Reichman and Hershfield's Tuberculosis: A Comprehensive, International Approach, Third Edition (Two-Volume Set) (Lung Biology in Health and Disease)

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Reichman and Hershfield's

Tuberculosis A Comprehensive, International Approach

Third Edition Part A

Edited by

Mario C. Raviglione World Health Organization Geneva, Switzerland

New York London

This volume is not an official publication of the World Health Organization, and the opinions expressed herein do not necessarily represent the views of the Organization.

Informa Healthcare USA, Inc. 270 Madison Avenue New York, NY 10016 © 2006 by Informa Healthcare USA, Inc. Informa Healthcare is an Informa business No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number-10: 0-8493-9271-3 (Hardcover) International Standard Book Number-13: 978-0-8493-9271-9 (Hardcover) This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright. com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Visit the Informa Web site at www.informa.com and the Informa Healthcare Web site at www.informahealthcare.com

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Introduction

The year 2006 is an important year in the history of tuberculosis and in the fight to control it. As was declared during World TB Day in March 2006, the world showed a new resolve by announcing a ‘‘Global Plan to Stop TB, 2006–2015.’’ The goal of this worldwide effort, or global strategy, is to begin to reverse the incidence of tuberculosis by 2015. The TB Fact Sheet (1), published by the World Health Organization on the occasion of the 2006 World TB Day, provides staggering data from 2004 on the incidence, prevalence, and mortality from tuberculosis, indicating that there were as many as 1.7 million deaths. As we see such numbers, it becomes easy to also see the rationale for the Global Plan to Stop TB, 2006–2015. For this strategy to be successful, however, it will be necessary to have a solid foundation for the development of new actions, be they therapeutic or in the public health arena. However, just as well, it will require a strong and continuous international commitment to support and implement the program. Very likely, the cynics will say that this new program has a bit of ‘‘de´ja` vu.’’ Indeed, tuberculosis is not a new disease, and much work has been done over the years to combat it, but it is the first time that a strategic plan has iii

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Introduction

been formulated with the endorsement of health, business, and financial world leaders, not at the World Health Organization, but during the 2006 Economic Forum in Davos, Switzerland. The publication in 2006 of the third edition of Reichman and Hershfield’s Tuberculosis: A Comprehensive, International Approach, presented by the series of monographs Lung Biology in Health and Disease, may be a coincidence, but it is very opportune as it gives the reader not only a status report of where the field of tuberculosis is today, but also provides a panoramic review of the many new research avenues that are in need of investigation. The purpose of this volume, as stated by its editor, Dr. Mario C. Raviglione, is to show ‘‘what needs to be integrated in practice through effective collaboration between research scientists, physicians, public-health officials, epidemiologists, and policy makers’’ if indeed the Global Plan to Stop TB is to succeed. Truly, this volume gives us a road map to reach this goal! Dr. Raviglione, the chief officer of the World Health Organization tuberculosis program, has shown a remarkable vision in the preparation and development of this volume. Suffice it to review the list of contributors to see that they represent the ‘‘Who’s Who’’ of the tuberculosis field and that they have paved the way to reaching the Stop TB goal. As the editor of this series of monographs, Lung Biology in Health and Disease, I am immensely grateful to Dr. Raviglione and to all the experts who participated in the preparation of this volume for the opportunity to present this new edition of Reichman and Hershfield’s Tuberculosis: A Comprehensive, International Approach. Claude Lenfant, MD Gaithersburg, Maryland, U.S.A. Reference 1. World Health Organization Tuberculosis Fact Sheet #104. Revised March 2006.

Historical Background

Sixteen years ago, the first edition of Tuberculosis: A Comprehensive, International Approach was published; it was the first textbook on tuberculosis in several years. At that time, although very prevalent, tuberculosis was a forgotten disease. There had been no new drugs or diagnostic initiatives in several decades, the DOTS strategy had not been named, and the World Health Organization tuberculosis program was a small office with one professional and one support person. Advocacy and concerned groups of patients and caregivers relating to tuberculosis were not even a figment of one’s imagination. The relationship between tuberculosis and HIV was recognized but routinely ignored. Multidrug-resistant tuberculosis was scary but accepted without intervening or even treating patients so afflicted. Because of rapid advances in the field, a second edition was published in 2000. There was increasing interest and progress. Consequently, other textbooks devoted to this subject and its ramifications were published by many different publishers. Now we are pleased to see that the continuing vast progress and improvements in the field require a third edition of this text. There is nothing more fitting for us, then, to pass the editorship to an individual who is widely recognized for his tuberculosis expertise as well as his influence in v

