Tuberculosis and HIV Infection

46.6.3 MDR-TB Outbreaks

46.6.1 Introduction

These have occurred in hospitals in Europe (Hannan et al. 2001; Moro et al. 2000; Breathnach et al. 1998; Coronado et al. 1993; CDC 1993) and clinics in the USA (Pitchenik et al. 1990) for HIV positive patients, substance abusers (Conover et al. 2001) in prisons (CDC 1992), and homeless shelters. From 1990 to 1992 nine large outbreaks of MDR-TB were reported from the USA, all the organisms isolated were resistant to Isoniazid and Rifampicin (as this is a definition of MDR-TB) most had Streptomycin and Ethambutol resistance also. (Table 46.5). The HIV infection rate amongst these patients was from 20-100% and the mortality was from 60-89%. The interval from TB diagnosis to death was between 4-16 weeks. Various strains of MDR-TB were circulating at this time, especially the notorious ,W' strain, which infected 199 patients in New York from 1991-1994 and involved 30 hospitals (Shafer et al. 1995). Other types the named ,N2', ,WI' and ,AB' infected a large number of patients in 10-16 hospitals. The majority of these outbreaks were brought under control because of public health administrative measures including infection control policies for patients with HIV who have a cough, segregation of potential infectious patients, the use of negative pressure rooms and submicron masks (Moro et al. 1998; Maloney et al. 1995; Stroud et al. 1995). Procedures such as nebulisation of pentamidine for PCP prophylaxis, saline for induced sputa or even salbutamol for those with obstructive airway disease were no longer performed in open areas but confined to negative pressure rooms.

Outbreaks of multi-drug resistance tuberculosis (MDR-TB) amongst HIV-positive patients in the early 1990s especially in the USA highlighted the need for improvement in public health and hospital control of infection policy, laboratory and clinical management, research, development and education in tuberculosis. This new focus, together with an increase in financial investment, has led to many developed countries having a comprehensive tuberculosis control strategy for immunocompromised individuals, which is more robust.

46.6.2 HIVandTB The biggest single risk factor for developing tuberculosis is HIV infection. In some countries in the world especially sub-Saharan Africa the co-infection rate of HIV and TB is estimated to be over 1000 per 100,000 population. In spite of some excellent TB control programmes, many of these countries are still experiencing increases in tuberculosis case rates because of HIV co-infection. Few countries have universal HIV testing or comprehensive TB culture and drug-sensitivity reporting and so the global epidemiology of MDR-TB in HIV positive patients is as yet mostly unmeasured (Punnotok et al. 2000). In the US in 1998 it was estimated that 20% of all patients with TB were HIV co-infected but the proportion with MDR-TB was not known.

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46.6.4 Treatment

46.6.6 Contacts

The drug treatment regimen used for outbreak patients have been based on drug sensitivity patterns (see Table 46.5). Most of them included an 8 Quinolone such as Ofloxacin together with Amikacin and if sensitive, Pyrazinamide. Other drugs have been used but the long-term efficacy is unknown. Recently it has been shown that a combination of Amikacin, Sparfloxacin and Ethionamide was useful in patients who were sensitive to these drugs. The optimum duration of treatment for MDR-TB is still unknown and many cases are treated for two years after cultures convert to negative.

For close contacts of patients with MDR-TB there are no clear guidelines as to what to do. It is easier to decide on a chemoprophylaxis regime if the drug sensitivity patterns are known. However, it is still not known whether or not this type of prophylaxis would work. A 'Delphi symposium' decided that if infection and disease progression was likely then Ethambutol and Pyrazinamide or a Quinolone plus Pyrazinamide might be used (Passannante et al. 1992). The role of BCG in adults is still unknown. In New York it was reported that physicians had BCG in the hope that this might protect them if exposed.

46.6.5 Alternative Therapies

46.6.7 Prognosis and Predictors

Some patients with localised disease and those with good cardiac pulmonary reserve and low bacterial burden can be considered for either partial, or total, lung resection. Nebulised interferon has been used in rendering sputum smears negative in such patients prior to surgery. It has also been used as a method to prevent spread of infection when all other drug treatments have failed in non-HIV infected MDRTB cases. The use of the immunomodulation with M. vaccae has not yet been used in a formal trial of MDR-TB.

Prognosis in HIV patients who are HIV pOSItive and have MDR-TB has been very poor with between 25-30% of people surviving to 6 months if they are severely immune suppressed (Fischl et al. 1992). Most of the factors responsible for MDR-TB outbreaks have now been addressed by government, or federal, policy but are still important to help as the guiding principles for prevention. These include inadequate control programmes for TB; inadequate adherence to medication; infection control procedure breakdown by putting all the immune suppressed patients in one area such as an open hospital ward; having a low index suspicion for tuberculosis leading to the patients' infectiousness being prolonged and having poor laboratory communication with clinicians.

Table 46.5. HIV associated multi-drug-resistant tuberculosis Outbreaks January 1990 to August 1992 in USA Facility

Total Cases

Resistance Pattern

HospA

65

H, R, (E, Eth)

Hosp B

35

H, S, (R,E)

Hosp C

70

H, R, S, (E,Eth,Ka,B)

HospD

29

H, R, (E,Eth)

HIV infection %

Mortality

Median interval TB Diagnosis To death

93

72

7

100

89

16

94

82

4

91

83

4

Hosp E

7

H, R, S, (E,Eth,Ka,RB)

20

60

4

Hosp F

16

H, R, S, (Eth,Ka,RB)

82

82

4

HospG

13

HR (E)

100

85

4

Prison System

42

HR (S,E,Eth,Ka,RB)

91

74

4

826

The major risk factors for MDR-TB in HIV patients are the same as in the general population. There is a history of such as previous treatment, birth, travel or work in an area endemic for MDR-TB, a history of poor adherence, sputum positivity continuing after two months of treatment or being culture positive after three months. In addition some factors in the HIV population have been recognised as predictors of MDR-TB. Severely immune suppressed HIV positive patients seem more likely to develop MDR-TB probably related to the high risk of progression to disease once infected. A failure to become apyrexial by two weeks of treatment and development of hilar lymph nodes are other factors pointing towards possible MDR-TB (Telzak et al.1999; Salomon et al.I995). One of the best predictors that patients will survive is that they start on at least two drugs to which the organism is susceptible within two weeks of diagnosis. This often means a patient is given multiple drugs prior to the drug sensitivity patterns being available (Park et al. 1996; Turett et al.I995). In Europe there have been about six outbreaks involving around 225 patients and these have major implications for resource utilisation and public health (see Tables 46.6 and 46.7) they use a large number of staff in contact tracing and case finding. It was interesting to note that in the second outbreak in the UK very few people took up the prophylaxis and of those who did, almost all of them had stopped by two weeks. One of the largest outbreaks of MDR-TB occurred in Argentina over a fifteen-month period (Ritacco et al.I997).A total of 101 patients had resistance to five drugs and the survival rate was approximately 10%. Most of these patients were in contact with an intravenous drug user who adhered poorly to treatment and had developed resistance. There have been outbreaks of multi-drug resistant M bovis in HIV patients in Spain involving 19 cases over 15 months. Resistance to 11 drugs was found and all the patients died with a median survival of only 44 days. Their risk factor was severe immune suppression (Cobo et al. 2001). It was thought that poor drug absorption might increase the risk of HIV positive patients in developing MDR-TB but one study of drug absorption in AIDS patients (Taylor and Smith 1998) showed there was no difference in the T-max, C-max and median area under the curve (AUC) for AIDS patients compared with HIV-negative patients. In fact it appeared that the AIDS patients, even those with GI problems, were absorbing Rifampicin better than HIV negative matched controls. It has also been suggested that

P. D. O. Davies Table 46.6. Outbreak 1 UK Contact & Case Finding - Index + 7 other all HIV + 2 alive now - 187 HlV + contacts - 60 Staff - 57 Community contacts

Table 46.7. Outbreak 2 UK Contact & Case Finding - Index HIV- + 6 other HlV + - 1298 general medical patients exposed - 169 recalled - 898 staff - 64 HlV patients - 476 HIV outpatients - R H,R,ANS,Clo,Cyc1o+/-Z,Cla,Cip - S Eth,Cap,Strep,Ethio,Amik - Prophyaxis PAS + ETH offered to 400 - 12 on prophylaxis

10 stopped most by 2 weeks

HIV-positive patients required longer treatment for their tuberculosis and that inadequate length of treatment might lead to MDR-TB. However there is no evidence to support this as the duration of treatment and relapse are the same whether HIV patients are given six or nine months treatment for initial fully drugs susceptible disease.

46.6.8 Sporadic MDR-TB in HIV

In South Africa individuals were examined to see whether they were more likely to develop MDR-TB outside an outbreak event. It was found that 12% of the HIV-negative compared with 2% of HIV positive patients developed MDR-TB during the follow-up (Anastasis et al.I997). The reason for this is that good public health control can prevent outbreaks even in developing countries. Those HIV patients involved in outbreaks may have fewer episodes of cavitary disease; more fevers and be more immunosuppressed than those who develop sporadic MDR-TB (Sacks et al. 1999). Data from the South African goldmines in 1993-1997 where the potential for outbreaks was great, help shed more light on the association of HIV and MDR-TB. Miners' hostels accommodating 2000-3000 men showed an increase incidence of TB from 1174 to 2476 per 100,000 over a 6 year period from 1990-1996 with associated increase in HIV

827

Multi-Drug-Resistant Tuberculosis

rates. Despite an HIV positivity of 28% the MDR-TB in new patients was only 1% of total and even in retreatment cases was only 2.8%. There was no association between MDR-TB and HIV status. The reason for the low incidence seen in re-treatment cases, was that there was a very good Directly Observed Therapy, (DOTS) strategy with a completion rate of treatment 93% (Churchyard et al. 2000). A major concern for many is that HIV might cause global outbreaks of MDR-TB as more and more patients receive anti-tuberculosis therapy in an environment where the political and financial situation is unstable and DOT strategies are not implemented in full. The direct impact of this would be outbreak transmission to immunosuppressed patients and then onwards to immune competent individuals. As a result, the already fragile control programmes would be swamped. There have been cases of immunosuppressed patients being treated for fully drugsensitive TB and them being exposed and acquiring drug-resistant strains whilst on therapy for the fully sensitive strain (Drobniewski 1997).

46.6.9 The Financial Challenges of MDR-T8 Drug-resistant tuberculosis gives rise to challenges, which go far beyond the problems associated simply with the clinical care of the patient. At the level of the individual patient with MDR-TB, doctors and hospital managers are having to face the fact that managing even a single case of this condition is immensely more expensive than dealing with a case of sensitive disease. Just a few such additional patients may cause considerable budgetary problems in even a well-funded institution in the developed world. At a higher level, it has then to be recognised that as well as the costs associated with individual patients, the occurrence of MDR-TB in some patients may have implications for the cost of dealing with all patients. Once it is acknowledged that drug resistance is a possibility, the management of all cases of TB, and in particular their initial management, must be planned with that possibility in mind. At a higher level still, spending on public health measures to prevent the spread of MDR-TB, or to control and reverse the problem where spread has already occurred can have very large financial implications, even for the wealthiest countries. Finally, in addition to carrying the financial burden of treating the sick and of preventing others

Table 46.8. Cost of drugs used in the treatment of tuberculosis Drug and daily dose

Annual cost £ ($)

Amikacin 1 g

6430 (9655)

Capreomycin 1 g

6580 (9870)

Ciprofioxacin 1 g

980 (1470)

Clarithromycin 1 g

1040 (1560)

Clofazimine 300 mg

76 (114)

Cycloserine 500 mg

1685 (2530)

Ethambutol 1 g Isoniazid 300 mg PAS 7.4g

356 (535) 26 (39) 5190 (7785)

Prothionamide 750 mg

880 (1320)

Pyrazinamide 2 g

110 (165)

Rifabutin 900 mg

3140 (4710)

Rifampicin 600 mg Streptomycin 1 g

85 (127) 2450 (3675)

from becoming sick, countries have to face the problem of the lost productivity of those individuals. Long-term sick adults are a cost to the economy in more than one way: as well as costing money to treat and maintain, they are not contributing, in taxes or productivity, to the national economy. To this must be added yet a further cost if the responsibility of supporting their dependants falls on the state rather than on the extended family - and where it does fall on the family, the impact can be devastating (Rajeswari et al. 1997; Kamolratanaku et al. 1999).

46.6.10 Different Countries, Different Problems, Different Expectations TB is a global disease, and accordingly so is MDRTB. Self-evidently the financial problems, which MDR-TB produces are different in different parts of the world: London has relatively few patients and relatively lavish resources. Sub-Saharan Africa has many more patients and far fewer resources. Facilities and finances are different, but it is often forgotten that so are expectations. Doctors in resource rich countries can do some things beyond the dreams of their colleagues working in resource-poor countries. It must be kept in mind, though, that levels of public health protection which are - quite rightly - regarded in some countries as magnificent achievements with the resources available, could in some other countries be regarded as being so far below what is expected as to amount to medical malpractice.

828

The expectations of doctors and other healthcare workers dealing with MDR-TB will thus differ in different parts of the world. At least, though, healthcare professionals regard MDR-TB as one disease, whoever it is that has the disease, and wherever they are. There may be different constraints upon what we can deliver for our patients, but we all know what it is that we ought to deliver in an ideal world. To the policy makers, and the money providers, however, MDRTB is many different diseases depending upon your viewpoint. The cost of MDR-TB in many countries is perhaps about using DOTS-plus - can it be afforded (probably yes), and can the system possibly afford drug susceptibility testing on all initial isolates of TB (almost certainly not). By contrast, in many parts of the USA and increasingly in some parts of Western Europe, the political and societal imperatives regarding the financing of MDR-TB are to identify enough money to put into negative pressure isolation every single patient coming through the door of the hospital who might possibly have pulmonary TB, and keep them there until it has been proven not to be MDR. There is, accordingly, no "one world" message: the costs of MDR-TB will depend upon these political and societal imperatives, and the expectations that they produce.

46.6.11 The Individual Patient with MDR-TB In managing the individual patient with MDR-TB, the first and most obvious expense is the cost of drugs. Second line drugs are more expensive, and those first line drugs which, may still be effective may be used for longer periods - ethambutol, for instance, is markedly more expensive than rifampicin or isoniazid. Table 46.8 shows the average costs in the UK of some of the drugs used in MDR-TB. A WHO/IUATLD survey suggests that the cost of a one month course of streptomycin is about $38, for amikacin the monthly cost is $640, and for ofloxacin the price ranges between about $88 and $200 dollars per month, with cycloserine and PAS being similarly priced. As has been pointed out, in many countries just one month's supply of just one of those drugs exceeds the entire annual per capita health expenditure (JCRC 1998). In those countries where they can be (fairly) readily afforded, the expectations for levels of care are high. To the drug costs must accordingly be added the costs of toxicity monitoring: plasma levels; audio-

P. D. O. Davies

grams; and assessments of renal impairment. But the question of drug, and associated, costs is only just the start. The cost of managing tuberculosis starts to escalate when in-patient care of patients is necessary (Salomon et al. 1995; Park et al. 1996). Negative pressure rooms for isolation of infectious MDR-TB incur both capital (building) and annual running costs. These costs can be predicted for the anticipated useful life of the facility, and costs per room/day calculated. These calculations, however, are themselves likely to underestimate the cost of managing an individual case of MDR-TB unless predictions of bed occupancy rates are robust. If a patient is placed in a negative pressure room for two or three weeks, the institution pays not just for the nights the patient actually occupies the room, but also for when the room is empty and available. Moving beyond the physical facility, there is the matter of nursing intensity. Staffing levels on the negative pressure unit of 10 beds at St Bartholomew's Hospital in London are 50% higher than on other wards in the hospital. This probably reflects the pattern elsewhere. Quite apart from medical time and nursing staffing levels, there is the increased input of other healthcare professionals. Our experience is that there is a very significant psychological, and indeed psychiatric, morbidity in individuals with long-term isolation. Turning from the mental to the physical, the assessment of costs needs to consider the additional medical care which may be more likely to be necessary in MDR-TB than drug-sensitive disease: the possibility of thoracic surgical intervention is just one of them. There have been a number of estimates produced for the costs involved in the care of individual patients with MDR-TB in resource-rich countries. Values for individual, very expensive, patients running into hundreds of thousands of pounds are probably well known to many of us. It has been our experience that those responsible for the allocation of resources are unimpressed by the example of single very expensive cases with many complications, so in our institution we examined a small series of patients, and looked at those only with straightforward pulmonary MDRTB and who were HIV negative (White and MooreGillon 2000). In this study, we attempted to take into account all the factors mentioned above, and came up with a minimum mean cost of £60,000 ($90,000) per patient. We know that this underestimates the true sums, because in making the calculations about facility costs we have, for instance, assumed 100% bed occupancy in our negative pressure suite over an assumed 15 year life for the facility, and we know that is not

829

Multi-Drug-Resistant Tuberculosis

the case. These values have been helpful in drawing to the attention of our local health care planners and government that even though the numbers of cases are relatively small, MDR-TB is a very real financial issue in our inner cities, which cannot just be picked up in the standard respiratory medicine budget.

46.6.12 The Consequences for Others Moving beyond the individual patient, the consequences for others can be considered in at least two ways. The first of these is the relatively superficial analysis of the consequences if the patient with MDR TB passes the disease on to somebody else. This next person then becomes another individual with MDRTB, with all the costs that are discussed above. The cost of one multi-institutional outbreak of MDR TB in New York City was estimated as in excess of $(US) 25 million, when calculated on the number of days in hospital alone, and the full cost is bound to be far higher than that (Frieden et al. 1996). Further, as more than one hospital in London has discovered, the costs of transmission to others are not purely medical; they have been sued when hospital in-patients have been infected by patients with MDR-TB, and the damages in some cases have been very large. At its very simplest, this has led to subtle changes in initial drug regimens in many cases. In the UK, although the national guidelines have superficially not changed very much (Farmer et al. 1998; Kuaban et al. 2000) clinical practice has changed. The way that most clinicians used to think about TB was that an initial three-drug regimen was used as routine, and a four-drug regime was to be used if there was reason to think there may be an increased risk of drug resistance. The has been reversed: so that a four-drug regime is routine, and three drugs are only used if the patient is regarded as being at very low risk. This increases the cost of the standard regimen by about 30%, since ethambutol - the usual fourth drug - is significantly more expensive than the others. It has had the desirable effect of making clinicians keener on obtaining microbiological confirmation of the disease, particularly non-pulmonary disease. This is because the sensitivities are so important, and data from the British Public Health Laboratory Service year on year shows an increasing proportion of microbiological confirmation (Espinal et al. 1999). Again it must be kept in mind that this additional invasive sampling and laboratory examination is an

increased expense brought about by increased fears about drug resistance. Additionally, supplemental second-line drugs may be used initially if there is a strong clinical suspicion of resistant disease, and their use is continued until it is confirmed that the disease is, after all, fully sensitive. There is thus more expense: for drugs, for their monitoring and for toxicity testing, and there is the increased risk to the patient. The doctor may well- in pulmonary disease - use strict isolation procedures, until it is known that the disease is sensitive and the regimen is appropriate. All these consequences flow not from the fact that the patient himself has MDRTB, but purely from the fact that others have it and so he might have it. Is there anything that can be done to reduce these costs? It is absolutely clear that if the time needed for sensitivity testing can be reduced then there is at least the potential to save money. This should be viewed from the right direction: not much money is saved by proving somebody is drug resistant more quickly. On the other hand, because most of the patients are drug sensitive and are unnecessarily expensive if they are initially managed as being possibly drug resistant, a great deal of money may be saved by proving more quickly that patients are drug sensitive. There have been a number of publications that have looked at various tests and their cost effectiveness, but one of the best analyses comes from Drobniewski and colleagues, clearly demonstrating the overall economic benefits of expenditure on molecular diagnosis of tuberculosis and drug resistance (Iseman 2000).

46.6.13 Implications for Public Health and the Wider Economy These factors relating to the implications of MDR-TB for others who may not have the disease relate very closely to the wider public health costs. There is a clear need to have measures in the community to control the spread of resistant disease - but even more importantly to prevent the emergence of resistant strains. Reversing the problems of New York, which developed in the 1980s is estimated to have cost $1 billion (Kritski et al. 1996). In London, a study commissioned by the Regional Public Health Office estimated that MDR-TB, about 2.5% of culture confirmed cases, accounted for 20% of spending on TB (Rullan et al. 1996). This was, as the authors acknowledged, only a fairly crude analy-

P. D. O. Davies

830

sis since it was not the main focus of the paper, but it does give an idea of the scale of the problem. Beyond immediate public health issues like these is the impact of the disease in terms of the economy as a whole. Where the burden falls is dependent upon national wealth and the national culture. In a country like the United Kingdom, the burden that the state places upon the family is essentially zero. Many families do of course contribute to care, but if they don't the state will more or less cover all the costs. The state will pay for the fact that the individual is ill, and pay for the fact that they cannot work. The state will bear the burden of lost tax revenue and it will bear the cost of supporting the dependants if the ill person was the breadwinner. In other countries, there may be no such support from the state at all. In many, the situation is intermediate between those two extremes. Although not specifically in the context of resistant disease, there have been numerous excellent studies from India. One such paper, by Rajeswari and colleagues, investigated a mixed population treated by government healthcare, non-governmental organisations and private practitioners showed that the total costs, particularly indirect costs, were very high (Rajeswari et al. 1997). Expenditure due to TB accounted for as much as 40% of the patients mean annual income. Also, strikingly, almost 20% of school age children of infected parents had to discontinue their school studies, either to care for their parents or to start work to contribute to the family income An excellent paper from Thailand starkly demonstrates the importance of interpreting economic statistics with a full awareness of the issues which underlie them: increased expenditure on food in tuberculous households was not a reflection of an awareness of the need for good nutrition, but simply because one in six households had to sell part of their property to pay their bills and could no longer rely on home-grown produce (Kamolratanaku et al. 1999). In industrialised nations, economic discussions about healthcare interventions are now commonplace. For example, when a major pharmaceutical company applies to the licensing and national healthcare bodies for funding for its new anti-influenza drug, part of the data it submits is the saving to the national economy which it says will result from its Widespread use. There are similar arguments for new asthma drugs and new interventions in coronary artery disease. Are there similar arguments in developed countries for new tuberculosis interventions? No, but then the concept of the cost to the economy of lost productivity is harder to sell as an idea to the

UK Government since in this and many other countries the majority of patients with TB are not working anyway. Can countries afford not to treat MDR-TB? There is at present an interesting debate on this issue. It certainly is a debate or discussion, rather than an argument, because the protagonists are all, essentially on the same side. Greatly simplified, the arguments of Farmer and colleagues might be summed up by stating that we cannot afford not to treat MDR-TB with individualised regimes, however poor the environment in which we are trying to work (Farmer et al.I998). On the other hand, Espinal et al.'s argument is that resources are invariably finite, and often very limited, and that there will be «an optimal allocation of funds that minimises current and future illness and death" (Espinal et al. 1999). Further, the case has not been proved that expenditure on individualised regimens rather than standardised third line regimens will be that optimal allocation of funds. Iseman has addressed this debate in a short but thought-provoking editorial (Iseman 2000). The utilitarian philosophers Jeremy Bentham and John Stuart Mill explored the concept of following policies, which led to the greatest good or happiness to the greatest number. As Iseman puts it: «To what extent can and should we divert energies and monies to the care of the relatively small number of patients with MDRTB? Will such efforts impede the implementation of DOTS programmes, the current utilitarian strategy favoured by the WHO". On the other hand, would a true utilitarian approach really favour diverting the funds to MDR-TB, because over the long term that will result in the greatest happiness to the greatest number, the utilitarian ideal.

46.6.14 Is There One World Message After All?

It's a tough job to persuade a Government in London that putting money into Africa will eventually make voters happier about their record on TB locally in the UK - not least because it will take a few years to have an effect and by then the next Government may get the credit. The battle against TB has to be fought in the corridors of power in Washington, London, Paris and Berlin, as well as out in the field. It has been argued that where some drug resistance occurs introducing the standard four-drug regimen of isoniazid, rifampicin, pyrazinamide and ethambutol followed by isoniazid and rifampicin may augment drug resistance. If the standard re-

831

Multi-Drug-Resistant Tuberculosis

treatment regimen including only the addition of streptomycin is introduced then five-drug resistance will emerge. This has been termed the amplifier effect of short-course chemotherapy (Farmer et al. 1998). The authors site evidence of this having occurred in Peru during the 1980s. Furthermore MDR-TB strains, created in Peru have now shown up on the eastern seaboard of the USA. Transmission within hospital settings is also problematic (Kritski et al. 1996; Rullan et al. 1996). This may be some evidence for a much greater problem (World Health Organization 1997d). A possible 50 million people across the globe may be infected with an MDR-TB strain (Small et al. 1993). The authors define DOTS-plus as the provision of drugs, second line if necessary, to provide appropriate treatment for the MDR-TB patient. This may not necessarily be based on sensitivity results, which would not be obtainable in many settings where the DOTS-plus regimen may be required. Rather it would be based on failure of the standard regimens and would provide second line drugs, which the patient would not have been exposed to previously. When MDR-TB occurs the only way of treating the patient effectively is to provide expensive second line drugs. But the problem arises as to how these can be afforded. Farmer and colleagues argue that unless the problem of treating MDR-TB is addressed, and funded, the problem can only get bigger. They point out that untreated MDR-TB causes a series of sub-epidemics in a susceptible population: the so-called fast MDRTB of primary disease. But in addition there will be a slow epidemic caused by reactivation of latent MDR infection at any time between a year and a lifetime from the initial infection. If MDR-TB is ignored the relative contribution of these resistant strains to the overall caseload can only increase year by year. Though it is true that overall rates of drug resistance have fallen when well-functioning DOTS programmes are introduced, in no setting in the world has already established MDR-TB rates fallen when DOTS short course therapy (with no other intervention such as second line drugs) has been introduced. The argument that second line drugs cannot be afforded in developing countries, whereas they can in the developed world implies a second-class citizenship of poorer nations. Farmer and colleagues go on to berate the complacency that refuses to fund the treatment of MDR-TE. If we do not practice a form of DOTS-plus now, providing specific treatment of MDR-TB, we will be forced to spend a greater amount

later when the epidemic 'time bomb' explodes. Farmer points to five signs for optimism in the battle against MDR-TB. First, we know that MDR-TB is not necessarily an incurable disease. Our pharmacological armamentarium is understocked but it is a failure to treat rather than a treatment failure, which results in the majority of MDR-TB deaths (World Health Organization 1997b). Second, patients and their families are ready to go to any sacrifice to attempt cure. It is also the experience of most clinicians that they will go to any lengths possible to achieve the best for their patients. Third, we cannot hide the destitute sick of the world from the rest of us. The world is increasingly a global village and the drug-resistant patient is no more than 24 hours fiying time from anywhere in the world (Pablos-Mendez and Lessnau 2000). The fourth reason derives from the third. If the destitute MDR-TB sufferer turns up in New York, or London, no rightful humanitarian is going to say they cannot be treated. Thus the hypocrisy of saying they can be treated in New York, but not Lima Peru, for example is exposed. The fifth reason is that we do have the resources necessary to confront MDR-TB, especially if we act promptly and in a co-ordinated fashion. Delaying our response will only increase future outlays. As WHO has warned" once MDR-TB is unleashed we may never be able to stop it." There is compelling evidence from Peru to show that DOTS-plus, a strategy which targets specifically MDR-TB as well as drug susceptible disease has had good results (Farmer 2001). This provides a new strategy that would target for treatment all patients with active disease, including those with MDR-TB (Farmer and Kim 1998). Side effects were not apparently a great problem (Furin et al. 2001). Ineffective treatment of MDR-TB with short course chemotherapy may increase the costs of tuberculosis treatment and prevention in the long run (Heifets 1994). There is certainly good evidence that public governmental or non-governmental organisational pressure is helping to steadily reduce the cost of previously expensive chemotherapy (Coghlan 2001).

46.6.15 Transmission of MDR-TB A recent study from Los Angeles has re-opened the issue of whether drug-resistant tuberculosis is less infectious than drug-resistant disease {Nitta et al.

832

2002). Strain typing was done on isolates of 102 pulmonary multidrug-resistant cases and a total of 94 (92%) were sputum smear-positive for acid-fast bacilli and 71 (70%) had cavitary lesions. The great majority could therefore be described as being infectious. Four molecular clusters of two cases each and one closely related pair were identified among the 102 cases. Among 946 contacts identified 6% had a positive tuberculin skin test. The authors imply from their discussion that they regarded this as a low rate of transmission. They attribute this to good control measures. An accompanying editorial points out that the paper is flawed by a lack of controls (Daley 2002). The authors do not provide a comparison with a matched group who had drug susceptible tuberculosis by which true transmissibility could be determined. An earlier study in a similar area showed much the same incidence of TST conversion in contacts of patients with drug-susceptible strains (Marks et al. 2000). The editorial also points out the reduced transmission may be due to reduced virulence of the drugresistant organism. Other evidence is referenced showing that drug-resistant isolates are less likely to be associated with molecular-based case clustering compared with drug-susceptible controls (van Soolingen et al. 1999). Also isoniazid-resistant strains cause significantly less disease in guinea pigs than drug-susceptible strains, and mutations or deletions within the katG gene result in a decrease in the pathogenically of isoniazid-resistant strains of M. tuberculosis (Li et al. 1998). The editorial concludes that the multi-drugresistant organisms, being 'less fit' may have more limited transmissibility than drug-susceptible organisms. In the practical management of tuberculosis control it is prudent to treat the drug-resistant strains as being as infectious as the drug-susceptible strains until more evidence emerges.

46.7 Conclusions The potential for mortality and morbidity as a result of MDR-TB, especially in conjunction with HIV is immense. The question is whether existing structures can prevent or contain the disease. The fact that MDR-TB exists at all and is a major problem in many parts of the world suggests that we are failing to prevent and cure the disease. The extent of the problem is a manifestation of the medical incompetence, which has caused it. A very recent publication gives some grounds for optimism (Dye et al. 2002).

P. D. O. Davies

The authors believe that standard short-course chemotherapy, based on a combination of cheap and safe first-line drugs, can prevent the build up of resistance in a population in which most are drug sensitive. They believe they have evidence that using first-line drugs correctly can actually reduce drug resistance. Resistant strains may be less virulent. Long-term trends indicate that MDR can be contained without expensive second-line drugs. Also on a broad geographical scale they do not believe that HIV has exacerbated MDR spread. But, they admit the evidence to support these claims is not incontrovertible. The jury is still out but the situation may not be as bad as was feared. Prevention of MDR by excellent medical practice must be of greatest importance.

Acknowledgements. The author would like to thank The Annals of the New York Academy of Science for allowing some reproduction from the monograph

Drug-resistant tuberculosis. From Molecules to Macroeconomics. Edit: Peter Davies. Annals of the New York Academy of Science 2001 ;953:87-253. Also to Mario Raviglione, Zarir Udwadia, Alwyin Mwinga, Vivien Stern, Francis Drobniewski, Douglas Young, Paul Farmer, Peter Ormerod, Anton Pozniac and John Moore-Gillon, who have given permission to use some of their manuscripts in this chapter.

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47 Monitoring Treatment Efficacy P. H.

LAGRANGE,

N. SIMONNEY, A. O. SOUSA, A. WARGNIER, J. L. HERRMANN

CONTENTS 47.1 47.2 47.2.1 47.2.1.1 47.2.1.2 47.2.1.3 47.2.2 47.2.2.1 47.2.2.2 47.2.3 47.2.3.1 47.2.3.2 47.3

Introduction 839 Clinical and Bacteriological Monitoring of TB Patients 839 Monitoring Patients with TB Involves Three Main Objectives 839 Susceptibility Testing 840 Compliance of the Treated TB Patient 840 Early Follow-up of the Patient and the Culture Conversion 840 Diagnostic Methods 841 TB Infection 841 TB Disease 841 Immunological T- and B-Cell Responses in TB Patients 842 Ex Vivo T-Cell Immune Responses 842 In Vitro B-Cell Immune Responses 842 Conclusions 849 References 850

47.1 Introduction Tuberculosis (TB) remains the most frequent lethal infection observed in socio-economically deprived populations in which effective long term treatment P. H. LAGRANGE, MD Service de Microbiologie, H6pital Saint Louis, Assistance Publique-H6pitaux de Paris, Universite Denis Diderot, 1, avenue Claude Vellefaux, 75475 Paris, France N. SIMONNEY, MD Service de Microbiologie, H6pital Saint Louis, Assistance Publique-H6pitaux de Paris, Universite Denis Diderot, 1, avenue Claude Vellefaux, 75475 Paris, France A. O. SOUSA, MD Service de Microbiologie, H6pital Saint Louis, Assistance Publique-H6pitaux de Paris, Universite Denis Diderot, 1, avenue Claude Vellefaux, 75475 Paris, France A. WARGNIER, MD Service de Microbiologie, H6pital Saint Louis, Assistance Publique-H6pitaux de Paris, Universite Denis Diderot, 1, avenue Claude Vellefaux, 75475 Paris, France J. 1. HERRMANN, MD Service de Microbiologie, H6pital Saint Louis, Assistance Publique-H6pitaux de Paris, Universite Denis Diderot, 1, avenue Claude Vellefaux, 75475 Paris, France

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

is difficult to accomplish. Sub-optimal TB treatment is always associated with an increased risk of dissemination into the general population and support emergence of multiple-drug-resistant strains. Early identification and effective treatment of active TB have been the key element in TB control and prevention. Adequate therapy for patients with TB is the single most important strategy for the prevention of drug-resistant TB. Effective treatment of infectious patients can also significantly reduce the new transmission in preventing the occurrence of disease. However, TB must be treated for a relatively long duration compared with the treatment of many other infectious diseases. Because of the potential emergence of multiple-drug-resistant TB and patient non-adherence to treatment, it is essential to monitor the treatment effectiveness. Patients under treatment are presently monitored by direct smear examination and culture of clinical samples (Rieder 1996). However, the long time required for M. tuberculosis culture is one of the major limitations. Furthermore, effective monitoring of socially and economically deprived populations presents additional problems. There is therefore an urgent need for rapid, simple, and reliable methods for the evaluation of both the efficiency and outcome of treatment. The developments of new immunological tests as surrogate markers for TB monitoring are the subject of this review.

47.2 Clinical and Bacteriological Monitoring of TB Patients 47.2.1 Monitoring Patients with TB Involves Three Main Objectives The first objective is the diagnosis: of TB infection by active or passive case finding. This is in order to follow the annual rate of transmission (at the population level) and to begin the preventive chemotherapy in order to prevent the occurrence of TB disease (at

P. H. Lagrange et al.

840

the individual level). The diagnosis of TB disease should be made in order to detect any active TB cases, to treat them, cure the patients and decrease the transmission to the community (WHO recommendations = 70% detection and 85% treatment) using the DOTS strategy (WHO 200l). The second objective is to predict, as soon as possible, the patient's compliance, effectiveness of the specific antibiotics prescribed, with simple and robust biological tests with the aim of discontinuing the isolation of the 'hospitalised' TB patient (Small and Fujiwara 200l). The third objective is to detect pre-clinical and bacteriological relapse by sequential follow-up of the patient during, and after, therapy using for example sputum culture conversion (Liu et al.1999). In order to predict the potential effectiveness of the treatment, several tools exist involving the TB bacilli susceptibility testing, assessing patient compliance, allowing early and sequential follow-up of culture conversion. 47.2.1.1 Susceptibility Testing

In vitro susceptibility testing of the isolated TB bacilli to the three or four drugs being usually administered remains the most pertinent test. Nevertheless, such susceptibility tests need locally available, and operational, culture facilities. Moreover, the results are often delayed, depending on the number of viable bacilli present in the tested specimen and the methodologies performed. New alternatives are genomic approaches such as amplification (PCR-SSCP), sequencing, hybridisation to detect known mutations associated with antibiotic resistance (for instance for rifampin or isoniazid). It is also possible to follow the content and the decay ofmessenger RNA from the TB bacillus in the specimen during therapy (Kennedy et al. 1994). However, such approaches have not been yet validated and remain to be shown practicable in routine laboratories. 47.2.1.2 Compliance of the Treated TB Patient

The compliance of the patient during the whole six months of treatment is very important. The first three to six weeks are particularly important since the majority of treatment failures occur during this period. Cessation of one, or more, drugs is usually associated with the selection of mutants involved in secondary resistance.

Compliance can be improved by the administration of a single tablet containing three to four drugs (such as RIFATER), and with follow-up of the excretion of drugs in the urine. It is most important for the patient's compliance that comprehensive information is provided by the physician, that the treatment needs to be taken regularly and that the entire course is taken for the defined period of time, without cessation. The direct observation therapy (often referred to as DOT) strategy is actually recommended in patients with a high risk of non-adherence (Small and Fujiwara 200l). 47.2.1.3 Early Follow-up of the Patient and the Culture Conversion

The need for early follow-up (during the first 2-3 weeks) is usually based on clinical symptoms (cough, appetite, weigh gain and fever) which are often associated with a true effectiveness of the treatment. The rapidity of symptom resolution, although helpful in assessing an individual patient's response to therapy, can be highly variable (Barnes et al. 1987). Moreover, around 5-10% of patients do develop some paradoxical reactions during this period (Smith 1987). These clinical manifestations, together with a visual worsening of the chest radiographs, might confuse the expected evolution and give the impression of a treatment failure. The early bactericidal activity test (EBA) performed during the first two or three days has been used to demonstrate the efficacy of the drugs administrated (Jidani et al. 1980). However, its technical realisation is demanding and has limitations such as the calibration of the specimen. It is often used retrospectively to evaluate new drugs or combinations of drugs (Sirgel et al. 2001). In patients with positive sputum cultures, the conversion to negative cultures provides the only objective measure of successful treatment, and cultures should be obtained monthly until conversion is documented. More than 85% of patients who received both isoniazid and rifampin have negative sputum cultures within two months after initiation of treatment (Small and Fujiwara 200l). Continued monthly monitoring of sputum after culture conversion identified a very small number of patients who had culture reversion. Nevertheless, patients who cannot tolerate, or adhere, to a standard regimen may need continued monitoring to assess response to treatment. For all patients a specimen should be

841

Monitoring Treatment Efficacy

collected at the end of treatment to document cure (Sundaram et al. 2002). The TB patients follow-up during, and after, the treatment is very important, since it has been shown that almost all failures have been observed when patients were not followed-up regularly (Sevim et al. 2002). This follow-up is appropriate to verify the patient's cure and the absence of relapse. The cure can be declared at the end of the recommended duration of the treatment (being usually six months), but the absence of relapse is only confirmed after the second year after finishing the treatment. Usually at the end of the treatment both the clinical status and radiological findings agree that the patient's health has been restored(in these patients the bacteriological tests are negative without any isolation or smear positive results). It is only after the second year (after the end of the treatment) that the complete cure can be definitely assessed if there have been no detected relapses. However, this is certainly accurate for non-immunocompromised TB patients. In fact, a recent study demonstrated that in HIV-co-infected TB patients, relapses occur quite frequently and necessitate secondary preventive chemotherapy for a minimum of one year of isoniazid (Sonnenberg et al. 2001).

There are several tools to achieve the diagnosis of TB infection or TB disease. 47.2.2.1 T8 Infection

The only available method to detect TB infection is the Mantoux test (tuberculin skin test, TST). This in vivo skin test reaction has several drawbacks. The first limitation is the poor diagnostic and predictive values: sensitivity and specificity are variable, influenced by environmental factors and individual responses. False-positive and false-negative responses are common (Chaparas et al. 1985). The second limitation lies in the variability inherent in its application and reading: the strict intra-dermal inoculation, the measurement performed two days after inoculation and the interpretation of the results. New tests which are more specific and less ambiguous, need to be developed. Some are now undergoing evaluation, either in vivo or in vitro in man and in animals (Andersen et al. 2000).The use of specific M. tuberculosis antigens, such as ESAT-6 or CFT-10, antigens for the in vitro production of interferongamma (IFN-y) by the patient's PBMC has been demonstrated as being more specific than the in vivo PPD skin test (Ravn et al.1999). Such tests have been used in order to detect high-risk contacts, but until now, in contrast to the TST, no field-research has 47.2.2 been performed to evaluate its potential for disease Diagnostic Methods prevention in prescribing chemotherapy in highly positive subjects (Vekemans et al. 2001). Apart from the gold standard of bacteriological demThere is actually no immunological test availonstration of the presence of M. tuberculosis there able to monitor the efficacy of preventive therapy is a very well defined place for the immune-based in patients with a primary TB infection. Treatment assays to diagnose TB in patients. These assays are efficacy is usually evaluated in terms of the absence either direct or indirect. of occurrence of disease during or after the complete The direct approach involves the detection of chemotherapy. TB-specific antigens (Sada et al. 1992) and the best results have been demonstrated in cerebrospinal fluid 47.2.2.2 (CSF) in TB meningitis cases(Araj et al.1993). Several T8 Disease new approaches using monoclonal antibodies have shown promising results with pulmonary specimens The two gold standards are the smear test for acid(Pereira Arias-Bouda et al. 2000). However, the diag- fast bacilli (AFB) and the isolation of the causative nostic value was not higher than those obtained with bacteria from the specimens. However the smear test classical bacteriological tests. has a variable sensitivity in diagnosing pulmonary The indirect approach involves the detection of TB, as it is able to detect bacilli (limit of detection any B- or T-cell mediated responses to any specific being 10 000 bacilli/ml) in almost 65% (at best) of antigenic components of the tubercle bacillus. Such active TB cases and less than 30% of cases in some approaches have been developed for more than a cen- recent African surveys (Shinnick 2000). The sensitivtury, and one is still recommended in the normal med- ity of smear microscopy can be increased to 50-80% ical practice (the skin test against tuberculin), others if specimens are liquefied and the bacilli concenare presently evaluated but none are yet validated. trated before AFB microscopy.

842

Culture and isolation of the TB bacillus are never obtained in 100% of cases, and are usually positive only in 70-80% of the patients with pulmonary TB (Stone et al. 1997). The extent is even lower among patients with extra-pulmonary TB, HIV-co-infected patients and in childhood TB (Eamranond and Jaramill 2001). New tests using molecular and genetic techniques have been developed, but their results are not superior to those obtained with the culture from smear positive patients (Soini and Musser 2001). In some clinical settings, more invasive methods are needed to obtain specimens contributing to the diagnosis of TB by pathological findings. Thus, there is an urgent need for applying new tests which are cheap, rapid, more specific, with an higher sensitivity, and are capable of being easily performed. Such tests have been sought for a long time, and antibody detection has been proposed as good complementary method.

47.2.3 Immunological T- and B-Cell Responses in TB Patients The peripheral immunological responses are classified according to the identification of specific cellular (lymphocytes) or serum (antibody) components that the immune system developed after TB infection and during the TB disease. The specific T-cell mediated immune responses are detected in TB patients using the TST and more recently with the use of ex vivo assays (Andersen et al. 2000). The specific B-cell mediated immune responses are detected in nearly all studies by the measurement of circulating antibodies using ELISA tests with native, or recombinant, purified proteins (Daniel and Debanne 1987). There are also some studies demonstrating the presence of antibodies and specific antigens in circulating immune complexes (Simonney et al. 1997). Some others have looked at the cellular levels in body fluids, such as the CSF (Lu et al. 1990), and here we will present recent data, concerning the numeration, in the peripheral blood, of specific secreting B-cells that recognise specific secreted antigens from M. tuberculosis (Sousa et al. 2000).