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policy matters, Dr. Mario C. Raviglione. He has put together a table of contents that is a ‘‘Who’s Who’’ of the unquestionable world leaders in the field. He has also made provisions to distribute the book at a reduced cost to developing nations where the global burden of tuberculosis is most strongly reflected. It is with humility and pride that we hand over the editorship of this volume to our successor, and our gratitude goes to him and the publisher, Informa Healthcare, for extending and enhancing the franchise of Reichman and Hershfield’s Tuberculosis: A Comprehensive, International Approach. Lee B. Reichman, MD, MPH Newark, New Jersey, U.S.A. Earl S. Hershfield, MD Winnipeg, Manitoba, Canada

Preface

Tuberculosis, an ancient scourge of humanity known for several thousands of years, is still a major public health challenge in many countries today. Global targets for tuberculosis control by the year 2005 were set by the World Health Assembly to encourage a concerted worldwide effort to end this situation. It is therefore timely and appropriate for the international tuberculosis control and research community to assess what has been achieved in the past decade since the launch and promotion in 1995 of a modern tuberculosis control strategy, branded under the name of ‘‘DOTS’’a. It is also time to consider what more needs to be done to eliminate tuberculosis as a significant disease threat. Looking back, there have been remarkable achievements in recent years. They include: the rapid adoption of the DOTS strategy, which is now being applied in most countries; the high rate of cure demonstrated a The DOTS strategy has five essential components: government commitment to tuberculosis control; diagnosis via bacteriology through an effective laboratory network; standardized short-course chemotherapy with supervision and full patient support throughout treatment; uninterrupted supply of quality-assured anti-tuberculosis drugs; and recording and reporting to measure patient and program outcomes.

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among millions of infectious tuberculosis patients throughout the world; the efforts to tackle multi-drug resistant tuberculosis and human immunodeficiency virus–associated tuberculosis; the launch of successful initiatives, such as the Global Drug Facility and the Green Light Committee, to provide access to anti-tuberculosis drugs in resource-poor countries; the inclusion of tuberculosis among the targeted diseases for support by new international financial mechanisms, which are mobilizing unprecedented resources; and major public–private research initiatives to develop new tools to improve the diagnosis, treatment, and prevention of tuberculosis. This is undoubtedly an impressive track record that has been widely supported and facilitated by the establishment in 2001 of the global coalition to fight tuberculosis: the Stop TB Partnership. However, despite substantial progress in many countries, tuberculosis still kills 1.7 million people and affects 8.9 million new patients every year. Clearly, more detailed knowledge is necessary to strengthen research efforts toward development of new diagnostics, new anti-tuberculosis drugs, and an effective vaccine. Better understanding of pathogenesis, for instance, is crucial. At the same time, while awaiting the tools of the future, we cannot afford to relax our efforts to control tuberculosis using the current tools more effectively in the (often weak) health systems existing today in the world. On the contrary, the threat of resistance to anti-tuberculosis drugs, especially in the former USSR, and the overlap of the tuberculosis and human immunodeficiency virus/acquired immunodeficiency virus epidemics, especially in Africa, oblige us to reinforce DOTS programs everywhere by promoting public–private approaches and engaging communities to reach more patients, establish collaboration between tuberculosis and human immunodeficiency virus/acquired immunodeficiency virus programs, and contribute to health system strengthening to address, for instance, the scarcity of human resources capable of delivering high quality tuberculosis services. With this in mind, the new Stop TB Strategy recently announced by the World Health Organization was formulated to widen the focus of DOTS and address all modern challenges. All these issues, whether they are in the field of research or that of program implementation, deserve our full attention. Therefore, in preparing the third edition of this widely respected book, I sought to link the clinical ‘‘state of the art’’ to the principles of programmatic tuberculosis control and to current and upcoming research initiatives, thereby integrating on paper what needs to be integrated in practice through effective collaboration between research scientists, physicians, public health officials, epidemiologists, and policy makers. The book’s 50 chapters bring together our current knowledge of tuberculosis, its control, and related scientific discoveries. It is addressed to all who work in the field of tuberculosis control, whether in low-income, high-prevalence areas or in low-prevalence industrialized countries. As a compendium of information on all aspects of tuberculosis, it enables up-to-date knowledge to reach