P. H. Lagrange et al.

cells are cultured for five days in the presence of ESAT-6, CFPlO antigens or PPD. Production of IFN-"{ is measured in the supernatant (Ravn et al. 1999). Different cut-off points are used in order to evaluate the diagnostic values. The results showed that, even if the specific antigens ESAT-6 and CFP-I0 are associated with a lower sensitivity compared with the tuberculin, they are to a great extent more specific than the PPD (van Pinxteren et al. 2000). For instance, when cut-off values were either 300 or 1000 pg/ml, these tests were more able to discriminate the patients not infected by the TB bacillus. Using the same ex vivo model, the diagnostic value of ESAT-6 has been evaluated in our laboratory looking at a group of 23 TB patients compared with 16 healthy controls, or hospitalised patients not having TB. A statistically significant (p
47.2.3.7 Ex Vivo T-Cell Immune Responses

In almost all the reported experimental TB studies, the B-cell immune response has never been associated with any protection against the TB bacillus, neither using B-cell depleted mice (using anti-IgG antibodies or in KO mice) nor after using passive transfer of immune sera from infected, or surviving mice, or rats after infection with the TB bacillus (Flynn and Chan 2001). However a puzzling observation published several years ago (Forget et al. 1976) concerned the capacity of a rabbit immune serum to increase the bacteria replication in target organs. This increase was observed only when a low infec-

Several authors have used the in vitro production of IFN-"{ by Peripheral Blood Mononuclear Cells (PBMC) from patients with TB or from healthy donors. These

a pertinent explanation for this phenomenon. In Bcell immuno-compromised human condition, such as the agammaglobulinaemia, the frequency of TB is

tive dose was used. No one has been able to provide

Monitoring Treatment Efficacy

not greater than in the environmental population of children with the same age. The only interesting clinical observation, concerning the potential antibody protection in TB children, was those establishing a correlation between the serum very low levels of anti-LAM antibodies and the frequency of disseminated TB in children less than four years of age (Costello et al. 1992). The interpretation, given by the authors, was the well known limited capacity of these children to mount an antibody response to the polysaccharide antigen at that age. On the other hand, there are several published reports (over several decades) describing the real capacity of the infected TB hosts to produce specific antibodies during TB (Hoffenbach et al. 1985; Daniel 1988). Also, many attempts have been made to translate this into a diagnosis test, but without any success. This was due mainly due to the use of non-purified cross-reacting antigens and the non-validation of the techniques proposed (Daniel and Debanne 1987). Since the 1980s,newer approaches have been selected using Enzyme-Linked Immunosorbent Assays (ELISA) and more purified antigens produced by recombinant technologies. The results demonstrated a great potential for diagnosis of active pulmonary TB, but it has been recently noted that the host presents an heterogeneous production of antibodies to several antigens, requiring a multiple antigens approach (Genarro 2000). The real advantages of ELISA tests using purified protein antigen are their rapidity (less than 24 hours) and simplicity, with comparable, or higher, sensitivity and specificity with the AFB test. However, several authors have reported that HIV-co-infected TB patients were usually poor responders to these protein antigens (Verbon et al. 1993; Daniel et al. 1994). Thus, other antigens and specifically non-protein antigens need to be tested. It is important to note that the absent, or very low, specific antibody levels in serum could be due to the presence of circulating immune complexes (CIC), not being detected by classical ELISA tests. In fact, several authors have demonstrated the occurrence of specific CIC in TB patients, showing the presence of specific antibodies and/or antigens in these CIC (Raja et al.1995; Simonney et al.1997). However, during the six months of therapy and long after, several authors reported evidence that the specific antibody levels either increased or remained usually high; their decay began normally after several months or years of chemotherapy. It was felt that early TB-treatment monitoring using antibody level follow-up was not helpful (Kaplan and Chase 1980; Drowart et al. 1991).

843

By contrast, evidence was given recently that the number of circulating specific B cells, able to secrete antibody (Antibody-Secreting Cells - ASC), is increased in TB patients before, and during, the first week of their treatment (Sousa et al. 2000). It is worth noting that these elevated numbers of Bcells began to decrease during the second week after the onset of an efficient treatment with an exponential decay, these ASC being virtually absent after one month of efficient chemotherapy. Two techniques have been used to demonstrate the presence of ASC in the peripheral blood, the so-called IVAP and the ELISPOT, as shown below. The results of these new techniques were compared to the classical serum antibody evaluation. Prospective Antibodies Study of Patients with TB The detection of specific antibodies in patients' serum was first performed in patients before the beginning of the treatment with an ELISA test using one of the three glycolipid antigens that are specific for the M. tuberculosis complex. Several sets of data have shown that they are specific for the M. tuberculosis complex, which are not present in all atypical mycobacteria (Cruaud et al.1990).This work was undertaken following the published results from Cruaud and colleagues describing the reliable diagnostic values of an ELISA test using two (the DAT and the PGLTb 1) of these antigens (Cruaud et al. 1990). A third specific glycolipid antigen, the lipo-oligosaccharide (LOS), which was described as being only present in M. tuberculosis, and not in M. bovis, M. africanum and M. microti (Papa et al. 1993) has been evaluated concomitantly. The three purified glycolipid antigens were kindly provided first by Papa from the Pasteur Institute (Paris), and later by Dafft (CNRS, Toulouse, France). These three glycolipids have been purified after chloroform/methanol extraction from M. tuberculosis (H37Rv strain). The three antigens were the lipooligosaccharide (LOS), the diacyl-trehalose (DAT) and the phenolic glycolipid (PGL-Tb1). These three antigens are located at the external surface of the M. tuberculosis bacillus. Initially, both IgG and IgM antibodies were evaluated, but the IgM responses were found to be less discriminating compared with the IgG antibodies (Daleine and Lagrange 1995), thus all the data presented here will concern only the antibodies IgG responses. The population of tested patients consisted of 149 patients with documented TB (either after being shown to be culture positive or after pathological confirmation). The vast majority of these TB patients were HIV tested, because such testing has been recom-

844

mended in France since 1994 for all new TB case. A total of 134 healthy control individuals, mostly from the Hospital Saint Louis Blood Bank, were also included in this study in order to evaluate the specificity of our ELISA test. The group ofTB patients was classified into two main subgroups according to the HIV status (HIV positive or negative) and further subdivided according to location of the disease (pulmonary or extra-pulmonary) and the results of the AFB test. Nearly 75% of the patients were HIV negative (25% positive) and the median age was not statistically different in these two groups. However, when looking at the TB localisation, it was quite interesting to note, as already reported in the current literature, that HIV-positive TB patients presented a higher proportion of extra-pulmonary disease (53%) compared with HIV-negative TB patients (27%). Moreover, it was also observed that the AFB tests were more often positive in HIV-positive patients compared with HIV-negative TB patients with extra-pulmonary disease, since there were more invasive pathological samples in the former. The varying OD values did show a statistically significant difference (p
P. H. Lagrange et al.

In contrast, our domestic ELISA tests using the three glycolipid antigens always showed an higher sensitivity for each antigen tested in HIV-positive TB patients compared with HIV-negative TB patients (Table 47.2). The cumulative sensitivity of the three combined tests was 85.2% for all TB patients, but 95.2% in the HIV-positive group. Similar sensitivities (95%) were observed in HIVpositive patients with pulmonary, or with extra-pulmonary, TB disease. The lowest sensitivity (68%) was observed in HIV-negative patients with extra-pulmonary TB. There was no significant difference between ELISA sensitivity in smear-positive and smear-negative patients with pulmonary TB, for all HIV immune status and sites of diseases. The main value of the Elisa test using the glycolipids is thus to provide early complementary information by antibody detection in HIV-positive TB patients, particularly those with a negative smear test. Retrospective Study in a Cohort of TB Patients The ELISA test has been then tested retrospectively using the serum from several individuals belonging to a cohort of HIV-positive and HIV-negative TB patients, followed for several months at varying timepoints before and after the diagnosis of tuberculosis. The sera have been conserved at -80 0 C, and all the tests have been blinded. In this cohort of 27 TB patients, 11 were HIV positive and 16 were HIV negative. For a specificity higher than, or equal to, 93%, the sensitivity for each ELISA test using individual antigen (DAT and PGL-Tb 1) was found to be almost 80% in proven TB patients and 100% in culture-negative TB patients (clinical and radiological assessments and treatment efficacy). As described previously, the sensitivity was again higher in HIV-positive patients compared with HIV-negative TB patients (100% and 81.3%, respectively). In several TB patients, sequential sera have been harvested at various times before TB diagnosis, during and long after the 6 months treatment. The dynamics of the IgG antibody response to the DAT and PGL Tbl antigens was then evaluated using several sera from each patient. The results of such an approach using the DAT antigen are shown in Fig. 47.1. The means of anti-DAT antibodies (OD values) were higher than the cut-off level found in a control group for all the period of time under study. In the HIV-positive TB patients the values increased and reached a peak at the time of the TB clinical and/or bacteriological diagnosis. This is in sharp contrast with the relative delayed occurrence of the anti-

Monitoring Treatment Efficacy

845

Table 47.1. IgG antibody levels against lipo-oligosaccharide (LOS), diacyl-trehalose (OAT) and phenolic glycolipid (PGL-Tbl) measured by ELISA in the sera of 149 adults with documented tuberculosis and 134 healthy controls (mean±SEM) Optical density (mean±SEM)

TB patients Controls p Values

LOS (n)b

OAT (n)

PGL-TBI (n)

134.3±1O.7 (116) 13.7±2.1 (105) p <0.0001

200.0±13.8 (149) 46.9±3.4 (134) p <0.001

164.8±14.3 (149) 25.1±17 (134) p <0.001

'Absorbance at 414 nmxlO-3 bNb of serum tested Table 47.2. Comparative sensitivity of the ELISA tests using the three glycolipid antigens (LOS, OAT and PGL-Tbl) and the cumulative results in the total tested population, in 42 HIV-positive and 107 HIV-negative patients with documented tuberculosis Antigen

Sensitivity'

LOS OAT PGLTbl Cumulative results

HIV Positive

Negative

Total

82.5 73.8 88.1 95.2

75.0 64.5 65.4 81.3

77.6 67.1 71.8 85.2

(33/40)b (31/42) (37/42) (40/42)

(57/76) (69/107) (70/107) (87/107)

(90/116) (100/149) (107/149) (127/149)

'Cut-off values: LOS:0.043; DAT:0.110; PGLTbl:0.043 bNb of positive serum/Nb of serum tested

It

I

·15

·10

·5

Q" o

.....--+---,,--+,10

15

20

>----1 25

30

tim. (month)

Fig. 47.1. Kinetics of free circulating IgG antibody levels against diacyl-trehalose (OAT) measured by ELISA in sequential serum from 11 HIV-positive (black squares) and 16 HIVnegative (open squares) patients with tuberculosis during anti tuberculosis treatment (mean ± SEM). The horizontal dotted line represents the cut-off value calculated with control sera and the open arrow the onset of treatment

than those in HIV-negative patients. However, at 15 months in HIV-negative and 30 months in the HIVpositive treated TB patients, the remaining antibody levels against DAT remained still higher than the threshold level . If this ELISA test is used systematically, it will not discriminate new TB patients from non-active TB in already treated patients. Similar results have been obtained using the PGL-Tbl antigen (data not shown) In conclusion, according to these data, two points are worth noting. First, the antibody follow- up do not seem to be very useful at monitoring early treatment efficacy, since both the anti-DAT and anti-PGLTbl antibody levels decline very slowly during the 6 months period of treatment. Second, when a new patient is suspected of TB disease and for the interpretation of the anti-glycolipid antibodies results, it is quite important to know if the patient has been treated in the recent past for a first episode of TB. Prospective Study in TB Patients Under Treatment

body production in the HIV-negative group of TB patients. It is also important to note that, even if the mean antibody titres showed a dramatic decline in this long term follow-up study, the slope of the curve appears to be less pronounced in HIV-positive TB patients

In a group of23 HIV-negative patients with documented TB, 13 were followed sequentially from the onset of the treatment to its completion. During this follow-up, one tube ofserum was harvested every week during the first month and at monthly intervals thereafter.

846

ELISA tests were performed using several individual sera and the dynamics of the free circulating IgG antibodies against a recombinant protein antigen (r38 kDa) and a purified carbohydrate antigen (LAM) were evaluated (Sousa et al. 2000). In all sera, a small but consistent decrease in antibody levels over the first two weeks of chemotherapy was observed. This decrease was followed by a gradual increase in the case of both anti-38 kDa and antiLAM. Thereafter, the mean level of anti-38 kDa IgG decreased from day 60 up to day 180. In all cases, this decreased was observed after M. tuberculosis culture conversion. In contrast, the mean level of anti-LAM IgG remained elevated for the complete duration of follow-up of patients. These results are in agreement with our preceding findings concerning the antibodies against the three glycolipids and also with those against proteins reported in the literature (Kaplan and Chase 1980; Drowart et al. 1991). Circulating Immune Complexes (CIe) Before and During Therapy Detection of Antibodies in the Circulating Immune Complexes In order to understand the false-negative ELISA tests in some TB patients, the presence of circulating immune complexes (CIC) in serum was first evaluated. Then, after CIC dissociation, the patient's anti-glycolipids IgG antibody contents were evaluated. The presence of anti-glycolipids within CIC in lepromatous leprosy sera has been already reported, often masking the real production of antibodies (Tomimori-Yamashita et al. 1999). CIC were isolated in the serum from adults, and children, with TB and in control sera using the 2.5% PEG precipitation technique. This has already been done with leprosy patient sera. Such PEG concentrations did not precipitate aggregated IgG, and all the CIC were precipitated after the first run. The quantity of CIC was measured at 280 nM with a spectrophotometer. CIC levels were significantly higher (p
P. H. Lagrange et aI.

As previously described, varying levels of the free anti-glycolipids IgG antibodies were observed in the sera of TB patients, and usually lower mean levels were observed in HIV-negative compared with HIV-positive TB patients. There was no direct correlation between the levels of free circulating IgG antibodies and the levels ofIgG antibodies detected within the CIe. The ELISA sensitivities were calculated for the free and the complexed antibodies present in the CIe. It was observed that almost all of the complexed antibodies were detected in false-negative HIV-negative TB patients and not in the HIV-positive TB patients. The number of ELISA-positive TB patients is higher in the HIV-negative compared to the HIV-positive TB patients. About 96% of the former had CIC containing specific antibodies to one, two or the three glycolipids compared to 72% in the later. Kinetics of Circulating Immune Complexes During Treatment Using the serum aliquots from this prospective study the dynamics of the total CIC and their anti-DAT IgG antibodies were evaluated during treatment. The kinetics of the mean levels of the total CIC in the serum according to the time is shown in Fig. 47.2. It is interesting to note that after a sharp and short increase during the first two weeks following the treatment onset, the total CIC reached a plateau for three months and gradually dropped to baseline level by day 120. Similar findings have already been described in the literature (Raja et al. 1995). The level of circulating free IgG antibody against the DAT antigen did not change significantly during the treatment (Fig.47.3 lower line), except for a slight drop during the first week. However, anti-DAT (Fig. 47.3 upper line) and anti-ST-CF (data not shown) IgG antibodies present in CIC, showed a marked increase as soon as the treatment started which mirrored the kinetics of free, or newly, synthesised circulating antibodies against STCF and DAT. Such findings were also observed for free IgG antibodies against LAM and the 38 kDa protein (data not shown). In conclusion, the levels of free circulating IgG antibody against several protein, carbohydrate or glycolipid M. tuberculosis antigens (38 kDa, ST-CF, LAM, DAT, PGL-Tbl), detected by ELISA in the whole serum, varied depending on the antigen used. The individual kinetics did not yield any information on early treatment outcomes. These data confirm the lack of predictive power of serological tests for the treatment monitoring as demonstrated previously (Drowart et al. 1991).

847

Monitoring Treatment Efficacy

Ex Vivo Numeration of Specific Secreting B Cells

Circulatin& luunYn cPUlplex

1 1 o

50

"1.00

"1.50

DAYS

Fig. 47.2. Kinetics of circulating total immune complex levels measured by 2.5% polyethylene glycol (PEG) precipitation in sequential plasma samples from 13 patients during anti-tuberculosis therapy (mean ± SEM) (from Sousa et al. 2000)

PAT ELISA

T

"!~'

1

T T 1 1 --1 _ ---__ -::r.

r r _- "

T

I

1 .

T

1

CIC-TgG

Free I g e

DAYS

Fig.47.3. Kinetics of specific free IgG (lower line), immune complex-associated IgG (upper line) antibody levels against diacyl-trehalose (DAT) measured by ELISA in sequential plasma samples from 13 patients during anti tuberculosis therapy (mean ± SEM) (from Sousa et al. 2000)

Nevertheless, the early increase in total CIC and complexed antibody to the DAT, PGLTbl and ST-CF antigens, associated with a modest decrease in circulating free antibodies to M. tuberculosis antigens, might be the consequence of an increase of released mycobacterial antigens, both at the infectious sites of the disease and in the peripheral blood, reflecting early bactericidal activity of anti-tuberculosis drugs. Such results confirm previous studies, showing that in CIC both specific antigens and antibodies were significantly elevated in TB patients (Bhattacharya et al. 1986; Dlugovitzzky et al. 1995). An increase in CIC levels after two months of treatment followed by a decrease at six months has already been reported by Raja and colleagues (1995). However, as shown in our study, no correlation was demonstrated with the early resolution of clinical TB disease under treatment.

Having demonstrated that free circulating antibodies were often associated with an increased of complexed specific IgG antibodies to M. tuberculosis antigens during the first two weeks of the treatment, this observation suggested a possible release of antigens, and also a possible reactivation of the B-cell immune system. In order to evaluate this event, the number of circulating specific B lymphocytes was first evaluated. Counting techniques for the circulating antibody secreting B cells (ASC) using ELISPOT assays have been developed for the diagnosis of several infectious diseases due to cytomegalovirus (Segondy et al.1990), HIV (Lee et al. 1989), Salmonella typhi (Kantele et al. 1986), Toxoplasma gondii (Vendrell et al.1993) Brucella spp. (Vendrell et al. 1992) and Chlamydia trachomatis (Ghaem-Maghani et al.1997). These studies have demonstrated a correlation between the detection of circulating ASC and the presence of antigens secreted by replicating micro-organisms. Therefore, the ELISPOT assays in TB patients have been performed to reach a diagnosis and also for their potential in monitoring treatment efficacy in TB patients. With the use of specific antigens (the short term culture filtrate - ST-CF), corresponding to secreted antigens released by replicating M. tuberculosis (Andersen et al. 1991), we reported the presence of specific ASC in a cohort of 13 patients with active TB before and their regular decline during recommended multiple-drug therapy (Sousa et al. 2000). Fresh PBMC were first enriched for Blymphocytes using positive selection, the isolated cell population contained around 90-95% B cells measured by cytometry analysis. ELISPOT plates were pre-coated with either ST-CF or goat anti-human IgG F(ab') antibody. Enriched B cells were added in complete culture medium to the ELISPOT plates and were incubated for overnight at 37°C. After washing the B cells extensively in PBS supplemented with Tween 20 (0.05%), the specific antibodies bound to the solid phase antigen were revealed by incubation with antihuman IgG Fc specific peroxidase-labelled antibody. Each spot on the nitrocellulose membrane (Fig.47.4) indicated the presence of an ASC specific to the coating antigens. The number of circulating ASC reactive to ST-CF was evaluated by ELISPOT for each TB patient before and at varying times during the treatment. The cut-off value of the normal level ofASC had been determined in a previous study using healthy controls and was found to be less than 150 ASCIl0 6 circulating B cells corresponding to a specificity of

848

P. H. Lagrange et al.

B cell ELiSP T Controls

ELISPOT 1500

T8 patients

Cut-off: 150 ASC/1 0 6 B cells

Fig.47.4. Two ELISPOT wells showing specific B cell spots against short term culture filtrate (ST-CF) on the nitro-cellulose membrane stained with goat anti-human IgG from PBMC of one control (left picture) and a tuberculosis patient

(right picture)

100%. Before initiation of therapy, 82% of TB patients had detectable specific ASC with a wide range among patients (200-5,460 ASC/I06 B cells). The kinetics of the ASC during the treatment are shown in the Fig. 47.5. From day 0 to day 8, the median numbers of specific ASC increased markedly and 100% of the patients had detectable numbers of circulating ASC on day 8. This peak was followed by a three-fold decrease of the median number at day 15, and a lO-fold decrease at day 30. It is noteworthy that one patient had persistently elevated numbers of ASC after two months, accounting for the large standard error in the mean at that time in the histogram. In all of the remaining cases, the levels of ASC decreased markedly and always before mycobacteria cultures turned negative. Moreover, this ACS decrease was detected either before (in eight cases) or at the same time (two cases) as the sputum smear conversion. The percentage of TB patients remaining positive for sputum smear and cultures after the onset of the treatment is shown in Fig. 47.6. Eleven patients had pulmonary TB with moderate to severe disease and two patients had pleurisy (shown to be positive by biopsy). In all patients with pulmonary TB, the sputum smears and cultures were positive for M. tuberculosis before therapy. Only patients with documented TB have been included in this study, to obtain comparative data with previous published studies of culture conversion time (Joloba et al. 2000) and to demonstrate the value of ASC numeration value for TB treatment monitoring. All patients responded well to treatment with culture conversion and clinical and radiological improvement. However, one patient was lost to follow-up after the second month and relapsed one year later. Among the 10 patients with pulmonary TB and a positive outcome,

o

8

'13

30

60

90

'120

'1.80

240

DAYS

•

Fig.47.S. Kinetics of the numbers of circulating antibodysecreting cells (ASC) per one million of B cells at varying time-point during anti-tuberculosis therapy in a group of 13 patients with pulmonary tuberculosis (median ± SEM). The horizontal dotted line represents the cut-off value calculated using control patients (from Sousa et al. 2000)

20

.10

1\0

80

100

120

IJO

IW

110

Days

Fig.47.6. Kinetics of the percentage of patients remaining bacteriologically positive for sputum smears (open squares) and cultures (closed squares) at varying time-points during anti-tuberculosis therapy (from Sousa et al. 2000)

the mean number of days from the initiation of appropriate therapy to obtain negative AFB smears was 27.4 ± 7.6 days. Similar values for the first negative sputum cultures were 45.0 ± 9.2 days with a range of 15-90 days. These results were almost identical with those described in the current literature (Joloba et al. 2000). In contrast to the exponential decrease of circulating specific ASC beginning after the 8 day of treatment, the mean level of circulating free anti-ST-CF IgG antibody tested by ELISA increased until day 60 and then declined slowly until the end of the treatment, confirming the preceding results obtained with other antigens. Thus, for the first time, there is evidence for the presence of M. tuberculosis specific circulating antibody secreting B cells (detected by an ELISPOT assay in the peripheral blood of TB patients), that can be

849

Monitoring Treatment Efficacy

used during the treatment follow-up and showed a predictive value for early and late treatment efficacy. This is in contrast to other immune markers. It is assumed that the kinetics of the specific B cell response might reflect the bacterial dynamics under anti-mycobacterial therapy. The possible reduction of the secreted antigens production may account for the decrease of anti ST-CF specific B cells. Similar findings has been already demonstrated by other authors for patients with chronic brucellosis (Vendrell et al. 1992). Detection of ASC in PBMC suggests that in acute, or chronic, infectious disease the host immune system is stimulated continuously by replicating antigens for several weeks, or months, after the onset of illness. This has been already observed in patients with TB meningitis by detecting anti-BCG secreting B cells in cerebral fluid and to a lesser degree in PBMCs (Lu et al. 1990; Baig 1995). A reduction of the antigenic load occurred in TB patients B during effective therapy either by detecting antigens in sputa (Wallis et al. 2001), in the peripheral blood (Sethna et al. 1998) or in the urine (Hamasur et al. 2001). At least, the great advantage of the ELISPOT technique is the ease of collecting peripheral blood, to quantify the circulating specific ASC and to use the results as a surrogate marker of the persistence of replicating mycobacteria in tissues. Thus, stopping the mycobacterial replication with an effective treatment is associated with a drastic reduction of M. tuberculosis secreted proteins, such as those contained in the ST-CF (Andersen et al. 1991) and this explained the concomitant rapid decrease in specific circulating B cells observed in the peripheral blood of well-treated TB patients. In Vitro Antibody Production

In order to simplify the ELISPOT assay (demonstrating the presence and the dynamics of the specific secreting B cell response) a new approach, looking at the In Vitro Antibody Production (IVAP), has been evaluated first for the diagnosis of TB patients. This has already used by several authors in other infectious diseases (Vendrell et al. 1992, 1993). It involves measuring the production of antibodies derived from the culture of PBMC from TB patients. The supernatants are harvested on the 6th day of the culture without any antigen and the antibodies are detected by ELISA using the same antigens as for the ELISPOT. The IVAP mean levels of anti ST-CF IgG antibody were significantly higher (p
By using a threshold cut-off (mean + 3 SD), giving a specificity of 100%, the sensitivity of this IVAP assay was 70.6%. This was about the same order that was obtained with the ELISPOT assay. Similar sensitivity but lower specificity were obtained for antibodies against ST-CF and PGLTbl tested in the plasma. A prospective follow up of TB patients under treatment is now being undertaken in our laboratory.

47.3 Conclusions The results obtained with our in-house ELISPOT and IVAP assays, using antigens present within the ST-CF, demonstrate that B-cell specific antigens from M. tuberculosis are useful and encouraging: firstly as a diagnostic tool and secondly for the monitoring of the TB disease in non-HIV patients. In contrast, specific M. tuberculosis free- and CIC-associated IgG antibodies against the glycolipid antigens were shown to be helpful especially as complementary tests for the diagnosis ofHIV-co-infected TB patients, but without any help for monitoring treatment efficacy. However, it is important firstly to mention the individual polymorphism of the B-cell immune responses and the need for using several antigens to detect positive TB patients. Secondly, the various types of antigen used might give different types of information. For example, glycolipid antigens, such as those used in our domestic ELISA test, were more effective in detecting TB in HIV-positive patients compared with the results obtained in HIV-negative patients. Such results contrast with the published results of ELISA tests using specific purified recombinant proteins (Daniel et al. 1994). It is possible that the results obtained using glycolipids might be due to the special restricted immune response, mediated through the CD1 pathway recently described for these lipid antigens (Park and Bendalac 2000), not affected by the HIV-induced CD4 depression. On the other hand, secreted antigens, such as those present within the ST-CF (a surrogate marker of bacterial multiplication) are of great interest for monitoring TB treatment. In fact, the elevated numbers of circulating specific M. tuberculosis secreting B cell occurring and persisting in a vast majority of TB patients and their rapid decrease after the onset of the treatment might be used as a strong surrogate marker of treatment efficacy and effective patient compliance. A secondary increase, or an absence of change in ASC numbers, evaluated by regularly harvesting peripheral blood samples during the treatment, might then

850

indicate a poorly compliant patient, or the presence of multiple-drug-resistant tuberculosis. Such ex vivo ELISPOT and in vitro IVAP tests have been shown to be as informative as the smear and culture conversion, but their results were obtained much earlier than the classical bacteriological gold standard tests.

References Andersen P et al (1991) Proteins released from Mycobacterium tuberculosis during growth. Infect Immun 99:1905-1910 Andersen P et al (2000) Review: specific immune-based diagnosis of tuberculosis. Lancet 356:1099-1104 Araj G et al (1993) Improved detection of mycobacterial antigens in clinical specimens by combined enzyme-linked immunosorbent assays. Diagn Microbiol Infect Dis 17:119-127 Baig SM (1995) Anti-purified protein derivative cell-enzyme linked immunosorbent assay, a sensitive method for early diagnosis of tuberculous meningitis. J Clin Microbiol 33: 3040-3041 Barnes PF, Chan LS, Wong SF (1987) The course of fever during treatment of pulmonary tuberculosis. Tubercle 68: 255-260 Bhattacharya A et aL,(1986) Antibody-based enzyme-linked immunosorbent assay for determinat!on of immune complexes in clinical tuberculosis. Am Rev Respir Dis 134: 205-209 Chaparas SD et al (1985) Tuberculin test. Variability with the Mantoux procedure. Am Rev Respir Dis 132:175-177 Costello AM et al (1992) Does antibody to mycobacterial antigens, including lipoarabinomannan, limit dissemination in childhood tuberculosis? Trans R Soc Trop Med Hyg 86:686-692 Cruaud P et al (1990) Evaluation of a novel 2-3-diacyltrehalose-2'sulfate (SL-IV) antigen for case finding and diagnosis of leprosy and tuberculosis. Res Microbiol 141: 679-669 Daleine G, Lagrange PH (1995) Preliminary evaluation of a Mycobacterium tuberculosis lipooligosaccharide (LOS) antigen in the serological diagnosis of tuberculosis in HIV seropositive and seronegative patients. Tubercle Lung Disease 76:234-239 Daniel TM (1998) Antibody and antigen detection for immunodiagnosis of tuberculosis: why not? What more needed? Where we stand today? J Infect Dis 158:678-680 Daniel TM, Debanne SM (1987) The serodiagnosis of tuberculosis and other mycobacterial diseases by enzyme-linked immunosorbent assay. Am Rev Respir Dis 135:1137-1151 Daniel TM et al (1994) Reduced sensitivity of tuberculosis serodiagnosis in patients with AIDS in Uganda. Tubercle Lung Dis 75:33-37 Dlugovitzky D et al (1995) Circulating immune complexes in patients with advanced tuberculosis and their association with auto-antibodies and reduced CD4+ lymphocytes. Brazil J Med Bioi Res 28:331-335 Drowart A et al (1991) Antibody levels to whole culture filtrate antigens and to purified P32 antigen during treatment of smear positive tuberculosis. Chest 100:685-687 Eamranond P, Jaramill E (2001) Tuberculosis in children: reas-

P. H. Lagrange et al. sessing the need for improved diagnosis in global control strategies. Int J Tuberc Lung Dis 5:594-603 Flynn JL, Chan J (2001) Immunology of tuberculosis. Annu Rev ImmunoI19:93-129 Forget A et al (1976) Enhancement activity of antimycobacterial sera in experimental Mycobacterium bovis (BCG) infection in mice. Infect Immun 13:1301-1306 Gennaro ML (2000) Immunological diagnosis of tuberculosis. Clin Infect Dis 30 [SuppI3]:S243-S246 Ghaem-Maghami S et al (1997) Characterisation of B-cell responses to Chlamydia trachomatis antigens in humans with trachoma. Infect Immun 65:4958-4964 Hamasur B et al (2001) Rapid diagnosis of tuberculosis by detection of mycobacteriallipo-arabinomannan in urine. J Microbiol Methods 45:41-52 Hirsch CS et al (1999) Depressed T-cell Interferon-g responses in pulmonary tuberculosis: analysis of underlying mechanisms and modulation with therapy. J Infect Dis 180: 2069-2073 Hoffenbach A, Lagrange PH, Bach MA (1985) Strain variations of lymphokine production and specific antibody secretion in mice infected with Mycobacterium lepraemurium. Cell ImmunoI91:1-11 Jidani A et al (1980) The early bactericidal activity of drugs in patients with pulmonary tuberculosis. Am Rev Respir Dis 121:939-949 Joloba ML et al (2000) Quantitative sputum bacillary load during rifampin-containing. short-course. chemotherapy in human 'immunodeficiency virus-infected and noninfected adults with pulmonary tuberculosis. Int J Tuberc Lung Dis 4:528-536 Kantele A, Arvilommi H, Jokinen I (1986) Specific immunoglobulin-secreting human blood cells after per-oral vaccination against Salmonella typhi. J Infect Dis 153: 1126-1131 Kaplan MH, Chase MW (1980) Antibodies to mycobacteria in human tuberculosis 1. Development of antibodies before and after antimicrobial therapy. J Infect Dis 142:825-834 Kennedy Net al (1994) Polymerase chain reaction for assessing treatment response in patients with pulmonary tuberculosis. J Infect Dis 170:713-716 Lalvani A et al (200l) Rapid detection of Mycobacterium tuberculosis infection by enumeration of antigen-specific T cells. Am Rev Respir Crit Care Med 163:824-828 Lee FK et al (1989) ELlSPOT: a new approach to studying the dynamics of virus-immune system interaction for diagnosis and monitoring of HIV infection. AIDS Res Hum Retrovirus 5:517-523 Liu Z, Shilkret KL, Ellis HM (1999) Predictors of sputum culture conversion among patients with tuberculosis in the era of Tuberculosis resurgence. Arch Intern Med 159: 1110-1116 Lu CZ et al (1990) Early diagnosis of tuberculous meningitis by detection of anti-BCG secreting cells in cerebral fluid. Lancet 336:517-523 Papa F et al (1993) Isolation and characterisation of serology reactive lipo-oligosaccharide from Mycobacterium tuberculosis. Res Microbioll44:91-99 Park SH, Bendalac A (2000) COl-restricted T-cell responses and microbial infections. Lancet 406:788-792 Pereira Arias-Bouda LM et al (2000) Development of antigen detection assay for diagnosis of tuberculosis using sputum samples. J Clin Microbiol 38:2278-2283

Monitoring Treatment Efficacy Raja A et al (1995) Characterisation of mycobacterial antigens and antibodies in circulating immune complexes from pulmonary tuberculosis. J Lab Clin Med 125:581-587 Ravn P et al (1999) Human T cell response to the ESAT-6 antigen from Mycobacterium tuberculosis. J Infect Dis 179:637-645 Rieder HL (1996) Sputum smear conversion during directly observed treatment of tuberculosis. Tuberc Lung Dis 77: 124-129 Sada E et al (1992) Detection of Lipoarabinomannan as a diagnostic test for tuberculosis. J Clin MicrobioI30:2415-2418 Segondy M et al (1990) Cytomegalovirus-specific Bcell activation as a potential marker for the diagnosis of cytomegalovirus infection. Eur J Clin Microbiol Infect 9:745-750 Sethna KB et al (1998) Longitudinal trends in serum levels of mycobacterial secretory (30 kDa) and cytoplasmic (65 kDa) antigens during chemotherapy of pulmonary tuberculosis patients. Scand J Infect Dis 30:363-368 Sevim T et al (2002) Treatment outcome of relapse and defaulter pulmonary tuberculosis patients. Int J Tuberc Lung 6:320-325 Shinnick TM (2000) Diagnostic test needs for evaluating anti-tuberculosis vaccines. Clin Infect Dis 30 [Suppl 3): S276-S278 Simonney N et al (1996) Comparison of A60 and three glycolipid antigens in ELISA test for tuberculosis. Clin Microbiol Infect 2:214-222 Simonney N et al (1997) Circulating immune complexes in human tuberculosis sera: demonstration of specific antibodies against Mycobacterium tuberculosis glycolipid (DAT, PGLTbl, LOS) antigens in isolated circulating immune complexes. Eur J Clin Invest 27:128-134 Simonney N, Bourrillon A, Lagrange PH (2000) Analysis of circulating immune complexes (CICs) in childhood tuberculosis: levels of specific antibody to glycolipid antigens and relationship with serum antibody. Int J Tuberc Lung Dis 4:152-160 Sirgel F, Venter A, Mitchison DA (2001) Sources of variations in studies of the early bactericidal activity of antituberculosis drugs. J Antimicrob Chemother 47:177-182 Small P M, Fujiwara PI (200 I) Management of tuberculosis in the United States. N Engl J Med 345:189-200 Smith H (1987) Paradoxical responses during chemotherapy of tuberculosis. J Infect 15:1-3

851 Soini H, Musser JM (200 I) Molecular diagnosis of Mycobacteria. Clin Chern 47:809-814 Sonnenberg P et al (2001) HIV-l and recurrence, relapse, and re-infection of tuberculosis after cure: a cohort study in South African mineworkers. Lancet 358:1687-1693 Sousa AO et al (2000) Kinetics of circulating antibodies, immune complex and specific antibody-secreting cells in tuberculosis patients during 6 months of antimicrobial therapy. Tuberc Lung Dis 80:27-33 Stone BL et al (1997) The diagnostic yield of acid-fast-bacilIus smear positive sputum specimens. J Clin Microbiol 35: 1030-1031 Sundaram V et al (2002) Yield of continued monthly sputum evaluation among tuberculosis patients after culture conversion. Int J Tuberc Lung Dis 6:238-245 Tomimori-Yamashita J et al (1999) Antibody-based ELISA for determination of anti-PGLl specific circulating immune complex in leprosy. Leprosy Rev 70:261-271 Van Pinxteren LAH et al (2000) Diagnosis of tuberculosis based on the two specific antigens ESAT-6 and CFPI0. Clin Diagn Lab Immunol 7:155-160 Vekemans J et al (2001) Tuberculosis contacts but not patients have higher gamma Interferon responses to ESAT-6 than do community controls in the Gambia. Infect Immun 69: 6554-6557 Vendrell JP et al (1992) In vitro antibody secretion by peripheral blood mononuclear cells as an expression of the immune response to Brucella spp in humans. J Clin Microbiol 30: 2200-2203 Vendrell JP et al (1993) In-vitro synthesis of antibodies to Toxoplasma gondii by lymphocytes from HIV-1-infected patients. Lancet 342:22-23 Verbon et al. (1993) Evaluation of different tests for the serodiagnosis of tuberculosis and the use of likelihood ratios in serology. Am Rev Respir Dis 148:378-384 Wallis R et al (2001) Induction of isoniazid-induced expression of Mycobacterium tuberculosis antigen 85 in sputum: potential surrogate marker in tuberculosis chemotherapy trials. Antimicrob Agents Chemother 45: 1302-1304 WHO (2001) Global tuberculosis control. World Health Organisation, Geneva, WHO/CDSI287

Control and Prevention

48 Tuberculosis Control in Developing and Developed Countries KEVIN SCHWARTZMAN

CONTENTS 48.1 48.2 48.2.1 48.2.2 48.3 48.4 48.4.1 48.4.1.1 48.4.1.2 48.4.1.3 48.4.1.4 48.4.2 48.4.3 48.5 48.5.1 48.5.2 48.5.2.1 48.5.2.2 48.5.3 48.5.4 48.5.4.1 48.5.4.2 48.5.4.3 48.5.4.4 48.5.4.5 48.6 48.6.1 48.6.2 48.6.3 48.6.4 48.6.5 48.6.6 48.7 48.7.1 48.7.2 48.7.3

Introduction 855 Overview of Interventions for Tuberculosis Control 856 Preventing Tuberculous Infection 856 Preventing Progression and Reactivation 856 Cost-Effectiveness of Tuberculosis Treatment 857 The World Health Organization's DOTS Strategy 858 Description 858 Government Commitment 858 Standard Diagnostic Approach 858 Supervised Provision of Standard Treatment Regimens 859 Documentation and Surveillance 859 Status of the DOTS Strategy 860 Controversies 861 Other TB Control Interventions 862 Active Case-Finding in Resource-Poor Areas 862 Screening Interventions in Resource-Rich Areas 862 Screening of Migrants to Low-Incidence Countries 863 Screening and Control in Specialized Settings 864 Bacille Calmette-Guerin (BCG) Vaccination 865 Challenges to Global TB Control 866 Overcoming Neglect 866 The HIV Pandemic 866 Multiple Drug-Resistant Tuberculosis 867 The Private Health Care Sector 868 Population Movement 869 Recent Global Initiatives in TB Control 869 Global Partnership to Stop TB 869 The Global Fund to Fight AIDS, Tuberculosis and Malaria 870 Global Alliance for TB Drug Development 870 Global Drug Facility 870 TB-HIV 870 DOTS-Plus and the Green Light Committee 871 Recent Developments in Tuberculosis Control: Examples from the Field 871 India 871 China 873 South Africa 873

K. SCHWARTZMAN, MD, MPH, FRCPC Assistant Professor, Departments of Medicine and Epidemiology and Biostatistics, McGill University, Respiratory Epidemiology Unit, Montreal Chest Institute, Room K1.23, 3650 St. Urbain, Montreal, Quebec, Canada H2X 2P4

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

48.7.4 48.7.5 48.7.6 48.7.7 48.8.

Peru 873 United States 874 England and Wales Russia 876 Conclusion 877 References 877

876

48.1

Introduction

In 1993, the World Health Organization declared tuberculosis to be a global public health emergency. The vast worldwide burden of mortality and suffering attributed to tuberculosis has been reviewed elsewhere (see Chapter 3): an estimated 9 million people develop active TB each year, and 2 million die as a result. Yet from a medical standpoint, the vast majority of tuberculosis patients can readily be treated and cured, using medications that have been available for decades. Why, then, has it been so difficult to make sustained progress toward reducing the burden imposed by tuberculosis? Several factors contribute to this seeming paradox. The explosion of tuberculosis in sub-Saharan Africa, in the context of the recent HIV pandemic, has been widely publicized. So, too, has the growing threat of multi-drug-resistant tuberculosis in a variety of settings- in both 'developed' and 'developing' countries. Both these phenomena have highlighted, and further eroded, the limited infrastructure available for tuberculosis control in many areas of the world. The World Health Organization (WHO), the International Union Against Tuberculosis and Lung Disease (IUATLD), and other organizations have developed and promoted systematic approaches to TB control - based on sound medical, epidemiologic, and public health evidence. However, successful implementation hinges on sustained political will as well as the necessary material resources. Tuberculosis control refers to the comprehensive interventions directed toward individuals, communities and populations, with the goal of reducing and

856

ultimately eliminating the morbidity and mortality related to tuberculosis. Optimal medical treatment of individuals with tuberculosis is a cornerstone of TB control, but is not sufficient in and of itself. While more money and greater political will must be mobilized to fight TB, they alone are likewise insufficient to contain and conquer it. Instead, funds and political commitment are needed to secure and maintain a systematic approach to TB control in every corner of the globe. Such an approach must of course reflect fundamental knowledge about the pathogenesis and transmission of M. tuberculosis - but it must also reflect an understanding of public health in every sense of the phrase. Hence effective TB control involves not only prompt diagnosis and suitable prescriptions, but also such considerations as: i\Il optimal delivery of care and of medications, suited to local conditions • recognition of important beliefs and practices surrounding illness It accurate surveillance, which in turn permits: fI early identification of changes in epidemiologic parameters " proactive management of complex human and health systems issues In this chapter, the current context of TB control activities is briefly reviewed. Core tenets of TB control are described. Key challenges faced by developing and developed countries are summarized, as are several recent strategies and initiatives. Recent developments in several countries are highlighted as examples- with the caveat that the complexity of the problem, and hence the diversity of local conditions and programs, is vast, and clearly not amenable to simplification.

48.2 Overview of Interventions for Tuberculosis Control Fundamental medical interventions in tuberculosis control are best understood with reference to the pathogenesis of the disease (Fig. 48.1).

K.

Schwartzman

sons with contagious tuberculosis- that is, pulmonary or laryngeal disease. Styblo described a linear relationship between the incidence ofsmear-positive active TB and the annual risk of tuberculous infection, based on observations in a variety of countries. He estimated that for every 1% annual risk of infection, the corresponding increase in annual incidence of smear-positive disease was 49 cases per 100,000 population (95% confidence interval 39-59 per 100,000) (Styblo 1985). The longer that persons with contagious TB remain untreated (or ineffectively treated), the more persons they will infect. Hence prompt diagnosis and effective treatment of pulmonary and laryngeal TB represent the highest priority and most cost-effective TB control activities - just as they represent the surest means to reduce individual morbidity and mortality (Borgdorff et al. 2002). Active case-finding refers to interventions which identify individuals with active tuberculosis who have not yet sought medical attention for TB-related symptoms. The goal is to begin treatment earlier in the course of the disease, thereby reducing the numbers of infected contacts. On the other hand, passive casefinding occurs when the diagnosis of active tuberculosis is made only after patients have sought help for symptoms of disease. Nonetheless, efficient passive case-finding remains an important goal- delayed and missed diagnoses must be minimized, once patients seek help for symptoms. Behavioral, administrative, and technical interventions also reduce infection risk. Patients are urged to cover their mouths when they cough. In resourcerich areas, a number of interventions reduce risks to health care personnel and other patients when exposure is anticipated, e.g. respiratory isolation protocols for TB suspects, high-performance masks, negativepressure ventilation, ultraviolet light fixtures. However, even in these settings the most substantial risk reductions stem from prompt diagnosis and management of infectious patients.

48.2.2 Preventing Progression and Reactivation

48.2.1

Interventions which prevent progression and reactivation aim to reduce tuberculosis incidence among persons who have already acquired tuberculous infection. To the extent that these interventions suc-

Preventing Tuberculous Infection

ceed in reducing the incidence of active TB, they also

The incidence and prevalence of tuberculous infection in any community reflects the level of exposure to per-

prevent subsequent transmission in the community. Once infected with M. tuberculosis, some patients progress rapidly to active tuberculosis (notably the

857

Tuberculosis Control in Developing and Developed Countries

I

I Active Tuberculosis

I Case Finding (Passive or Active)

I

I Effective Drug Treatment

I I

I Patient Behaviour (e.g. Cover Mouth)

I Airborne Droplets I Progression or I Reactivation

I

BCG Vaccination

I Treatment Diagnosis and of Latent TB

I

I

I

I

I Respiratory Isolation

I

I Ventilation and Air Filtration

I

I Ultraviolet Light

I

I Inhalation by Others I

I Antiretroviral Therapy I forHIV I

I Latent Infection

I

HIV-infected), some reactivate years later, and most remain with lifelong latent infection, if untreated. The primary goal of BeG vaccination is to prevent progression to active TB following infection in infancy or early childhood. Antibiotic treatment for latent infection ('preventive therapy', 'chemoprophylaxis') is used primarily in resource-rich areas, to prevent progression to active TB among recently infected contacts. It is also used to prevent reactivation, particularly among persons at elevated risk such as the HIV-infected, and those with radiographic evidence of extensive scarring related to presumed prior active TB. In resource-rich countries, certain screening activities target persons with latent infection - e.g. among new immigrants. However, treatment of latent infection is of lower priority; it is thus often neither feasible, nor appropriate, in low-income, high-burden areas. Just as HIV infection represents the strongest known risk factor for reactivation of latent infection, effective management of HIV disease substantially reduces the likelihood of reactivation. This point was demonstrated by Badri and colleagues in South Africa, who attributed an 81 % reduction in reactivation risk to the use of highly active antiretroviral therapy (Badri et al. 2002). However, even among HIV-seropositive individuals who received antiretroviral therapy, the incidence of active TB remained 2.4 per 100 person-years, 8-10 times higher than among HIV-uninfected persons in the same area. Nonetheless, HIV treatment, where feasible, is an increasingly

Fig. 48.1. Overview of tuberculosis control interventions. Prompt diagnosis and suitable treatment of persons with active TB are the most important and cost-effective measures to reduce community TB incidence

important aspect of tuberculosis control in areas where the two epidemics overlap.

48.3 Cost-Effectiveness of Tuberculosis Treatment Systematic treatment of TB within national control programs is one of the most cost-effective public health interventions worldwide. Murray and colleagues evaluated the cost-effectiveness of shortcourse therapy for smear-positive TB under program conditions in Malawi, Mozambique, and Tanzania (Murray et al.I991). The treatment regimen consisted of two months of isoniazid, rifampin, pyrazinamide, and streptomycin, followed by six months of isoniazid and ethambutol. The analysis reflected program costs for treated patients. It did not include program costs for management and diagnosis of TB suspects, or costs borne by patients and family members. Even with hospitalization during the intensive phase, the estimated total program cost per year of life saved was $1 to $3 US, suggesting that shortcourse TB therapy was even more cost-effective than immunization for measles and neonatal tetanus, oral rehydration therapy for diarrhea, and blood-bank screening for HIV - all of which were estimated to cost $5-10 US per year of life saved. The same analysis suggested that treatment of HIV-infected persons

858

is nearly as cost-effective, since much of the benefit relates to reductions in subsequent TB incidence - among both HIV-seronegative and HIV-seropositive individuals -through interruption of community transmission. Even when costs of establishing the public health control framework are considered, TB treatment remains higWy cost-effective. Expansion of the Indian national tuberculosis program to cover 43% of the country's population cost $50 million US over 8 years, and saved an estimated 200,000 lives, for an average cost of $250 US per life saved. When indirect benefits (avoiding lost earnings) are considered, this $50 million investment generated estimated societal benefits of over $400 million (Khatri and Frieden 2002). A computer simulation model of TB cases and costs in Thailand predicted that expansion of the Thai TB control program to meet WHO benchmarks (70% case detection, 85% cures) would likely save US $8 million in health care costs, and $2.5 billion in lost productivity, over a 20-year period (Sawert et al. 1997).

48.4 The World Health Organization's DOTS Strategy

K. Schwartzman

ally districts with populations of 100,000 to 150,000 - and was designed to be integrated into public health activities at the district level. It was successfully adopted in Tanzania in the early 1970s, followed by other low-income, high-incidence countries. 48.4.7.7 Government Commitment

Each element of the DOTS strategy carries a number of implications. Government commitment to TB control activities means recognition of the serious burden that TB represents, as well as concrete steps to control it. Hence it means not only stable funding, but also political and administrative support - including the establishment and maintenance of regional, and national, tuberculosis control programs. These provide supervision as well as technical and logistical support to district-level activities, and are responsible for broader surveillance. Political commitment also entails working productively with international partners (including donor agencies, and non-governmental organizations) to foster improvements in TB treatment and control. In resource-rich countries, political commitment also entails support for TB control in poorer regions of the world.

48.4.1 Description

Standard Diagnostic Approach

DOTS is the 'brand name' for the tuberculosis control strategy promoted by the World Health Organization since the early 1990s. The acronym stands for Directly Observed Therapy, Short-Course. In fact, it is a comprehensive management approach that goes far beyond the mechanics of administering short-course TB therapy. The key elements of the DOTS strategy are outlined in Table 48.1. The DOTS strategy reflects the approach to TB control pioneered by Karel Styblo and the IUATLD. The strategy takes advantage of existing health units - usu-

The DOTS strategy emphasizes the use of sputum microscopy for diagnosis of active pulmonary tuberculosis, among persons with compatible symptoms ('TB suspects'). This means that individuals with the most advanced and highly contagious disease - smear-positive pulmonary TB -are diagnosed (and then treated). While persons with smear-negative pulmonary TB can and do transmit infection, they infect about 20% as many others as do those with smear-positive disease (Behr et al. 1999a). Hence they represent a lower priority for detection, but will

48.4.7.2

Table 48.1. The WHO DOTS strategy (Maher and Mikulencak 1999) Government commitment to sustained TB control activities Case detection by smear microscopy among symptomatic patients self-reporting to health services Standardized treatment regimen of six to eight months for at least all confirmed sputum smear positive cases, with directly observed treatment (DOT) for at least the initial two months, and direct observation whenever rifampin is used A regular, uninterrupted supply of all essential anti-TB drugs A standardized recording and reporting system that allows assessment of treatment results for each patient and of the TB control program overall

Tuberculosis Control in Developing and Developed Countries

859

subsequently be diagnosed if smear-positive, under the DOTS strategy. Mycobacterial culture and sensitivity testing are not part of the DOTS strategy, as their widespread use is beyond the means of most resource-poor countries. The most cost-effective means to reduce transmission, morbidity, and mortality is provided by diagnosis and empirical, standardized treatment of smear-positive cases. However, the success of this approach may be compromised when multi-drug resistance is highly prevalent. Although chest radiography is a standard diagnostic and screening tool in many resource-rich countries, the chest radiograph alone cannot make or exclude the diagnosis of active pulmonary TB. Limitations with respect to sensitivity, specificity, and consistency of interpretation have been widely reported, and chest radiography is not feasible in many remote districts. On the other hand, the DOTS strategy requires the availability of dependable sputum microscopy at the local level - meaning that microscopes, supplies, and trained technicians must be available, with suitable quality control and maintenance of proficiency. The International Union Against Tuberculosis and Lung Disease has published detailed guidelines for sputum microscopy (Enarson et al. 2000). Beyond the procedural aspects of sputum microscopy, the success of the DOTS strategy depends on prompt diagnosis among patients who seek help for TB-related symptoms. Hence providers must consistently and rapidly refer 'TB suspects' for sputum analysis, ensure that microscopy has in fact been completed, and check and act on the results (optimization of passive case-finding). In addition, authorities must recognize and address obstacles to prompt diagnosis such as ignorance ofTB signs and symptoms (among both providers and patients), financial barriers, and limited accessibility of health facilities.

this period, as adherence ensures rapid killing of M. tuberculosis organisms and hence a rapid reduction in the degree of contagiousness. During the continuation phase of treatment for new cases (the subsequent 4-6 months), therapy may be observed or self-administered. However, the WHO has urged maintenance of directly observed treatment when the continuation phase includes rifampin. This reflects the major adverse consequences of rifampin resistance which is more likely to develop with poor adherence to self-administered rifampin-based regimens (Espinal et al. 2000). For the same reasons, the WHO also recommends the use of fixed-drug combination pills, which reduce the likelihood that partial adherence will result in acquired drug resistance. Short-course treatment regimens are listed in Table 48.2. The WHO recommends an empirical retreatment regimen for treatment failures and relapses, and situations where treatment has been interrupted (Table 48.2). Patients who remain sputum smearpositive after completion of a directly observed re-treatment regimen are likely to harbor multidrug-resistant organisms, and should be referred for treatment accordingly. Approaches to the control of multi-drug-resistant TB are discussed later in this chapter. Just as the successful diagnosis of TB suspects requires suitable equipment and technicians, the successful treatment of TB patients hinges on the consistent availability of effective medications and capable health workers. These must be available to every district, and in turn to every patient. Hence, to ensure treatment completion, health workers may need to travel to patients' homes and workplaces.

48.4.7.3 Supervised Provision of Standard Treatment Regimens

Once the diagnosis of active TB has been made by smear microscopy, successful treatment hinges on rapid institution of a standardized patient management strategy. At a minimum, the WHO recommends that for new cases, the intensive phase of short-course therapy (the first two months) involve direct observation of every drug dose - meaning that the health worker watches the patient ingest every dose of medication. Direct observation is emphasized during

48.4.7.4 Documentation and Surveillance

Often overlooked is the importance of documentation and surveillance, which is the final key component of the DOTS strategy. At the individual patient level, this means: • practitioners and laboratory personnel must ensure that three sputum samples are obtained and then analyzed for every TB suspect health workers must document drug dispensing and ingestion providers must document results of repeat sputum microscopy during the continuation phase of treatment (i.e. assessment of sputum conversion) ;II providers must maintain follow-up and document clinical outcomes

K. Schwartzman

860 Table 48.2. Standardized empiric treatment regimens. Modified from Maher et al. (2002) Treatment Patients category

n

III IV

Standard treatment regimens

New smear-positive pulmonary TB New smear-negative pulmonary TB with extensive parenchymal involvement New cases of severe forms of extra-pulmonary TB. Re-treatment: Sputum smear-positive, with: Relapse Treatment failure Treatment after interruption. New smear-negative pulmonary TB (other than in Category I) New, less severe forms of extra-pulmonary TB. Chronic cases (still sputum-positive after supervised re-treatment)

Initial phase (daily or 3 times per week)

Continuation phase

2 EHRZ or 2 SHRZ

6 HE or 4 HR or 4 H3R3

2 SHRZ then 1 HRZE

5 H3R3E3 or 5 HRE

2 HRZ

6 HE or 4 HR or 4 H3R3

Refer to WHO guidelines for use of second-line drugs in specialized centers

Drug abbreviations: streptomycin (S), isoniazid (H), rifampicin (R), pyrazinamide (Z) and ethambutol (E). Each regimen consists of 2 phases. The numbers before a phase is the duration of that phase in months. A number in subscript (e.g. 3) after a letter is the number of doses of that drug per week. If there is no longer a subscript after a letter, then the treatment with that drug is daily. An alternative drug (or drugs) appears as a letter (or letters) in brackets

Table 48.3. Treatment outcomes for standardized reporting among new and re-treatment patients with smear-positive pulmonary tuberculosis (Uplekar 2002) Cure, defined as a patient who is sputum smear negative during the last month of treatment, and at least once previously Treatment completion, defined as a patient who has completed treatment but does not meet criteria for cure or failure Treatment failure, defined as a patient who is sputum smear positive at five months or later during treatment Death Default, defined as treatment interruption for two or more consecutive months Transfer out, defined as a patient who has moved to another reporting unit and for whom treatment outcome is unknown Treatment success is defined as the sum of patients cured plus those who completed treatment

At the district level, this means • the microbiology laboratory must keep a log of all microscopy results, with positive smears flagged and responsible personnel (health worker, nurse, physician) informed • the district TB control worker must maintain a registry of all patients diagnosed with TB 11 district authorities must make accurate notification (count) data made available to central authorities, including categories of reported cases (e.g. new versus re-treatment)
through ongoing evaluation and operations research. Key treatment outcomes are listed in Table 48.3, as defined by the WHO. The WHO and the International Union Against Tuberculosis and Lung Disease have developed standardized materials for documentation and surveillance (Enarson et al. 2000).

48.4.2

Status of the DOTS Strategy The first step in the DOTS strategy is the establishment of a centrally administered National Tuberculosis Program (NTP) in every country. This unit is then responsible for development and implementation of a systematic national program of TB control - a program which functions in, and is adapted to, every district, and which reflects the key elements of the DOTS package. Following implementation, the WHO has set two key benchmarks (Uplekar 2002):

Tuberculosis Control in Developing and Developed Countries

1) In each country, at least 70% of estimated smearpositive cases of pulmonary TB should be detected within the DOTS program, meaning diagnosed and reported by practitioners who work within the DOTS framework. 2) In each country, at least 85% of smear-positive cases should successfully complete short-course treatment, meaning the proportions of definite cures plus treatment completers. The target is higher (95%) for resource-rich countries. During 2001, the WHO surveyed 210 countries with respect to TB control strategies and notifications in 2000 (Blanc et al. 2002). By the end of 2000, 148 countries had implemented or were implementing the DOTS strategy (up from lOin 1990), and 55% of the world's population lived in areas covered by DOTS. However, the 1.02 million smear-positive cases detected under DOTS represented just over a quarter of the estimated total number. DOTS programs successfully treated 80% of all new smear-positive patients registered in 1999, but this corresponded to only 19% of all estimated smear-positive cases that year. Of the 22 highest-burden countries, only Vietnam had reached the targets for 70% case detection and 85% successful treatment. The target date for global attainment of these benchmarks was originally set for 2000, and then revised to 2005. However, at current rates of expansion of the DOTS program, these targets will only be reached in 2013. Hence the WHO and other organizations have urged substantial acceleration in the pace of DOTS expansion.

48.4.3 Controversies While there is no doubt as to the importance and benefit of systematic TB control programs worldwide, some elements of the DOTS strategy have been questioned. In particular, some authors have suggested that the direct observation of every treat- . ment dose may not be necessary in all cases or settings. Community-based directly observed treatment after a brief hospitalization is certainly cheaper than hospitalization throughout the two-month intensive phase of treatment (Floyd et al. 1997; Murray et al. 1991). In Hlabisa Health District, South Africa, the estimated total cost of community-based DOT was one-third that of hospital-based treatment ($741 vs. $2048 US per patient) (Floyd et al.1997). Communitybased DOT was at least as effective as hospital-based

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treatment, and hence substantially more cost-effective ($891 vs. $2096-3700 per patient cured). However, in some treatment settings the value added by direct observation of medication ingestion is less certain, as compared with self-administered treatment within a well-structured program of treatment and diagnosis. A randomized, controlled trial in Pakistan compared three treatment strategies for newly diagnosed sputum smear-positive TB (Walley et al. 2002). Treatment involved two months of isoniazid, rifampin, pyrazinamide, and ethambutol, followed by an additional six months of isoniazid and ethambutol. A total of 497 adults were randomized to one of 1) treatment directly observed by a health worker; 2) treatment directly observed by a family member, who collected medication from the health center and recorded all doses; or 3) self-administered treatment, with the patient required to collect his/her medication from the health center every two weeks. Outcomes were very similar in the three treatment arms: cure rates were 64%, 55%, and 62%, and rates of successful treatment completion were 67%, 62%, and 65% respectively. Hence in the setting of a randomized trial, within a TB control program that incorporated the other elements of the DOTS strategy, direct treatment observation itself did not contribute to successful treatment outcomes. However, in other program settings it may be difficult to separate treatment observation from other aspects of the DOTS package, particularly when there are substantial barriers to patient (or provider) adherence. It is also noteworthy that in all three arms of the Pakistan study, treatment success rates were substantially below the 85% benchmark. Finally, the ultimate costs and impact of patient nonadherence, when new rifampin monoresistance is the result, cannot be captured by this type of study. Volmink and colleagues identified several co-interventions that frequently accompany directly observed therapy, but have not been explicitly labeled as part of the 'official' WHO DOTS strategy (Volmink et al. 2000). Examples include provision of incentives or enablers, patient-centered approaches to treatment and care, tracing of defaulters (and potential legal action), specific measures to promote motivation and supervision of health workers, strengthening of other program components, and additional financial support. These additional interventions contribute to high treatment success rates, beyond direct observation alone. Although direct treatment observation itself is a relatively cheap intervention on a per-case basis, the large number of patients involved makes it a major source of expense. Clearly, additional operational

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research is urgently required to identify the most cost-effective strategies in various resource-poor settings - that is, the strategies which provide the highest cure rates at the lowest possible cost.

48.5

Other T8 Control Interventions 48.5.1 Active Case-Finding in Resource-Poor Areas In resource-poor areas, the highest priority remains efficient and effective passive case-finding, case-holding, and treatment, for persons with smear-positive disease. However, simple symptom screens among particularly high-risk groups can identify large numbers of patients with previously undiagnosed TB. Important targets for active case-finding are close contacts of smear-positive patients, and HIV-infected persons - particularly those attending counseling and testing centers. Symptoms of tuberculosis may in fact prompt such visits for HIV-related care. For example, a symptom screen among persons newly diagnosed with HIV infection at voluntary HIV counseling and testing (VCT) centers in Zambia led to the diagnosis of TB among 10% of those screened; 42% of these TB-HIV patients were sputum smear-positive (Ginwalla et al. 2002). Hence VCT centers represent an important opportunity for active case finding.

48.5.2 Screening Interventions in Resource-Rich Areas In resource-rich countries, the goals of tuberculosis screening interventions are often broadened to include not only active case-finding for current active TB, but also the identification of persons with latent infection with an elevated risk of subsequent active TB. This is only appropriate to the extent that individuals with latent infection will receive effective treatment. At the same time, the identification and treatment of latent infection must not detract from the management of persons with active TB, which is of a much higher priority. Hence emphasis on treatment of latent infection is only appropriate within the framework of a coherent TB control program once successful program management of active TB has been secured and documented. As in resource-poor areas, the highest priority groups for screening activities are close contacts of

K. Schwartzman

contagious patients, and HIV-infected persons. This reflects the relatively high prevalence of active disease at screening, but also the high risk of subsequent active disease among persons who are newly infected with M. tuberculosis, and among those co-infected with HIY. Among persons with dual HIV-TB infection the annual risk of active disease is 5-10% or more (Antonucci et al. 1995; Selwyn et al.1989).Among persons newly infected with M. tuberculosis, the annual risk of active disease is approximately 1-2% during the first 2-3 years after infection (Canadian Lung Association 2000). Following diagnosis of an infectious TB patient, the risks of contagion must be assessed, based on clinical and demographic factors, and the patient's physical and social environment. Contact investigation follows the 'concentric circle' approach. Household members and/or others with the most extensive contact with the index patient - and hence the highest risk of new infection -are first evaluated. If there appears to be an excess prevalence of latent infection (compared to estimated background probability for the group in question), or if there are secondary cases of active TB, then the contact investigation is extended to workplace, school, and more casual contacts (Menzies et al. 1999). Although TB contact investigation is considered a high-priority public health activity in high-income countries, it can be challenging to execute. Patients may refuse to identify contacts, and contacts may in turn be difficult to locate. In a U.S. multi-center study, 13% of patients with active TB yielded no identified contacts, while 39% of identified contacts failed to complete the screening process (Reichler et al. 2002). Depending on local epidemiology, other high-risk groups may be identified for active case-finding or for screening for latent TB. Examples include prisoners, residents of long-term care facilities, homeless persons, and aboriginal populations. While clinical evaluation and chest radiography are the primary screening tools for active TB, the diagnosis of latent infection hinges on the tuberculin skin test. The limitations of the tuberculin test are well known (see Chapter 62). They include inconsistent performance and measurement, limited sensitivity (notably among the HIV-infected) and poor specificity (notably where there is substantial confounding by BCG vaccination after infancy, and/ or by environmental exposure to non-tuberculous mycobacteria). The tuberculin skin test does not distinguish persons at high risk of subsequent active TB from those whose risks are decidedly modest. Hence screening and treatment activities based primarily on mass

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tuberculin skin testing provide very little benefit in terms of prevention of active disease, unless groups at higher risk are specifically targeted. Recent changes in u.s. and Canadian recommendations for identification and management of latent tuberculous infection emphasize the targeted selection of persons for tuberculin testing based on priorities and medical risk, so that only persons at high priority for treatment are tested (American Thoracic Society 2000; Canadian Lung Association 2000). "A decision to test is a decision to treat" (American Thoracic Society 2000).

Indeed, in many immigrant subgroups the incidence initially mirrors that in their countries of origin (Rivest et al. 1998; Zuber et al. 1997). British authorities estimated the incidence among United Kingdom residents born in sub-Saharan Africa to be 230 per 100,000 - nearly 20 times the overall national incidence (Public Health Laboratory Service 2002). Hence, the United States Institute of Medicine and other national authorities within low-incidence countries have identified the foreign-born as a priority group for screening and prevention activities (United States Institute of Medicine: Committee on the Elimination ofTuberculosis in the United States 2000). Prospective migrants applying for immigrant or refugee status must undergo medical evaluation. For example, persons applying from abroad for residence in the United States or Canada must undergo a screening chest X-ray (Binkin et al. 1996; Dasgupta et al. 2000). Screened persons are referred for supplementary microbiological testing (sputum analysis) where the clinical and/or radiographic evaluation indicates the possibility of active TB. Immigrant applicants diagnosed with smear-positive TB must document smear conversion before they can enter the US, while applicants to Canada must complete treatment of active TB prior to arrival. Refugee claimants who arrive with active disease must complete treatment before they can be accepted as refugees. In addition, prospective migrants who are found to have inactive TB, meaning stable radiographic abnormalities and latent infection, are required to undergo further medical evaluation and surveillance in the destination country. The goals are 1) to detect additional cases of active TB, which were either missed or not yet evident at the time of the

48.5.2.1 Screening of Migrants to Low-Incidence Countries

The foreign-born account for an increasing proportion of tuberculosis incidence in the United States, Canada, and Western Europe. For example, in Montreal, Canada 80% of reported cases of active TB now occur among the foreign-born, while for Canada as a whole the figure was 65% for the year 2000 (Nault et al. 2002; Rivest et al. 1998). In the United States 50% ofTB cases in 2001 occurred among the foreignborn (compared to 27% in 1991), while in the United Kingdom the proportion now slightly exceeds 50% (Division of Tuberculosis Elimination 2002; Public Health Laboratory Service 2002). Fifty percent, or more, of the excess incidence among the foreign-born occurs during the first five years after arrival in the destination country, although TB incidence remains higher than that of the native-born population for at least 20 years (Zuber et al. 1997; McCarthy 1984). Figure 48.2 demonstrates the preponderance of cases within the first years after arrival, in a group of Asian immigrants to the United Kingdom (McCarthy 1984).

40,--------------------------,

35

30 • Cases in Persons Who Did Not Subsequently Visit Asia (128 Cases Total)

Fig. 48.2. Tuberculosis cases among Asian immigrants to West Ham (London), 1976-80. Data are from McCarthy (1984). McCarthy demonstrated that most cases which occurred over 10 years after immigration occurred shortly after return visits to Asia - suggesting that patients became infected during visits to their countries of origin. The data shown are for patients without known TB contacts in the United Kingdom

25 o Cases in Persons Who Subsequently Visited Asia (59 Cases Total)

20

15

10

3

4

5

6

7

8

9

10

11

12

Years Sinee Arrival

13

14

15

16

17

18

19

20 Over 20

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earlier screen, and 2) the provision of treatment of latent infection to those without active TB, since both recent migration and radiographic abnormalities place them at increased risk of reactivation. Formal evaluations have questioned the effectiveness and yield of these programs, which are extremely complex to administer, and require a high degree of coordination between far-flung providers and health authorities. In Montreal, 17 (0.13%) of 12,898 screened immigrant and refugee applicants screened during 1996-7 had active TB, for an estimated total program cost of $31,418 Canadian ($20,422 US) per case detected and treated (Dasgupta et al. 2000). During the same period, of 644 new permanent residents in Montreal who were referred for surveillance of inactive TB,401 (64%) reported for evaluation and four had active TB. The estimated total surveillance program cost was $55,728 Canadian ($36,223 US) per case detected and treated. Based on the treatment actually administered to these cohorts for latent TB infection, the immigrant screening and surveillance programs were even more costly per future active case prevented ($73,000-$155,000 Canadian) (Dasgupta et al. 2000). Among 5,739 foreign-born persons screened for permanent residence (1997-98) after arrival in five US jurisdictions, no cases of active TB were found (Saraiya et al. 2002). In Seattle, Washington the prevalence of active TB among new immigrants referred for surveillance (1992-94) of inactive TB identified by overseas screening was similar to that in Montreal- 1.1 % (Wells et al. 1997). However, among immigrants whose screening chest X-rays suggested active TB, but whose sputum smears were negative at overseas screening, the prevalence of active disease at re-examination in Seattle was 10.5%. In this way, programs that successfully target and follow the highest-risk migrants are likely to be relatively cost-effective, with respect to the detection and treatment of active or latent TB. Undocumented migrants are obviously missed by these screening programs. In areas where migrant workers and other undocumented foreign nationals are concentrated, these groups are a major concern with respect to TB incidence, morbidity, and transmission. This reflects not only the risk ofTB itself, but also barriers to health care after symptoms develop, which prolong the time for transmission. Key factors include migrants' fear of arrest and deportation, and limited access to suitable care and follow up. Short-term visitors are also missed, as are residents of low-incidence countries who travel to high-incidence areas. Lobato documented strong associations between latent tuberculous infection

K. Schwartzman

in US-born children in California and a history of travel to and/or household visitor from higherincidence countries, notably Mexico - illustrating the potential influence of short-term visits on TB transmission and incidence (Lobato and Hopewell 1998). McCarthy demonstrated a rebound in TB occurrence among Asian immigrants in London who subsequently visited their home countries, as shown in Fig. 48.2 (McCarthy 1984). Cobelens estimated an infection rate of 3.5 per 100-person-months among Dutch-born visitors to endemic areas, based on serial tuberculin testing (Cobelens et al. 2000). This represents an annual risk of infection of 4.2%, which in fact equals or exceeds estimated risks for inhabitants of high-incidence countries. 48.5.2.2 Screening and Control in Specialized Settings In resource-rich areas, TB control authorities and providers have emphasized control of transmission in hospitals, prisons, homeless shelters, and other institutions where persons with TB are likely to be housed. The approach involves a 'hierarchy of controls' - the most important of which relates to provider behavior. Persons with symptoms, signs, or radiographic features suggestive of active TB must promptly undergo suitable diagnostic testing, and treatment where indicated. Delays in diagnosis of hospitalized patients lead to increased mortality and promote nosocomial transmission to other patients as well as staff and visitors. The dramatic US hospital TB outbreaks reported in the early 1990s- as well as subsequent systematic surveys - highlighted the importance of prompt diagnosis, and reinforced the need for immediate treatment as well as suitable isolation of highly infectious patients. In Atlanta, aggressive implementation of hospital control measures reduced the potential exposure of staff and patients by nearly 90%; the frequency of skin test conversions among workers decreased to the same degree (Blumberg et al. 1995). Unfortunately, broad application of these measures is costly, and many patients are subjected to unnecessary isolation. However, simple clinical prediction rules are of limited benefit in reducing unnecessary use of isolation facilities (Bock et al.1996). Hospitalized patients who are smear-positive should remain in respiratory isolation, in hospital, until there is clear evidence of bacteriological and clinical response, and appropriate public health interventions (e.g. contact investigation, provisions

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for follow-up) are underway. Repeat sputum smears offer the best means to assess microbiologic response. There is rapid mycobacterial kill (and hence reduction in contagiousness) with standard intensive-phase drug therapy. However, the increasing prevalence of drug resistance limits the validity of empiric discharge recommendations for smear-positive patients (e.g. the widely held belief that patients are no longer infectious after two weeks of therapy). Two weeks is likely sufficient for initially smear-negative patients, when there is a suitable clinical response. Nonetheless, patients with presumed, or proven, active pulmonary TB should remain isolated for as long as they are hospitalized, as there remains some potential for transmission - which is of particular concern given the frequent presence of persons with HIV, or other immunosuppressive conditions, on general medical and respiratory wards. Providers must also consider the patients' home and social environments when planning discharge, e.g. presence of young children in the home, homelessness, etc. For a more detailed review of nosocomial tuberculosis control consult Schwartzman and Menzies 1999. Within hospitals,national TB control authorities have suggested engineering interventions to reduce the risk of nosocomial transmission. Hence, US and Canadian authorities recommend the use of negative pressure rooms, with a minimum of six air changes per hour, to house infectious TB patients or suspects. Higher rates of negative pressure ventilation (15 air changes per hour) are recommended for high-risk procedure areas, including facilities for cough-inducing procedures (e.g. bronchoscopy, sputum induction rooms), as well as autopsy rooms and clinical mycobacteriology laboratories (Canadian Lung Association 2000). Another important technical intervention is the routine use of high-efficiency masks (which filter at least 95% of particles in the respirable range) by personnel in contact with potentially infectious patients, as well as the patients themselves. Personal respirators afford additional protection in the highest risk situations, e.g. airway procedures in patients with suspected or known multi-drug-resistant TB (Fennelly and Nardell 1998). Further reductions in airborne mycobacteria can be achieved by filtration of supply air with high-efficiency particulate air filters (HEPA filters), and ceiling ultraviolet light fixtures (Fennelly and Nardelll998; Ko et al. 2001; Riley et al. 1962). Indeed, ultraviolet fixtures have been installed in some bronchoscopy suites and homeless shelters in North America. Outside the scope of large-scale public health programs, tuberculosis screening is also conducted

in specialized occupational and clinical settings, in resource-rich areas. Health care workers are generally screened for latent infection upon hiring, and may be regularly reevaluated for skin test conversion if they are in close or frequent contact with tuberculosis. Patients who will be heavily immunosuppressed for long periods, such as those for whom a solid-organ transplant is anticipated, represent an important target for screening and treatment of latent infection - because of the potential for death from disseminated TB. Another group at risk is patients undergoing long-term dialysis - because of both the immunosuppression associated with end-stage renal disease, and the potential for spread within hospital dialysis units.

48.5.3 Bacille Calmette-Guerin (BCG) Vaccination The use of BCG vaccination has been reviewed elsewhere (see Chapter 49). A rigorous meta-analysis estimated an overall protective efficacy of 50-51% with respect to the development of TB, but individual studies have shown tremendous variation- from no effectto 80% protection (Colditz et al.1994). Potential reasons for this variation include changes in the M. bovis BCG strains, differences in tuberculosis epidemiology and ascertainment, and host differences. Rieder concluded that there was strong evidence to support the use of BCG vaccination in newborns and infants in high-incidence areas, because of associated reductions in disseminated and meningeal TB in childhood, as well as reductions in childhood TB mortality (Rieder 2002). The vaccine, therefore, continues to be part of the WHO's Expanded Programme on Immunization, with estimated global coverage of 86% among infants in 2000 (Vaccine Assessment and Monitoring 2002;World Health Organization 2002). The vaccine continues to be widely used in most areas of the world, although the estimated infant coverage rate was lower in sub-Saharan Africa (67% in 2000) than in other regions (Vaccine Assessment and Monitoring 2002). The WHO does not recommend repeat administration, or administration to older children or adults. As infants are not routinely HIV-tested in most high-incidence areas, the WHO recommends administration to all except those with clinical evidence of immune suppression. However, in the United Kingdom the use of BCG vaccination is discouraged among HIV-positive children as well as those with other forms of immunosuppression (e.g. hemato-

866

logic malignancies), because of the possibility of disseminated BCG disease (Department of Health and the Health Education Authority 1998). In North America and Western Europe, the use of BCG vaccination is variable. It is no longer routinely administered in the United States or Canada. Canadian authorities recommend its use among aboriginal infants, particularly those living on reserves, and newborns born to infectious mothers (Canadian Lung Association 2000). In both countries, it may also be considered for healthcare workers with a high risk of repeated exposure to multi-drug-resistant TB. The rationale for discontinuation of BCG vaccination relates to the low overall incidence of TB in these countries, particularly among infants and young children. Moreover, BCG vaccination administered after the of age two years confounds the subsequent interpretation of tuberculin skin tests (Menzies and Vissandjee 1992). Detection and treatment of latent infection in higher-risk groups represents an important TB control strategy for these countries, so optimal interpretation of tuberculin tests is essential. In the United Kingdom, TB control authorities have recommended BCG vaccination: 1) for newborns and infants born to parents from high-incidence countries; 2) for tuberculin-negative schoolchildren at ages 10-14. The U.K. authorities continue to monitor and re-evaluate the need for vaccination among school children (Department of Health and the Health Education Authority 1998). Development of an improved tuberculosis vaccine is a high priority for researchers and TB control authorities. Of particular interest are genotypic differences in BCG vaccines which correlate with varying reports of efficacy (Behr et al. 1999b). Knowledge of the key bacterial components responsible for efficacy will permit refined design of future vaccines (Mostowy and Behr 2002).

48.5.4 Challenges to Global TB Control 48.5.4.7 Overcoming Neglect

In many areas of the world, TB has been primarily a disease of the poor and the powerless. In resourcerich areas, it has increasingly been concentrated among the foreign-born and among poor urban residents. Hence TB has not been an important part of the political agenda. Control activities have frequently not been emphasized, or accorded stable

K.

Schwartzman

human and financial resources. The impact of neglect was felt acutely in the United States during the early 1990s. Many resource-poor countries lack the material resources needed to effectively control TB on their own, and must rely on foreign aid and other partners. However, until recently the resource-rich countries have provided little support for TB control activities elsewhere. A major limiting factor has been the cost of TB medications in populous, resource-poor countries; this has been the impetus for recent initiatives such as the Global Drug Facility (discussed below). The training, supervision, and payment of community health personnel also represents a substantial cost to overburdened health ministries where there are many competing agendas - again underlining the importance of sustained government commitment to TB control. 48.5.4.2 The HIV Pandemic

HIV co-infection is the strongest known risk factor for TB reactivation, with up to a 100-fold increase in risk. HIV-infected persons who subsequently acquire tuberculous infection are also at high risk for rapid progression to active disease. Of an estimated 36.1 million persons living with HIV/AIDS worldwide at the end of 2000, 25.3 million were believed to reside in sub-Saharan Africa and 5.8 million in Southeast Asia - both extremely high-burden areas for TB (UNAIDS 2002). In addition, there is grave concern about rapid acceleration of the HIV pandemic in China and India. The HIV epidemic has been linked to rapid increases in TB incidence in countries where the TB control programs were previously highly successful - notably in sub-Saharan Africa. In many sites within that region, 30-40% of persons newly diagnosed with smear-positive pulmonary TB have been HIVseropositive; in some locations the proportion has reached 70% (Maher et al. 2002). It is also noteworthy that 'mini-epidemics' of TB reported in the United States in the early 1990s were frequently associated with HIV infection (Alland et al. 1994; Coronado et al. 1993; Daley et al. 1992; Fischl et al. 1992). The increasing prevalence of HIV infection has a number of implications for TB control. Most obviously, the high risks of both progressive post-primary disease and reactivation have greatly increased the incidence of TB in many areas - often overwhelming existing treatment and control resources. In turn, this perpetuates the transmission of new infection and

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the development of subsequent active TB, among both HIV-seropositive and HIV-seronegative individuals in these communities. TB can be difficult to diagnose in the context of advanced HIV disease, with nonspecific symptoms and a higher frequency of smear-negative disease, extra-pulmonary disease, and atypical radiographic presentations. Hence providers may not obtain suitable material for diagnosis as promptly as in HIV-seronegative persons with typical respiratory symptoms - potentially prolonging community exposure to contagious cases. Moreover, a diagnostic strategy based largely on sputum smears cannot directly address the burden of morbidity, mortality, and transmission attributable to smear-negative tuberculosis among the HIV-infected. On the other hand, the prevalence of previously undiagnosed active TB among persons seeking voluntary HIV counseling and testing can be surprisingly high, as discussed earlier. Another implication of the association between HIV and active TB is the risk of outbreaks resulting from transmission within healthcare facilities. Following dramatic reports of TB outbreaks in US facilities, primarily involving HIV-infected patients, infection control activities were reinforced - including aggressive protocols for hospital isolation of patients with respiratory symptoms. In resource-poor areas, active TB case-finding at HIV care centers represents an important step in reducing ongoing transmission. Treatment of latent tuberculosis infection was not previously part of the standard approach to TB control in high-burden areas, because of the high c6st and low yield relative to diagnosis and management of smear-positive cases. However, with progression of the HIV pandemic, treatment of latent TB among HIV-seropositive persons is now being advanced as a potential control strategy in resource-poor areas where dual HIV-TB infection is highly prevalent (Creese et al. 2002; Maher et al. 2002). In a Brazilian cohort study among HIV patients, treatment for latent TB was associated not only with the expected reduction in incidence of active TB, but also with a 76% reduction in the risk of death (Pinho et al. 2001). In resource-rich areas, HIV-infected persons with latent TB represent the highest priority group for treatment with isoniazid or alternatives, given the estimated annual reactivation risks of 5-10% (American Thoracic Society 2000; Antonucci et al. 1995; Canadian Lung Association 2000; Selwyn et al. 1989). In North America, the standard regimen for latent tuberculosis is a nine-month course of isoniazid.