Preface

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all parts of the world, especially those settings where access to modern scientific ideas may still be difficult. I am immensely grateful to Lee B. Reichman and Earl S. Hershfield for inviting me to continue the successful tradition of their book. Aspiring to match their previous standards, I have asked many of the world’s leading authorities on tuberculosis to contribute chapters to this book and I thank them for their generous and expert collaboration. Finally, I thank my family for patiently tolerating my enthusiasm for this important endeavour to share knowledge on the global fight against tuberculosis. Mario C. Raviglione

Acknowledgments

First of all, I would like to thank Dr. Kitty Lambregts-van Weezenbeek for her contributions in the initial phase of preparation of this new edition and for providing input for the preface, the structure, and the outline of the book. Her advice has been particularly important for the identification of the contributors and the organization of the table of contents. Second, I would like to thank the technical editor, Dr. Lindsay Martinez, for having worked with me very closely throughout the production of the book and for carefully reviewing the scientific language style used by the contributors and making it as consistent as possible for a multiauthor book. Third, I would like to recognize the work of Ms. Monika Tatranska and Ms. Michelle Lavergne for having helped in coordinating the production, especially the tasks of contacting peer-reviewers and compiling information for the contributors. Their support has been crucial and the book would not have been possible without them. Finally, I would like to thank all the peer reviewers who patiently provided their assistance to the contributors in ensuring that the chapters were of the highest standards: C. E. Barry, M. Behr, N. Binkin, A. Bone, M. W. Borgdorff, M. Bugiani, K. Caines, P. Caminero, P. Cegielski, P. Chaulet, xi

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Acknowledgments D. Chemtob, R. L. Cowie, M. R. Dal Poz, P. R. Donald, K. Duncan, N. Ezard, A. Fanning, J. I. Figueroa, T. Frieden, P. Fujiwara, J. Foulds, G. Gargioni, H. Getahun, J. Glynn, P. Gondrie, A. Gori, S. Graham, J. Grosset, E. Heldal, S. Hoffner, E. Jaramillo, S. H. E. Kaufmann, D. Kibuga, S. J. Kim, A. Laszlo, M. Levy, K. Lo¨nnroth, F. Luelmo, D. Maher, R. Matiru, J. Mazurek, A. Mwinga, E. Nathanson, C. Nolan, R. O’Brien, V. Pathania, T. Pennas, M. Pomerantz, R. Pray, S. Rangan, H. L. Rieder, J. Sbarbaro, J. C. Sadoff, H. Sawert, F. Scano, R. Scherpbier, L. Schlesinger, K. Siddiqi, G. Steenbergen, W. Stewart, E. A. Talbot, F. Varaine, A. Vernon, J. Walley, R. S. Wallis, C. Wells, B. G. Williams, V. G. Williams, J.-P. Zellweger.

Contributors

Francis Adatu-Engwau National Tuberculosis and Leprosy Programme, Wandegeya, Kampala, Uganda Chantelle Allen

ADRA Nepal, Kathmandu, Kingdom of Nepal

Virginia C. Arnold Office of the Director–General, World Health Organization, Geneva, Switzerland Mohamed Abdel Aziz Geneva, Switzerland

Stop TB Department, World Health Organization,

Marcel A. Behr Department of Medicine, Research Institute of the McGill University Health Centre, McGill University, and Division of Infectious Diseases and Medical Microbiology, Montreal General Hospital, Montreal, Quebec, Canada William R. Bishai Division of Infectious Diseases, Department of Medicine, Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A. Leopold Blanc Stop TB Department, World Health Organization, Geneva, Switzerland Kai Blo¨ndal-Vink The Netherlands

KNCV Tuberculosis Foundation, The Hague,

Fadila Boulahbal Mycobacteriology, National Reference TB Laboratory, Institut Pasteur d’Alge´rie, Alger, Alge´rie Roland Brosch Unite´ de Ge´ne´tique Mole´culaire Bacte´rienne, Institut Pasteur, Paris, France xiii

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Contributors

Kenneth G. Castro United States Public Health Service and Division of Tuberculosis Elimination, National Center for HIV, STD, and Tuberculosis Prevention, Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, U.S.A. Antonino Catanzaro Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, San Diego, School of Medicine, UCSD Medical Center, San Diego, California, U.S.A. Peter Cegielski United States Public Health Service and Division of Tuberculosis Elimination, National Center for HIV, STD, and Tuberculosis Prevention, Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, U.S.A. Rosella Centis World Health Organization Collaborating Centre for Tuberculosis and Lung Diseases, Fondazione Salvatore Maugeri, Care and Research Institute, Tradate, Italy Richard E. Chaisson Johns Hopkins University Center for Tuberculosis Research, Baltimore, Maryland, U.S.A. Pierre Chaulet

Faculty of Medicine, University of Algiers, Algiers, Algeria

Gavin J. Churchyard Aurum Institute for Health Research, CAPRISA, University of Kwa-Zulu Natal, Marshalltown, Gauteng, South Africa Jacqueline S. Coberly Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, Maryland, U.S.A. David L. Cohn Denver Public Health and the Division of Infectious Diseases, Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado, U.S.A. George W. Comstock Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, Maryland, U.S.A. Ma´ire A. Connolly Disease Control in Humanitarian Emergencies, Communicable Diseases, World Health Organization, Geneva, Switzerland Elizabeth L. Corbett Clinical Research Unit, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine Funded by the Wellcome Trust, London, U.K. Peter D. O. Davies Tuberculosis Research, Cardiothoracic Centre and University Hospital Aintree (NHS) Trusts, Mercers, Liverpool, U.K.

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Isabel N. de Kantor Tuberculosis Consultants Panel, World Health Organization, Buenos Aires, Argentina T. Mark Doherty Department of Infectious Disease Immunology, Statens Serum Institute, Copenhagen, Denmark Gilles Dussault Human Development, World Bank Institute, Washington, D.C., U.S.A. Christopher Dye Stop TB Department, World Health Organization, Geneva, Switzerland Jerrold J. Ellner Department of Medicine and Ruy V. Lourenco Center for the Study of Emerging and Reemerging Pathogens, UMDNJ—New Jersey Medical School, Newark, New Jersey, U.S.A. Wafaa M. El-Sadr Division of Infectious Diseases, Harlem Hospital Center and International Center for AIDS Care and Treatment Programs (ICAP), Columbia University, College of Physicians and Surgeons, and Mailman School of Public Health, New York, New York, U.S.A. Gijs Elzinga National Institute of Public Health and the Environment, Bilthoven, Utrecht, The Netherlands Donald A. Enarson International Union Against Tuberculosis and Lung Disease, Paris, France Marcos A. Espinal Fuentes Stop Tuberculosis Partnership Secretariat, World Health Organization, Geneva, Switzerland Sue C. Etkind Division of Tuberculosis Prevention and Control, State Laboratory Institute, Massachusetts Department of Public Health, Boston, Massachusetts, U.S.A. Anne Fanning Faculty of Medicine and Dentistry, Walter McKenzie Health Sciences Center, University of Alberta, Edmonton, Alberta, Canada Kevin P. Fennelly Department of Medicine, Center for the Study of Emerging and Re-emerging Pathogens, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey, U.S.A. Jose´ I. Figueroa Public Health Improvement, City and Hackney Primary Care Trust, London, U.K.

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Contributors

Mark FitzGerald Centre for Clinical Epidemiology and Evaluation, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada Katherine Floyd Stop TB Department, World Health Organization, Geneva, Switzerland Michelle Gayer Disease Control in Humanitarian Emergencies, Communicable Diseases, World Health Organization, Geneva, Switzerland Ann Ginsberg Clinical Department, Global Alliance for TB Drug Development, New York, New York, U.S.A. Peter Godfrey-Faussett Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, U.K. Ruth Griffin CMMI, Department of Infectious Diseases and Microbiology, Imperial College London, London, U.K. Malgorzata Grzemska Geneva, Switzerland

Stop TB Department, World Health Organization,

Maria-Cristina Gutie´rrez Laboratoire de Re´fe´rence des Mycobacte´ries, Institut Pasteur, Paris, France Christy L. Hanson Division of Infectious Disease, Bureau for Global Health, U.S. Agency for International Development, Washington, D.C., U.S.A. Anthony D. Harries HIV Unit, Ministry of Health, Lilongwe, Malawi, and Family Health International, Arlington, Virginia, U.S.A. Leonid Heifets Mycobacteriology Clinical Reference Laboratory, National Jewish Medical and Research Center, Denver, Colorado, U.S.A. Petra I. Heitkamp