However, the optimal treatment regimen for latent TB with concomitant HIV infection remains uncertain in high-incidence areas. Among HIV-infected persons in Uganda, the protective efficacy of a sixmonth isoniazid course began to wane one year after treatment completion (Johnson et al. 2001). After three years, the cumulative incidence of active TB was equal to that among placebo-treated subjects. This is very different from earlier findings of twenty years' benefit among Alaskan aboriginals in the preHIV era (Comstock et al. 1979). The discrepancy could relate to subsequent reactivation, among those individuals in whom six months of isoniazid monotherapy is insufficient to eradicate latent infection. In the Ugandan study, the protective effect of combination treatment for latent infection (three months of isoniazid!rifampin or three months of isoniazid! rifampin!pyrazinamide) lasted at least three years (Johnson et al. 2001). Another potential explanation is TB re-infection - in communities with extremely high TB incidence, individuals may simply become exposed and reinfected after they have completed treatment for the original latent infection. In a group of South African gold miners who completed treatment for active TB, Sonnenberg and colleagues demonstrated that over one third of episodes of recurrent TB resulted from reinfection with distinct strains; virtually all those with re-infection were HIV-coinfected (Sonnenberg et al. 2001). The HIV pandemic has also exacted a considerable toll on healthcare workers themselves - notably in sub-Saharan Africa. Not only does HIV increase the risk of active TB among those caring for TB patients - it also decimates the ranks of TB control staff and community workers in many areas where they are most urgently needed. 48.5.4.3 Multiple Drug-Resistant Tuberculosis

Drug resistant tuberculosis;' develops as a result of improper treatment - inadequate prescription, and! or inadequate adherence to therapy. Isoniazid resistance is the most common resistance phenotype of clinical concern. The median estimated prevalence of isoniazid monoresistance among new cases of tuberculosis at 58 sites surveyed by the WHO and IUATLD during 1996-99 was 3.0%, but ranged from zero in New Caledonia (Oceania) to 28.1% in Latvia (Espinal et al. 2001). Although isoniazid resistance (without rifampin resistance) was associated with a slightly lower prob-

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K. Schwartzman

ability of treatment success, 82% of patients with three months, followed by isoniazid, rifampin, and isoniazid resistance were successfully treated for an ethambutol for an additional five months. Moreover, initial episode of TB using a standard empiric WHO 9% of new cases and 11 % of re-treatment cases with regimen (isoniazid, rifampin, pyrazinamide, plus MDR-TB died, as compared with 2% of new cases and ethambutol or streptomycin for two months; iso- 3% of re-treatment cases with fully susceptible TB. niazid and rifampin for an additional four months). The increasing prevalence of multi-drug-resistant These patients were treated in South Korea, Peru, M. tuberculosis strains poses a serious threat to indiHong Kong, Russia (Ivanovo Oblast), the Dominican vidual health, in terms of treatment failure and morRepublic, and Italy. In the same study, the probability tality. It also represents a dire threat to tuberculosis of treatment success was 85% among patients with control, since standard (and relatively cheap) treata first episode of fully drug-susceptible tuberculosis ment regimens are frequently ineffective, and may (Espinal et al. 2000). In areas where drug susceptibil- even foster additional drug resistance. For example, ity testing is routinely available, continuation phase patients with MDR-TB who receive the empirical therapy is lengthened and modified to account for re-treatment regimen effectively receive ethambutol isoniazid monoresistance. monotherapy during the continuation phase, which Of much greater concern is the increasing incidence promotes the development of resistance to ethambuof multi-drug resistant TB - defined as TB caused by tol. Hence MDR isolates of M. tuberculosis often demM. tuberculosis organisms that are resistant to both onstrate resistance to all first-line drugs (in addition isoniazid and rifampin, with or without additional to isoniazid and rifampin) (Frieden et al. 1996; Moss drug resistance. In the 1996-99 WHO-IUATLD survey, et al. 1997). the median estimated prevalence of multi-drug-resisThe presence of large numbers of patients with tant TB was 1.0% among new cases and 9.3% among ineffectively treated MDR-TB promotes further re-treatment cases (Espinal et al. 2001). However, spread -- a fact demonstrated dramatically in prisons among new cases the estimated prevalence of multi- of the former Soviet Union (Kimerling et al. 1999). drug-resistant TB exceeded 10% at two sites (Estonia Yet early identification of such individuals through - 14.1 % and Henan Province, China - 10.8%), while it routine drug susceptibility testing is impossible for ranged from 5-10% in 5 additional sites (Latvia, two most high-burden countries, as they simply do not Russian sites, Iran and Israel) (Espinal et al. 2001). The have the material or financial resources for suscephigh burden of multi-drug-resistant TB among new tibility testing. Moreover, the cost of effective treatpatients indicates extensive transmission of multi- ment for MDR-TB has until recently been prohibitive drug-resistant organisms in these areas - notably - $10,000 US or more per patient, in high-income countries (Gupta et al. 2001). In most areas, the treatwithin the former Soviet Union. Other countries where the estimated overall ment of MDR-TB with expensive second-line drugs prevalence of multi-drug resistance exceeds 5% shifts limited public health funds away from other include Dominican Republic, Ivory Coast, Afghani- basic elements of TB management and control. stan, Armenia, Azerbaijan, Egypt, Georgia, Kyrgyzstan, Mongolia, Pakistan, Papua New Guinea, Sudan, 48.5.4.4 Syria, Tajikistan, Turkmenistan, Ukraine, Uzbekistan The Private Health Care Sector and Yemen (Dye et al. 2002). The WHO regions with the highest estimated prevalence of MDR-TB are the A key challenge for health authorities is the integration Eastern Mediterranean region (7.9%) and the East- of private practitioners into a systematic TB control ern European region (5.5%). The overall estimated framework - meaning providers who work outside the prevalence worldwide was 3.2%. government-run public health system. For example, in US reports of MDR-TB outbreaks highlighted the India 50% of TB patients received some, or all, of their high risks of treatment failure and mortality among treatment in the private sector (Pathania et al. 1997). affected individuals, who were frequently HIV-sero- Among patients with TB symptoms in the Philippines, positive (Frieden et al.1996; Moss et al.I997). In Espi- 11.8% consulted a private practitioner, while 7.5% connal's study of six countries, only 52% of new cases sulted a public health center and 4.4% sought attention with MDR-TB were successfully treated with the six- at a hospital (Tupasi et al. 2000). Potential problems with private sector care month regimen, while only 29% of re-treatment cases with MDR-TB were successfully treated with the include missed or delayed diagnoses, non-standard empiric re-treatment regimen - isoniazid, rifampin, or inadequate treatment regimens, unreliable drug pyrazinamide, ethambutol, and streptomycin for availability and preparations, limited follow-up, and

Tuberculosis Control in Developing and Developed Countries

869

incomplete reporting. In a survey of staff members at 147 private pharmacies in Ho Chi Minh City, Vietnam, only 18% of respondents listed TB as a possible diagnosis for a fictitious case describing fever and cough for four weeks. Respondents also estimated that 24% of their customers who had purchased antituberculosis drugs during the previous four weeks had done so without a prescription (Lonnroth et al. 2000). Gaps in private sector care are not limited to lower income countries. In a 1992 U.S. national physician survey, 59% of respondents were able to list a recommended tuberculosis treatment regimen, while 28% described excessive regimens and 12% described inadequate regimens. A total of 4% described using a single drug to treat active tuberculosis. The vast majority of respondents worked in the private sector (Sumartojo et al. 1997). Even when private practitioners can assure optimal treatment with appropriate supervision (which is in fact often lacking), it is extremely difficult to collect systematic case reporting and outcome data in settings where a large number ofsuch practitioners provide TB care. Hence public health authorities in diverse locations have collaborated with private sector providers in joint efforts to promote systematic diagnosis, treatment, and reporting (Uplekar et al. 2001).

increased emphasis on screening of new arrivals has been reviewed earlier in this chapter. In addition, the problem of tuberculosis among foreign-born persons creates many logistical challenges for health authorities, including: ~ the need to communicate effectively in a variety of linguistic and cultural settings lIl! the need to enlist the cooperation and support of community leaders ~ the need to overcome patients' fear of authorities, and often of deportation • the need to reach, evaluate, and care for persons without legal status in their destination country (e.g. undocumented migrants) • the need to address complex psychosocial issues (e.g. financial concerns, stigmatization, separation from family members, post-traumatic distress) if TB management is to prove successful

48.5.4.5 Population Movement

Movement of populations, both within and between countries, represents yet another challenge to TB control (MacPherson and Gushulak 2001). The model promoted by the WHO and IUATLD emphasizes diagnosis, treatment, and surveillance at the local district level. Yet patients may move between districts or regions temporarily (e.g. as part of agricultural work), or permanently (in search of economic opportunities), so that responsibility for their care shifts from one jurisdiction to another. Larger population groups may be internally displaced by famine, conflict, political or economic instability, leading to congregation of large numbers in refugee camps or shantytowns. These represent formidable challenges for sustained health care delivery, and also foster the spread of tuberculosis and other communicable diseases. Finally, movement of persons between countries (refugees, immigrants, migrant workers) means that tuberculosis affects every part of the world. In many low-incidence countries, foreign-born persons now account for the majority of TB incidence. The

48.6 Recent Global Initiatives in T8 Control Since the WHO declared TB a global health emergency, heightened interest in TB control has fuelled a number of promising new initiatives. Several initiatives directly address the key challenges outlined above.

48.6.1 Global Partnership to Stop T8 This organization (the 'Stop TB Partnership') was established in 1998, and includes over 200 organizations worldwide. Partner groups include intergovernmental and governmental organizations, as well as academic institutions, non-governmental organizations, and others. The WHO has established the Stop TB secretariat to support and co-ordinate the partnership. Publication of the Global Plan to Stop TB (2001) was a sentinel event in the partnership's history. The plan has four primary objectives (Castro et al. 2001b): fit To expand the DOTS strategy, in order to promote access to effective diagnosis and treatment • To adapt the strategy, to address the challenges of HIV and TB drug resistance II To improve existing tools by development of new diagnostics, drugs, and vaccines ill To strengthen the Stop TB Partnership, so as to

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advance the application of TB control strategies The partnership incorporates six working groups, designed to address the objectives of this plan. The working groups are devoted to DOTS expansion, TB-HIV, MDR-TB, new diagnostics, new drugs, and new vaccines. Each working group has identified and published its own objectives, targets, mechanisms, and milestones. For example, the Working Group on DOTS Expansion has identified one of its targets as the presence of a national tuberculosis reference laboratory and an effective network of smear microscopy in every country with a TB incidence rate above 20 per 100,000 by 2005.

48.6.2 The Global Fund to Fight AIDS, Tuberculosis and Malaria The Global Fund to Fight AIDS, Tuberculosis and Malaria was established in 2001. Its goal is to obtain and distribute additional resources for control of these diseases, in those areas where they are most urgently needed. As of October 2002, the fund had collected over US$2.1 billion in pledges, from governments, foundations, non-profit organizations, and individuals. The fund provides grants for worthy programs which further the control of these diseases, based on a competitive evaluation process administered by scientific experts, community representatives, and other key stakeholders (Global Fund 2002).

48.6.3 Global Alliance for TB Drug Development The Global Alliance for TB Drug Development was established in 2000, as a public-private partnership dedicated to the development of new anti-tuberculosis drugs. It has become "the lead agency for the TB Drug Development Working Group" of the Stop-TB Partnership (Castro et al. 2001a). The Alliance promotes the development of new drugs by financing research and development initiatives in the public, academic, and industrial sectors. In the past, financial constraints have discouraged 'for-profit' companies from the substantial investments needed to develop new TB drugs, since the vast majority of the market is in resource-poor areas. The Global Alliance reduces this financial disincentive, by actively supporting the costs of research and development. New drugs will be an essential step forward in global TB control: drugs are urgently needed

to shorten and simplify treatment of susceptible TB, improve the treatment of MDR-TB, and promote treatment of latent infection. The Alliance's stated objective is to have at least one new anti-TB drug licensed by 2010, and available to high-burden countries by 2012 (TB Alliance 2002).

48.6.4 Global Drug Facility Even existing anti-TB drugs - effective for the vast majority of TB patients - often do not reach the areas where they are most needed. The Global Drug Facility (GDF) is an initiative of the Stop TB Partnership, begun in 2001. It was developed to increase access to high-quality tuberculosis drugs (Global Drug Facility 2002). The GDF aims to provide drugs for the treatment of 10 million patients over five years, thereby accelerating the expansion of the DOTS strategy. Countries and non-governmental organizations working within the DOTS framework can apply to the GDF for grants of TB drugs; they can also benefit from low-cost purchase arrangements through pooled buying of high-quality drugs. Hence the GDF has already achieved a 30% reduction in TB drug prices. As of October 2002, 23 countries - including several of the highest-burden countries in Africa and Asia -had been granted drugs from the GDF.

48.6.5 TB-HIV The WHO and other TB control authorities have increasingly recognized the close relationship between the dual HIV and TB epidemics. Beyond the development of specific TB control measures in the clinical context of HIV infection, public health authorities are now integrating TB and HIV control activities in settings where both are highly prevalent. For example, within the Stop TB Partnership, the Working Group on TB/HIV published a "Strate-

gic Framework to Decrease the Burden of TB/HIV" (Maher et al. 2002). This includes recommended packages of interventions for HIV-infected persons in low-, middle-, and high-income countries, based on the cost-effectiveness of these measures. Some of the interventions target TB directly: effective use of the DOTS strategy, case finding, enhanced diagnosis of smear-negative and extrapulmonary TB, possible treatment oflatent TB with isoniazid. Some interven-

Tuberculosis Control in Developing and Developed Countries

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tions target other infectious complications, such as cotrimoxazole prophylaxis for pneumonia. It is worth noting that the recommendation that highly active antiretroviral therapy be provided to HIV-infected persons in middle-income countries - indirectly reducing TB incidence.

(Gupta et al. 2002). The Green Light Committee reviews projects requesting access to the second-line drugs at reduced prices, to ensure that such projects adhere to published guidelines-including the presence of an established core TB control program. As of September 2002, the Committee had approved 10 proposals: countrywide projects in Estonia, Latvia, and Malawi, and district-, state-, and prison-level projects in Mexico, Peru, the Philippines, and the Russian Federation. The Green Light Committee has also provided technical assistance, in the form of training sessions for the clinical management of patients with MDR-TB. Using an individualized treatment approach within the DOTS-Plus framework, Farmer and colleagues from Partners in Health demonstrated an 85% cure rate - based on sputum culture conversion - in a pilot project among 74 Peruvian patients with MDR-TB, many of whom had resistance to all first-line drugs (Farmer 2001). The ultimate goal of the DOTS-Plus strategy is to build and implement a systematic approach to MDR-TB, based on this type of successful experience.

48.6.6 DOTS-Plus and the Green Light Committee DOTS-Plus is a WHO initiative designed to address the growing problem of multi-drug resistant TB. The Working Group on DOTS-Plus for MDR-TB is one of the six working groups of the Stop-TB Partnership. DOTS-Plus builds on the DOTS framework by incorporating systematic approaches to the detection, management, and surveillance of MDR-TB - designed for areas with a high prevalence of MDRTB. As of October 2002, elements of the DOTS-Plus strategy were still under development and testing; pilot projects were underway in Latvia, Estonia, the Philippines, Peru, and several areas of the Russian Federation (DOTS-Plus 2002). In 2000, the WHO published guidelines for the establishment of DOTS-Plus pilot projects. Consideration of such pilot projects is only appropriate in sites where the core tuberculosis control program is already functioning at a high level; otherwise, implementation of the key elements needed for detection, treatment, and surveillance of drug-sensitive TB remain the first priority. The DOTS-Plus strategy includes two potential approaches to the problem of multi-drug resistance: 1) standardized therapy with second-line drugs, based on the empiric diagnosis of multi-drug resistant TB, and knowledge of local multi-drug resistance patterns; or 2) individualized therapy, based on drug susceptibility results for each patient's isolate. Even more than with drug-sensitive TB, a key limitation to control of MDR-TB is consistent access to effective, high-quality medications - largely secondline anti-TB drugs. A crucial accomplishment of WHO's working group on DOTS-Plus for MDR-TB was the negotiation of major price reductions for second-line anti-tuberculosis drugs - up to 99% in resource-poor settings, e.g. $0.06 US per 250 mg tablet of ciprofioxacin, vs. a reference price of $8.91 in the US (Gupta et al. 2001). To promote access to reduced-price second-line drugs within systematic control programs, the WHO established the Green Light Committee in 2000, as a subgroup of the working group on DOTS-Plus

48.7 Recent Developments in Tuberculosis Control: Examples from the Field A total of22 high-burden countries account for an estimated 79% of the world's nearly 9 million tuberculosis cases.(Table 48.4) However, resources as well as incidence, outcomes, and recent trends vary widely among these 22 countries as well as in lower-burden areas. The final section of this chapter outlines recent developments in TB control in several high-burden countries, in the United States, and in England and Wales.

48.7.1 India Although second only to China in population, India accounts for the largest number of tuberculosis patients worldwide (21%), because estimated incidence is much higher in India than in China (184 per 100,000 in India in 2000). Notifications were 111 per 100,000 in 2000 (Blanc et al. 2002). India is the site of remarkable success in expanding coverage of the DOTS program (Khatri and Frieden 2002). The Revised National Tuberculosis Control Program was initiated in 1993, after a review

872

K. Schwartzman

Table 48.4. Estimated incidence of TB: high-burden countries, 2000. Data from Blanc et al. (2002) Number estimated All cases

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

Smear positive cases

Country

Population (1000 s)

Thousands

Rate per 100,000 pop

Thousands

Rate per 100,000 pop.

India China Indonesia Nigeria Bangladesh Ethiopia Philippines Pakistan South Africa Russian Federation DR Congo Kenya Viet Nam UR Tanzania Brazil Thailand Uganda Myanmar Mozambique Cambodia Zimbabwe Afghanistan Total, high-burden countries Global total

1,008,937 1,275,133 212,092 113,862 137,439 62,908 75,653 141,256 43,309 145,491 50,948 30,669 78,137 35,119 170,406 62,806 23,300 47,749 18,292 13,104 12,627 21,765 3,781,004 6,053,531

1,856 1,365 595 347 332 249 249 247 228 193 163 149 148 126 116 88 82 80 79 75 74 70 6,910 8,735

184 107 280 305 242 397 330 175 526 132 320 484 189 359 68 140 351 168 433 572 584 321 183 144

831 588 267 150 149 105 112 111 93 87 70 62 66 54 52 39 35 36 33 33 30 31 3,033 3,836

82 46 126 132 109 166 148 78 214 59 138 201 85 153 30 62 149 76 180 256 234 144 80 63

conducted in 1992 indicated that less than half of TB patients were accurately diagnosed, and less than half of those diagnosed were effectively treated. The revised national program is based on the DOTS strategy, with diagnosis of TB based primarily on sputum microscopy. The standard treatment regimen for newly diagnosed patients with positive sputum smears involves directly observed administration of isoniazid, rifampin, pyrazinamide, and ethambutol for two months; this is followed by isoniazid and rifampin for an additional four months, with at least one dose per week directly observed. The program is run at the district level, with support and administration at the state and central government levels. In addition, the WHO hired, trained, and assigned physician-consultants to central, state, and local governments. After eight years, the program had expanded to 211 districts of 19 states, covering 43% of India's population. As a result of the program, nearly 200,000 health workers had been trained and over 3,000 laboratories were upgraded. A total of 666,000 patients were registered in the program, with an 83% treatment success rate overall. Khatri and Frieden estimated that the

Cumulative incidence (0/0) 21 37 44 48 51 54 57 60 63 65 67 68 70 72 73 74 75 76

77 77 78 79 79 100

program had prevented over 200,000 deaths, while the cost of program expansion was $50 million US over 8 years (Khatri and Frieden 2002). Despite these milestones in rapid expansion, India continues to face considerable challenges. Much of the population remains difficult to reach, and over half resides outside DOTS program areas. Even in areas now covered by the revised national program, at least 40% of TB patients obtain diagnosis and treatment in the private sector. The HIV epidemic has reached India, with at least four million HIVinfected persons, and an estimated prevalence of HIV infection of 0.8% among adults aged 15-49 (UNAIDS 2002). As in Africa, even the most successful TB control strategies will be compromised by further expansion of the HIV epidemic. Based on local survey data, the WHO estimated that 3.3% of TB cases in India involved multi-drug resistance. Inadequate treatment and supervision outside the DOTS program, as well as ongoing transmission of MDR strains, will only worsen this problem. Hence continued DOTS expansion and constructive engagement of the private sector are urgently

Tuberculosis Control in Developing and Developed Countries

needed. Indeed, with the support of the World Bank India will further extend the revised national program, with the goal of DOTS coverage of 80% of the country by 2004 (Blanc et al. 2002).

873

(behind Zimbabwe and Cambodia) among the 22 highest-burden countries. The WHO estimates that 60% of TB patients aged 15-49 are HIV-infected, while the estimated overall prevalence of HIV infection in the same age group was 20.1% (Blanc et al. 2002; UNAIDS 2002). South Africa now accounts for 3% of the world's patients with active TB. 48.7.2 China However, South Africa has made considerable progress with respect to DOTS coverage. A revised China is second only to India in numbers of TB cases, national TB control program including the DOTS and accounts for 16% of the world's TB patients. In strategy was first established in 1996. By the end of 2000, estimated incidence (all types) was 107 per 2000, 77% of the country was covered. An estimated 100,000, with a notification rate of 36 per 100,000; the two-thirds of smear-positive cases were detected latter had not changed since 1998 (Blanc et al. 2002). under the DOTS program - close to the WHO benchCoverage under the DOTS program expanded mark of 70%. Unfortunately, even within the DOTS considerably during the early 1990s, due largely to program overall treatment success rates have fallen a World Bank loan which covered half the country. (from 73% in 1997 to 60% in 1999), likely because of By 2000, 68% of the population resided in areas with HIV (Blanc et al. 2002). The estimated prevalence of access to the DOTS program, but only an estimated MDR-TB is 1.5% among new cases; while MDR-TB 33% of new smear-positive cases were diagnosed has been relatively infrequent to date, the extent of under the DOTS strategy. Furthermore, only 13% the HIV epidemic makes an increase in the incidence of patients diagnosed with TB were referred to TB of MDR-TB likely in the coming years. dispensaries operating within the DOTS program. The severity of the TB-HIV epidemic has made TB Patients treated within the program have excellent control a priority for the South African government. outcomes, with over 90% of new smear-positive The high incidence has also spurred international patients cured (Feng-Zeng et al.1996). research collaborations dedicated to epidemiology, China has anticipated an additional expansion of clinical trials, and public health operations. the DOTS program from 2002 onwards, with funds from the World Bank and other agencies. However, challenges to TB control are similar to those encoun- 48.7.4 tered elsewhere. Most patients continue to be diag- Peru nosed and treated outside the DOTS program. Limited information is available about the extent Peru has witnessed remarkable successes in TB of HIV disease is China, but the United Nations has control over the last decade. This reflects sustained estimated that there were 850,000 persons living with effort at all levels of the health system, beginning with HlV in China at the end of 2001, corresponding to a the introduction of a revised National Tuberculosis 0.1% prevalence among adults aged 18-49 (UNAIDS Control Program in 1990. The revised program incor2002). In Henan province, 10.8% of isolates from newly porates all elements of the DOTS strategy, and was diagnosed patients were multi-drug resistant during rapidly implemented in all areas of the country. From 1996-99; the prevalence of MDR-TB among new cases 1989 to 2000, the number of sputum microscopy laboin four other areas ranged from 1.4-4.5% (Espinal et ratories quadrupled. With respect to diagnostics, the al. 2001). As in India, MDR-TB will be a growing threat Peruvian approach goes beyond the basic DOTS to Chinese TB control in coming years. strategy, because patients with persistent respiratory symptoms and negative sputum smears are referred for more complete medical evaluation which can 48.7.3 include chest radiography and sputum mycobacteSouth Africa rial cultures (Suarez et al. 2001). From 1990-93, immediately after introduction of The HlV pandemic has devastated South Africa, as the revised program, case notifications increased, it has the other countries of sub-Saharan Africa. As most likely because of expanded access to diagnostic a result, a dual TB-HlV epidemic is in full force; facilities. However, from 1993-2000 reported cases of in 2000, the estimated TB incidence was 526 cases pulmonary TB declined by an average of 7.4% annuper 100,000, placing South Africa third in incidence ally. Hence in 2000, the reported incidence was 136

874

per 100,000 - compared to 170 per 100,000 in 1990. In 1990, before adoption of the revised program, only 40% of smear-positive patients successfully completed treatment. By 2000, the proportion exceeded 90%. The revised program averted an estimated 91,000 deaths, or 70% of the deaths from tuberculosis that would have been expected, in the absence of the expanded program (Suarez et al. 2001). The accomplishments of the Peruvian TB control program highlight the impact of widespread systematic diagnosis and treatment on TB incidence and mortality. Another key factor was the relative rarity of HIV infection in Peru - estimated to be present in only 0.56% of adults (Suarez et al. 2001). However, multi-drug resistance exists in Peru, as elsewhere; in 1999, 3% of new patients and 12.3% of retreatment patients harbored multi-drug-resistant isolates (Espinal et al. 2001). To address this challenge, Peru developed a national program for standardized 18-month treatment of 'chronic' patients with suspected MDR-TB - primarily those who remained sputum smear-positive despite fully supervised administration of the standard WHO retreatment regimen. The 18-month regimen included kanamycin, ciprofloxacin, ethionamide, pyrazinamide, and ethambutol; all doses were provided on an outpatient basis in local health clinics. With the standardized empiric regimen, the overall cure rate was 48%, while 12% died. The program authorities estimated that addition of this regimen reduced the risk of death by 36% among those treated. The average cost for a complete course of treatment was US$2381, of which US$824 was the cost of the drugs themselves. Other major costs included visits for directly observed therapy (US$507), food parcels given to patients weekly (US$390), and physician consultations (US$213) (Suarez et al. 2002). While expensive compared to first-line TB control interventions, the Peruvian program nonetheless demonstrates the feasibility of a systematic approach to MDR-TB in a middle-income country. Other reports from Peru have documented the success of DOTS-Plus pilot projects which incorporated drug susceptibility testing and individualized treatment regimens with second-line drugs, in limited areas (Farmer 2001). However, programs for treatment of MDR-TB are only relevant in sites where the basic TB control system is already functioning with a high level of success, as was the case in Peru. The sustained drop in TB incidence has in fact resulted in Peru's removal from the list of the 22 highest-burden countries - the only country to accomplish this feat thus far. The accomplishments

K.

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of the Peruvian program, over a single decade, serve as a powerful reminder that successful control of TB is indeed possible. It hinges on the systematic adoption of the basic DOTS strategy for implementation, diagnostics, treatment, and surveillance.

48.7.5

United States The United States witnessed a steady decline in tuberculosis incidence and deaths from the early 1950s to 1984. From 1985-92, incidence initially reached a plateau at 9.3-9.4 cases per 100,000 annually, then in fact increased to a peak of 10.5 cases per 100,000 in 1992 (Division of Tuberculosis Elimination 2002). This resurgence during the late 1980s and early 1990s rekindled concern about a disease largely forgotten in the US. Mini-epidemics of multi-drug-resistant TB in inner cities and hospitals exposed major deficiencies in the TB control infrastructure - notably the lack of resources available to ensure prompt diagnosis, initiation and completion of appropriate treatment. The spread of multi-drug resistance indicated a breakdown of the public health system for TB control, so that patients received inadequate and incomplete treatment - due to non-standard treatment regimens and/or poor patient adherence - and transmitted drug-resistant strains to others in their communities. If the Peruvian experience of the 1990s illustrates the potential benefits of successful implementation of a systematic TB control strategy, the US experience of 1985-92 highlights the disastrous consequences of its abandonment. Nowhere was this phenomenon better demonstrated than in New York City. As reported by New York's TB control team, "By 1992, the situation in New York City looked bleak. The number of cases of tuberculosis had nearly tripled in 15 years. In central Harlem, the case rate of 222 per 100,000 people exceeded that of many Third World countries. Outbreaks of multidrug-resistant tuberculosis had been documented in more than half a dozen major hospitals, with case fatality rates greater than 80 percent, and health care workers were becoming ill and dying of this disease. Nearly one in five patients with tuberculosis in New York City had multi-drug-resistant strains, and the proportion of patient with multi-drug resistance had more than doubled in seven years. In the first quarter of 1991, with three percent of the country's population, New York City accounted for a remarkable 61 percent of cases of multi-drug-resistant tuberculosis

Tuberculosis Control in Developing and Developed Countries

875

in the United States:' (Frieden et al.1995) New York's TB epidemic occurred in the context of major shifts in the epidemiology of tuberculosis, with the growing contribution of the HIV epidemic, immigration from high-prevalence countries, homelessness and poverty. However, the TB epidemic also reflected drastic reductions in public health activities; the TB control staff had been severely reduced, the number of TB clinics had decreased by two-thirds, and by 1989 less than 50% of patients who began treatment were cured (Frieden et al.I995). Interventions which ultimately brought TB under control in New York included 1) massive expansion of directly observed therapy, with a four-fold increase in TB control staff from 1988-1994, and a 10-fold budget increase (from US$4 million to US$40 million annually); 2) heightened infection control measures in hospitals, jails, and homeless shelters; 3) systematic treatment of TB patients with at least four anti-tuberculous drugs. Treatment completion rates increased to 90% by 1994 (Frieden et al.I995). In New York as elsewhere, renewed investment in TB management has led to major gains in TB control. From 1993 onward, US TB incidence again declined steadily, reaching 5.6 cases per 100,000 in 2001 - a 47% reduction in incidence compared to 1992 (Division of Tuberculosis Elimination 2002). Figure 48.3 illustrates these recent trends in US TB incidence. However, the cost of the TB resurgence was enormous. In New York alone, the TB epidemic was associated with an estimated excess of 20,000 cases over 15 years, with an estimated cost of over US$1 billion (Frieden et al.I995). As TB has abated in the US inner cities, other aspects of TB epidemiology and control have come under

increased scrutiny. In 2001, the number of reported foreign-born TB patients exceeded the number of reported US-born patients, for the first time; each group accounted for 49% ofTB incidence overall, with the remaining 2% of unknown origin. The three top countries of origin were Mexico (23% of all foreignborn patients), the Philippines (12%), and Vietnam (8%) (Division of Tuberculosis Elimination 2002). In 2001, the incidence of TB among foreign-born persons in the US was 26.6 per 100,000 - compared to 3.1 per 100,000 among US-born persons. During the decade from 1991-2001, the nationwide incidence of TB in the US-born declined by 63%, while among the foreign-born it fell by a more modest 22%. This was not surprising, in that intensified control measures in the inner cities were most effective in reducing ongoing transmission, which largely involved the US-born (Jasmer et al. 1999). Hence, the US Institute of Medicine, in its landmark report entitled "Ending Neglect: the Elimination of Tuberculosis in the United States:' identified intensified screening of new immigrants from highincidence countries as a key step toward enhanced TB control (United States Institute of Medicine: Committee on the Elimination of Tuberculosis in the United States 2000). The goal of such screening is the identification (through tuberculin skin testing) and treatment of new arrivals with latent infection, among whom the incidence of TB is highest during the first years after immigration. Most TB in these groups reflects infection acquired in the countries of origin (Jasmer et al. 1999; Kulaga et al. 2002), so that further reductions in incidence will more likely occur from treatment of latent infection rather than intensified contact investigation or other measures

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targeting transmission within the US. However, large-scale implementation of screening programs based on tuberculin testing is extremely costly to organize and administer; many of the targeted individuals are in fact at relatively low risk for reactivation (Schwartzman and Menzies 2000). Ultimately, sustained reductions in TB incidence among migrants to low-incidence countries will result from improved TB control in their countries of origin.

48.7.6 England and Wales Recent trends in tuberculosis in England and Wales parallel those in the US in the late 1980s and early 1990s. Incidence fell steadily from 1950 to 1988; in 1988, TB incidence reached a nadir of 9.4 cases per 100,000. However, from 1988 to 1998 incidence rebounded, reaching 10.9 cases per 100,000 in 1998. In 1999 incidence once again fell to 10.2 per 100,000 (Public Health Laboratory Service 2002). As in the US, the TB resurgence has occurred mainly in the largest cities - notably London, which has the highest TB incidence in the United Kingdom. In 1999, the incidence in London (32.2 per 100,000) was over three times the national average. Available reporting data implicate HIV in only a small minority ofTB cases - 3.3% of British adult patients in 1998, somewhat more in London (5.4% ofTB patients aged 16-54). Multi-drug resistance has never reached the levels seen in the US; in 1999,0.8% of initial isolates (those obtained at start of treatment) in England and Wales demonstrated multi-drug resistance. In London, the proportion was 1.8% during 1994-99 (Public Health Laboratory Service 2002). However, as in New York and other U.S. cities in the early 1990s, TB in inner-city London is characterized by a large burden of disease due to recent transmission; a 12-month molecular epidemiological survey in inner London indicated that 27% of patients had isolates identical to those obtained from at least one other patient (Hayward et al. 2002). To date, direct observation of treatment has been rare, and comprehensive data on treatment completion and other outcomes have been unavailable (Hayward and Coker 2000). The foreign-born account for a higher proportion of TB cases than in the US, and this proportion has been increasing. British surveillance data have categorized patients by ethnicity rather than place of birth. In 1999, patients from the Indian subcontinent accounted for 38% of all cases, while those from sub-Saharan Africa accounted for 15%; other 'non-Whites' accounted for

K. Schwartzman

14%. Among persons from sub-Saharan Africa, the estimated incidence reached 230 per 100,000 in 1999, compared with 3.7 per 100,000 among 'Whites' (the term used by public health authorities) (Public Health Laboratory Service 2002). As described earlier in this chapter, BCG vaccination has remained a core element of TB control in the United Kingdom. To better address recent challenges to TB control, a system of enhanced national TB surveillance was introduced in 1999. The surveillance system will also incorporate routine reporting of patient outcome data - in the same format used by national TB programs in high-burden countries. Other improvements to the TB control infrastructure will target coordination between local health authorities, and more systematic screening and follow-up of new arrivals.

48.7.7 Russia Since the collapse of the Soviet Union, TB morbidity and mortality have increased dramatically in Russia. The notification rate increased from a nadir of 34 per 100,000 in 1990 to 95 per 100,000 in 2000; reported TB mortality reached 20.4 per 100,000 in 2000 (Blanc et al. 2002; Shilova 2000). Russia ranks tenth in total TB cases among the highest burden countries, and now accounts for 2% of the world's TB patients (Blanc et al. 2002). TB care and control are delivered by a network of facilities, including dispensaries and hospitals, which is not integrated into the general health system. The DOTS strategy has not been implemented, except within localized pilot projects. Drug and laboratory supplies have been inconsistent, further hampering TB control and potentially promoting drug resistance. The estimated prevalence of multi-drug resistance among Russian TB patients overall is 6.0%, making drug resistance a major limiting factor to treatment success. The situation is even more dramatic in Russian prisons, where TB notifications were 3,118 per 100,000 in 2000. In a survey of 164 patients housed in a Siberian TB referral prison, the prevalence of initial multi-drug resistance was 22.6%, while 35% of all patients in the prison failed directly observed treatment with the empirical WHO re-treatment regimen (Kimerling et al. 1999). While HIV infection was initially uncommon in Russia, local survey data suggest its prevalence is now increasing rapidly. In Ore! Oblast (a rural area 300 km southwest of Moscow), HIV seroprevalence increased from 0.001% in 1996 to 0.12% in 2000

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(Kazionny et al. 2001). Regional pilot projects based on the DOTS strategy have yielded variable results. In Ivanovo Oblast, where the strategy was implemented in 1995, a survey conducted from April-June 1999 indicated that only 57% of smear-positive patients were successfully treated. None of these patients had MDR-TB (Centers for Disease Control and Prevention 2001a). After these suboptimal outcomes were identified, the program was enhanced: patients were offered food supplements or free transportation to clinic, public health staff were provided with transportation so as to locate treatment interrupters, and providers were offered bonuses for treatment completion by their patients. In Orel Oblast, where the DOTS strategy was implemented in 1999, treatment success rates were much higher: 81% for new smear-positive patients from October 1999-March 2000. Three percent of patients had MDR-TB (Centers for Disease Control and Prevention 2001b). Clearly, TB control in Russia represents an enormous challenge. The Russian president has identified TB as a national priority. A host of international aid and public health agencies, as well as nongovernmental organizations, have aided Russian TB control efforts. Russia will also receive a US$150 million loan from the World Bank, to support drug procurement (Munro 2002). Although the DOTS strategy differs from previous approaches to TB control within Russia and the Soviet Union, there is evidence of its effectiveness in the Orel pilot project - as well as in other countries - which should promote its use in Russia. Ongoing collaboration with the WHO and other partners will also promote a more consistent and integrated approach to TB control, and improve essential infrastructure.

Major new public health and funding initiatives for TB control are concrete evidence of this heightened awareness. The last decade has seen dramatic challenges, political mobilization, innovative programs, and remarkable success in a number of countries. These successes offer important lessons, as well as inspiration toward continued progress. Just as sustained commitment is essential, complacency remains the worst enemy of TB control - and even the funds now available will not be sufficient. The WHO estimates that an additional US$3.8 billion are needed, if the 22 highest-burden countries are to execute their current plans for expansion of the DOTS strategy over the next five years. The author hopes that readers responsible for TB treatment and control will continue to act as strong advocates for their patients-and that in so doing, they ensure that urgently needed resources indeed become available.

48.8. Conclusion The vast majority of tuberculosis patients can be cheaply and effectively treated, using standard drug regimens known for decades. Tuberculosis can be effectively controlled in large populations, using a simple yet comprehensive strategy which was first developed and proven 20-30 years ago -in several of the poorest countries of the world. Nonetheless, tuberculosis continues to be a leading global cause of morbidity and mortality. Recent years have brought renewed concern about tuberculosis, fueled by the ravages of the dual TB-HIV epidemics and of multi-drug-resistant TB.

Acknowledgements. The author is supported by a Chercheur-Boursier Clinicien career award from the Fonds de Recherche en Sante du Quebec. The author acknowledges the secretarial assistance of Elizabeth Lustig and Catherine Michaud.

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Tuberculosis Control in Developing and Developed Countries PE, Raviglione MC (2001) Responding to market failures in tuberculosis control. Science 293:1049-1051 Gupta R, Cegielski JP, Espinal MA, Henkens M, Kim JY, Weezenbeek C, Lee JW, Raviglione MC, Suarez PG, Varaine F (2002) Increasing transparency in partnerships for health - introducing the Green Light Committee. Trop Med Int Health 7:970-976 Hayward AC, Coker RJ (2000) Could a tuberculosis epidemic occur in London as it did in New York? Emerg Infect Dis 6:12-16 Hayward AC, Goss S, Drobniewski F, Saunders N, Shaw RJ, Goyal M, Swan A, Uttley A, Pozniak A, Grace-Parker J, Watson JM (2002) The molecular epidemiology of tuberculosis in inner London. Epidemiol Infect 128:175-184 Jasmer RM, Hahn JA, Small PM, Daley CL, Behr MA, Moss AR, Creasman JM, Schecter GF, Paz EA, Hopewell PC (1999) A molecular epidemiologic analysis of tuberculosis trends in San Francisco. Ann Intern Med 130:971-978 Johnson JL, Okwera A, Hom DL, Mayanja H, Kityo CM, Nsubuga P, Nakibali JG, Loughlin AM, Yun H, Mugyenyi PN, Vernon A, Mugerwa RD, Ellner and Whalen CC for the Uganda - Case Western Reserve University Resarch Collaboration (2001) Duration of efficacy of treatment of latent tuberculosis infection in HIV-infected adults. AIDS 15:2137-2147 Kazionny B, Wells CD, Kluge H, Gusseynova N, Molotilov V (2001) Implications of the growing HIV-l epidemic for tuberculosis control in Russia. Lancet 358:1513-1514 Khatri GR, Frieden TR (2002) Controlling tuberculosis in India. N Engl J Med 347:1420-1425 Kimerling ME, Kluge H, Vezhnina N, Lacovazzi T, Demeulenaere T, Portaels F, Matthys F (1999) Inadequacy of the current WHO re-treatment regimen in a central Siberian prison: treatment failure and MDR-TB. Int J Tuberc Lung Dis 3:451-453 Ko G, Burge HA, Nardell EA, Thompson KM (2001) Estimation of tuberculosis risk and incidence under upper room ultraviolet germicidal irradiation in a waiting room in a hypothetical scenario. Risk Anal 21:657-673 Kulaga S, Behr M, Musana K, Brinkman J, Menzies D, Brassard P, Kunimoto D, Tannenbaum TN, Thibert L, Joseph JF, Boivin JF, Schwartzman K (2002) Molecular epidemiology of tuberculosis in Montreal. CMAJ 167:353-354 Lobato MN, Hopewell PC (1998) Mycobacterium tuberculosis infection after travel to or contact with visitors from countries with a high prevalence of tuberculosis. Am J Respir Crit Care Med 158:1871-1875 Lonnroth K, Lambregts K, Nhien DTT, Quy HT, Diwan VK (2000) Private pharmacies and tuberculosis control: a survey of case detection skills and reported anti-tuberculosis drug dispensing in private pharmacies in Ho Chi Minh City, Vietnam. Int J Tuberc Lung Dis 4:1052-1059 MacPherson DW, Gushulak BD (2001) Human mobility and population health: new approaches in a globalizing world. Perspect Bioi Med 44:390-341 Maher D, Mikulencak M (1999) What is DOTS? A guide to understanding the WHO-recommended strategy known as DOTS. World Health Organization, Geneva Maher D, Floyd K, Raviglione MC (2002) Strategic framework to decrease the burden of TB/HIV. World Health Organization, Geneva McCarthy OR (1984) Asian immigrant tuberculosis - the effect of visiting Asia. Br J Dis Chest 78:248-253

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Menzies D, Tannenbaum TN, FitzGerald JM (1999) Tuberculosis: 10. Prevention. CMAJ 161:717-724 Menzies D, Vissandjee B (1992) Effect of bacille CalmetteGuerin vaccination on tuberculin reactivity. Am Rev Respir Dis 145:621-625 Moss AR, Alland D, Telzak E, Hewlett D Jr, Sharp V, Chiliade P, LaBombardi V, Kabus D, Hanna B, Palumbo L, Brudney K, Weltman A, Stoeckle K, Chirgwin K, Simberkoff M, Mogzadeh S, Eisner W, Lutfey M, Kreiswirth B (1997) A city-wide outbreak of a multiple-drug-resistant strain of Mycobacterium tuberculosis in New York. Int J Tuberc Lung Dis 1:115-121 Mostowy S, Behr MA (2002) Comparative genomics in the fight against tuberculosis: diagnostics, epidemiology, and BCG vaccination. Am J Pharm Genom 2: 189-196 Munro R (2002) Path paved for release of $100 M loan for TB. The Moscow Times. 21 Oct 2002. Ref type: newspaper Murray CJL, DeJonghe E, Chum HJ, Nyangulu DS, Salomao A, Styblo K (1991) Cost effectiveness of chemotherapy for pulmonary tuberculosis in three sub-Saharan African Countries. Lancet 338:1305-1308 Nault P, Phypers M, Deeks S (2002) Tuberculosis in Canada 2000: pre-release. Health Canada, Ottawa. Ref type: report Pathania V, Almeida J, Kochi A (1997) TB patients and forprofit health care providers in India. World Health Organisation, Geneva Pinho AMF, Santoro-Lopes G, Harrison LH, Schechter M (2001) Chemoprophylaxis for tuberculosis and survival of HIV - infected patients in Brazil. AIDS 15:2129-2135 Public Health Laboratory Service, United Kingdom (2002) Tuberculosis Epidemiological Data for England and Wales. Public Health Laboratory Service, London. www.phls.co.uk! topics_az/tb/TB_tables_figures/. Accessed 28 Nov 2002 Reichler MR, Reves R, Bur S, Thompson V, Mangura BT, Ford J, Valway SE, Onorato 1M (2002) Evaluation of investigations conducted to detect and prevent transmission of tuberculosis. JAMA 287:991-995 Rieder HL (2002) Interventions for tuberculosis control and elimination. International Union Against Tuberculosis and Lung Disease, Paris Riley R, Mills C, O'Grady F (1962) Infectiousness of air from a tuberculosis ward - ultraviolet irradiation of infected air: comparative infectiousness of different patients. Am Rev Respir Dis 84:511-525 Rivest P, Tannenbaum T, Bedard L (1998) Epidemiology of tuberculosis in Montreal. CMAJ 158:605-609 Saraiya M, Cookson ST, Tribble P, Silk B, Cass R, Poonja S, Waiting M, Howland N, Paz EA, Cochran J, Moser KS, Oxtoby MJ, Binkin NJ (2002) Tuberculosis screening among foreign-born persons applying for permanent US residence. Am J Publ Health 92:826-829 Sawert H, Sukhontha K, Payanandana V, Akarasewi P, Nunn PP, Raviglione MC (1997) Costs and benefits of improving tuberculosis control: the case of Thailand. Soc Sci Med 44: 1805-1816 Schwartzman K, Menzies D (1999) Tuberculosis: 11. Nosocomial disease. CMAJ 161:1271-1277 Schwartzman K, Menzies D (2000) Tuberculosis screening of immigrants to low-prevalence countries. A cost-effectiveness analysis: Am J Respir Crit Care Med 161:780-789 Selwyn PA, Hartel D, Lewis VA, Schoenbaum EE, Vermund SH, Klen RS, Walker AT, Friedland GH (1989) A prospective study of the risk of tuberculosis among intravenous drug

880 users with human immunodeficiency virus infection. N Engl J Med 320:545-550 Shilova MV (2001) Specific features of the spread of tuberculosis in Russia at the end of the 20th century. Ann NY Acad Sci 953:124-132 Sonnenberg P, Murray J, Glynn JR, Shearer S, Kambashi B, Godfrey-Faussett P (2001) HIV-l and recurrence, relapse, and reinfection of tuberculosis after cure: a cohort study in South African mineworkers. Lancet 358:1687-1693 Styblo K (1985) The relationship between the risk of tuberculosis infection and the risk of developing infectious tuberculosis. Bull Int Union Against Tuberc 60:117-119 Suarez PG, Watt CJ, Alarcon E, Portocarrero J, Zavala 0, Canales R, Luelmo F, Espinal MA, Dye C (2001) The dynamics of tuberculosis in response to 10 years of intensive control effort in Peru. J Infect Dis 184:473-478 Suarez PG, Floyd K, Portocarrero J, Alarcon E, Rapiti E, Ramos G, Bonilla C, Sabogal I, Aranda I, Dye C, Raviglione MC, Espinal MA (2002) Feasibility and cost-effectiveness of standardised second-line drug treatment for chronic tuberculosis patients: a national cohort study in Peru. Lancet 359: 1980-1989 Sumartojo EM, Geiter LJ, Miller B, Hale E (1997) Can physicians treat tuberculosis? Report on a National Survey of Physician Practices. Am J Publ Health 87:2008-2011 TB Alliance (2002) The global alliance for TB drug development. www.tballiance.org. Accessed 28 Nov 2002. Ref type: pamphlet Tupasi TE, Radhakrishna S, Co VM, Villa MLA, Quelapio MID, Mangubat NV, Sarol IN, Rivera AB, Pascula MLG, Reyes AC, Sarmeinto A, Solon M, Solon FS, Burton L, Mantala MJ (2000) Bacillary disease and health seeking behavior among Filipinos with symptoms of tuberculosis: implications for control. Int J Tuberc Lung Dis 4:1126-1132

K. Schwartzman UNAIDS (2002) Joint United Nations Programme on HIV AIDS. Report on the global HIV I AIDS epidemic. UNAIDS, Geneva United States Institute of Medicine (2000) Committee on the Elimination of Tuberculosis in the United States, Division of Health Promotion and Disease Prevention. Ending Neglect: The Elimination of Tuberculosis in the United States (Geiter LJ ed). National Academies Press, Washington DC Uplekar M (2002) An expanded DOTS framework for effective tuberculosis control. World Health Organization, Geneva Uplekar M, Pathania V, Raviglione MC (2001) Involving private practitioners in tuberculosis control: issues, interventions, and emerging policy framework. World Health Organization, Geneva Vaccine Assessment and Monitoring (2002) WHO vaccinepreventable diseases: monitoring system. 2002 global summary. World Health Organization, Geneva. Available at www.who.int/vaccines-documentsl Volmink J, Matchaba P, Garner P (2000) Directly observed therapy and treatment adherence. Lancet 355:1345-1350 Walley JD, Khan MA, Newell IN, Khan MH (2002) Effectiveness of the direct observation component of DOTS for tuberculosis: a randomised controlled trial in Pakistan. Lancet 357:664-669 Wells CD, Zuber PLF, Nolan CM, Binkin NJ, Goldberg SV (1997) Tuberculosis prevention among foreign-born persons in Seattle-King County, Washington. Am J Respir Crit Care Med 156:573-577 World Health Organization (2002) BCG vaccine factsheet. World Health Organization, Geneva. www.who.inUvaccineslen/ tuberculosis.shtrnl. Accessed 28 Nov 2002. Ref type: pamphlet Zuber PLF, McKenna MT, Binkin NJ, Onorato 1M, Castro KG (1997) Long-term risk of tuberculosis among foreign-born persons in the United States. JAMA 278:304-307

49 BeG and New Tuberculosis Vaccines ZHOU XING

CONTENTS 49.1 49.2 49.3

Introduction 881 BCG Vaccine 881 Major Obstacles to Successful Development of Improved TB Vaccines 883 49.4 Immunological Considerations 883 49.5 Selection of Immunogenic M. tuberculosis Antigens for Recombinant TB Vaccine Development 885 49.6 Selection of Cytokines As Immune Adjuvants for TB Vaccine Formulations 886 49.7 New TB Vaccines 887 49.7.1 Mycobacterial-based Vaccines 887 49.7.2 Subunit-based Vaccines 888 49.7.3 Plasmid DNA-based Vaccines 889 49.7.4 Viral-based Vaccines 889 49.8 TB Vaccine Target Populations and Potential Need for Different TB Vaccine Formulations 890 References 891

49.1 Introduction Tuberculosis (TB) remains a global epidemic. TB is primarily a pulmonary infectious disease and it is caused by exposure to airborne M. tuberculosis bacilli. Approximately one third of the world population has been infected by M. tuberculosis and 10% of these people may develop active TB at some point of their lives when their host defense is weakened. Thus, each year eight million people develop TB worldwide and two million of people die from the disease (Kaufmann 2001). The risk of developing active TB in HIV-infected patients is 30-fold greater than HIV-negative patients. More than 10 million people are co-infected with both M. tuberculosis Z.XING,MD Associate Prof. Pathology & Molecular Medidine, Head, Division of Infectious Diseases, Centre of Gene Therapeutics, McMaster University Health Sciences, 1200 Main Street W, Hamilton, Ontario L8N 3ZS, Canada

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

and HIV worldwide and at least a half million of these people die from TB each year, thus bringing the annual TB-related death toll to 2.5 million. The increasing emergence of multi-drug-resistant (MDR) strains of M. tuberculosis further compounds the TB epidemic, as a result of poor compliance with anti-TB therapeutic regimens (50 million people have been infected with MDR-TB). Normally, a combination of several anti-TB antibiotics needs to be taken daily for a minimum of 6-12 months. A similar regimen is also recommended for preventive chemotherapy in TB-infected HIV patients who have not yet developed active TB. It is noteworthy that the difficulty in completing such lengthy regimens is encountered widely, not only in the developing countries, but also in disadvantaged groups in the developed countries (Kaufmann 2001; Ginsberg 2000).

49.2 BCGVaccine Currently, the only TB vaccine in use is BCG, an attenuated strain of M. bovis, which has been used for 80 years and is now the most widely administered vaccine in the world with a global coverage of more than 80% of world population (WHO 2000). There are a small number of countries including the USA, Canada, Australia and some developed European countries where BCG has not been a part of their national immunization programs for a long time; some other countries that have recently ceased the use of BCG on a national scale. Regardless of the substantial global coverage of BCG vaccination, the current ongoing TB epidemic indicates the ineffectiveness of the BCG vaccine in controlling this disease. It has been estimated that BCG prevents only 5% of all vaccine-preventable deaths by TB. There has been much controversy surrounding the widely varying results obtained from a number of BCG immunization trials (0-77% protection rate) (Roche et al. 1995).

882

Z.Xing

While they remain largely to be verified, many reasons may have contributed to the ineffectiveness of the BCG vaccine (Xing 2001a). These include: 1) M. tuberculosisand M. bovis are different, about 100 genes were found to be missing from all the strains of BCG including the gene encoding an immunogenic antigen ESAT-6. (Immunogenic MPT-64 is also missing in a large number of strains of BCG). 2) Many varying immunization schedules are used in different countries. These range from one immunization to four immunization protocols, spanning from the time of birth to adolescent ages (Table 49.1) (WHO 2000). There is no scientific justification for these variations. It is also unclear whether the intradermal route of immunization is better than paracutaneous route or vice versa. 3) Differences in the host genetic background, nutritional levels and M. tuberculosis strains used may significantly affect, or obscure, the relative efficacy of BCG. Regardless of the genes missing in the BCG genome, inclusion of an immune adjuvant formulation to BCG vaccine may help overwrite the difference in immunogenicity of the BCG vaccine among genetically diverse human populations. 4) BCG does not confer a long-lasting immunity which wanes in about 10-15 years. There is evidence that in some countries the immunity may wane even faster. This further favours the use of an immune adjuvant together with BCG and the implementation of a vaccination regimen that involves repeated immunizations with a mycobacterial, or recombinant, booster. Recent experimental evidence suggests that preexisting anti-mycobacterial immunity decreases the ability of BCG to replicate upon inoculation. This therefore favours the use of a non-mycobacterial-based booster. 5) The immune history of BCG vaccinated individuals may also affect the immunogenicity of BCG vaccine. This represents a very understudied area. Conceivably, infection (heterologous infection) that occurs before or after BCG vaccination will influence either negatively, or positively, the longevity and quality of type 1 immune responses triggered by BCG vaccine. Such

infections could be parasitic, or viral, in nature, and are particularly prevalent in developing countries. The nature of such heterologous infection perhaps constitutes an important mechanism. A type 2 infection may weaken the type 1 immunity triggered by BCG. However, a type 1 infection may also negatively affect BCG-mediated immunity because of immune competition and suppression. 6) Although BCG is not recommended for use in symptomatic HIV-infected patients due to safety concerns, it is still being given to potentially HIV-infected infants in many countries. As the HIV epidemic worsens, it is likely that more people will not receive BCG immunization. It is believed that if the current BCG vaccine is ineffective in protecting from adult TB, its immunogenicity will be even worse in patients with varying degrees of CD4 T-cell impairment. Therefore, we need improved TB vaccines. The development of such vaccines represents a daunting challenge to the TB vaccine research community and requires a long-term global commitment , by scientists, governments, healthcare personnel and commercial partners. The paradox is that the developed countries usually have a much lower incidence of active TB and yet naturally have much greater resources for TB vaccine development than underdeveloped countries. Thus, some of these countries often demonstrate apathy towards TB vaccine programs. The perception that TB may be stopped at the border must be abandoned. It would be ludicrous ifwe ignore that in the modern world infectious diseases travel across borders. On the optimistic side, there is no better time to push forward TB vaccine research programs: the entire genomic sequence of M. tuberculosis (or BCG) is now available; the WHO has been reinforcing the global TB prevention/treatment programs; a Blueprint for TB Vaccine Development was released by the NIH (US) together with the Advisory Committee for Elimination of TB and the National Vaccine Program Office; the European Commission, the NIH and private foundations including the Sequella Global Tuberculosis Foundation have escalated their support for TB vaccine development; and

Table 49.1. Varying BeG immunization regimens adopted by different countries Three immunizations

One immunization

Two immunizations

Birth 15 day 1 month 3 months <1 year

Birth/6-7 year/ll-12 year birth/6-7 years Birth/ll month/6-7 years birth/1l-12 years birthl7 years (if no scar) Birth/8 y/1s years 1 month/1 year/12 years birth/14 month

Four immunizations birthl2 years/6-7 years/14-1syears

From WHO Vaccine Preventable Disease Monitoring System (2000) Global summary.

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a U.S. Millennium Vaccine Initiative was announced to boost vaccine development for HIV, malaria and TB (Ginsberg 2000).

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vaccines may not only shorten the course of chemotherapy but also help combat drug-resistant TB.

49.4 Immunological Considerations 49.3 Major Obstacles to Successful Development M. tuberculosis is an intracellular pathogen of macof Improved T8 Vaccines While the global effort in TB vaccine development has escalated remarkably in the past decade, we are still facing many practical and scientific hurdles (Xing 2001a; Orme 1999). 1) Almost all of the current vaccines in use provide protection through antigen-specific antibodies. We have relatively little experience in the rational design of vaccines capable of adequately stimulating T-cell-mediated immunity. 2) An improved TB vaccine may require an immune adjuvant (s) and this may be true for both mycobacterial-based and recombinant forms of a vaccine. The current adjuvant approved for human use is aluminium that is inappropriate for TB immunization. The potential immune adjuvant may be chemical, or biological, molecules including immune modulatory cytokine proteins/transgenes which can be mixed and delivered together with TB vaccine. The bacterial plasmid or viral backbone of a recombinant TB vaccine serves as immune adjuvant. 3) The current BCG vaccine has been used for 80 years and given to infants in most countries. A new, or improved, TB vaccine has to be proven to be more effective than BCG. Ideally this should be both in terms of the level and duration of anti-TB immunity before it replaces the current BCG. It may take decades before this can happen worldwide. It is possible that the current BCG vaccine will continue to be used but a boosting regimen will be introduced. However, the nature of such a booster vaccine, and the regimen, remain yet to be established. 4) A total of 1/ 3 of the world population has been infected with M. tuberculosis. Vaccination strategies must be developed to prevent active TB not only in infants but also in populations with latent TB. While considerable experience has been accumulated through administering BCG to infants, little is known about how to effectively immunize infected patients with, or without, previous BCG immunization. 5) The HIV epidemic and poor compliance with antiTB chemotherapy cause an ever-increasing number of drug-resistant strains of M.tuberculosis. To effectively control the TB epidemic, there is a need to develop therapeutic vaccines that can be used as adjuncts to anti-TB chemotherapy. Such therapeutic

rophages. Macrophages take up mycobacteria via the surface complement and mannose receptors and 'toll-like' receptors 2/6. It is believed that alveolar macrophages are the primary cells within the airway space (including alveoli) that phagocytose mycobacteria. However, it is known that there are abundant dendritic cells within the airway epithelium and the bronchial-associated lymphoid tissue (SchonHegrad et al. 1991); these cells could also phagocytose mycobacteria as bacteria cross the airway epithelium (Henderson et al. 1997). The extent to which mycobacteria enter the airway tissue before phagocytosis by macrophages is unclear. Presumably in the initial stage of infection (by a small number of mycobacterial bacilli) only a few bacilli will be phagocytosed by the dendritic cells. However, as the infection evolves, and if the host immunity fails to contain infection, the balance may shift and free mycobacteria may travel across the epithelial barrier and subsequently may be phagocytosed by dendritic cells residing within, and beneath, the epithelium. Infected dendritic cells mature and are activated to release, or express, a number of immune modulatory molecules on their surface. Unfortunately, relatively little is known regarding the functional connection and difference between alveolar macrophages and dendritic cells upon mycobacterial infection. Phagocytosed mycobacteria reside in the phagosomes, or endocytic vacuoles, of macrophages and evade the anti-bacterial activities through preventing phagosome-lysosome fusion and acidification (Hingley-Wilson et al. 2000). Cytokine interferon (IFN)-gamma-activated macrophages acquire phagolysosomal endocytic vacuoles of lower pH, mycobacteria and MHC II molecules (Schaible et al. 1998). How exactly the host eventually controls the intracellular replication of mycobacteria and eradicates these pathogens, is still unclear. Nitric oxide seems important in this process. While it is believed that macrophages are important effectors with direct killing capacity, both T and NK cells are able to lyse infected macrophages and directly kill mycobacteria in vitro (Xing 2001a). The initial T-cell activation during primary TB infection, or after vaccination, is believed to take place

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in the local draining lymph nodes. Such activation requires the interaction between antigen-presenting cells including both dendritic cells and macrophages, and antigen-specific T cells. Both CD4 and CD8 T cells are activated through MHC class II and MHC class I-restricted pathways, respectively. Exogenous antigens can also be processed and presented via the MHC I pathway by a mechanism called 'acrosspresentation' (Albert et al. 1998). It is not yet entirely clear how certain antigens leak from phagosomal, or endocytic vacuoles, into the cytosol where they are degraded into peptides (in the proteosomes) and are subsequently transported into the endoplasmic reticulum and loaded onto MHC class I molecules by the TAP heterodimer (composed of type 1 and type 2 transporter associated antigen processing [TAP]). Activation of CD8 T cells following intramuscular vaccination with recombinant DNA-based TB vaccines is the best support for this mechanism (Seder and Hill 2000). In this case, transfected myoblasts express, and release, an M. tuberculosis antigen which is taken up by antigen-presenting cells. antigen-specific T cells activated in this way, or those that picked up apoptotic myocytes, migrate to the lymph nodes to activate both CD4 and CD8 T cells. Both antigen presentation by antigen-specific T cells and the interaction of B7 molecule on APC with CD28 on T cells are required for T-cell activation. In addition, type 1 cytokine interleukin-(IL)12 released from activated antigen-specific T cells also plays a crucial role in the initiation of type 1 T-cell differentiation during primary mycobacterial infection or vaccination (Wakeham et al. 1998; Xing 2001 b). Thus, adequate activation of antigen-specific T cells is essential to antigen-specific T-cell expansion and activation. Activated antigen-specific T cells demonstrate higher levels of MHC class I and II and co-stimulatory molecules including B7 molecules, enhanced antigen presentation and IL-12 release. In addition, antigen-specific T cells also release other cytokines which participate in orchestrating optimal immune responses. The quality and longevity of such immune responses are dictated by a blend of these immunologically active molecules, both soluble and membrane-bound, present at the site of infection and antigen presentation. The make-up of this blend of molecules is determined by the nature and dose of the pathogen, the character of the tissue site where the pathogen enters, the host's genetic make-up and the history of the host's immune system (which is dependent on its exposure to various pathogens (heterologous infection), or other immunogens before or after TB infection or vaccination) (Bentwich et al.

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1999). The use of immune adjuvant in TB vaccine formulations may help enhance antigen-specific T cells activation and antigen presentation and turn the unfavourable tissue micro-environment into the one that favours the activation of anti-TB type 1 T cells (Xing 2001a; Matzinger 1998). After activation the majority of T cells die and a small fraction may become memory T cells and live much longer (Seder and Hill 2000). Antigen-specific memory T cells undergo quick expansion and activation upon re-exposure to M. tuberculosis or their antigens. Both CD4 and CD8 T cell subsets and B cells may assume the memory phenotype. Recent evidence suggests that the gamma/delta T-cell subset may also possess the memory T cell function after BCG vaccination (Shen et al. 2002). Much less is known about the mechanisms of the development of anti-TB memory T cells after BCG immunization or following a natural TB infection. It is possible that a similar set of factors involved in the initial T-cell activation are also important in the generation of TB specific memory T cells. Experimental evidence suggests that both CD4 and CD8 memory T cells can persist in the absence of specific antigen presentation, or in the absence of MHC class II and class I molecules. This is in sharp contrast to the homeostasis of naive T cells (Bevan and Goldrath 2000). However, the immune quality of these memory T cells may have been altered in the absence of continuous antigenic stimulation and thus the immune quality does not necessarily correlate with their number and longevity (Kassiotis et al. 2002). The immune protection, if any, triggered by BCG vaccination, diminishes within 10-15 years or even sooner in certain countries (Orme 1999). This coincides with the loss ofPPD skin reaction which wanes after 5-10 years aftre neonatal immunization. Successful generation of long-term memory type 1 T-cell responses is central to the development of improved TB vaccines. In summary, there are several important immunological considerations that need to be taken into account for the design of new TB vaccines (Xing 2001a): 1) adequate levels of exposure of host's immune system to immunogenic TB antigens which may ensure effective epitope display and antigen presentation; 2) effective reciprocal co-stimulation between antigen-presenting cells and T cells; and 3) creation of a favourable tissue micro-environment rich in pro-immune cytokines and other molecules. Experimental evidence using recombinant BeG vaccine supports the notion that increased amounts of a single immunogenic M.tuberculosis antigen could make a big difference in immune protection

BeG and New Tuberculosis Vaccines

(Horwitz et al. 2000). Cytokines play an important role in creating an environment favourable to the generation of long-term memory T cells. T cells with a memory phenotype are believed to have a more rapid turn-over rate and are sensitive to the effect of T-cell active cytokines. Certain cytokines such as IL-15 can stimulate the expansion of CD8 T cells of memory phenotype in the absence of a specific antigen. Unfortunately, little is known about the nature of such cytokines involved in the generation of anti-TB memory T cells. It is likely that some of these cytokines may overlap with those involved in the initiation of primary immune responses against mycobacterial infection. In this regard, IL-6 was found to be required for the optimal level of primary immune responses to mycobacterial infection but not for the maintenance of memory immunity. On the other hand, IL-12 was found to be required for sustaining the response of Th1 cells to secondary leishmania infection. The timing of the presence of a given cytokine is also important. For instance, IL-2 is a T-cell growth factor and when present at the time of initiation of immune response, it enhances the level of memory T-cell response whereas when present in the maintenance stage, it downsizes the population of memory T cells.

49.5 Selection of Immunogenic M. tuberculosis Antigens for Recombinant 18 Vaccine Development Mycobacterium tuberculosis has approximately 4000 gene products and it is anticipated that more TB antigens with previously unknown functions will turn out to be immunogenic. A challenge to TB vaccine researchers is to find out whether these new antigens are superior to other previously known immunogenic antigens and to select a few of the best candidates to be incorporated into recombinant TB vaccines. At present, the majority of recombinant TB vaccines only express a single TB antigen. This will result in the activation of limited antigen-specific T cell clones. Thus, concurrent expression of multiple immunogenic antigens in a multivalent TB vaccine will be highly desirable (Xing 2001a).

Criteria for Selection. There has not been a set of standards developed to aid the selection of antigens. However, several immunological aspects are worthwhile for consideration (Xing 200Ia):

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1) Secretory antigens are better candidates for the activation of both CD4 and CD8 T cells. This is perhaps why up to now, the majority of immunogenic TB antigens are those present in the culture filtrate of M. .tuberculosis, or BCG, and live organisms are superior to dead ones for immunogenicity. 2) Dominant T-cell antigens ought to be those that account for a major fraction (s) of TB-specific T cells or memory-T cell clones found both in infected humans and mice, and these include the Ag85 complex antigens and ESAT-6. In humans, these antigen-specific T cells may be detected in hosts who were infected with M. tuberculosis but have not developed TB and those who have active TB. 3) Universal immunogenic antigens. Multiple epitopes may span the large portion of a given antigenic protein. Thus, antigen-presenting cells from hosts of different HLA haplotypes will be able to present one or more immunogenic epitopes from the same antigen. M. tuberculosis Ag85A (Smith et al. 2000), ESAT-6 (Mustafa et al. 2000a), Ag85B(Mustafa 2000), MPT64 (Mustafa 2000) and hsp70 all fall into this group of antigens. 4) Promiscuous immunogenic epitopes. An epitope of a given antigen may be presented by APC of mismatching haplotypes. Ag85A, Ag85B, ESAT-6 and MPT64 possess multiple epitopes recognizable by T cells in a HLA-non-restricted manner. Such promiscuity of M. tuberculosis epitopes was also observed in rodents (Vordermeier et a1.1994). In contrast, each epitope of hsp70 is presented only by one particular HLA molecule (Oftung et al. 1994). 5) Dominant T cell antigens that are released from M. tuberculosis but are missing from BCG vaccines, which include ESAT-6 and MPT-64 (Behr et aI. 1999). Among M. tuberculosis antigens each of which has been expressed in a DNA vaccine, are Ag85A, Ag85B, Ag85C, ESAT-6, hsp70 (or hsp65 from M. leprae), Pst-I, Pst-2, PstS-3, KatG, HBHA, MPT-63 or MPT-64, MPT83. While Ag85C, Pst1, Pst-2 are weak immunogenic antigens, other antigens expressed in DNA-based vaccines have been shown to be immune-protective to varying degrees in mouse models of T8. Among all of the tested immunogenic antigens, Ag85A or Ag85B, ESAT-6 or hsp65 appears superior to the others.

The M. TB Ag85 Complex (30-32 kDa). This group of outer wall antigens include Ag85A, Band C. They are the major secreted proteins in M. tuberculosis or BCG

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culture filtrate. These antigens are highly conserved among all mycobacterial species. Their function is to bind to fibronectin and thus may be involved in the macrophage phagocytic process. In experimental models,Ag85A and Bare among a handful of memory T cell-stimulating antigens. These antigens stimulate a strong CD4 and CD8 T cell response both in humans and experimental animals (Smith et al. 2000). Ag85B (MPT59) contains multiple human T-cell epitopes that scatter throughout the entire protein and several epitopes are promiscuous T-cell epitopes and thus could stimulate T cells by HLA-DR-mismatched antigen-presenting cells (Mustafa et al. 2000b). Thus, at least one of Ag85A and B antigens should be incorporated into a multivalent TB vaccine.

ESAT-6 (6 kDa). This is a small molecular weight, secreted antigen. The gene coding for ESAT-6 is not present in any BCG strain although it is in virulent M. bovis and M. tuberculosis. Of importance, a large proportion of memory T cells in M. tuberculosisinfected mice are ESAT-6-reactive (Andersen et al. 1995). Furthermore, this antigen also stimulates a strong human T-cell response and similar to Ag85, contains multiple T-cell epitopes that span the entire ESAT-6 protein (Mustafa et al. 2000a). Thus, ESAT-6 is a dominant human T-cell antigen which could be presented by antigen-presenting cells of a wide spectrum of HLA-DR haplotypes. This antigen warrants serious consideration for a multivalent formulation of TB vaccine. MPT64 (26 kDa). This antigen is also among the major secreted proteins. The gene coding for this protein is present only in some BCG strains (Tokyo, Russia, Sweden and Morau) but not in other strains (Danish 1331, Glaxo, Pasteur and Tice). MPT64 is also one of human dominant T-cell antigens (Mustafa 2000) and can be recognized by T cells from the majority of TB patients. DNA vaccine expressing MPT64 conferred protection in mouse models of TB. Thus, this antigen is worthy of consideration for recombinant TB vaccines.

hsp proteins (l0, 18, 60, 65, 70 kDa). This represents a group of secreted heat shock proteins of diverse molecular weights. They are widely conserved in prokaryotes and eukaryotes, involved in the protein folding, unfolding and assembly processes. These proteins are induced both in infected antigen-presenting cells and M. tuberculosis under any stressful conditions including elevated temperature. The initial success in using DNA-based TB vaccines express-

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ing mycobacterial hsp to protect mice with TB infection has generated a considerable level of excitement (Tascon et al. 1996). With regard to hsp70, multiple human T-cell epitopes have been identified but each epitope is presented only by antigen-presenting cells of a particular HLA molecule, hence the lack of promiscuity (Oftung et al. 1994). Due to the high homology of these proteins with mammalian counterparts, expression of hsp proteins in TB vaccines raises a serious concern regarding their potential to trigger an autoimmune response. Indeed, a recent study demonstrates an autoimmune-like tissue response in guinea pigs immunized with DNA vaccines expressing M. tuberculosis hsp antigens and subsequently challenged by M. tuberculosis (Turner et al. 2000).

49.6 Selection of Cytokines As Immune Adjuvants for TB Vaccine Formulations Cytokines that can act at a point along the cascade of anti-TB immunity may be used as an adjuvant for both live mycobacterial-based and recombinant forms of TB vaccines (Xing and Wang 2000; Xing 2001a). The rationale is to create a cytokine-rich tissue microenvironment at the site of initial vaccine inoculation or antigen expression/presentation. As such, antigen presentation may be enhanced via increased recruitment and activation of antigen presenting cells (APC) and increased epitope display on APC, and more T cells may be recruited to the site of immune activation. Improved antigen presentation will lead to activation of a larger repertoire of T cells while activation of APC facilitates the type 1 polarization of these antigen specific T cells and perhaps the generation of memory T cells.

Cytokines Active on Antigen-presenting Cells. These include GM-CSF, IL-3, Flt-3 and MIP-3 alpha. GMCSF is a hematopoietic cytokine capable of multiple functional activities with a prominent effect on the activation of myeloid dendritic cells and macrophages (Xing et al.1996; Wang et al. 2000). Thus, GMCSF may enhance the immunogenicity of TB vaccine by acting on the early events of immune cascade. Indeed, by using a GM-CSF-expressing adenoviral vector as an adjuvant, we were able to enhance the immunogenicity of BCG vaccine in genetically weak responders Balb/c mice (Wang et al. 2002). Flt-3 is also a hemotopoietic cytokine capable of mobilizing and activating dendritic cells. MIP-3 alpha is a che-

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mokine chemo-attractive to both dendritic cells and memory T cells (Cook et al. 2000).

Type 1 Differentiating Cytokines. IL-I2 is an indispensable type I-differentiating cytokine, particularly in host defense against non-viral intracellular infections (Xing 200Ib). The inclusion of this cytokine or its transgene formulation has been shown to enhance the immunogenicity of vaccines against a number of intracellular infectious diseases in experimental models. Recombinant IL-I2 increased immune protection by BCG vaccination against M. tuberculosis infection. We have recently found that subcutaneous, or intranasal, co-administration of an adenoviral vector expressing IL-I2 with BCG enhances the immunogenicity of BCG (Xing 200Ia). IL-I8 and IL-23 are also type I-like cytokines capable of potentiating a number of biological activities mediated by IL-I2. IL-IS, however, differs from IL-I2 as it can be released by a variety of cell types and by itself it cannot directly activate type I differentiation since expression of the receptor for IL-IS on T cells is dependent on the action of IL-I2. Lymphocyte- or Memory T Cell-stimulating Cytokines. These include IL-2, IFN-gamma and such cytokines as IL-IS capable of stimulating memory CDS T cells (Ku et al. 2000). IL-2 is a T-cell-proliferation growth factor and has a dual role in the generation and maintenance of CDS memory T cells (Dai et al. 2000). This cytokine may not be an ideal adjuvant for TB vaccine due to its notorious cytotoxicity. At the moment, relatively little is known about the nature of the cytokines that are important in the generation of anti-TB memory T cells post-vaccination since the majority of cytokine biological studies in the TB arena, or in any other intracellular infection, have been carried out in models of primary infection. However, evidence suggests that the size of the initial antigen-specific effector pool is proportionate to the size of memory T-cell population (Seder and Hill 2000). Thus, conceptually, cytokines that potently activate the development of primary T cell activation will subsequently have a positive impact on the memory T-cell pool.

Chemokines Active on Lymphocytes and Monocytesl Macrophages. Lymphocyte chemo-attractive cytokines include RANTES and lymphotactin. Many of these chemokines are also active on monocytes/ macrophages (Hogaboam et al. 2000). These cytokines may enhance the immunogenicity of TB vaccine by recruiting more antigen-specific T precursors to the site of antigen presentation and creating a less

dangerous environment for strong type I differentiation. MIP-3 alpha is a chemokine active on both dendritic cells and memory T cells (Cook et al. 2000).

Choice of Cytokine Formulations. Recombinant cytokines are not only expensive but also short-lived in vivo (Xing and Wang 2000).And the storage conditions are tricky as well which will hinder their use in many developing countries. The best strategy is to express cytokine in vivo in the form of a transgene which is not only economical but renders a sustained level of cytokine in the vicinity of antigen delivery/expression. Currently there are three strategies for consideration: 1) Engineered live organisms stably expressing a cytokine. 2) Plasmid-DNA based Cytokines may be expressed by a separate cassette or co-expressed in the same TB-DNA vaccine. The latter is more logical and practical. While this represents an attractive strategy for DNA-based TB vaccination, it will be less ideal for other formulations of TB vaccines since the DNA vector is expressed best only in the muscle and this will detract from the co-delivery when TB vaccines are given mucosally or para-cutaneously. 3) Viral-based. This strategy allows not only the efficient expression of cytokine but flexible routes of administration. For instance, we have shown that adenoviral gene transfer vector efficiently transduce the transgene at the muscle, intradermal or subcutaneous compartment, or mucosa. Furthermore, viral cytokine vector may be mixed with either live organism TB vaccine or viral TB vaccine. The dose of such viral-based vectors can be kept to a minimum since expression is highly efficient and only a local effect is desired.

49.7 New T8 Vaccines 49.7.1 Mycobacterial-based Vaccines

Current BCG Vaccine and Vaccination Regimen. It will be difficult to abandon the use of current BCG on a global scale in the near future. It may be much easier to change the regimen or to add a straightforward immune adjuvant to the current BCG vaccine. Currently, BCG is being given paracutaneously in humans. The potential advantage of the mucosal route of immunization via the airway has not been extensively studied. It is interesting that oral BCG immunization does not seem to convert a PPD skin test (Hoft et al. 2000). Furthermore, BCG immuniza-

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tion by aerosolization in rhesus monkeys generated minimal side effects and only a small skin reaction to PPD while it protected against airway M. tuberculosis infection (Barclay et al. 1973). Therefore, it is possible that the benefit of respiratory mucosal immunization may outweigh potential side effects. The current BCG immunization schedules vary widely across the world and there is a lack of logic as to why BCG should be administered only once or several times, or how long the intervals should be if given several times. Studies are urgently needed to investigate whether repeated BCG vaccinations help maintain the memory response. If not, other booster formulations need to be defined. Not only is BCG vaccine ineffective in protecting humans, but also a natural TB infection may not necessarily protect the host from a second TB infection (van Rie et al. 1999). This strongly suggests that the current BCG vaccine, if it is to be continued to be used for the next several decades, needs an adjuvant to heighten the level and longevity of immunity.

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isms cannot replicate, and survive, like their wild type counterparts and will persist only long enough to activate immune components. Some of these auxotrophs have been shown to confer a level of immune protection similar to the wild-type BCG in mice and guinea pigs (Guleria et al.1996).At the moment, these live, replication-deficient mutants represent the best candidate vaccines to be used in immuno-compromised hosts. However, little is known about whether any live mycobacterial organism-based vaccine will be effective in immune-compromised hosts such as HIV-infected patients who suffer impaired CD4 T cell functions. Basic research and assessment are urgently needed in this regard. The childhood immunization with BCG seems to reduce the risk of disseminated TB in HIV-infected adults (Marsh et al. 1997). A vaccine may be needed for the adults who suffer HIV infection with varying degrees of CD4 T-cell deficiency but who were never immunized against TB. In this case, even with an auxotrophic form of TB vaccine, an adjuvant formulation will be highly desired to target CD8 T cell-based immune mechanisms.

Recombinant BCG. Plasmid DNAs containing transgenes encoding cytokines were introduced by stable transformation into the BCG genome. Cytokines expressed by such recombinant BCG organisms include IL-2, IFN-gamma and GM-CSF (Murray et al. 1996). These cytokine-secreting BCG vaccines were shown to enhance the immunogenicity of BCG in mouse models. One of these vaccines secreting IL-2 was also recently evaluated in deer with no increased immunogenicity. These vaccines have not yet been extensively tested in TB challenge models. Whether the random insertion of plasmid DNA into the BCG genome will have any effect on the expression of dominant mycobacterial antigens is unknown. It is also of potential concern that cytokine release will continue as long as the BCG lives and this may cause some undesired effects. A M. tuberculosis Ag85B gene was stably transformed into BCG and such recombinant BCG vaccines were found to provide a better protection than BCG in a susceptible guinea pig model of TB. Since M. tuberculosis Ag85B and BCG Ag85B differ only in two contiguous amino acids, this finding suggests that it is the level of this antigen that is crucial to the difference in the level of immune protection.

Rapid-growing Mycobacteria. Fast-growing mycobacterial species including M. smegmatis and M. vaccae are among potential TB vaccine candidates. The concept of using a strain of mycobacterium cross-reactive to the pathogenic one in order to overcome the unresponsive state of immune system, is supported by recent successful immunotherapy for lepromatous leprosy (Talwar 1999). Heat-inactivated M. vaccae appeared to provide some immune protection against M. tuberculosis challenge in experimental models. It also seems immunogenic in HIV-infected humans. However, a recent clinical trial indicates that when used as a therapeutic vaccine in patients with TB, it provides no clinical benefit (Durban Immunotherapy Trial Group 1999). While the fast-growing mycobacterial species share some immunogenic antigens with BCG and M. tuberculosis, it is hard to conceive that they will be any better than BCG if no adjuvant is used. Moreover, use of dead M. vaccae is unlikely to be advantageous over auxotrophic BCG or M. tuberculosis. It is worth noting that the NIH has supported Phase lIII trials involving the use of inactivated M. vaccae and recombinant IL-2.

Auxotrophic Mutants. Taking advantage of the fact that mycobacteria depend on their own synthesis of certain amino acids for replication, BeG or M. tuberculosis auxotrophs have been developed by deleting the mycobacterial genes required for the biosynthesis of these amino acids. As a result, the mutated organ-

49.7.2 Subunit-based Vaccines

These vaccines consist of defined secreted M. tuberculosis proteins/peptides or simply the entire reper-

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toire of unfractionated M. tuberculosis culture filtrate proteins (Orme 1999). The safety is a prominent feature of these vaccines. Furthermore, subunit-based vaccines do not seem to convert skin PPD reaction. However, the major limitations to the application of such vaccines include: 1) an adjuvant formulation such as incomplete Freund's adjuvant (IFA), dimethyl dioctadecyl ammoniumbromide (DDA) and Quil-A saponin, and multiple doses are required for immunogenicity; 2) in general these vaccines are poor stimulators of CD8 T cells; and 3) they are relatively expensive to produce. Furthermore, there has been a lack of comparative studies addressing the potential difference in antigen presentation, T-cell subset activation and the longevity of immune activation between these vaccines and live organism-based or recombinant vector-based vaccines. Experimental studies demonstrate that protein-based TB vaccines can protect mice, or guinea pigs, from M. tuberculosis challenge but the protection level generally is not greater than BCG. Notwithstanding, the EAST-6 subunit vaccine, with DDA and MPL (monophosphoryl lipid A) as an adjuvant, elicited a level of protection against M. tuberculosis comparable to that of BCG (Brandt et al. 2000).

49.7.3 Plasmid DNA-based Vaccines Bacterial plasmid DNA is rich in CpG motifs which directly or indirectly activate the innate and adaptive immune components and thus have a potent immune adjuvant effect in mammalian organisms. The CpG motif consists of an unmethylated cytidinephosphate-guanosine dinucleotide with appropriate flanking regions (Gurunathan et al. 2000). Although non-living, plasmid DNA vectors allow the expression of foreign transgene(s) under appropriate control and subsequent production of the transgene protein by transfected cells in vivo - a process similar to that by live intracellular infection. As a result, plasmid DNA-based vaccines trigger both humoral and cell-mediated immune responses by activating B, CD4 and CD8 T cells, without the need for additional adjuvant. DNA-based TB vaccines, similar to subunitbased vaccines, do not convert the skin PPD reaction. Compared to such viral vectors as adenoviral vector, plasmid DNA vectors elicit lower levels of expression due to Iowa transfection efficiency. Human clinical trials are underway to test the safety and efficacy of DNA-based vaccines. Although the effect of DNA vaccination has not been reported, there have been suc-

cessful uses of DNA-based vector for topical cytokine delivery in treating cardiovascular diseases. The transgene coding for a number of immunogenic M. tuberculosis antigens including Ag85A, Ag85B, ESAT-6, MPT64, PstS-1I2/3, KatG, hsp65 and hsp70 have been expressed in plasmid DNA vector. These DNA vaccines, when used individually, or in combination, have demonstrated impressive immunogenicity in mice but the level of conferred immune protection against subsequent M. tuberculosis infection hardly exceeds that by BCG (Tascon et al. 1996). A DNA vaccine expressing Ag85A was shown to elicit a stronger and broader CD8 T cell response specific to Ag85A than a natural M. tuberculosis infection (Denis et al.1998). Secreted forms of these TB antigens from a plasmid DNA vector appear to elicit a better immune response than non-secreted forms. The best route of DNA-TB vaccination is intramuscular injection. It is worth noting that these DNA vaccines tend to work effectively in mice while they are much less effective in guinea pigs. This finding casts a shadow over their effectiveness in humans. In addition to a prophylactic effect, some of DNA-TB vaccines (but not a single dose of BCG) have been proven therapeutic in mouse models of primary i.v. M. tuberculosis infection and reactivation (Lowrie et al. 1999). This represents an important step forward in rationalizing the use of DNA-based TB vaccines in humans.

49.7.4 Viral-based Vaccines

Vaccinia Virus. Vaccinia virus is a commonly used poxviral vector. Vaccinia virus replicates in the cytoplasm and is normally highly toxic to the infected cells. Since only poxviral, but not strong viral, promoters, can be used for the expression of heterologous genes in poxviral vector (Hitt and Gauldie 2000), transgene expression is usually very low. Like adenoviral-based vectors, the vaccinia viral genome does not integrate into the host genome. Recombinant vaccinia viral vector can harbor up to 25 kb of heterologous transgene sequences. Poxvirus-based vaccines have been widely used to immunize cattIe, chickens, raccoons and foxes against viral infections. Recent human clinical trials using vaccinia vector expressing immune-modulatory cytokine, or HIV envelope proteins, have provided promising results. Vaccinia virus vector has also been exploited to express mycobacterial antigens and demonstrated certain protective effects in mouse models (Zhu et al.1997). However, this vector is unlikely be a major platform for a TB vaccine due to low expression of TB antigens.

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Notwithstanding, this vector may be potentially useful as a boosting vaccine following BCG, or DNA-based priming, vaccination (McShane et al. 2001).

49.8 T8 Vaccine Target Populations and Potential Need for Different T8 Vaccine Formulations

Adenovirus. The potential for adenovirus for gene

In order to effectively control the current global TB epidemic, there are several human groups who may need TB vaccine of different forms (Xing 2001a): 1) Neonates who need to be protected from TB immediately after birth; 2) BCG-immunized adults who may have been infected with M. tuberculosis and are no longer protected by the initial BCG vaccination in adulthood; 3) Non-immunized populations who were infected with M. tuberculosis in a developed nation; 4) High risk populations who were never immunized with BCG including health workers, the elderly, the homeless and prisoners in the developed countries; 5) BCG immunized or non-immunized immunecompromised individuasl; and 6) TB patients. The vaccine designed for the immunization of the newborn has to meet the conventional expectations for a vaccine used on a global scale (simple formulation and regimen, easy to produce, transport, store and administer, and cheap). The vaccine to be used for people who have previously been immunized with BCG and infected by M. tuberculosis, may not be the same vaccine used for newborns. Such a vaccine should prove effective in previously immunized hosts and it may be a BCG vaccine with an adjuvant or a recombinant viral TB vaccine. The vaccine used for non-immunized but TB-infected patients, and non-immunized high-risk patients, are mostly in the developed countries where BCG is not part of immunization program. This vaccine may be the same vaccine used for newborns if it proves effective in TB-infected hosts, or it may be a strengthened formulation that is different from the one used for newborns. The vaccine designed for use in HIV patients has to be the one tailored to target CD8 and other subset T cells. Such a vaccine ought to be safe and is likely to require a potent adjuvant formulation. The vaccine designed as an immune therapeutic adjunct to chemotherapeutics in patients with active TB, particularly drugresistant TB, is likely different from the one used in newborns and could also be different from the one designed for HIV patients. This vaccine ought to be able to overwrite the anergy that allows the development of TB after infection both in BCGimmunized and non-immunized individuals.

therapy, or gene transfer, both in experimental animals and human trials has widely been explored (Hitt and Gauldie 2000). Experimental evidence also supports the potential use of adenovirus-based vaccines for preventing infectious diseases (Imler 1995). However, this viral vector has not been explored for TB vaccination. We have initiated a program to develop adenoviralbased recombinant TB vaccines and this program is built upon our expertise in study of adeno-vectors and gene transfer (Hitt and Gauldie 2000; Xing et al. 1996). Our initial results indicate that adenoviral TB vaccine hold great promise to be a mainstay, or booster, TB vaccine platform (Xing 2001a). Recombinant adenoviral-based vaccines are effective in protecting against several infectious diseases in animals including chimpanzees. Although originally designed for treating genetic disease, the adenoviral vector, when used as a vaccine, is associated with several advantages: 1) Ample safety data are available from well-documented human immunization programs (Gurwith et al. 1989) and the adenoviral genome does not integrate into the host genome and thus does not cause mutagenesis; 2) Adenoviral vector has been genetically rendered unable to replicate, hence it is safe; 3) Compared to other vectors including plasmid DNA, the adenoviral vector is the most efficient in driving transgene expression for 2-3 weeks; 4) Adenovirus has a broad range of target cells in vivo. This allows the use of adenoviral vaccine at a preferred tissue site of choice; 5) Adenoviral vector may harbor up to 8.3 kb of foreign DNA sequences. This allows expression of multiple TB antigens in one vaccine (multivalent); 6) Adenoviral vector per se is a type 1 immune adjuvant; and 7) Evidence obtained from clinical trials by us, and others, suggests that adenoviral gene transfer is feasible in spite of pre-existing anti-adenoviral antibodies in some subjects. Adenoviral-based TB vaccines have the potential to be used not only to immunize newborns but to boost the immune response in BCG vaccinated patients who have been infected with M. tuberculosis. Compared to BCG, they will be a safer vaccine for potential use in HIV-infected hosts.

BCG and New Tuberculosis Vaccines

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References Albert ML, Sauter B, Bhardwaj N (l998) Dendritic cells acquire antigen from apoptotic cells and induce classl-restricted CTLs. Nature 392:86-89 Andersen P, Andersen AB, Sorensen AL, Nagai S (1995) Recall of long-lived immunity to Mycobacterium tuberculosis infection in mice. J ImmunoI154:3359-3372 Barclay WR, Busey WM, Dalgard DW, Good RC, Janicki BW, Kasik JE, Ribi E, Ulrich CE, Wolinsky E (l973) Protection of monkeys against airborne tuberculosis by aerosol vaccination with bacillus Calmette-Guerin. Am Rev Respir Dis 107:351-358 Behr MA, Wilson MA, Gill WP, Salaman H, Schoolnik GK, Rane S, Small PM (l999) Comparative genomics of BCG vaccines by whole-genome DNA microarray. Science 284: 1520-1523 Bentwich Z, Kalinkovich A, Weisman Z, Borkow G, Beyers N, Beyers AD (1999) Can eradication of helminthic infections change the face of AIDS and tuberculosis? Immunol Today.20:485-487 Bevan MJ, Goldrath AW (2000) T-cell memory: you must remember this... Curr BiollO:R338-R340 Brandt L, Elhay M, Rosenkrands I, Lindblad EB, Andersen P (2000) ESAT-6 subunit vaccination against Mycobacterium tuberculosis. Infect Immun 68:791-795 Cook DN et al (2000) CCR6 mediates dendritic celliocalization, lymphocyte homeostasis, and immune responses in mucosal tissue. Immunity 12:495-503 Dai Z, Konieczny BT, Lakkis FG (2000) The dual role of IL-2 in the generation and maintenance of CD8+memory Tcells. J ImmunoI165:3031-3036 Denis 0, Tanghe A, Palfliet K, Jurion F, van den Berg TP, Vanonckelen A, Ooms J, Saman E, Ulmer JB, Content J, Huygen K (l998) Vaccination with plasmid DNA encoding mycobacterial antigen 85A stimulates a CD4+ and CD8+ T-cell epitopic repertoire broader than that stimulated by Mycobacterium tuberculosis H37Rv infection. Infect Immun 66:1527-1533 Durban Immunotherapy Trial Group (1999) Lancet 354:116 Ginsberg AM (2000) A proposed national strategy for tuberculosis vaccine development. Clin Infect Dis 30 [Suppl): S233-S242 Guleria I, Teitelbaum R, McAdam RA, Kalpana G, Jacobs WR Jr, Bloom BR (l996) Auxotrophic vaccines for tuberculosis. Nat Med 2:334-337 Gurunathan S, Klinman DM, Seder RA (2000) DNA vaccines: immunology, application, and optimization. Annu Rev ImmunoI18:927-974 Gurwith MJ, Horwith GS, Impellizzeri CA, Davis AR, Lubeck MD, Hung PP (l989) Current use and future directions of adenovirus vaccine. Semin Respir Infect 4:299-303 Henderson RA, Watkins SC, Flynn JL (l997) Activation of human dendritic cells following infection with Mycobacterium tuberculosis. J ImmunoI159:635-643 Hitt M, Gauldie J (2000) Gene vectors for cytokine expression in vivo. Curr Pharm Des 6:613-632 Hingley-Wilson SM, Sly LM, Reiner NE, McMaster WR (2000) The immunobiology of the mycobacterial infected macrophagesModAsp. Immunobiology 1:96-101 Hogaboam CM, Bone-Larson C, Matsukawa A, Steinhauser ML, Blease K, Lukacs NW, Kunkel SL (2000) Therapeutic use of chemokines. Curr Pharm Des 6:651-663

Hoft DF,Brown RM,Belshe RB (2000) Mucosal bacille CalrnetteGuerin vaccination of humans inhibits delayed-type hypersensitivity to purified protein derivative but induces mycobacteria-specific interferon-gamma responses. Clin Infect Dis 30 [SuppI3]:S217-S222 Horwitz MA, Harth G, Dillon BJ, Maslesa-Galic S (2000) Recombinant bacillus Calmette-Guerin (BCG) vaccines expressing the Mycobacterium tuberculosis 30-kDa major secretory protein induce greater protective immunity against tuberculosis than conventional BCG vaccines in a higWy susceptible animal model. Proc Nat! Acad Sci USA 97:13853-13858 Imler JL (l995) Adenovirus vectors as recombinant viral vaccines. Vaccine 13:1143-1151 Kaufmann SH (2001) How can immunology contribute to the control of tuberculosis? Nature Rev Immunol 1:20-30 Kossiotis G, Garcia S, Simpson E, Stockinger B (2002) Impairment of immunological memory in the absence of MHC despite survival of memory T cells. Nat ImmunoI3:244-250 Ku CC, Murakami M, Sakamoto A, Kappler J, Marrack P (2000) Control of homeostasis of CD8+ memory T cells by opposing cytokines. Science 288:675-678 Lowrie DB, Tascon RE, Bonato VLD, Lima VMF, Faccioli LH, Stalvropoulos E, Colston MJ, Hewinson RG, Moelling K, Silva CL (l999) Therapy of tuberculosis in mice by DNA vaccination. Nature 400:269-271 Marsh BJ, von Reyn CF, Edwards J, Ristola MA, Bartholomew C, Brindle RJ, Gilks CF, Waddell R, Tosteson AN, Pelz R, Sox CH, Frothingham R, Arbeit RD (l997) The risks and benefits of childhood bacille Calmette-Guerin immunization among adults with AIDS International MAC study groups. AIDS 11 :669-672 Matzinger P (l998) An innate sense of danger. Semin Immunol 10:399-415 McShane H, Brookes R, Gilbert SC, Hill AV (2001) Enhanced immunogenicity of CD4(+) t-cell responses and protective efficacy of a DNA-modified vaccinia virus Ankara primeboost vaccination regimen for murine tuberculosis. Infect Immun 69:681-686 Murray PJ, Aldovini A, Young RA (l996) Manipulation and potentiation of antimycobacterial immunity using recombinant bacille Calmette-Guerin strains that secrete cytokines. Proc Nat! Acad Sci USA 93:934-939 Mustafa AS (2000) HLA-restricted immune response to mycobacterial antigens: relevance to vaccine design. Hum ImmunoI61:166-171 Mustafa AS, Amoudy HA, Wiker HG, Abal AT, Ravn P, Oftung F, Andersen P (1998) Comparison of antigen-specific T-cell responses of tuberculosis patients using complex or single antigens of Mycobacterium tuberculosis. Scand J Immunol 48:535-543 Mustafa AS, Oftung F, Amoudy HAl, Madi NM, Abal AT, Shaban F, Krands IR, Andersen P (2000a) Multiple epitopes from the Mycobacterium tuberculosis ESAT-6 antigen are recognized by antigen-specific human T cell lines. Clin Infect Dis 30 [SuppI3):S201-S205 Mustafa AS, Shaban FA, Abal AT, Al-Attiyah R, Wiker HG, Lundin KA, Oftung F, Huygen K (2000) Identification and HLA restriction of naturally derived Thl-cell epitopes from the secreted Mycobacterium tuberculosis antigen 85B recognized by antigen-specific human CD4(+) T-cell lines. Infect Immun 68:3933-3940

892 Oftung F, Geluk A, Lundin KA, Meloen RH, Thole JER, Mustafa AS, Ottenhoff THM (1994) Mapping of multiple HLA class II-restricted T-cell epitopes of the mycobacterial70-kilodaltonheatshockprotein. Infect Immun 62:5411-5418 Orme 1M (1999) New vaccines against tuberculosis. The status of current research. Infect Dis Clin North Am 13:169-185 Roche PW, Triccas JA, Winter N (1995) BCG vaccination against tuberculosis: past disappointments and future hopes. Trends Microbiol 3:397-401 Schaible UE, Sturgill-Koszycki S, Schlesinger PH, Russell DG (1998) Cytokine activation leads to acidification and increases maturation of Mycobacterium avium-containing phagosomes in murine macrophages. J Immunol160: 1290-1296 Schon-Hegrad MA, Oliver J, McMenamin PG, Holt PG (1991) Studies on the density, distribution, and surface phenotype of intraepithelial class II major histocompatibility complex antigen (Ia)-bearing dendritic cells (DC) in the conducting airways. J Exp Med 173:1345-1356 Seder RA, Hill AVS (2000) Vaccines against intracellular infections requiring cellular immunity. Nature 406:793-798 Shen Y, Zhou D, Qiu L, Lai X et al (2002) Adaptive immune responses of Vgamma2Vdelta2 T cells during mycobacterial infections. Science 295:2255-2258 Smith SM, Klein MR, Malin AS, Sillah J, Huygen K, Andersen P, McAdam KPWJ, Dockrell HM (2000) Human CD8+ CTL specific for the mycobacterial major secreted antigen 85A. J ImmunoI165:7088-7095 Talwar GP (1999) An immunotherapeutic vaccine for multibacillary leprosy. Int Rev ImmunoI18:229-249 Tascon RE, Jo Colston M, Ragno S, Stavropoulos E, Gregory D, Lowrie DB (1996) Vaccination against tuberculosis by DNA injection. Nat Med 2:888-892 Turner OC, Roberts AD, Frank AA, Phalen SW, McMurray DM, Content J, Denis 0, D'Souza S, Tanghe A, Huygen K, Orme 1M (2000) Lack of protection in mice and necrotizing bronchointerstitial pneumonia with bronchiolitis in guinea pigs immunized with vaccines directed against the hsp60 molecule of Mycobacterium tuberculosis. Infect Immun 68:3674-3679

Z.Xing Van Rie A, Warren R, Richardson M, Victor TC, Gie RP, Enarson DA, Beyers N, van Heiden PD (1999) Exogenous reinfection as a cause of recurrent tuberculosis after curative treatment. N Engl J Med 341:1174-1179 Vordermeier HM, Harris DP, Moreno C, Ivanyi J (1994) Promiscuous T cell recognition of an H-2 lA-presented mycobacterial epitope. Eur J ImmunoI24:2061-2067 Wakeham J, Wang J, Magram J, Croitoru K, Harkness R, Dunn P, Zaganiacz A, Xing Z (1998) Lack of both types 1 and 2 cytokines, tissue inflammatory responses, and immune protection during pulmonary infection by Mycobacterium bovis bacille Calmette-Guerin in IL-12-deficient mice. J ImmunoI160:6101-6111 Wang J, Snider D, Hewlett B, Lukacs NW, Gauldie J, Liang H, Xing Z (2000) Transgenic expression of GM-CSF induces the differentiation and activation of a novel dendritic cell population in the lung. Blood 95:2337-2345 Wang J, Zganiacz A, Xing Z (2002) Enhanced immunogenecity of BCG vaccine by using a viral-based GM-CSF transgene adjuvant formulation. Vaccine 20:2887-2898 WHO (2000) WHO vaccine preventable diseases - global summary Xing Z (2001a) The hunt for new tuberculosis vaccines: antiTB immunity and rational design of vaccines. Curr Pharm Des 7:1015-1037 Xing Z (2001b) Breach of IL-12 monopoly in the initiation of type 1 immunity to intracellular infections:IL-12 is not required for host defense against viral infection. Cell Mol Bioi 47:689-694 Xing Z, Wang J (2000) Consideration of cytokines as therapeutics agents or targets. Curr Pharm Des 6:599-611 Xing Z, Braciak T, Ohkawara Y, Sallenave J-M, Foley R, Sime PJ, Jordana M, Graham FL, Gaudie J (1996) Gene transfer for cytokine functional studies in the lung: the multifunctional role of GM-CSF in pulmonary inflammation. J Leukoc Bioi 59:481-488 Zhu X, Venkataprasad N, Ivanyi J, Vordermeier HM (1997) Vaccination with recombinant vaccinia viruses protects mice against Mycobacterium tuberculosis infection. Immunology 92:6-9

50 Tuberculosis in Animals P. L. NICOLETTI

CONTENTS 50.1 50.2 50.2.1 50.2.2 50.2.3 50.3 50.3.1 50.3.2 50.3.3 50.3.3.1 50.3.3.2 50.3.3.3 50.3.3.4 50.3.3.5 50.4 50.4.1 50.4.2 50.4.3

Introduction 893 Agents 893 Classification 893 Morphology 894 Properties 894 Hosts, Pathogenesis and Diagnosis 894 Hosts 894 Pathogenesis 895 Diagnosis 898 Cattle 898 Deer 899 Non-human Primates 899 Swine 900 Elephants 900 Public Health: Epidemiology and Control Public Health 900 Epidemiology 900 Control 901 References 902

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50.1

Introduction

Tuberculosis is one of the oldest recognized diseases of man and animals. DNA containing fragments suggestive of tuberculosis has been extracted from the bones of the extinct long-horned bison which lived over 17,000 years ago (Rothschild et al. 2001). Ancient Judaic teaching from the Talmud warned that any animal carcass showing adhesions between the lungs and the pleura was unsatisfactory for human consumption. This admonition is believed to be due to tuberculosis and suggests that animal to human transmission has long been recognized. In 1882, Koch identified Mycobacterium tuberculosis and demonstrated that it could be transmitted to animals. He believed that organisms in humans and

P. 1. NICOLETTI, DVM, MS College ofVeterinary Medicine, Department ofVeterinary Pathology, P.O. Box 110880, Gainseville, Florida 32611 0880, USA

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

cattle were the same. Later studies by many workers concluded they were different. The relationship between bovine tuberculosis, milk and human disease has been known for over a century. Hundreds of children have died of tuberculosis meningitis, or the miliary form, as a result of ingestion of contaminated milk. These and other observations led to campaigns in many countries to eliminate bovine tuberculosis. In industrialized countries, animal tuberculosis control and eradication programs have drastically reduced M. bovis infection in both animals and humans. In Europe and North America, only 0.51.0% of human cases are believed to be from M. bovis. Estimates of previous decades were between 5-20%. In developing countries, however, animal tuberculosis is widely distributed and control measures poorly applied. The incidence of HIV-attributable tuberculosis cases have increased in many African and Asian countries.

50.2

Agents 50.2.1 Classification Mycobacteriosis is a chronic infectious disease of animals, birds, reptiles, fish and humans caused by Mycobacterium spp and characterized by inflammatory and necrotic processes. The mycobacteria are divisible into a few obligate pathogens and a much larger number of environmental pathogens and nonpathogens. The Genus Mycobacterium has been classified in several ways. The Mycobacterium tuberculosis complex (MTC) (M. bovis, M. microti, and M. tuberculosis) and the Mycobacterium avium complex (MAC) (M. intracellulare and three subspecies of M. avium; M. avium subsp. avium. M. avium subsp. paratuberculosis and M. avium subsp. silvaticum). In addition, other mycobacteria that may infect animals include

894

M. marinum (fish), M. ulcerans (animal models, e.g. mice), and M. leprae (armadillo). It has been suggested that the MTC produces disease should properly be called 'tuberculosis' while other infections caused by the MAC should be called 'mycobacteriosis'.

50.2.2 Morphology

Mycobacteria are small, aerobic, gram-positive, acidfast, non-motile and non-spore-forming bacilli. They may survive in phagocytic cells (Fig. 50.1).All species have a high cell-wall lipid content. The growth rate is important in classification and speciation. Special media are required and it may take up to several months to develop visible colonies (Fig. 50.2). The optimum incubation temperature is 28-33°C and a pH of 5-5.5. It may be difficult to determine species and often requires the submission of isolates to reference laboratories.

P. 1. Nicoletti

50.2.3 Properties

The degree of susceptibility to infection by certain mycobacteria among animal species varies and has been a criterion for differentiation of mycobacterial species. Other criteria include the photochromogenic property, biochemical analyses, and DNA probes. Mycobacteria can survive in soil and fomites for days to months depending upon local environmental conditions such as sunlight. A review of studies on survival of M. bovis in the environment has been published by Morris et al. (1994). Examples cited are 150-332 days at 12-24°C in shade, 18-31 days at 24-34°C in sunlight, in deep soil at depths of 5 cm for up to 2 years and in tap water for 236 days at 18-24°C. Cresylic, or substitutedphenol, disinfectants should be used in concentrations of 2-5% to kill mycobacteria (Thoen et al.1984). The literature provides no evidence that there are any measurable differences in virulence between strains of M. bovis with the notable exception of the artificially attenuated strain BCG (Morris et al. 1994).

50.3 Hosts, Pathogenesis and Diagnosis 50.3.1 Hosts

Fig. 50.1. Intracellular mycobacteria

Fig. 50.2. Mycobacteria colonies of solid medium

In general, members of the genus Mycobacterium have one of the highest host ranges of any pathogen. M. bovis causes tuberculosis in a large number of mammalian hosts including cattle and other ruminants, felids, canids, lagomorphs, porcids, camelids, cervids and primates including humans. It has been reported to cause disease in over 40 species of wild and exotic animals. The degree of susceptibility to infection varies widely from one animal species to another. Genetic resistance has not been conclusively demonstrated. Age, sex, reproductive status and other characteristics have no proven influence on transmission or course (Morris et al. 1994). Tuberculosis (MTC) in non-human primates is most commonly found in the Old World species. Tuberculosis in cattle and other large ruminants is almost exclusively caused by M. bovis. Natural cases of MTC infection in sheep and goats are rare. Dogs are susceptible to both M. bovis and M. tuberculosis. Cats appear to be more resistant to M. tuberculosis than M. bovis since infections in the former are rare (Hines et al. 1995). M. bovis infections have now been established in badgers

Tuberculosis in Animals

(Meles meles) in the United Kingdom and Ireland, in brush-tailed possums (Trichosurus vulpecula) and farmed deer in New Zealand, and in captive and feral deer (Odocoileus virginianus) in the United States. MAC infections occur in a large number of animal hosts. The most common in cattle and other large ruminants is caused by M. avium subsp . paratuberculosis. Other MAC infections in cattle do not result in clinical disease. MAC infections are common in swine causing a localized lymphadenitis. All domestic fowl and many wild species of birds are commonly infected with MAC but are generally resistant to MTC. The incidence of MAC infections is highest in zoological parks and aviaries (Hines et al. 1995). Some non-human primates have been reported to be infected with M. leprae and in the late 1960s it was reported that the nine-banded armadillo (Dasypus novemcinctus) could be experimentally infected. Natural infections were later discovered in Texas and Louisiana and the armadillo became a host for laboratory studies.

895

Fig. 50.3. Granulomas in soft tissue

50.3.2 Pathogenesis Mycobacterial infections are transmitted by inhalation, direct contact with mucous membranes (ingestion) or through broken skin. Eighty to ninety per cent of cattle are infected by inhalation (Morris et al. 1994). Only about 1% of calves born to tuberculosis cows have congenital infection. Transmission of M. avium subsp paratuberculosis is via direct ingestion of feces, environmental contaminants, colostrum or the placenta. Ingestion of other MACs most commonly leads to extra-pulmonary disease. Some sites include the lymph nodes, skeletal, genitourinary and central nervous system. The pathogenesis of mycobacterial infections is influenced by species of the genus and animal host, host factors such as immune status, and the route and numbers of exposure. The disease depends upon the ability of the mycobacteria to infect and grow within host cells. M. bovis is phagocytized by macrophages and carried to lymph nodes and other sites. They survive within macrophages by fusion of phagosomal compartments and are thus able to multiply, destroy phagocytes and escape into intracellular spaces. This stimulates accumulation of other phagocytes creating typical histopathological lesions called granulomas (Figs. 50.3, 50.4). High numbers of acid-fast bacilli may be seen with Ziehl-Neelsen staining. Nodules of 1-5 cm may

Fig. 50.4. Granulomas in thorax of a cow

be seen in many tissues such as enlarged mesenteric, hepatic and mediastinal lymph nodes or in the pleura where the presence of hard white nodules has been called 'pearl disease'. There may be caseous necrotic coalescence. Calcification is common (Neill et al.1994). Data from a large number of cattle with lesions of tuberculosis showed that 57% had lesions confined to the bronchial and/or mediastinal nodes. Only 3.2% had mesenteric lymph node lesions (Neill et al. 1994). These data may have been influenced by the early removal of tuberculosis infected cattle prior to the spread of the infection to other body areas. Though primary genital infections are not common, the uterus or epididymis may be infected. The mammary gland may also be infected resulting in shedding of organisms in milk. Both antibody and cell-mediated immune responses can develop following mycobacterial infections. It is generally accepted that the cell-mediated immune system has the most significant role in protective

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P. L. Nicoletti

immunity. There appears to be an inverse relationship between cell-mediated and humoral responses from natural M. bovis infection in cattle (Neill et al.1994). The pathogenesis of M. bovis in other animal species ranges from a single lymph node to rapidly spreading fulminating disease (Figs. 50.6, 50.7). The lymph nodes of the nasopharynx, lung or mediastinum are affected. Tuberculosis in non-human primates is usually due to M. tuberculosis and is often transmitted to them by infected humans. The route of infection may be cutaneous, or via the alimentary or respiratory tracts. When the alimentary route is involved, there may be pharyngeal involvement (scrofula), intestinal ulceration and mesenteric lymphadenopathy with caseous necrosis. In the respiratory form, tubercles are present within the lung (Fig.50.8), intercostal spaces

(Fig. 50.9), and bronchial lymph nodes. Primary tubercles may be seen in the liver, or spleen, with or without pulmonary involvement. Other foci may include the kidney, brain, meninges, bone, skin, endocrine glands and eye (Hines et al. 1995). Lesions caused by M. bovis have been described in numerous animal species besides ruminants, e.g. badgers and brush-tailed possums. Lesions in the latter are mostly in the respiratory tract (Morris et al. 1994). The superficial lymph nodes may be infected and result in discharges. There is progressive disease and nodules have central necrotic areas. Tuberculosis in badgers is primarilya chronic respiratory disease (de Lisle et al. 2001). The severity varies from no lesions to generalized disease with massive excretion of M. bovis. There have been several recent reports of M. tuberculosis infections in elephants, which were infected

Fig. 50.5. Granulomas in the pleura of a cow

Fig.50.7. Acute tuberculosis with necrosis and suppuration in an elk

Fig. 50.6. Multiple granulomas in the lungs of an elk

Fig. 50.8. Tubercles in the lung of a monkey

Tuberculosis in Animals

Fig. 50.9. Tubercles in the intercostal areas of a monkey

by humans. Between August 1996 and June 2000, 17 cases were confirmed in North America in Asian elephants (Mikota et al. 2000). Non-specific signs include weight loss and lethargy. Granulomatous nodules may be found in bronchial lymph nodes (Fig. 50.10). Elephants may die from caseocalcareous and cavitating lesions with pulmonary abscesses. MAC infections have received the most attention as pathogens of avian species. These have an initial involvement in the intestines and liver (Fig. 50.11). Other organs may be affected such as spleen, lungs and air sacs and bone marrow. The disease may result in weight loss, depression, diarrhea and polyuria. The tubercles are non-caseated, non-mineralized and contain a large number of acid-fast intracellular bacilli. MAC infections in swine are usually in the lymph nodes of the head and/or mesentery (Fig. 50.12). Generalized disease is rare. In cattle, lesions due to the MAC are usually transient and indistinguishable from those caused by M. bovis. The primary veterinary importance is sensitization which leads to positive intradermal tests using M. bovis tuberculin. Some non-human primates are susceptible to infections of M. leprae and are used as laboratory models. In the lepromatous form there are small lesions on the cooler areas of the body such as hands and face. In the tuberculoid form, dermal granulomas appear. Naturally occurring leprosy in armadillos begins with hepatomegaly and splenomegaly with subsequent lesions in numerous tissues. M. avium subsp paratuberculosis causes a chronic disease of cattle and other ruminants (Johne's disease) which results in a malabsorption syndrome with diarrhea,weight loss and reduced milk production. The initial infection occurs primarily in young calves but cIinical signs appear most frequently in cows aged 3-6 years.

897

Fig. 50.10. Granulomas in bronchial lymph nodes of an Asian elephant

Fig. 50.11. M. avium infection of an avian liver

Fig. 50.12. M. avium complex infections of swine lymph nodes

P. 1. Nicoletti

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Infected cattle develop chronic granulomatous enteritis, primarily in the ileum. There is no caseation, calcification, or fibrosis associated with lesions of paratuberculosis in cattle. Organisms may be excreted in feces, milk, semen, and urine. Occasional cases of MAC infections in horses have been reported. There is a proliferative enteritis with nodular lesions in the lungs, spleen, and liver.

50.3.3 Diagnosis 50.3.3.1 Cattle

In control programs, diagnosis of possible tuberculosis usually begins with a postmortem examination of selected tissues (Fig. 50.13). Lymph nodes of the head and thorax are sliced and observed for the presence of tubercles. Possible further gross pathology lesions may be observed in lungs, spleen, kidney, udder or male reproductive tissues. Specimens are collected for histopathological and bacteriological studies. A definite diagnosis depends upon isolation of Mycobacterium spp. A major problem is the long period required for culture confirmation. Further, routine postmortem examinations may fail to detect approximately half of infected carcasses while more thorough procedures may detect up to 90% (Corner 1994). Proper care and storage of tissues is very important along with culture techniques. The preferential sites for M. bovis infection specimen collection, and the microbiological procedures have been published (Corner 1994).

Fig.50.13. Bronchial lymph node of a cow with suspected

tuberculosis

Diagnosis of mycobacterial infections in live animals may be difficult. The disease is difficult to distinguish at the initial clinical, radiological or pathologic examinations. It is interesting that over 100 years since Koch described the delayed type hypersensitivity test (DTH), it remains the primary method of diagnosis of individual animals. The procedure has many disadvantages. Questions have often been raised about the sensitivity, specificity, standards and quality of the tuberculin used. False-positive reactions may be due to sensitization caused by non-tuberculous mycobacteria. Tuberculins are a complex mixture of soluble antigens produced by M. bovis or M. avium. Purified protein derivative (PPD) is the antigen of choice and is prepared by chemical fractionation. It is used as a 100 III volume either in the caudal fold (Fig. 50.14), single intradermal cervical, or intradermal comparative cervical (Fig. 50.15) locations. Increases in skin thickness (Fig. 50.16) are detected by manual palpation and/or measurements using calipers (Fig. 50.17) at 72 h post-injection. These procedures require handling of animals at least twice. Due to possible desensitization, testing of the same animal within 60 days is not recommended. The diagnostic efficacy of the skin test in cattle ranges from 70-90% in sensitivity while estimated specificity varies from 75-90% (Adams 2001). Many factors affect the accuracy of skin tests such as the interpretation of responses, quality and dose of tuberculins, timing of prior tuberculin tests, crossreactions due to environmental mycobacteria and other organisms, skill of application, and others. A presumptive diagnosis of tuberculosis based upon responses to tuberculins is further made

Fig.50.14. Injection of tuberculin into the caudal fold of a

cow

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Tuberculosis in Animals

Fig. 50.15. Comparison of reactions of separate tuberculins

Fig. 50.17. Measurement of response to tuberculin

supplement the intradermal tests. Antibody production is variable and largely undetectable during the early subclinical stages of infection. It usually occurs when CMI tests may be negative (Adams 2001). Antibody detection procedures are based mostly on the enzyme-linked immunosorbent assay. In Australia, Wood and Rothel (1994) developed a gamma interferon (IFNd) assay as a simple and rapid in vitro cellular assay for the diagnosis of bovine tuberculosis. The specificity in over 6000 cattle varied between 96.2-98%. The sensitivity among cattle in herds, which were de-populated because of tuberculosis was between 76.8-93.6%. Fig. 50.16. Reaction to tuberculin in the caudal fold of a cow

50.3.3.2 Deer

through histopathology, Cultures and other techniques such as immunohistochemical staining using M. bovis-specific probes (Adams 2001). In some laboratories, PCR techniques have provided a useful tool for the rapid detection of slow growing pathogens (Wards et al. 1995). These have been shown to be faster and more sensitive than traditional methods including histopathology. Procedures for application of DTH tests in cattle vary from country to country. Clearly, improved tests are needed. Many false-positive reactions are observed. Recently it has been found that infected cattle may fail to respond to intradermal tuberculins for many days (anergy). Poor nutrition and pregnancy have been suggested as factors. A sensitive, and specific, serological test to detect antibodies to M. bovis antigen in livestock and sylvatic populations would be very useful to replace or

Conventional intradermal tuberculin tests may be unsatisfactory (Griffin and Macintosh 2000). Falsepositive reactions are common and infected deer may be anergic. The above authors have developed a cell-based lymphocyte transformation (LT) test with a reported sensitivity of greater than 95% and a specificity of greater than 98%. 50.3.3.3 Non-human Primates

Intradermal tuberculosis of M. tuberculosis or M. bovis are used of apparent equal efficacy. There is a much lower response than in humans. The eyelid (palpebra) and peri-umbilical skin of the abdomen are sites of injection. Animals with advanced tuberculosis may be anergic. Cultures may be obtained from throat swabs or gastric lavage. DNA probes

900

and nucleic acid amplification procedures along with ELISA have been used. 50.3.3.4 Swine

The diagnosis of MAC is with 0.1 ml of PPD-A in the dorsal surface of the ear with an observation at 48 h. A swelling of 3 em or greater in diameter is usually considered positive. The diagnosis of MAC infection in birds may be with intradermal PPD-A. Also slide agglutination and ELISA have been used. In the future, DNA probes and PCR used in specimens from humans may prove to be useful. 50.3.3.5 Elephants

Intradermal tests correlate poorly with cultures. There is a high degree of culture positive/test negative results. Currently, cultures of respiratory secretions obtained by trunk lavage are recommended. Details have been published by Montali et al. (2001). For the diagnosis of paratuberculosis in cattle and other large ruminants, an ELISA screening test may be used. There are many false-positives and cultures of ELISA positive animals range from 33-84% (Wells et al. 2002). The sensitivity of cultures of fecal samples in sub-clinically infected cattle has been estimated to be only 40-50%.

50.4

Public Health: Epidemiology and Control 50.4.1 Public Health Tuberculosis in humans is usually caused by M. tuberculosis and has no direct zoonotic relationship. However, an unknown proportion of cases are due to M. bovis. This is particularly true in countries without organized control programs. It is estimated that 5-10% of cases in developing countries may be due to M. bovis (O'Reilly and Daborn 1995). In Latin American, it is estimated that 2% of pulmonary and 8% of extrapulmonary cases are caused by M. bovis (Cosivi et al. 1998). M. bovis infections in humans are clinically indistinguishable from those caused by M. tuberculosis. Most cases caused by M. bovis occur in young persons and result from drinking contaminated milk. Cervi-

P. 1. Nicoletti

cal lymphadenopathy, intestinal lesions, chronic skin (lupus vulgaris) and other non-pulmonary forms are common. Cases are now rare in developed countries due to the compulsory pasteurization of milk and the slaughter of infected cattle. There is published evidence of aerosol transmission of M. bovis and direct contact with tuberculous animals. Fanning and Edwards (1991) described a case of M. bovis in a human who was in contact with an infected elk. There were 446 persons with identified elk contacts and 81 of 394 were skin-test positive. Of these, 50 had been in contact with culture-positive animals. The results of tests may have been influenced by previous BCG vaccination in several persons. Humans who routinely ingest pork have no differences in hypersensitivity rates using different PPDs compared with those who do not consume pork. There appears to be no proof of a direct relationship between swine and human mycobacteriosis. Intravenous injection of serotypes of M. avium-intracellular complex have not resulted in isolations from muscle tissue. M. avium infections in humans have increased in the past 20 years or so, principally in human immunodeficiency virus-infected patients. Disseminated infections occur frequently in the late stages of AIDS. The potential zoonotic risk of MAC infections in humans which are derived from avian species is somewhat unclear. The risk of transmission appears to be extremely small. In general, M. avium infections in birds and mammals (including humans) are environmentally derived and not passed from bird to mammal. Clearly, some forms of tuberculosis in humans are of animal origin (e.g. from non-human primates) and these zoonotic infections can best be controlled by reducing possible exposure through direct or indirect contacts with infected animals and through pasteurization of milk.

50.4.2 Epidemiology Morris et al. (1994) have published an excellent and extensive review of many aspects of the epidemiology of M. bovis infections. They especially place emphasis on the role of wildlife as maintenance hosts and the difficulties that this causes in controlling and eradicating the disease in domestic animals. In addition, the survival of the organisms in the environment for substantial periods further complications elimination of the disease. In many countries, the increasing demand for animal protein and milk has resulted in larger herds

Tuberculosis in Animals

with greater animal density. This and the frequent and close contacts between humans and animals have resulted in a higher incidence of tuberculosis in both animals and humans.

50.4.3 Control

Cosivi et al. (1998) have published an excellent review of the status of tuberculosis due to M. bovis in developing countries. Of 55 African countries, only seven apply disease control measures. Approximately 85% of cattle are in areas where bovine tuberculosis is either partly controlled or not al all. Among 36 Asian nations, only seven apply control measures and only 6% of cattle are in countries which attempt to control tuberculosis. Of 34 Latin American or Caribbean countries, only 12 apply a test and slaughter policy. However, 76% of the cattle are in countries where test and slaughter policy is used. During the 1800s and early 1900s, bovine tuberculosis was the most prevalent infectious disease of cattle in the USA. Over 80% of the carcass condemnations were from tuberculosis. It is estimated that 5% of cattle were condemned. The National Cooperative State-Federal Tuberculosis Eradication Program was initiated in 1917 and continues. The program is similar to those in many other developed countries and is based upon surveillance at postmortem, tests and slaughter of tuberculin positive animals, and subsequent investigation of herds epidemiologically connected to infected animals and herds. Depopulation of infected herds is optimal. Nearly all areas are now accredited and prevalence is less than 0.02%. Similar data exist from many other countries. However, total eradication of cattle tuberculosis has been difficult in several countries due to wildlife reservoirs such as badgers, wild and domesticated deer, and possums. It is important to understand the role of a potential host in maintenance and transmission of M. bovis within animal populations. Additional problems are anergy and false-positive tuberculin test, which create livestock owner distrust and permits infected animals to go undetected. The difficulties of eliminating animal tuberculosis through test and slaughter have led to suggestions of possible alternate methods, or adjuncts such as treatment and/or vaccination. Many anti-tuberculosis drugs have been studied in selected animal species. These have included isoniazid, pyrazinamide, rifampin and ethambutol. Combination of streptomycin and isoniazid have been used successfully for M. tuberculosis in non-human primates (Ward et al.1985).

901

Unlike test and slaughter procedures for livestock, current guidelines allow for treatment of tuberculous and suspect elephants under conditions of quarantine and travel restrictions (Mikota et al. 2000). In very valuable avian species, there have been reported successes in treating MAC infections using drugs such as ethambutol, rifampin, amikacin, streptomycin, ciprofloxacin and enrofloxacin. To date, the possible treatment of animals with tuberculosis has been limited to very valuable, mostly exotic species and with varying success. Clearly, treatment is not an alternative to slaughter of tuberculous livestock due to costs, lengthy regimens and limited success. The implementation of national bovine tuberculosis programs in many industrialized countries based upon regular tuberculin testing and removal of infected animals has led to successful eradication of major reductions in the incidence of cattle and farmed deer tuberculosis. In some countries, alternative strategies are needed since test and slaughter is economically and socially unacceptable. One possible strategy is vaccination. The requirements for a satisfactory vaccine are many such as immunogenicity, no causation of hypersensitivity to dermal tuberculins, minimal adverse host response, practical application, and acceptance by other countries. Skinner et al. (2001) have reviewed the subject of vaccination of animals against M. bovis. Experiments using the bacillus of Calmette-Guerin (BeG) in cattle have been summarized and the authors concluded the results of experiments have been generally disappointing. The conferred resistance to natural or artificial infections has been short lived. An added disadvantage was the sensitization to tuberculins. The authors concluded that a reduced dose of BCG may preferentially stimulate cellular immunity with minimal effect on skin test. Buddie et al. (1999) summarized experiments in deer, possums, badgers and ferrets. In deer, two doses ofBCG produced significant protection against infection and disease with live but not heat-killed organisms. Lower doses were superior. An orally administered BCG produced a 100-fold lower lung bacterial counts in possums. BCG vaccinated (10 6 CFU) badgers had higher lymphocyte blastogenic responses than controls. They also shed fewer bacilli. The authors concluded that future studies may develop improved vaccine and methods of administering them in selected hosts. The increase in knowledge of mycobacterial genetics and immune responses in recent years suggests that development of an effective vaccine for cattle, deer and wildlife is a realistic goal

902

(BuddIe et al. 1999). Although protection may not be complete, vaccination may reduce economic losses in developing countries. Clearly, the elimination of reservoir hosts such as badgers in the UK is impractical and unacceptable to many concerned organizations. When there is an interplay between infection in wildlife and domestic animals, eradication of the disease becomes impractical (Morris et al. 1994). In the absence of a wildlife reservoir of M. hovis, tuberculosis is a readily controllable disease (Morris et al. 1994). Test and removal of infected animals at intervals of less than a year can eliminate the infection from herds provided that an epidemiologically sound control policy is followed. The first step is to motivate livestock owners to co-operate. However, in many countries there are severe restraints. These include limited financial resources, lack of trained professionals, lack of laboratory support and since, the disease is not usually epidemic, more dramatic diseases receive the most attention. Conversely, there must be a commitment by farmers and governmental officials to control measures. An organized meat inspection program to detect cases must exist. Adequate funding for a long-term effort is necessary. Control measures have significant economic consequences: These are expensive and labor intensive which include testing of animals, slaughter of test positives, disinfection and public education. It seems obvious that the many technical and logistical factors involved in the control of tuberculosis will assure the persistence of the disease for many decades.

References Adams LG (2001) In vivo and in vitro diagnosis of Mycobacterium bovis infection. Rev Sci Tech Off Int Epiz 20:304-324 BuddIe BM et al (1999) Differentiation between Mycobacterium bovis BCG-vaccinated and M. bovis-infected cattle by

P. 1. Nicoletti using recombinant mycobacterial antigens. Clin Diagn Lab Immun 6:1-5 Corner LA (1994) Post mortem diagnosis of Mycobacterium bovis infection in cattle. Vet Microbiol 40:53-63 Cosivi 0 et al (1998) Zoonotic tuberculosis due to Mycobacterium bovis in developing countries. Emerg Infect Dis 4: 59-70 De Lisle GW et al (2001) Mycobacterium bovis in free-living and captive wildlife, including farmed deer. Rev Sci Tech Off Int Epiz 20:86-111 Fanning A, Edwards S (1991) Mycobacterium bovis infection in human beings in contact with elk (Cervus elaphus) in Alberta, Canada. Lancet 338:1253-1255 Griffin JFT,Macintosh CG (2000) Tuberculosis in deer: perceptions, problemsand progress. Vet J 160:202-219 Hines ME et al (1995) Mycobacterial infections of animals: pathology and Pathogenesis. Lab Anim Sci 45:334-351 Mikota SK et al (2000) Tuberculosis in elephants in North America. Zoobiology 19:393-403 Morris RS et al (1994) The epidemiology of Mycobacterium bovis infections. Vet MicrobioI40:153-177 Neill SD et al (1994) Pathogenesis of Mycobacterium bovis infections in cattle. Vet MicrobioI40:41-52 O'Reilly LM, Daborn CJ (1995) The epidemiology of Mycobacterium bovis infections in animals and man; a review. Tubercle Lung Dis 16 [SuppI1]:1-46 Rothschild BM et al (2001) Mycobacterium tuberculosis complex DNA from an extinct bison 17,000 years before the present. Clin Infect Dis 33:35-311 Skinner MA et al (2001) Vaccination of animals against Mycobacterium bovis. Rev Sci Tech Off Int Epiz 20:112-132 Thoen CO et al (1984) Mycobacterium avium complex. In: Kubica GP, Wayne LG (eds) The Mycobacteria, a sourcebook, part B. Dekker, New York, pp 1251-1257 Ward GS et al (1985) Use of streptomycin and isoniazid during a tuberculosis epizootic in a rhesus cynomolgus breeding colony. Lab Anim Sci 35:395-399 Wards BJ et al (1995) Detection of Mycobacterium bovis in tissues by polymerase chain reaction. Vet Microbiol 43: 227-240 Wells SJ et al (2002) Sensitivity of test strategies used in the Voluntary Johne's Disease Herd Status Program for detection of Mycobacterium paratuberculosis infection in dairy cattle herds. J Am Vet Med Assoc 220:1053-1057 Wood PR, Rothel JS (1994) In vitro immunodiagnostic assays for bovine tuberculosis. Vet MicrobioI40:125-135

Subject Index

A A60 Antigen 189 A-a 02 gradient 389 Abdomen, shielding of the 307 Abdominal imaging 670 Abdominal mass 717 Abdominal pain 703,717 Abdominal tuberculosis 659,661,682 - direct spread from 702 Abscess - cold (empyema necessitatis) 375,484,522 - formation 482,692, 711, 716 - metastatic tuberculous (gumma) 639 - multiloculated paravertebral 514 - orbital 736 - paraspinal 485,486,538 - paravertebral 486, 494 - periappendiceal 662 - prostatic tuberculous 712 - retropharyngeal 743 - subcutaneous 630 - tuberculous of the brain 537 - tuberculous of the breast 639 - urethral abscess 703 Abscess drainage 710 - CT guided 486 Accuprobe system 124 Achilles tendon 599 Acid - pyrazinoic 789 - tuberculostearic 188 Acne agminata (lupus miliaris disseminatus facie!) 647 Actinomycosis 342 Actinomyces 115 Active case-finding 862 - in resource-poor areas 862 Active disease - absence 413 - extent of 415 - progression to 35 ADA, pleural 353 Addison 751 Addison's disease 297 Adenoids 447 Adenopathy - mediastinal 380 - mesenteric 684 - paratracheal 340,451 Adenosine deaminase activity 434 Adenovirus 890 - based vaccine 890

Adherence to treatment 809 Adhesive arachnoiditis 541 Adhesive ependymitis 539 Adjunctive treatment 474 Administrative support 858 Adolescence, tuberculosis during 255 Adrenal enlargement, bilateral 753 Adrenal gland 752 - MRI 753 Adrenal - insufficiency 752 - irregularly enlarged 753 - steroids 145 - tuberculosis 751 Adrenalitis 752 - tuberculous 752 Adult respiratory distress syndrome (see also ARDS) 276 - and disseminated intravascular coagulation 292 Adult-type apical lesions 255 Adult-type progressive tuberculosis 330 Advocacy 807 Aerosol transmission 900

AFB

- and culture 448 - smear 199 - smear-negative 199 - smear-positive 450 After treatment, recurrence 472 Ag85b (MPT59) 236 Agar-based media 121 Agent, single 784 AhpC gene 790 AIDS - co-infected with 349 - epidemic 536 - impact 37 - pandemic 455 - patients 660 - - therapy in patients with 675 - related deaths 456 Air-bone 266 - infection 315 - transmitted 104 Air filters 865 Air-fluid levels 373 Airway infiltration, direct 331 Airway obstruction, mechanisms of 387 Albucasis 18 Alcoholic 789 Alcoholism, malnutrition, diabeter 275 Alexandria, Egypt 481

904 Alimentary route 896 Al Kindi 18 Alkyhydroperoxide reductase 790 Alternative therapies 825 Alveolar arterial oxygen gradient 389 Alveolar macrophages 883 Ambulatory chemotherapy 805 Amebiasis 662 Amenorrhea 719 American Academy of Pediatrics 786 American Thoracic Society 822 Amikacin 792, 825 Aminoglycosides 790 Amplicor M. tuberculosis ( PCR) Test 125 Anal TB 688 Ancesort, common 79 Ancient Egypt, tuberculosis 3 Ancient Egyptian art 5 Anemia 215,216,794 Anergic response 458 Aneurysm 371 - mycotic 771 - subaortic 440 - submitral 440 - tuberculous 771 - - mycotic 771 - ventricular 440 Angiographic and postmortem studies 551 Angiography - cerebral 542 - and dynamic CT 557 Angular deformity 523 Animal - pathogen 78 - tuberculosis 893 - - eliminating 901 Ankh-my, tomb of 5 Ankle, tuberculosis of the 592,621 Ankylosis 611 Annual incidence 856 Annual risk 856 Antenatal 254 Anterior debridement 522 Anterior decompression and fusion 523 Anterior radical debridement and fusion 519 Anterior radical surgery 523 Anterior spinal cord decompression 524 Anterior spinal surgical technique 493 Anthracofibrosis, bronchial 330 Antibiotics - prophylactic 465 - with surgery 518 - without surgery (MRC Trials) 518 Antibody 899 - antinuclear 790 - complexed 847 Antibody card test, rapid 192 Antibody levels, specific 843 Antibody secreting B cells (ASC) 847 Antibody secreting Cells 843 Anti-DAT antibodies 844 Anti-diuretic hormone secretion, inappropriate 540 Antigen

Subject Index -low-molecular-weight ESAT-6 (6 KDa) 237 - for recombinant TB vaccine 885 - released mycobacterial 847 Antigen 5 (38 kDa Antigen) 188 Antigen p90 189 Antigen presenting cells (APe) 884,886 Antigen specific T cells 884 Anti-glycolipids IgG antibody 846 Anti-LAM 846 Anti-leukemic therapy 218 Antimicrobial susceptibility testing 126 Antinuclear antibodies 790 Antiretrovirals 791 - with anti-tuberculosis drugs 470 Anti-retroviral therapy for poor developing countries 469 Anti-ST-CF IgG antibody 848 Anti-TB immunity 886 Anti-tuberculosis chemotherapy 342 - prophylactic 473 - for spinal tuberculosis 490 Anti-tuberculous drugs, endocrine and metabolic effects 766 APC (antigen presenting cells) 884,886 Apoptotic debris 459 Apoptotic mycocytes 884 Appendicitis, subacute 670 Appendicular fistulas 702 Appendicular tuberculosis 672 Appendix, tuberculosis 686 Apple jelly nodules 746 Aqueous smear 737 Arachnoiditis - adhesive 541 - spinal 574 ARDS (see also adult respiratory distress syndrome) 274, 292,389 - diagnosis of 293 - and tuberculosis 319 Arterial hypoxemia 389 Arteriography 321,360 Arteritis 540,551 - tuberculous 772 Artery, tuberculous 320 Arthritis, tuberculous 588 Arthrodesis 595 - surgical 596 ASC - on day 8 848 - during the treatment 848 Ascitic fluid 667 - adenosine deaminase 669 Asherman's syndrome (synechia uteri) 721 Aspergilloma (mycetoma) 319,386 Aspergillus fumigatus 319,378 Aspergillus hyphae 378 Aspirate, nasopharyngeal 253 Aspiration biopsies, imaging-guided 694 Aspiration, gastric 251,253,339 Asthma 329 - bronchial 342 Atelectasis 370 Atrophy - cortical 552 - optic 735

905

Subject Index ATS recommendation 784, 785 ATS/CDC/IDSA Committee 451 ATS-CDC recommendation 785 Automated systems 817 Autonephrectomy 701 Autopsy studies 465 Auxotrophic mutants 888 Avenbrugger, Leopold Joseph 19 Avicenna 17 Axillary 447 -lymph 447 Azoospermia, obstructive 717,712

B Bacilli Calmette Guerin (see also BCG) 628 - intravesicular 735 - vaccination 260,865 Bacilli-laden macrophages 153 Bacilliuria 700 - intermittent 703 BACTEC 352,817 - system 339,817 BACTEC 460 TB instrument 121 BACTEC MGIT 960 122 Bactericidal activity 847 Bacteriological relapse 840 Bacteriology 339 Badgers 896 BAE (bronchial artery embolization) 317 Ball of wind 662 Balloon dilatation, endoscopic 343 Barium - enema 664 - studies 681, 682 - swallow 672, 683 Basal cisterns 549 Basal contrast enhancement 549 Basal inflammatory exudate 554 Basalleptomeninges 549 Bayle 20 B-cell response, immunological 842 BCG (see also Bacilli Calmette-Guerin, disseminated) 160, 447 - administration, intravesical 772 - in cattle 901 - discontinuation of 866 - genome 888 - history 27 -lymphadentis 261 - protective efficary 145 - recombinant 884, 888 - therapy, intravesical 274,277,773 - and new tuberculosis vaccines 881 - vacccination 187, 259 - - and cutaneous tuberculosis 641 - - and HIV serostatus 475 -vaccine 253,881,884 - - cytokine-secreting 888 - - irnmunogenicity of 882 - - ineffectiveness of 881, 882 BDProbe Tec ET 124 Beny Hassan 5 Beta-endorphin 764

Betiatide MAG3 419 Bifacetal dislocation 530 Birnaristan 18 Bioinformatics 82 Biopsy 622 - endometrial 720, 723 - endoscopic 681,686 - - mucosal 664 - laparoscopic 669 - pleural 353 - surgical 448 - testicular 717 - trans-sphenoidal 759 Biosafety 105 Biphasic media 121 Birds 893 Bladder augmentation 710 Bladder capacity, reduced 704 Bladder symptoms, irritative 712 Bladder ulceration 701 Blastomycosis 565 Bleeding, gastrointestinal 673 Blindness 792 Blood cultures 225 BM culture 225 BM histology 225 Body morphotype 171 Bone - ethmoid 447 - small round 597 Bone and joint tuberculosis 422 Bone marrow infiltration 222 Bone-strut grafting, autologus (Medical Research Council Working Party) 518 Bony ankylosis 611 Booster 235,882 - vaccine 883 Boosting regimen 883 Bovine tubercle bacillus 116 Bovine tuberculosis 75,315 - control of 659 Brachytherapy 346 Brain 573 - abscess, tuberculous 560 - infarction 550 Brain stem infarction 553 Breast feeding 787 - and its contraindication 307 Breast milk, heating 308 British Medical Research Council (BMRC) 801 Bronchial anthracofibrosis 330 Bronchial artery embolization (BAE) 317 Bronchial aspirate, microbiology of 321 Bronchial asthma 342 Bronchial carcinoma 316 Bronchial dilatation 369 Bronchial involvement, location of 336 Bronchial lumen, obstruction of the 333 Bronchial obstruction 331 Bronchial stenosis 337,395 Bronchial wall - infection 318 - thickening 341,369,372

906 Bronchiectasis 246, 318, 330, 346, 363, 372, 386, 388 Bronchitics, nonspecific 332,336 Bronchogenic dissemination 363 Bronchogenic spread 315,371 Bronchography 321,360,373 Broncholglandular fistula 335 Broncholith 346 Bronchoplastic surgery 346 Bronchopleural fistula 315,375,386,395,401,406 Bronchopneumonia 369 Bronchoscopic biopsy 330 Bronchoscopic diagnosis 321 Bronchoscopy 269,330,339,341,399,450 - broncho-alveolar lavage 461 Bronchostenosis 329,332,343,363 Bronchovascular markings, accentuated 369 Bronchus - contours of large 341 - erosion 447 - thickening of 372 Bullate formation 370 Bursitis - tuberculous 621 - - of the greater trochanter 599 Buttock sinuses, discharging 594

C Cairo Museum 5 Calcification 246,370,379,447,630,701,722 - parenchymal 362 - pleural 375 Calcified primary focus 267 Caliectasis 705 Calvarium 563 Calyces 704 Calyx 701 Canon of Medicine 17 Capreomycin 794 Captain of all of these men of death 455 Carbamazepine 790 Carbohydrate antigen, purified 846 Carcinoma - bronchial 316 - colon 662 Carcinomatosis, meningeal 576 Cardiac catheterization 438 Cardiac mass 440 Cardiac tamponade 431,433 Care, postoperative 400 Carotid artery 744 Carpal tunnel syndrome 599 Carpectomy 595 Case finding 804 - active 839 - passive 839,856,859,862 Caseation - actively 332,333 - central 320 Caseous focus 273

Caseous serofibrinous phase 610 Catheterization 434 Cattle 897

Subject Index Cauda equina 572 Cavernous sinus 758 -lesion of the 561 Cavitation 246,370 - miliary 379 Cavity, tuberculous 315 CC, cerebral 565 Cd-l- restricted T cells 137 CD4+ - cell count 222 - defects in the 458 - lymphocytes, depletion of 458 - T cells 459 CD8+ - cytotoxic T cells 136 - cytotoxin T lymphocytes 351 - IFN-y-seceting T cells 136 CD8 T cells, activation of 884 Cecum, contraction 685 Cecum, retracted 664 Cell-mediated immune response (CMI) 266,276 Cell wall 116 Cell-mediated immunity (CMI) 351 Cellular immune response 459 Cell-wall biosynthesis 819 Central nervous system 159 Centrifugation 542 Century of tuberculosis 25 Cerebritis 553 - subcortical 550 Cerebrospinal fluids (see also CSF) 277,537 Cervicitis, tuberculous 721 Cervico-thoracic spine 530 Cervix 718 Chancre, tuberculous 629 Chemokines 351 - active on lymphocytes and monocyteslmacrophages 887 Chemoprophylaxis 97,259,857 - regime 825 Chemotherapy - and debridement 518 - history 27 - preventive 839,881 - regimen of 807 - supervised 807 - with immobilization 518 - with mobilization 518 Chest computed tomography 437 Chest pain 432 Chest radiography 253,293,307,341,859 Chest wall tuberculosis 618 Chest X-ray 436 Chiasm, optic 758 Child bearing age 301 Childhood respiratory diseases, the dilemma of multiple aetiology of 465 Childhood tuberculosis 193,243,251 - clinical manifestations of 2245 - epidemiology 243 - and HIY/AIDS 251 - incidence of 243 Children 786 - facial palsy in children 564

Subject Index China 873 Chorionic villi, amniotic fluid 302 Chronic cases 803 Chronic tuberculous postprimary disease 330 CIC (see also circulating immune complex), total 847 Cicatrization 370 Ciprofloxacin 204,793 Circle of Willis 552 Circulating antibodies 842 Circulating ASC 847 Circulating hormones 764 Circulating immune complexes (CIe) 842,846 Circumcision 629 Clarissmus Galenus 481 Classification 332,894 Clavicle 597 - lateral end of the 598 Clinical and bacteriological monitoring 839 Clinical feature 351,447,483,588,630-632,635,636,639, 642-645,647-653,712,713 - atypical 268 - of adrenal TB 752 - and complications 315 - and diagnosis 268, 599 - of female genital tuberculosis 719 - of miliary/disseminated tuberculosis 277 - of penile tuberculosis 713 - of tuberculosis in these groups 724 - of tuberculosis prostatitis and seminal vesiculitis 712 - of tuberculous epididymo-orchitis 712 - other 703 Clinical history 338 Clinical manifestation 736,662,666,670 Clinical pathophysiology 439 - and epidemiology 433 Clinical presentation 608 682 Clinics in the USA 824 Clustered regularly interspaced short palindromic repeats (CRISPRs) 81 Clustering 100 CMI (cell-mediated immunity) 351 CNS, tuberculosis 420,535 Coagulation abnormalities 226 Co-infection rate 824 Cold abscess (empyema necessitatis) 375,484,522 - formation 694 Colitis - tuberculous 687 - ulcerative 662,680 Collapse therapy 395 Colon, tuberculosis 661 Colonoscopy 664 Color vision 792 Comb sign 686 Community epidemiology 65 Community prevalence 784 Compliance 257,543,823 - poor 310 Complications, postoperative 401 Computed tomography (see also CT) 340,360,614,663, 682 - cranial 249 - scan 705

907 Confirmation - histologic 330 - microbiogical 269 - rapid 297 Conjunctival tuberculosis 732 Conjunctivits, phlyctenular 630 Consequences for others 829 Consolidation 246, 340, 369 - segmental 369 Constrictive pericarditis 435 Constrictive pericitis 431 Contact 255,338,825 - and outbreak investigations 62 - study 100 Contagion, risk of 862 Contagious spread 660 Contraceptives, oral 791 Control 901 - inadequate 825 - programmes 824 Convention cultures 353 Conventional tomography 486,514 Cor pulmonale 389 Cord - displacement of 486 - Factor 190 Corneal disease 733 Correctional facilities 98 Cortical atrophy 552 Corticosteroid 297,543,786 Corticosteroid treatment 343 Corticotropin releasing hormone (CRH) 764 Cortico-white matter junction 555 Cortisol 764 Cost-effective approach 805 Cost-effective method 235 Cost-effectiveness 468 - of tuberculosis treatment 857 Costotransversectomy 524 Cough, persistent 252 Course 630,632,633,635,636,639,642-644,646,647 Course of action when the diagnosis is unclear 674 Cow's milk, infected 746 Cr51EDTA 707 Cranial nerve 537 - palsies 539,758 Cranial neuropathies 540 Craniocervical junction 484 - tuberculosis 483 Creatine kinase 600 CRH (corticotropin releasing hormone) 764 CRISPRs (clustered regularly interspaced short palindromic repeats) 81 Crohn's disease 659,662,685 Cross-reactivity 187 Cryotherapy 346 Cryptic angiomatous malformation 569 Cryptococcus neoformans infection 565 CSF (see also cerebrospinal fluids) - adenosine deaminase concentrations 249 - polmerase chain reaction 249 - in TBM 248 - white cellcount 249

908 CT (see also computer tomography) 541,752,716,758 - angiography 557 - combined with water-soluble myelography 572 - dynamic 557 - enhanced 451 - features 514 - - of adrenals tuberculosis 752 - findings 667 - guided procedures 622 - myelography 575 - of prostatic tuberculosis 716 - of the thyroid 757 - scanning 486, 549 Culture 119,466,899 - conversion 840 - media 120 - positive 257 Cure rate - greatly increased 802 - of surgical treatment 402 Cycloserine 790,791,794 Cystic erosion 622 Cysticercosis 565 - in the spine 581 Cystoscopy 707 - of urinary tuberculosis 707 Cytokines 266, 885, 888 - active on antigen-presenting cells 886 - expression 138 - IFN-y 276 - IL-12 276 - as immune adjuvants for TB vaccine formulations 886 - recombinant 887 - TNF-a 276 Cytologic findings 448, 707 Cytopenias 215

D Dactylitis 620 Dairy herds 315 DAT 843 Daughter lesions 561 DCC (disseminated cerebral coddidioidomycosis) 565,578 De Quervain's-like disease 599 Deafness 540 Death, sudden 441 Death, vaccine-preventable 881 Debris, apoptotic 459 Decalcification 494 Decidua 302 Decompression 523 Decortication 406 - pleural 319 Deep vein thrombosis 226 Deer 899 Defination 330 Deformed cone-shaped 664 Deir el-Bahri temple 12 Delayed type hypersensitivity test (see also DTH) 351,898 Demographic changes 40 Demonstration area 806 Demyelination 541

Subject Index Destruction, avoidance of 142 Developing countries 831 Diabetes insipidus 758 Diabetes mellitus, tuberculosis 765 Diabetics 52,93 Diagnosis 306,352,436,440,441,487,541,632,653,662,666, 670,736,897 - criteria 252,266 - cytological 448,522 - and differential diagnosis 631, 634, 637,639, 641, 643, 644, 646-653 - histological 757 - rapid 296 - serological 129 Diagnostic investigation 252 Diagnostic methods 841 Diagnostic test 436 Diastolic filling, rapid 435 DIC (disseminated intravascular coagulation) 215,226,293 Diffusing capacity 389 Digital subtraction angiography (DSA) 552,561 1,25 dihydroxycholecalciferol (1,25 OH) 761 Dilatation - bronchial 369 - cystoscopic 710 - post-stenotic 372 Direct spread 718 Directly observed treatment 801 Directly observed treatment strategy (see also DOTS) 801 Disc destruction 486 Disc tubercle, optic 735 Disease - activity of 413 - inactive 411 - risk of 34 Disseminated anergic tuberculosis 458 Disseminated Bacille Calmette-Guerin (BCG) 160 Disseminated cerebral coccidioidomycosis (DCC) 565,578 Disseminated intravascular coagulation (01C) 215, 226, 293 Disseminated NTM infection 165,175 - with AIDS 175 Disseminated tuberculosis 389,463,661,691 Distant septic foci 425 Distant skip lesion 494 Division of tuberculosis elimination 874 DNA - based TB vaccination 887 - fingerprinting 35,467,810 - probe analyses 199 - vaccine 886 Documentation and surveillance 859 Dominant T-cell antigens 885 Doppler - discharging 432 - echocardiography 438 - hemodynamics shown by 433 - tracings 435 Dose modification 725 DOTS (see also directly observed treatment strategy) 451 - assessing results 807 - impact advantages of 802 - and its impact in India 811 - implementation, approaches to 806

Subject Index - plus and the green light committee 871 - quality control of 807 DOTS strategy 39,810,811 -limitations of 808 - status of the 860 Doughy sensation 719 Drainage 623 - of abscesses 522 - of hydronephrosis 710 - lymphnodes 662 - sinuses 715 Drawings 5 Dripping candle 574 Droplet nucleus 267 DR-RFLP 88 Drug absorption, poor 827 Drug - abusers 97 - cost of 828 - induced liver disease 788 - interaction 789 - most important 791 - second line drugs 828, 831 - sensitivity patterns 825 - side effects, increased 471 Drug regimen 308 - initial 829 - standard 674 - for treatment of tuberculosis in HIV-negative individuals 468 Drug resistance 472,782,785 - acquired 811 - epidemiology of 51 - in M. tuberculosis 202 - patterns 816 - in prisons 816 - risk of 803 Drug-resistant tuberculosis in childhood 257 Drug-susceptibility 787 - testing 810 - - conventional 202 DSA (digital subtraction angiography) 552,561 DTH (tissue-damaging delayed hypersensitivity) 266,276, 899 - reaction 232 DTPA 419,421 Duodenal obstruction 683 Duodenal tuberculosis 673 Duodenocolic fistula 683 Duodenum, tuberculosis 683 Duration of treatment see treatment Dyspareunia 722 Dysregulation of the cortisol-cortisone 145

E Eales' disease and tuberculin hypersensitivity 735 Ear, tubercular infection 747 Early bactericidal activity test (EBA) 840 Early changes of the disc 518 EBA (early bactericidal activity test) 840 Ebers papyrus 10,445 EeG 432

909 Echocardiogram 432,440 Echocardiography 434 - and doppler studies 438 - two-dimensional 438 Echo-doppler techniques 434 Echo-free space 433 Economic risk 820 Edematous-hyperemic type 332,333 Effective and appropriate therapy, barriers to 471 Egyptian art, ancient 5 Egyptian mummies 8 Ehrlich 24 Eighth nerve toxicity 792 Ejaculatory duct obstruction 717 Elbow joint tuberculosis 595 Elbow tuberculosis 621 Elderly 52 Electrocautery 343 Electrolyte abnormalities 754 Electrosurgery 346 - endobronchial 346 Elephants 896,900 ELISA 129, 188,842,843 - sensitivities 846 - tests 844 ELISPOT 843 - technique 849 EmbAB gene 792 Emergency decompression 524 Emergency operative management 710 EMG 600 Emphysema, paraciatricial 373 Empyema 315 - persistencet 386 - tuberculous 403 Encephalitis 539 Encephalomalacia 552 Encephalopathy, tuberculous 541 Endemic areas 306 Endobronchial 334 Endobronchial disease 371 Endobronchial involvement 315 Endobronchial tuberculosis (see also tuberculosis) 329,386, 387,681 - incidence of 330 Endocarditis 431 - tuberculous 439 Endocrine perturbations related to systemic tuberculosis 761 Endocrine tuberculosis see tuberculosis Endogenous reactivation 313,314 Endogenous reinfection 330 Endometrial aspirates 720 Endometritis, tuberculous 720 Endometrium 718 Endopthalmitis 735 Endoscopic examination 662 Endoscopy, upper gastrointestinal 672 End-plate destruction 514 Enema, small bowel 664 Engineered live organisms 887 England 876 Enhancement 557

910 Enhancement of nerve roots 575 - of nerve roots 541 Enzyme-inducing effect 793 Eosinophilia 792 Ependymitis 550 - adhesive 539 Epidemiological typing 78 Epidemiology 301,330,349,445,482,536,588,599,627,659, 700,710,724,771 - in developed countries 76,77 - in Saudi Arabia 45 Epididymal enlargement 713 Epididymitis 711 - tuberculous 712 Epididymo-orchitis 711,713 Epidural granulomatous mass, isolated 573 Epidural tuberculous infection 539 Episodic hematogenous spread 276 Epithelial barrier 883 Epitope - multiple 885 - promiscuous immunogenic 885 Epituberculosis 331 Epsilometer ( E-) test 128 Erythema induratum 644 Erythema nodosum 597,645 ESAT-6 (6 kDa) 882,886 Esophageal tuberculosis 672 Esophagus - phrenic nerve 269 - tuberculosis 683 Ethambutol 204,789,792 - emission of 821 - inclusion of 821 - resistance 792 Ethionamide 794 Ethnic and racial difference 274,700,701 Ethnic immigrant 301 Etiology 645 Etionamide 787 Etiopathogenesis 628 Euthyroid syndrome, sick 757,764 Ex vivo screen 820 Excision arthroplasty 596 Excretion 419 Exotic dairy breeds 77 Extensive patterns of resistance 399 Extent of involvement 422 External disease 731 Extrabronchial 332 Extradural granulomatous 486 Extramedullary disease 571 Extrapleural pneumonectomy 406 Extra-pulmonary disease 445 Extrapulmonary sites 304 Extrapulmonary tuberculosis, incidence of (see also tuberculosis) 48 Extraspinal bone, diagnosis 590 Extrinsic compression 341 Eyelid - disease 732 - tuberculosis 732

Subject Index F Facial palsy in children 564 Fallopian tube 718 - tuberculosis 719 Familial syndrome 171 Farm worker 106 Fastrack diagnostic service 819 FDA 787 Feasibility 473 Features and investigations 719,721 Female genital tract 158 Female genital tuberculosis 717 - epidemiology 717 Fertility, primary 722 Fetal ingestion 303 FGTB, treatment of 723 Fibrosis 144,332 - parenchymal 363, 704 - pulmonary 379 - and strictures 705 Fibrostenotic 332-334 Fibrous stricture 662 Financial problems 828 Fine needle aspiration (FNA) 160,322,448,716,756 - and biopsies 713 - transrectal 716 - transthoracic image guided 450 - under ultrasound guidance 716 Fine needle aspiration cytology (FNAC) 448,742 First dorsal retinacular compartment 599 First trimester 307 Fish 893 Fish tank granuloma 175 Fistula 683 - appendicular 702 - bronchoglandular 335 - nephrocutaneous 703 - tubointestinal 720 - urethral 703 - vesicovaginal 719 Fistulogram 318,375,694 Fistulous (or gandular) 332 FLAIR (fluid attenuation inversion recovery) 550 Flan pain 703 Flank tenderness 703 Flat bones 597 Fleischner's sign 664, 684 Flow rates 389 Fluid attenuation inversion recovery (FLAIR) 550 Fluid bronchogram 369 Flu-like syndrome 791 18 fluorodeoxyglucose position emission tomography 418 Fluorodeoxyglucose position emission tomography 415,421 Fluoroquinolones 204, 793 FNA (fine needle aspiration) 160,322,448,716,756 FNAC (fine needle aspiration cytology) 448,742 Focal epilepsy 556 Foci, metastatic 363 Foot, tuberculosis 592, 618 Foreign-born 863,876 Fortress mycobacterium, breaching the wall of 819 Fructose measurement 717 Function 419

911

Subject Index Functional imaging 411 Funds 856 Fungal disease 578 Fungal infection 342,461 Fungoid cheesy form 610 Fungus ball 378

G Gadolinium enhanced images 550 Galen of Pergamon 15,481 Gallium 67 see gallium citrate Gallium citrate (67 Ga) 412,416,420,425,432,683 Gas exchange 389 Gas trapping 389 Gatifioxacin 793 Gelationous material 330 Gene expression 821 Genes and mutations 817 Genes encoding enzymes 819 Genetic loci 820 Genital tract - female 158 - tuberculosis 702, 717 Genitourinary tract (see also MAC, M. chelonae) 165,175, 893 Genitourinary tuberculosis (GUTB) 699 Genome microarray technologies 62 Genomes, bacterial 58 Genomic sequence 882 Genomics 82 - comparative 78 Genotypic detection 818 Genotyping methods 57 Geographic distribution 57 Geographic distribution and dissemination 67 GFR (glomerular filtration rate) 420 GG (groundglass opacity) 296 GH (growth hormone) 758,765 Ghon complex 156,267 Ghon focus 246,266,330 Gilbert's syndrome 789 Giovanni Cosimo Bonomo 18 Gland, small fibrotic 753 Gliosis 537 Global drug facility 866,870 Global epidemiology 33,881 - of drug-resistant TB 810 Global fund 870 Global TB - epidemic 890 - prevention/treatment 882 Glomerular filtration rate (GFR) 420 Glorious Galen 481 Glove finger appearance 721 Glucocorticoid therapy, adjunctive 675 Glycolipid - antigen 190,843 - purified extracted 188 GM-CSE (granulocyte macrophage colony-stimulating factor) 178, 886 - expressing adenoviral vector 886 Gonadotropin 758,764 Gout 791

Government commitment 805,858 Gradenigo's syndrome 747 Granular type 332,335 Granulocyte macrophage colony-stimulating factor (GM-CSE) 178,886 Granuloma 154 - caseating 275 - miliary 701 - subependymal 537 - subpial 537 Granulomatous diseases, other 579 Granulomatous response 459 Grape-duster like 537 Great mimicker 681 Great white plague 455 Grepafioxacin 793 GRF (glomerular filtration rate) 420 Groundglass opacities (GGs) 296 Growth hormone (GH) 758,765 Guidlines 310 - and cateria 268 Gumma, spinal 579 GUTB (genitourinary tuberculosis) 699 - a large series of one thousand patients with suspected GUTB 707

H

HAART (highly active anti-retroviral therapy) 470,471 Haemophilus infiuezae 565 Haly Abbas 17 Hand, tuberculosis 618 Harun AI-Rashid 18 Health care - prenatal 306 - quality of 474 - workers 101 Health sector reform 808 Healthy individuals 136 Heamoptysis 378 Hearing loss 747 Heart valves, prosthetic 175 Heart, tuberculosis of the 431 Heat shock proteins 821, 886 Hematogenous 350 Hematogenous dissemination 273,758 Hematogenous route 701 Hematogenous seeding 331 Hematologic abnormalities, prognostic significance of 219 Hematologic disorders 226 Hematologic findings 213 - mechanisms of 217 Hematopoiesis 217 Hematuria 703,712 - painless 703 Hemisphere, cerebral 538 Hemodialysis 89 - patients 53 Hemodynamic alterations 438 Hemodynamic changes 432 Hemodynamic findings 438 Hemophagocytic syndrome 217, 223

912 Hemoptysis 319 - massive 315,395,773 - - in tuberculosis 316 - in pulmonary tuberculosis 316 - significant 386 Hemorrhage - intraocular 735 - intraparenchymal 540 Henle, Jacob 18 Hepaticportal 447 Hepatitis 785 - fatal 788,790 - granulomatous 671 - of rifampin 791 - viral 789 Hepatosplenomegaly 252 Hepatotoxicity 788,789,791 Herxheimer-type reaction 474 Heteroduplex analysis 818 High prevalence 38 High resolution CT 296, 360 High-burden countries 38 High-efficiency masks 865 Highly active anti-retroviral therapy (HAART) 470,471 High-risk groups 723 Hilar lymph node 331 Hilar lymphadenopathy 269 - pleural effusions 462 Hilaradenopathy 268 Hip, tuberculosis 617 Hippocrates 15 Hippocratic doctrine 18 Hippuran 419 Histology 647 - findings 448 Histopathological findings 354,487 Histopathology 353,631-635,637,639,641,643-646,649-653, 899 - of intracranial tuberculosis 548 Histoplasmosis 565 - gastrointestinal 662 Historical aspects 15 History 648 - BCG 27 - chemotherapy 27 - and physical findings 436 HIVIAIDS (see also human immunodeficiency virus) 445 - childhood tuberculosis 464, 251 - children 251 - co-infection 448,451,866 - epidemic 275,302,304,329,350,468,772 - homosexuals 711 - impact 37 - individuals 193 - infection, hematologic complications 220 - pandemic 855,866 - patients 700 - - co-infected with M.bovis 315 - patients with tuberculosis, immune interactions in 459 - pregnant women 306 - related tuberculosis - - in children 465 - - clinical features of 460

Subject Index - serostatus, BCG vaccination 475 - sputum smear in 467 - TB co-epidemic 808 - transmission to infants 308 - and tuberculosis 456, 824 - - governmental responses to the threat posed by 475 - tuberculosis and co-infection 455 - and tuberculous lymphadenitis 446 - via breast milk 307 HLA haplotypes 885 Hollow viscus 681 Homeless shelters 824 Homosexuals with HIV 711 Hospital control measures 864 Hospital ward, open 825 Hospitalization, brief 861 Hospitals in Europe 824 Host 894 - defense 168,785 - immune response 314 - pathogenesis and diagnosis 894 Households contact 252 HPA (hybridisation protection assay) 128 Hsp70, multiple human T-cell epitopes 886 Human host 78 Human immune defects 169 Human immunodeficiency virus (see also HIV) 52,445 Humoral and cell-mediated immune responses 889 Hybridisation protection assay (HPA) 128 Hydrocephalus 277,539,543,550,551 Hydronephrosis, bilateral 710 Hydropneumothorax 375 Hypercalcemia 761,762 - mechanism of 761 - treatment of 762 Hypercapnia 389 Hyperinflation 246 Hypernatremia 763 Hyperprolactinemia 758 Hypersensitivity, cutaneous 471 Hypertension, pulmonary 389,399 Hypertonic saline 763 Hypertrophiclesion 661 Hyponatremia 540,762 - treatment of 763 Hypophysitis, granulomatous 758,759 Hypopituitarism 758 Hyporeactive response 459 Hypothalamo-pituitary-adrenal axis 145,764 Hypothyroidism, primary 756 Hypoventilation, regional patterns of 415 Hypoxemia, arterial 389 Hysterosalpingography 720,721

I 123 I (sodium 123 iodide) 415 Ibn barmak 18 ICSI (intracycoplasmic sperm injection) 712 ICT tuberculosis test 130,192 Identification of distant sites 417 Idiosyncratic reactions 219 IFN, systemic 178

913

Subject Index I1dl kinase defects 170 IFN-y 168,351,842 - control ofNTM 168 - production 236 - response 232 - therapy, aerosolized 178 IFN-y receptor 1 deficiency 169 IFN-y receptor 2 deficiency 170 IgE antibody 460 IgG antibodies 192,843,846 IL-2 887 IL-4 135,139,460 IL-I0 138 IL-12 135 - recombinant 887 - therapeutic use 178 IL-12 p40 deficiency 170 IL-12 receptor ~1 deficiency 170 IL-15 887 Ileocecal region 661 Ileum, tuberculosis 684 Ill-defined air space shadowing 379 Imaging 564 - of brain and spinal cord tuberculosis 547 - of complications of gastrointestinal TB 694 - of gastrointestinal tuberculosis 679 - findings 450 - of musculoskeletal tuberculosis 605 - of tuberculous meningitis 541 Imaging characteristics - ofTBM 549 - of tuberculomas 556 Imaging features 485,494, 713 - of foot and ankle tuberculosis 593 - of knee tuberculosis 592 - of pleural tuberculosis 354 - of post-primary pulmonary TB 320 - of tuberculosis of the hip 591 - unusual 269 Imaging methods in spinal neurotuberculosis 571 Immigrants 100,445 - illegal 98 Immobilization, longed 518 Immune adjuvant 883 Immune competition and suppression 882 Immune modulatory cytokine proteins/transgenes 883 Immune reconstitution syndrome 471 Immunity - long-lasting 882 - protective 266 Immunization - mucosal route of 887 - protocols 882 - repeated 882 Immunoassays 235,339 Immunocompromised 220 Immunogenic antigen ESAT-6 882 Immunological considerations 883 Immunomagnetic separation 119 Immunomodulation 825 Immunosorbent assay, enzyme-linked 130,542 Immunosuppression 94,175 Immunotherapy 146,177

implantation, direct 331 In vitro antibody production (see also IVAP) 849 In vitro fertilization 720 In vivo phenotype 820 - targeting persistent organisms 820 Incidence 265,274,301,629,632,635,636,642-645 - annual 856 Incision and drainage 743 Incompetent ileocecal valve 664 Incubation procedure 122 111 Indium (111 In) radiopharmaceuticals 415 India 811,871 Indian subcontinent, China, South East Asia 457 Infant feeding, affordable 308 Infarction - cerebral 551 - extensive cerebral cortical 552 - thalamic infarction 551 Infected sputum, swallowing of 660 Infection control 823 - policies 824 Infection - annual risk of 856 - exposure to 33,34 - from milk 330 - granulomatous 487 - incidence of 34 - intracellular 887 -latent 862 - -lifelong latent 857 - non-tuberculous 380,627 - - other non-tuberculous 381 - prevalence of 34, 49 - primary 349 - rate, tuberculosis 803 - transmission 456 - tuberculous 808 - worldwide 34 Infective dose 267 Infertility 712,717,719 - secondary 702 infiltrations 369 Infiltrative 332 Infiltrative-proliferative 332 Inflammation 330 Infriltrates, pulmonary 380 Inhalation 246, 302 Injections, painful 792 Inoculation procedure 122 Insidious begining 432 Instrumentation 523 Integral membrane antigens of M. habana TMC 5135 192 intensive phase, initial 468 Intercostal nerve 483 Interferon -level 434 - nebulised 825 Interleukin 351 Interleukin (IL-12)-12 136,168,884 Intermetaphyseal communicating vessels 485 Intermetaphyseal communication 494 Intermittent treatment 257 Internal jugular vein 744

914 International Union Against Tuberculosis and Lung Disease (IUATLD) 84,801,810,855 Interventional management 343 Intervertebral herniation of disc 494 intestinal obstructions, subacute 682 Intestine 157,330 Intrabronchial 332 Intrabronchial perforations 334 Intracanalicular spread 711 Intracellular killing, poor 459 Intracellular pathogen 883 Intracranial pressure 249 - increased 542 Intracranial sapce-occupying lesions 555 Intracytoplasmic sperm injection (ICSI) 712 Intradermal route 882 Intramedullary 538,581 Intraparenchymal 538 Intrapleural immune response, compartmentalized 351 Intrauterine adhesions 721 Intrauterine transmission 702 Intravenous excretory urography 704 Intravenous urography (IVU) 703,704,713 Invasion, direct 350 Invasive diagnostic intervention (CNS biopsy) 543 Investigation 724,776 - of female genital tuberculosis 722 Ipsilateral hilar region 369 Ipwy, tomb of 5 Irregular period 719 IS6100 80 IS6110-PCR 707 - assay 201 IS6110-RFLP 59,85 - typing 60 Isemann, Michael 824 Islamic medicine 16 Isocitrate lyase 820 Isocitrate lyase activity, inhibition of 820 Isocitrate lyase gene 820 Isolation measures 103 Isoniazid 28,785,788,790 - associated lupus 790 - diagnostic trials 738 - neuropathy 790 - resistance to 790, 817 Isotope scanning 614 IUATLD (International Union Against Tuberculosis and Lung Disease) 84,801,810,855 IVAP (in vitro antibody production) 849 - and the ELISPOT 843 - mean levels 849 IVU (intravenous urography) 703,704,713

J

Jails 98 Jaundice, obstructive 671 Jejunum, tuberculosis 684 Joint - destruction 588 - effusion 588 - space narrowing 611

Subject Index Joint tuberculosis - extraspinal bone 590 - sacroiliac 594 - sternoclavicular 596 K Kanamycin 792 Kansasii, mycobacterial 381 Kaposi's sarcoma 461 KatG gene 790 kDa (MPT64) 886 30 kDa antigen 189 38KDa antigen b 236 45/47 kDa antigen complex 190 916 kDa antigen 189 919 kDa antigen 189 Keratitis, interstitial 733 Kerley B lines 436 Kidney, hydronephrotic solitary 710 Kinetics - of circulating immune complexes during treatment 46 - on early treatment outcomes 846 King's evil 25,445 King's touch 25,445 Kissing sequestra 611 Knee, tuberculosis of the 591, 616 Koch phenomenon 22,134,142,143 Koch, Robert 21 Koch's oostulates 21 Kussmaul's sign 436 Kyphosis 484,518 - mobile 524 - progressive 523 - stabilization of 523 - surgical treatment of 524 - and wedging 494 L Laboratory - cross-contamination 68 - investigations 646 - testing 339,609 - workers 104 Lactic dehydrogenase (LDH) 669 Laennec's - stethoscope 19 - tubercles 19 LAM 846 Langhans giant cells 459,707 Laparoscopic examination 723 Laparoscopy 696,720 - with directed biopsies 669 Laparotomy 662,720 Laryngeal involvement 660 Laryngeal nerve - current 269 - recurrent 447 Laryngitis, tuberculous 745 Laryngoscopy 746 Laser photoresection 346 Late generalized tuberculosis (LGT) 273,275,276 Late stage appearances of tuberculomas 560 LCR (ligase chain reaction) 125,156

915

Subject Index LDH (lactic dehydrogenase) 669 - serum-ascitic fluid ratio of 669 Left heart failure 436 Leptomeningitis - infective 575 - suprasellar 554 Lesion - calcifying 560 - miliary 462 - multiple 422 - myelitic 570 - ulcerative 661 - ulcerohypertrophic 662 Leukemoid reactions 215 Leukocytes 418 Leukopenia 215,793,794 Leukorrhea 719 Levofloxacin 204,793 LGT (late generalized tuberculosis) 273,275,276 Lichen scrofulosorum 643 Lifetime risk 785 Ligase chain reaction (LCR) 125,156 Likehood of activity 370 Line probe assay (LIPA) 128 Linezolid 794 LIPA (line probe assay) 128,819 Lipoarabinomannan 191 Lipo-oligosaccharide (LOS) 843 Lipopolysaccharide antigen 192 Lipoproteins 140 Liquefaction and decontamination 119 Liquid automated culture system 121 Liver - abscess, tuberculous 671 - failure 789 - involvement 671 - normal 788 - toxicity 788 - transaminases 297 - transplantation 789 - - and tuberculosis 789 - tuberculosis 691 Liver disease 787, 789 - therapy in patients with 675 - and tuberculous peritonitis 660 Lobar collapse 246, 363 Lobar hyper-inflation 372 Lobectomy 319,395,400 Lobular emphysematous 373 Lobulated pleural collections 375 Localized wheezes 316 Long flight 267 Longitudinal ligaments 482,485 Long-term memory T-cells 885 Long-term neurological deficits 483 Long-term sick adults 828 LOS (lipo-oligosaccharide) 843 Lowenstein-Jensen (BACTEC, Ln 120,707 Low-income high-burden areas 857 Luciferase-based repoter phage 128 Lumbar puncture 542 Luminal narrowing 333 Lung 156

- biopsy, transbronchial 321 - cancer 320,342 - collapse therapy 26 - fibrosis 316 - infiltrates and consolidation 268 - lower lobes of the 460 - opacities, nodular 296 - perfusion scintigraphy 415 - resection 319,390 - shadowing, miliary 276 - volume, loss of 363 Lung disease - parenchymal 385 - restrictive 385 Lupus, isoniazid-associated 790 Lupus miliaris disseminatus faciel (acne agminata) 647 Lupus vulgaris 632,746 - mucosal 633 Lympadenitis - non-tuberculous mycobacterial 448,451 - outbreak of 261 Lymph node 157,246,895 - aspirates 448 - calcification 450 - classification of 362 - enlargement, paratracheal 269 - inguinal 447 - mediastinal 683 - regional 331 - submandibular 598 - superficial 896 - supratrochlear 595 Lymph, mediastinal 369 Lymphadenitis 266 - NTM 173 - treatment of mycobacterial 451 - tubercular cervical 742 Lymphadenopathy 250,252,269,362,464 - asymmetrical 463 - mesenteric 896 Lymphadentitis 350 - non-tuberculous 447 Lymphatic channels 331 Lymphatic spread 318 Lymphocyte or memory T-cell-stimulating cytokines 887 Lymphocytic hypophysitis 758 Lymphopenia and immunosuppression 219 Lymphotactin 887

M M. africanum 79,116,587 M.avium 793 M. avium complex (MAC) 165 M.bovis 315,446,482,587,701,746,772,893,894 - BCG 81 - developing countries 901 - epidemiology 75,900 - in humans 315,900 - molecular typing 87 - multi-drug resistant 826 - transmission 88 - wildlife reservoir of 901

916 M. chelonae (genitourinary tract, MAC) 165,175,893 M. marinum infection 649 M. microti 79,116,893 M. tuberculosis 893 - antigens 841 - drug resistance, molecular basis of 202 - genome sequence 819 - skin infections, treatment of 654 MAC (M. avium complex, M. chelonae, genitourinary tract) 165,175,893 - extrapulmonary 175 - pulmonary 176 Macrolides 175, 176 Macrophage 459 - apoptosis 141 - CD4+ T cell 276 - depletion of 458 - epithelioid 458 - function 106 - functional 141 - mycobactericidal mechanisms within 140 - phagocytic 351 - phagocytic process 885 Macroscopic pathology 156 Magnetic resonance arteriography (MRA) 552 Magnetic resonance imaging (MRI) 249,437,440,486,541, 550,557,572,616,663,682,707,716,758 MAl (mycobacterial a-intercellular complex) 380 Maintaining airway patency 344 Major blood vessels, compression of 477 Major obstacles to successful development of improved TB vaccines 883 Malabsorption 474 Malawi 457 Male genital tract 158 Male genital tuberculosis 710 - diagnosis of 713 Malignant diseases 96 Malignant tumors 565 Malnutrition 97 Management 432,434,439-441,543 - considerations in HIV-positive individuals 470 - proactive 856 - surgical 346 Mandible 598 Mantoux test 233,841 Marginal erosions 611 Marker, phenothypic 57 Marrow infiltrate 224 Masks, negative-pressure ventilation 856 Mass-like lesion 340 Mastoiditis 564 Matting 447 - of bowelloops 666 Maximum voluntary ventilation (MVV) 390 MB/BacT system 121 MBBacT microbial detection system 127 100-mBq99mDMSA 707 200-mBqTc99m DTPA 707 MDR-T, transmission of 832 MDR-TB (multi-drug resistant tuberculosis) 202,472,808, 817,877 - in Africa 812

Subject Index - areas of 811 - cost of 828 - definition of 824 - epidemiology 809 - financial challenges of 827 - in HIV, sporadic 827 - individual patient with 828 - isolation of infectious 828 - outbreak of 472,824,826 - possible 826 - spread of 810 - treatment of 821 Mechanical ventilation 297 Mediastinal 447 Mediastinal adenopathy 380 Mediastinallymph 369 Mediastinal lymph nodes 683 Mediastinoscopy 450 Mediastinum 483 Medicalmanagement 747 Medical papyrus 10 Medical papyrus of Ebers (Ebers papyrus) 10,445 Medical Research Council (MRC) 482 Medical Research Council of the United Kingdom 549 Medical treatment, preoperative 396 Medulla oblongata 573 Memory immunity 885 Memory T cells 884 Meningeal-parenchymal type 538 Meningioma 561 Meningitis 277,538,561 - spinal 569 - and tuberculomas in miliary/disseminated tuberculosis 277 Menopause 721 Menorrhagia 719 Menstrual disturbances 717 Mesentery 447,663 Mesothelial cell count 352 Mesue 17 Metastatic lesions 363 MGIT (mycobacterial growth indicator tube) 127 MIC (minimum inhibitory concentration) 817 Microbiology 536 - findings 448 Microlaryngoscopy 746 Micronodules, pulmonary 273 Microscopic examination 118 Microscopic pathology 154 Microscopy 466 Middlebrook 7HI0 and 7H11 media 120 Midexpiratory flow 389 Migrants, undocumented 864 Miliary cerebral tuberculomas 562 Miliary form 671,747 Miliary granulomas 701 Miliary lesions 462 Miliary tuberculosis (see also tuberculosis) 159,269,273,276, 363,364,389,440,441 - epidemiology 274 - laboratory diagnosis 296 - notification of 275 - of the skin, acute 631 - with multiple small tuberculi 439

917

Subject Index Military spread 380 Milk - borne infection 77 - consumption, raw milk 587 - contamination 33,315,660,893 - and human disease 893 - infection from 330 - pasteurization of 659 Mineralocorticoid deficiency 763 Mines 106 Minimum inhibitory concentration (MIC) 817 MIRU-typing 85 M-Mode echocardiography 438 Mnasoura University Hospital 707 Molecular beacons 206 Molecular diagnostic techniques 817 Molecular epidemiological studies 314 Molecular epidemiology 57,78 - future 69 Molecular genotyping 57 Molecular methods 466 Molecular techniques 738 - for identification of mycobacteria 123 Monarthritis, tuberculous 588 Monitoring treatment efficacy 839 Morbidity 35,254 - increased rate 470 Morphology 894 Mortality 36, 254 - during infancy 254 - increased rate 470 - obstetric 254 Moth eaten appearance 746 Mother, nursing 308 MOTT (Mycobacteria other than tuberculosis) 163 Movement disorder 539 Moxifloxacin 793 MPB64 antigen, dermal response to 192 MPT59(Ag85b) 236 MPT64 (26 kDa) 235,236,886 MRA (magnetic resonance arteriography) 552 MRC (Medical Research Council) 482 MRI (magnetic resonance imaging) 249, 437,440, 486, 541, 550,557,572,616,663,687,707,716,758 - of the adrenal glands 753 - of epididymal and testicular tuberculosis 716 - features 514 MTC (mycobacterium tuberculosis complex) 893 MTD test 124 Mucosal route of immunization 887 Mucosal ulceration 664 Dr. Muhny ad-Din at-Tatawi 16 Multi-drug resistance 826 - impact of 38 Multi-drug resistant tuberculosis see Tuberculosis, multidrug resistant and MDR- TB Multidrug-resistant strains 329,396 Multiple intrahepatic biliary strictures 671 Multiple lesions 422 Multiple sites 447 Multiple sclerosis 582 Multiple small nodular opacities 371 Mummy of Nespapheran 6

Mutant strain 821 Mutations 790 MVV (maximum voluntary ventilation) 390 Mycetoma 316 - formation 378 Mycetoma Rasmussen 371 Mycobacteria 115 - characteristics of 116 - classification of 628 - environmental 145 - nontuberculous 163,187,379 - rapid growing 165, 177, 888 - slowly growing 165 Mycobacteria other than tuberculosis (MOTT) 163 Mycobacterial a-intercellular complex (MAl) 380 Mycobacterial culture and sensitivity testing 859 Mycobacterial cutaneous infections, atypical 648 Mycobacterial growth indicator tube (MGIT) system 127 Mycobacterial infection and human immunocompromised virus (HIV) 379 Mycobacteriological burden 789 Mycobacteriosis, classification of nontuberculous 163 Mycobacterium avium complex (MAC) 165,175,893 Mycobacterium avium-intracellular complex infection 51 Mycobacterium bovis 75,107,274,277,747 - genotyping 86 Mycobacterium fortuitum complex infection 652 Mycobacterium haemophilum infection 653 Mycobacterium kansasii infection 650 Mycobacterium scrifulaceum infection 651 Mycobacterium tuberculosis 700 - genetic approach to the detection of drug resistance 127 - genetics 78 Mycobacterium tuberculosis complex (MTC) 893 Mycobacterium ulcerans infections 649 Mycobacterium, non-tuberculous 711,720 Mycocytes, apoptotic 884 Mycotic aneurysm, tuberculous 771 Myelitis 539 Myelofibrosis 215 Myelography 486,514,571 Myelopathy 541 Myeloradiculopathy, tuberculous 571 Myocarditis 431 - tuberculous 440 Myositis, tuberculous 599,600,610

N

Napkin ring sign 687 National Jewish Center group 396 National tuberculosis control 782 National Tuberculosis Control Programmes 476 National Tuberculosis Programme (NTP) 805,860 Nationwide coverage 805 Native-born 863 Natural Course of Endobronchial Tuberculosis 337 Natural human knockouts 136 Nd-YAG laser resection 343 Neck abscess, tuberculous 742 Necrosis - caseating 157 - gummatous 560

918 Needle biopsy (under fluoroscopic of CT guidance) 514,522 Neelsen 24 Negative pressure room 823 Negative pressure unit 829 Neoplasia 320 Nephrectomy, partial 710 Nephrostomy, percutaneous 710 Nephrotoxicity 792 Nephroureterectomy 710 Nerve root - enhancement 575 - entrapment 541 - systems 571 Neural arch tuberculous infection 494 Neuritis, optic 739,792 Neurobrucellosis, intracranial 567 Neurocysticerosis 581 Neurological deficits 483 Neurological deterioration, acute 519 Neuromyelitis optica syndrome 541 Neuropathy, optic 735 Neuroretinitis, tuberculous 735 Neurosarcoidosis 566,579 Neurosyphilis 579 Neurotoxicity 792 New cell-wall inhibitors 820 New smear-negative pulmonary tuberculosis 822 New sputum smear-positive tuberculosis 821 New York City 457 New York's TB control team 874 New York's TB epidemic 875 NFlCB essential modulator (NEMO) 170 Nocardia 115 Node - mesenteric nodes 667 - retroperitoneal 667 Nodular disease 671 Nodulation, miliary 379 Nodules - diffuse 380 - erythematous subcutaneous 631 - miliary 296 Non-eadiometic methods of drug susceptibility testing 127 Non-human primates 899 Non-MDR resistance, management of 822 Non-rigid kyphosis 526 Nonsteroidal anti-inflammatory drug 433 Nontuberculids 646 Non-tuberculous infections 380 Non-tuberculous lymphadentitis 447 Non-tuberculous mycobacteria 163,187,379 Non-tuberculous mycobacteriallymphadentitis 448,451 Nose, tubercular infection of the 746 Nosocomial transmission 865 Novel drug discovery programme 820 Novel inhibitory compounds 820 NTM disease, radiographic appearance of 172 NTM infection - cutaneous 175 - pulmonary 172 NTM lymphadenitis 173 NTM therapy 176 NTP (National Tuberculosis Programmes) 805,860

Subject Index Nucleic acid probes 124 Nursing Mother 308

o Obstruction - bronchial 331 - endobronchial 341 - pure 389 - subacute 670 Obstructive 331,385 Obstructive-restrictive pattern 387,389 Occipitocervial junction 486, 514 Occupational hazards 93,101 Occupational therapy 595 Ocular tuberculosis 731 Oculomotor palsies 540 Ofloxacin 204, 825 1,25 (OH)2D3 766 25 (OH)D3 766 Old tuberculin (OT) 231 Omental cakes (omental thickening) 666, 688 Omental thickening (omental cake) 666, 668 Omentum 663 Operative procedures, types of 400 Operative treatment 519 Optic 540 Oral cavitiy, tubercular infections of 746 Orange discoloration 791 Oropharyngeal mucosa 447 Oropharynx 746 Osteolytic lesion 610 Osteomyelitis - extraspinal tuberculous 597 - tuberculosis 494 Osteomyelitis of the chest wall, tuberculous 597 Osteomyelitis of the ribs, tuberculous 597 Osteomyelitis of the sternum, tuberculous 597 Osteoporosis 611 Osteosclerosis 611 OT (old tuberculin) 231 Otitis media, tuberculous 563,747 Otorhinolaryngeal manifestations 742 Otorrhoea 747 Ototoxicity 309 Outcome, postoperative 390 Outpatient facilities 259 Ovary, tuberculosis 719 Overcoming neglect 866 Overcrowding 101 Over-inflation 363 P P32 antigen 190 Pachymeningitis 554 Pachymenix 549 PAl (primary adrenal insufficiency) 751 Pain - abdominal 703 - flank 703 - readicular 538 Pancreatic head 694 Pancytopenia 216 Papillae, sloughing of the 704

919

Subject Index Papilledema 735 Para-aminosalicyclic acid (PAS) 28,781,794 Paracutaneous route 882 Paradoxical phenomenon 560 Paradoxical reactions 471,840 Paradoxical response 451, 543 Paradoxical transient worsening 270,361 Paradoxical transient worsening phenomenon 365 Paraparesis 485 Parapharyngeal space abscess 743 Paraplegia 485 - decompressive techniques and treatment of 524 Paratracheal 331,362 Parenchymal cerebral tuberculosis 554 Parenchymal disease 361,369 Parenchymal infiltration 268 Parenchymal tuberculosis, differential diagnosis 565 Paronychia, painless 630 Parotid gland 747 Parotid, tuberculosis 419 Partition test 421 PAS (para-aminosalicyclic acid) 28,781,794 Pasteur strain 261 Pasteurization 315 Patella 597 Pathogen, virulent intracellular 459 Pathogenesis 245,302,330,446,482,536,588,599,629,631, 632,635,636,639,642-645,647,649,652,661,666,670,680, 711,772,895 Pathogenesis and pathology of renal tuberculosis 701 - of female genital tuberculosis 718 - and pathology 313 - of primary pulmonary tuberculosis 266 - of tuberculous pleural effusion 350 Pathogenetic mechanisms 762 Pathology 331,537,606 - and pathogenesis of miliary/disseminated tuberculosis 275 - of tuberculosis 153 - - in HIV-infected individuals 458 Pathozyme TB complex test 130 PATHOZYME-MYCO - IgA test 130 - IgG test 130 - IgM test 130 Patient - compliance 785,840 - immunocompromised 433 - - with HIV 722 - immunosuppressed 663 PCP (pneumocystis carinii pneumonia) 461 PCR (see also polymerase chain reaction) 542,899 - in ancient Egyptian population 8 - based methods 59 - detection of drug resistance 204 - diagnosis 199 - - impact of 206 - DNA sequencing 204 - heteroduplex assay 205 - LiPA 206 - of M. tuberculosis 200 - of pleural tissue 354 PCR-single strand conformation polymorphism (PCR-SSCP) 450,818,840

- analysis assays 204 PCR-SSCP see PCR-single strand conformation polymorphism Pelvic examination, bimnual 719 Pelvis, tuberculosis 618 Pelviureteric junction 701,704 Pelviureteric obstructions 704 Pentavelent dimercaptosuccinic acid [(V) DMSA) 415 Penumonia, obstructive 372 Percutaneous debridement 524 Perforation and fistulae 662 Perfusion 419 - abnormality 415 Pericardial effusion 431 - and cardiac tamponade 433 Pericardial friction rub 432 Pericardial thickening 437 Pericarditis 363,431,463 - acute 431,432 - calcific constrictive 431 - tuberculous 431 Pericardium 269 - calcification 432,436 - tuberculosis 431 Perilymphadenitis 742 Peripancreatic 447 Peripheral nervous system 569 Peritoneal biopsy, blind 669 Peritoneum 663 Peritonitis - plastic 666 - purulent 666 - tuberculous 417, 660, 666, 696, 702 Persistent unilateral wheezing 339 Persistently culture positive 399 Peru 873 PET imaging 419 Peyer's patches 670 PFGE (pulsed field gel electrophoresis) 79 PGLTB1 843 PGRS-RFLP 81 PGRS typing 59 Phage genome 818 Phagocytosis, impaired 93 Phagosome 883 Pharyngeal involvement 896 Pharynx, tubercular infections of 746 Phenotypic methods 818 Phenytoin 790 - concentrations 790 Phlyctenulosis 733 Photodynamic therapy 346 Photoresection 343 Phthisis 15 Physical examination 339 Physical findings 436 Physiotherapy 595 Pia-arachnoid 571 Pituitary tuberculoma, diagnosis 759 Pituitary tumor, non-functioning 758 Pituitary-adrenal axis 765 Placenta 302 - tuberculous 702

920

Plain pelvic radiography 722 Plain radiographs 610,682 Plain Radiography 485,494,703 Plasmid DNA 888 - based cytokines 887 - based vaccines 889 Pleura, calcified 403 Pleural disease - and fibrothorax 386 - in post-primary tuberculosis 375 - in primary tuberculosis 364 Pleural effusion 268,269,380 - bilateral 436 Pleural fluid - culture 353 - cytokines 353 - examination 352 - loculated 86 - for microbiological examination 352 Pleural mesothelial cells 351 Pleural rub 352 Pleural space - drainage 405 - surgery for tuberculous infection of the 403 Pleural thickness 386 Pleural tuberculosis, primary 349 Pleurisy 463 Plombage 27 pncA genes, mutated 791 Pneumoconiousis 107 Pneumocystis carinii pneumonia (PCP) 461 Pneumonectomy 319,395,400 - extrapleural 406 Pneumonia 341 - tuberculous 369 Pneumonitis, obstructive 331 Pneumothorax - bilaterial 293 - as complication of post-primary pulmonary TB 318 - in miliary/disseminated tuberculousis 293 - spontaneous 371 Political change 808 Political commitment 856,858 Political will 856 Polycythemia 215 Polymerase chain reaction (see also PCR) 297,434, 450, 707, 713 - and genetic probes 339 Polymorphism 171 Polyneuropathy 571 Polyphosphonate 422 Polyps and masses 687 Poncet's disease 596 Poor developing countries, anti-retroviral therapy 469 Population - based molecular epidemiological study 63 - certain 51 - movement 869 Positive smears 542 Post-bronchoscopy sputum 339 Posterior decompression and internal fixation 524 Posterior fixation and fusion 519 Posterior instrumentation 523

Subject Index Posterior pharyngeal wall 743 Posterior spinal fixation 523 Posterior spinal fusion 493,523 Posterior subligamentous abscesses 514 Posterior synechiae 733 Posterior-element infection 494 Post-genomic era 819 Post-genomic tools 820 Post-mortem 441 - examination 898 Postnatal 254 Post-primary disease 275,330 Post-primary pulmonary tuberculosis 313,349 Postprimary TB 370 Post-Rifampin era and emergence of drug-resistant tuberculosis 396 Post-treatment prophylaxis 472 Post-tuberculous bronchiectasis 315,316 Potential drug recovery 820 Pott, Sir Percival 481,493 Pott's disease 519 Pott's puffy tumor 563 Poverty 40, 302,456 Power doppler sonography 450 PPD (purified protein derivative) 232,322,354,467,738,862 - induration 233 - strenght 232 PPD skin test 306 - conversion of 266 PPD testing - adverse reaction 235 - methodology 233 PPD-S 232 Practical problems DOTS faces in India 812 Pre-antibiotic era 274 Predynastic period 3 Pre-existing chronic obstructive pulmonary 379 Pregnancy 301,787 - outcome of 301 - termination of 309 - treatment - - of active TB during 308 - - of multidrug-resistant TB 309 - tuberculosis 301 - - interrelation 303 Preoperative evaluation 390,399 Presentation - unusual 269 - usual 269 Presenting symptoms 719 Pretreatment era 660 Preventive measures 103 Pre-vertebral soft tissue 743 Primary adrenal insufficiency (PAl) 751 Primary complex 330,701 Primary hematogenous dissemenation 537 Primary pulmonary tuberculosis 331 Prisoner of war 98 Private health care sector 868 Private sector 40 Productivity, lost 828 Prognosis 543 - and predictors 825

921

Subject Index Progressive primary 275 Prolapse, vaginal 717 Properties 894 Prophylaxis regimen 260 Proportion methods 817 Proptosis 736 Prostate, tuberculosis 712 Prostatic mass, cystic 712 Protection versus immunopathology 134 Protective clothing 105 Protective measures 103 Protein concentration 249 Protein levels 542 Pseudo-aneurysm 773 - mycotic 317 Psoas abscess 494,522 Psoas muscles, absence 485 Psychosis 794 Pubic symphysis 594 Public health 900 - and the wider economy, implications for 830 Public health issues 830 Pulmonary artery, peripheral 317 Pulmonary circulation and Ibn-an-Nafis 16 Pulmonary disease, atypical 460 Pulmonary function test 322,340,399 Pulmonary gangrene, tuberculous 320 Pulmonary tuberculosis, incidence of 46 Pulsed field gel electrophoresis (PFGE) 79 Punched-out defect 563 Puosalpinx, tuberculous 702 Purified protein derivative (PPD) 232 Purpura, thrombotic thrombocytopenic 227 Pyrazinamide (PZA) 203,789,791,825 Pyridoxine 790 Pyuria 703 PZA (Pyrazinamide) 203,,789,791,825

Q

Q-IFN 236 - assay 236 - kit 236 - test 237 Quadriceps muscle, wasting of the 594 Quality of health care 474 Quinolone 787,789

R Racail and ethnic difference 274,700,701 Radiculomyelopathy, tuberculous 570,571 Radiculopathy 485,541 Radiographic finding, unusual 268 Radiography, convertional 359 Radioisotope studies 610 Radiologic presentation 616 Radiological features, unusual 269 Radiometic method of drug susceptibility testing 126 Radionuclide thyroid scans 757 Radioscopic scans 683 RANTES 887 Rapid test - in routine use 819

- tuberculosis 130 Rash 790, 792 Rasmussen aneurysm 317,773 Raw milk consumption 587 REA (restriction enzyme analysis) 79,86 Reactivation 701 - of primary complex lesions 458 - tuberculosis 330 Reactive nitrogen intermediates 140 Reactive oxygen intermediates 140 Reanastomosis 710 Recent conversion 785 Reconstruction, urethral 710 Reconstructive surgery 709,710 Rectal examination 712 Rectal tenesmus 713 Reduced transmission 803 Reflux, ureterovesical 704 Regimen, shorter combination 473 Re-infection 57,458,701 - exogenous 66, 313, 314 Rejection 789 Relapse 57 - rate 822 Renal allografts 702 Renal cortex 701 Renal failure 789,792 Renal function 705 - restoration of 710 Renal parenchyma 157 - healing 701 Renal pelvis 701 - calyceal 701 Renal salt wasting replacement 763 Renal scintigraphy 707 Renal transplant 95 Renal tuberculosis 419,702 - bilateral 704 - congenital 702 Replication, intracellular 883 Reptiles 893 Resection - pulmonary 27,402 - - for multidrug-resistant tuberculosis 401 Resistance 792 - acquired 810 - among previously treated cases 810 - isolated 822 - ratio 817 Resource 855 Resource-rich areas 857 Respiratory failure 319,389 Respiratoryobstruction 744 Restriction enzyme analysis (REA) 79,86 Restriction fragment length polymorphism (RFLP) 58 Restriction 385 - pure 389 Retina, tuberculosis 735 Retreatment regimen, empirical 859 Retroperitoneal approach 524 Retroperitoneal tissue planes 494 Retropharyngeal mass 483,485 Reverse transcriptase PCR (RT-PCR) 819

922 Revised national program 872 RFLP (restriction fragment length polymorphism) 58 RFLP stain typing 253, 258 Rhazes 17 Rib destruction 375 Rice bodies 588, 599 Rifabutin 792 Rifampicin 28 - resistance 817,818 Rifampin 790 - alone 786 - based treatments 785 - resistance 791 - RMP 203 Rifapentine 793 Right heart catherization 399 Right-sided heart failure 435 Rigid deformity 526 Ring enhancing lesions 557 Ritual circumcision 713 Roentgenogram, simple 340 Rosacea-like tuberculid 647 rpoB genes 791 16S rRNA-PCR 707 RT-PCR (reverse transcriptase PCR) 819 Russia 876

S SAAG (serum-ascites albumin gradient) 669 Saccular true aneurismal dilatation 773 Salivary glands, tuberculosis 747 Sanatorial treatment 11 Sanatorium-Bomaristan or Deir el-Bahri 26 Satellite granulomas 665 Scarring 447 Schistosoma 580 Sciatica 484 Scintigraphy 486 Screening - and control in specialized settings 864 - interventions in resource-rich areas 862 - of migrants to low-incidence countries 863 Scrofuloderma 636 Scrotal mass 713 Secretory antigens 885 Segmentectomy 395 Seizures 541 Selection, criteria 885 Seminal vesicles 713,716 Septicaemia, tuberculous 245 Sequestrum formation 483 Serodiagnosis 434 Serological 466 Serum ADA 353 Serum-ascites albumin gradient (SAAG) 669 Seshen Nufer, tomb of 5 Sexual intercourse 711,718 Sexual transmission 702 Shadowing, parenchymal 361 Shelters 100 Shoulder joint -lesion 595

Subject Index - tuberculosis 595 Shunt, ventriculoperitoneal 540 Shwartzman reaction 143 SIADH (syndrome of inappropriate secretion of anti-diuretic hormone) 762 Sialogram 419 Side effects 785, 788 Silicosis 106, 785 Sinogram 612 Sinonasal 447 Sinus - charging 598 - cutaneous 448 - discharging 447,487,630 - sphenoid 758 - tract 713 - urethral 703 Sinus formation 447 - and fistula 683 Skeletal tuberculosis, active 422 Skeleton 425 Skin - lesions 463 - and soft-tissue infection 173 - spinal involvement 486 - test conversion 864, 865 - test interpretation, tuberculosis 234 - testing 231 - thickness 898 - tuberculosis 627,628 - - acute miliary 631 Skull vault 563 Slim disease 463 Small bowel follow-through 664 Smear-negative disease 256 Smear-positive disease 858 Smears and cultures 77 Social-economic reform 808 Socio-economically disadvantaged communities 457 Sodium 123 iodide (123 1) 415 Soft tissue 425 - calcification 486 Solid media 120 Solid organ transplantation 54, 175 Somatostatin 765 Sonographically echogenic debris 688 South Africa 873 - goldmines 827 South-East Asia 37,866 Spacer interspersed direct repeats (SPIDRS) 81 Sparfioxacin 793 Special groups and occupational hazards 93 Speciation 894 Specimen collection 117 Sperm retrieval 712 SPIDRS (spacer interspersed direct repeats) 81 Spinal canal 483,486,514 - encroachment 486, 514 Spinal fixation, external 524 Spinal fusion 523 Spinal instabilit) 519,530 Spinal meningitis, isolated 575 'ipinal neurotuberculosis 571

Subject Index Spinal tuberculosis 3,350,484,487,489 - surgical management 493 Spine - cysticerosis 581 - humped 5 Spirochetal disease 565, 579 Spirometric evidence 387 Spleen, tuberculosis 691 Spoligotyping 59,81 Spondylitis, tuberculous 538 Spread - hematogenous 275,302,660,701,711,718,736 - miliary 691 - subligamentous 518 - submucosal lymphatic 335 Sputum - induction 253 - microbiology of 321 - microscopy 859 - monitoring 840 - sample of 117 - smear in HIV-positive persons 467 Sputum culture 255 - conversion 840 Stabilization surgery 523 Stable funding 858 Staining properties 116,819 Standard diagnostic approach 858 Standard drug regimen 674 Stenosis 330 - bronchial 337,395 - cicatrical 332 - with fibrosis 332 - spinal 485 Stent - tracheobronchial 344 - types 344 Sternum 598 Steroids 433 Stierlin's sign 664,684 Stomach, tuberculosis 683 Straight leg raising test 594 Strain typing methodology 79 Streptomycin 27,787,789 - and other aminoglycosides 792 - STR 204 Strictures 664 Stridor 743 Strut graft 523 Studies - angiographic 551 - postmortem 551 Subarachnoid 551 Subluxation 494,530 Subpleural tuberculous lung parenchymal 350 Sub-Saharan Africa 37,302,457,824,855,863,866 Substance abusers 824 Subtile radiographic changes 784 Sudden death 441 Superior vena cava (SVC) 269 - obstruction 419 Supervised provision of standard treatment regimen 859 Suppuration 459

923 Suprasellar areas 549 Surgery - indications for 399,519,675 - role of surgery in the pre-Rifampin era 395 Surgical and collapse procedures 386 Surgical findings 758 Surgical intervention 451 Surgical technique 399 - approach 522 Surgical treatment 402,405 Surveillance, accurate 856 Susceptibility - genetics of 136 - testing 822, 840 SVC (superior vena cava) obstruction 269,419 Swimming pool granuloma 175 Swine 900 Symphysis pubis 596 Symptoms - constitutional 315 - frequency of 316 Synacthen stimulation 755 Syndrome of inappropriate secretion of anti-diuretic hormone (SIADH) 762 Synechia uteri (Asherman's syndrome) 721 Synergistic 792 Synovectomy, surgical 595 Systemic tuberculosis, endocrine perturbations related to 761 T T cells - gammaldelta (r/8) 137 - regulatory 138 Tachypnea 277 Tacrolimus 791 Tamponade 432 Target sign 559 Targeted populations, specific 192 Taste, unpleasant 794 TB control - cervical 530 - challenges to global 866 - drug development, global alliance for 820,870 - global partnership to stop TB 869 - patient, compliance of the treated 840 - vaccine formulations, cytokines as immune adjuvants for 886 TBM (tuberculous meningitis) 248,537,539,548 - differential diagnosis 565 - imaging characteristics of 549 - tuberculoma 554 TcDTPA 420 T-cell - activation 883 - epitopes, multiple 886 - response, immunological 842 Technetium (99 TcM) radiopharmaceuticals 414,420 TEE (transesophageal echo) 438 Tel El-Amarna 5 Ten commandments 824 Tendon sheaths - bones 175 - bursae 175

924 - joints 175 Tenosynovitis, tuberculous 599,610 Tentorial edge 561 Teratogenic effect 308, 309 Test - antimicrobial susceptibility 126 - diagnostic 436 - immunochromatagraphic 130 - susceptibility 822,840 Testis, hypoechoic 715 TGF-p 138 Thallium chlorid (201 TI) 124,414 Therapeutic outcome 332 Therapeutic response 414 - evalution 414 Therapy - alternative 825 - before 846 - climatological and sanatorium therapy 25 - directly observed, short-course 858 - during 846 -longer 786 - preventive 99,310,857 - - for tuberculosis 473 - prophylactic 473 Thoracoplasty 26, 406 Thoracoscopy in tuberculous patients 354 Thoracotomy 405,450 Thrombocytopenia 215,216,794 Thrombosis 540 Thrombotic occlusion 552 Thyroid gland, tuberculosis 747 Thyroid, FNA 757 Thyroiditis - subacute 756 - tuberculous 747 201 TI (thallium chlorid) 124,414 Tissue biopsy, CT guided 487 Tissue section 155 Tissue-damaging delayed hypersensitivity (DTH) 266,276 TLR (toll-like receptors) 140,170 T-lymphocyte cell 97 TNF 351 TNF-a (tumour necrosis factor) 136 - role of 138, 144 Toll-like receptors (TLR) 140,170 Tomb of Ankh-my 5 Tomb of Seshen Nufer 5 Tonsils 330,447,746 Toxicity 791, 792 - monitoring: plasma levels; audiograms, costs of 828 Toxoplasmosis 566 Traction bronchiectasis 370,372 Training course 806 Tranction bronchitasis 318 Transbronchial spread 318 Transcriptional signals 819 Transesophageal echo (TEE) 438 Transgene coding 889 Transgene encoding cytokines 888 Transient radiographic progression 379 Transmissibility 69 Transmission 85,259

Subject Index - of infection 456 - mode of 350 - sexual 702 Transpedicular instrumentation 524 Transplacental 254 Transplant patients 54 Transplantation 94 Transthoracic approach 524 Transvalvular flow velocities 434 Traveling 267 Treatment 270,354,591,646,647,649-653,674,738,776,825 - conservative 484,785 - daily 257 - duration of 787,808,825 - evolution 25 - failure 822 - monitoring 846 - - of the response to 738 - operative 519 - response 324,425 - short-course 807 - six-month 786 - surgical 405 Tree-on bud appearance 372,373 True worsening 368 TV (tuberculin unit) 233,322 Tubal obstruction 720 Tubercle 20, 115 Tubercle bacillus, the discovery of the 21 Tubercle, choroidal 733 Tuberculamate, intracranial 250 Tuberculid 642 - lichenoid 648 - papulonecrotic 642 Tuberculin 464 - conversion 266, 268 - response and protection 142 - testing 253 Tuberculin skin test (PPD) 322,354,467,738,862 Tuberculin test 340 - negative 253 Tuberculin unit (TV) 233,322 Tuberculin-positive 245 Tuberculoma 315,320,361,374,494,537,538,550 - of the cord 572 - imaging characteristics of 556 - intracranial 758 - intrasellar 538 - medullary 538 - miliary cerebral 562 - myelitic 569 - parenchymal 554 - 'en plaque' lesions 561 - suprasellar 565 - to treatment, paradoxical response of 560 Tuberculosis (see also) 600, 841 - activity of pulmonary 379 - during adolescence 255 - in adult, primary 265 - adult-type progressive 330 - in AIDS, miliary/disseminated 223 - in ancient Egypt 3 - in animals 893

Subject Index -

antigen, single 885 appendicular 672 arthritis 609 assessment of pulmonary 379 bilateral choroidal 733 bronchopleural fistula 319 century 25 CNS 420 colonic 687 congenital 641 contact investigation 862 contagious 856 control 801,855 - global 805 - recent developments in 871 cryptic disseminated 273,276 cryptic miliary 274 development of new drugs in the treatment 819 diagnosis - of miliary /disseminated 293 - of post-primary pulmonary 320 disseminated (see also disseminated tuberculosis) 273 distribution of the burden of HIV-related 457 effect on circulating hormones 764 endobronchial (see also endobronchial tuberculosis) 329, 386,387,681 - - in HIV-infected patients 337 - endocrine 751 - - and metabolic manifestations 751 - epidemic 802 - esophageal 672 - extrapulmonary (see also extrapulmonary tuberculosis) 194,315,446 786 - - in HIV-positive adults 463 - extraspinal musculoskeletal 587 - future trends 38 - gastric 672,673 - gebitourinary 699 - genital 702 - hepatobiliary 671,691 - hepatosplenic 692 - histology of adrenal TB 752 - HIV 870 - - co-infection with 455,824 - - endemic areas, control of 474 - - epidemiological considerations 456 - - global emergencies 456 - - governmental responses to the threat posed by 475 - - infected children 464 - - positive individuals, diagnosis 466 -HRCT 364 - hypertrophic ileocecal 662 - iatrogenic miliary/disseminated 274 - IgA EIA 130 - ileocecal 684 - imaging, mesenteric 681 - infection 841 - - rate 803 - intestinal 702 - intracranial 554 -laryngeal 745,856 - latent 134, 821 - - and paucibacillary 783

925 - - in pregnancy 787 - - new trends in diagnosing latent TB 235 - - therapy 785 - - treatment 867 -leptomeningeal 570 - lung cancer and other neoplasia 320 - meningitis 803 - mesenteric lymph nodes 670 - microbiology of drug-resistant 816 - miliary (see also miliary tuberculosis) 159,269,273,276, 363,364,389,440,441 - - epidemiology 274 - - in HIV 224 - - treatment 297 - mortality 802 - multi-drug resistant 396,794,809,822,859,867 - - epidemiology 809 - - treatment during pregnancy 309 - multifocal 598 - - osteoarticular 600 - muscles 610 - mycobacterial 380 - neonatal 302 - nonspecific tuberculids 644 - obstructive 717 - ocular manifestations of 731 - orbital 735 - osteomyelitis 609 - otorhinolaryngeal aspects 741 - outbreak of 64 - pancreatic 693 - parathyroid 760 - paucibacillary 784 - penile 713 - peritoneal 688 - pituitary 758 - portal vein of disseminated 691 - post primary 368,370 - post-primary pulmonary, treatment 322 - pregnancy 301 - prenatally acquired 702 - prevalence 803 - preventive therapy 473 - primary 360 - - in adult, epidemiology 265 - - group at risk 267 - - progressive 266 - - pulmonary 361 - - testicular 712 - prospective antibodies study of patients with 843 - prostatic and seminal vesicle tuberculosis 711 - pulmonary 304 - - in HIV-positive adults 461 - - resection for multidrug-resistant 401 - reinfection 330 - respiratory failure/hemodynamics 389 - retinal 735 - retrudescent 330 - risk factors for 456 - scleral 733 - serologic testing for 187 - skeletal 482 - smear-negative vs smear-positive 194

926 Tuberculosis (Continued) - smear-positive 801 - - cavitating pulmonary 243 - - pulmonary tuberculosis 805 - soft tissue 416 - spinal 3) 350,487) 493 - - versus spinal brucellosis 489 - - with neurological deficits 484 - splenic 671 - surgery for multidrug-resistant pulmonary 396 - suspects 859 - test, rapid 130 - thoracic surgery for 395 - thyroid 756 - tonsillar 746 - toxicity of anti 739 - treatment of 468 - - of active TB during pregnancy 308 - - of adrenal 753 - - of genitourinary 725 - - cost-effectiveness of 857 - - of in HIV-positive individuals 468 - - prophylactic 785 - - of renal 709 - - of spine 518 - - of upper limb joint 595 - and tuberculomas in miliary! disseminated 277 - vaccine - - multivalent 885 - - new 887 - vaginal 718 - verrucosa cutis 635 - vitamin D3 metabolism 144 - vulval 722 - water and sodium balance in 762 -meningitis in miliary! disseminated 277 - microbiology of 115 Tuberculosis in childhood - diagnosis 251 - prevention and control of 258 - treatment of 256 Tuberculosis of the ankle 592,621 Tuberculosis of the appendix 686 Tuberculosis of the calvarium with eNS lesions 563 Tuberculosis of the central nervous system 535 Tuberculosis cutis orificialis 637 Tuberculosis of the duodenum 683 Tuberculosis of the elbow 621 Tuberculosis in the elderly 193 Tuberculosis of esophagus 683 Tuberculosis of the eyelid 732 Tuberculosis of the fallopian tube and ovary 719 Tuberculosis of the foot 592,618 Tuberculosis, of other gastrointestinal sites 672 Tuberculosis of the hand 618 Tuberculosis of the heart 431 Tuberculosis of the hip 617 Tuberculosis of the hip joint 590 Tuberculosis in the immunocompromised, cutaneous 648 Tuberculosis of the jejunum and ileum 684 Tuberculosis of the joints of the upper extremity 594 Tuberculosis of the knee 591,616 Tuberculosis of the liver 691

Subject Index Tuberculosis lymphadenitis 690 Tuberculosis and mixed pattern of obstructive and restrictive abnormality 389 Tuberculosis and obstructive lung disease 387 Tuberculosis osteomyelitis 494 Tuberculosis in parotid 419 Tuberculosis in patients - with chronic renal failure 723 - on hemodialysis 723 - with renal transplant 723 Tuberculosis of the pelvis and sacroiliac joints 618 Tuberculosis of the penis) primary 712 Tuberculosis of the pericardium 431 Tuberculosis of the prostate 712 Tuberculosis of the retina 735 Tuberculosis of the salivary glands 747 Tuberculosis of the shoulder joint 595 Tuberculosis of the skin 627, 628 - due to M. bovis 629 - due to M. tuberculosis 629 - test interpretation 234 Tuberculosis of small bowel and colon 661 Tuberculosis of solid abdominal organs 671 Tuberculosis-specific antigens 841 Tuberculosis of the spleen 691 Tuberculosis of the stomach 683 Tuberculosis of the temporal bone 563 Tuberculosis of the thyroid gland 747 Tuberculosis of the uterine cervix 721 Tuberculosis of the uterus 720 Tuberculosis of the vagina 721 Tuberculosis of the vulva 722 Tuberculosis of the wrist 594 Tuberculous 537,482 Tuberculous infection) localizing sites of 413 - preventing 856 Tuberculous lesion, debridement of 522 Tuberculous lymphadenitis, and HIV 446 Tuberculous mass, atypical 561 Tuberculous meningeal mass 561 Tuberculous meningitis (TBM) 248,537,539,548 Tubular bones - long bones 597 - short 597 Tubular disease 671 Tumor 330 - malignant 565 Tumorous 332 Tumorous type 334 Tumour necrosis factor (TNF-) 136 Tunica vaginalis testis 711 Tunnel syndrome 595 Thrban shaped 746 Two-dimensional echocardiography 438 Type 1 differentiating cytokines IL-12 887 Type 1 response 135 Type 2 cytokine profile 139 Type 2 responses 135, 138 Typing Methods 59

927

Subject Index U mcer 330 - segmental 687 -vulval 719 Ulceration 330 - intestinal 896 - mucosal 664 Ulcerative 332 Ulcerative type 335 Ulcerative-granulative 332 mtrasound 614,663, 682, 704 - and color doppler 713 - transrectal 716 Ultraviolet light 856, 865 UNAIDS 465,471,873 UNESCO 7 UNICEF 308 Unilateral mass 753 United States 874 Unstable kyphotic deformities, bony bridge compression 485 Upperlobe infiltration 314 Upper urinary tract, reconstruction of 710 Ureter 701 - ulceration and fibrosis 704 Ureteral replacement 710 Ureteric stricture 710 Ureterocolic implant 710 Ureteroureterostomy 710 Ureterovesical junction stricture 710 Uric acid metabolism 791 Urinary bladder - tuberculosis 702 - thickness of the 704 Urinary dribbling 722 Urinary retention, recurrent 713 Urinary tract 157 Urinary tuberculosis - cystoscopy 707 - diagnosis 703 - general clinical features 702 - signs of 703 - surgery of 709 Urine culture 703 Urine samples 118 Urine sediments, staining of 703 US guidance 622 US guided procedures 622 US mini epidemics 874 USA, clinics 824 Using molecular epidemiology 62 Uterine cervix, tuberculosis 721 Uterus 718 - tuberculosis 720 Utonephrectomy 704 Uveitis 733,793

v V(V) DMSA (pentavelent dimercaptosuccinic acid) 415 Vaccina virus 889 Vaccination 145 - strategies 883 Vaccine

- design 146 - immunogenecity of 887 - mycobacterial-based 887 - preventable death 881 - recombinant adenoviral-based 890 - recombinant forms of 883 - subunit-based 888 - therapeutic 883 - viral-based 889 Vagina 718 - tuberculosis 721 Vaginal discharge 719,722 Vaginal prolapse 717 Vaginitis, atuberculous 722 Vas deferens 712 Vascular complications 540 Vascular occlusion 540 Vasculitis 250,539 - granulomatous 317 - pulmonary 320 - tuberculous 771 Vasography 717 Vein - pulmonary 331 - umbilical 303 Ventilation - altered 415 - mechanical 319,389 - perfusion scan 399 Ventriculitis 561 Vertebral body wedging 482 Vertebral damage 486 Villemin 21 Visitor, short-term 864 Visual acuity 792 Vital capacity 389 Vitamin D 761 - metabolism 766 Vitamin D3 metabolism in tuberculosis 144 Vitreous aspirate 737 Vitritis 735 VNTR - MIRU loci 83 - technique 84 Voiding, irritative 713 Volume reduction 387 Vulva - tuberculosis 722 - ulcers 717 W W strain 68, 824 Wales 876 Warfarin 791 Waterdrop-shape 334 Watermelon skin sign 716 Water-soluble contrast myelography (WSCM) 571 Water-soluble myelography, combined with CT 572 Watery phase 610 WBC, total 352 Weekly dosing 793 Wheezing 254,339 White blood cell abnormalities 216

Subject Index

928

White plague 20 White-stripe 494 WHO 810 WHO DOTS strategy 475,858 WHO/IUATLD global surveillance 811 WHOm notification to 35 Wind filled sail sign 620 World Bank 820,873 World Health Organization (WHO) 302,855 Wrist, tuberculosis 594 WSCM (water-soluble contrast myelography) 571

x

X desents 436

Y Y desents 436 Yersinia enterocolitis 662 Yield of bone marrow aspiration biopsy 224

Z Zambia 457 Zebu cattle 77 Ziehl 23 Ziehl-Neelsen stain 8,23,118, 155,297,321,450,895 - of urine 703 Zimbabwe 465 Zoonotic disease 15

About the Editor

M.MoNIR MADKOUR, MD,DM,FRCP (London) is a consultant physician at Riyadh Military Hospital, Saudi Arabia. He was born in Kafr Mishlah (Gharbiah), Egypt. He qualified from Alexandria University in 1968 and served in the Rural Medical Unit in his own village. He was then appointed Senior Resident at AI-Hussein University Hospital (AI-Azhar University), Cairo. In 1971, he traveled to Great Britain and was appointed Registrar and later Research Fellow at the University Department of Medicine, Glasgow. In 1977 he traveled to work in Saudi Arabia and was appointed Assistant Professor of Medicine at King Saud University, Riyadh, later joining the Military Hospital. In 1979 Dr. Madkour and three colleagues founded the first scientific medical journal in Saudi Arabia, the Saudi Medical Journal, and Dr. Madkour served as Associate Editor for 20 years (1979-1998). He collated some 100 years (1887-1984) of medical and paramedical research publications about Saudi Arabia into the Saudi Medical Bibliography, published in three volumes by Churchill Livingstone in 1983 and 1986. In 1986, Dr. Madkour established the first medical clinic devoted to the investigation of brucellosis. Experiences and scientific data gained from this clinic were published in the first edition of his book, "Brucellosis" (1989) by Butterworths. In 2001, the second edition, "Madkour's Brucellosis" was published by Springer-Verlag. Dr. Madkour has many other medical publications to his credit. He is the author of chapters on brucellosis in "Harrison's Principles ofInternal Medicine", 14th edn. (1998) and 15th en. (2001), and in the "Oxford Textbook of Medicine", 3rd edn. (1996) and 4th edn. (2003).