World Health Organization, Jakarta, Indonesia

Philip C. Hopewell Division of Pulmonary and Critical Care Medicine, Medical Service, San Francisco General Hospital, Francis J. Curry National Tuberculosis Center, and Department of Medicine, University of California, San Francisco, California, U.S.A. Michael F. Iademarco United States Public Health Service and Division of Tuberculosis Elimination, National Center for HIV, STD, and Tuberculosis

Contributors

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Prevention, Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, U.S.A. Ernesto Jaramillo Stop TB Department, World Health Organization, Geneva, Switzerland Sirinapha Jittimanee TB Cluster (NTP), Bureau of AIDS, TB, and STIs, Ministry of Public Health, Bangkok, Thailand Michael E. Kimerling Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, U.S.A. Phung K. Lam Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, San Diego, School of Medicine, UCSD Medical Center, San Diego, California, U.S.A. Kitty Lambregts-van Weezenbeek Hague, The Netherlands

KNCV Tuberculosis Foundation, The

Adalbert Laszlo Mycobacteriology Laboratory Consultant, Ottawa, Ontario, Canada Philip A. LoBue Division of Tuberculosis Elimination, Field Services and Evaluation Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, U.S.A. Knut Lo¨nnroth Stop TB Department, World Health Organization, Geneva, Switzerland Fabio Luelmo Tuberculosis Control Programmes Consultant, The Hague, The Netherlands Dermot Maher Stop TB Department, World Health Organization, Geneva, Switzerland Jaouad Mahjour Directorate of Epidemiology and Disease Control, Ministry of Health, Rabat, Morocco Dick Menzies Epidemiology, Biostatistics, and Occupational Health, Montreal Chest Institute, McGill University, Montreal, Quebec, Canada Giovanni Battista Migliori World Health Organization Collaborating Centre for Tuberculosis and Lung Diseases, Fondazione Salvatore Maugeri, Care and Research Institute, Tradate, Italy

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Contributors

John Moore-Gillon Department of Respiratory Medicine, St. Bartholomew’s and Royal London Hospitals, London, U.K. Flor M. Munoz Pediatrics Section of Infectious Diseases and Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, U.S.A. Edward A. Nardell Division of Social Medicine and Health Inequalities, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, U.S.A. Paul Nunn Stop TB Department, World Health Organization, Geneva, Switzerland Richard J. O’Brien Foundation for Innovative New Diagnostics, Geneva, Switzerland Philip Onyebujoh Implementation Research and Methods, UNICEF/ UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR), Geneva, Switzerland Salah-Eddine Ottmani Geneva, Switzerland

Stop TB Department, World Health Organization,

Kathleen R. Page Johns Hopkins University Center for Tuberculosis Research, Baltimore, Maryland, U.S.A. Mikhail I. Perelman Moscow, Russia

Sechenov Moscow Medical Academy,

Mark D. Perkins Foundation for Innovative New Diagnostics, Geneva, Switzerland Sharon Perry Division of Geographic Medicine and Infectious Diseases, Stanford University School of Medicine, Stanford, California, U.S.A. Antonio Pio Public Health and Respiratory Disease, Mar del Plata, Argentina Franc¸oise Portaels Department of Microbiology, Institute of Tropical Medicine, Antwerpen, Belgium Mario C. Raviglione Stop TB Department, World Health Organization, Geneva, Switzerland

Contributors

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Michael Leonard Rich Partners in Health, Division of Social Medicine and Health Inequalities, Brigham and Women’s Hospital, Boston, Massachusetts, U.S.A. Leen Rigouts Department of Microbiology, Institute of Tropical Medicine, Antwerpen, Belgium William Rodriguez Harvard Medical School Division of AIDS, The Landmark Center, Boston, Massachusetts, U.S.A. John A. Sbarbaro University of Colorado Health Sciences Center, University Physicians, Inc., Denver, Colorado, U.S.A. S. K. Schwander Department of Medicine and Ruy V. Lourenco Center for the Study of Emerging and Reemerging Pathogens, UMDNJ—New Jersey Medical School, Newark, New Jersey, U.S.A. Kevin Schwartzman Respiratory Division and Respiratory Epidemiology Unit, Montreal Chest Institute, McGill University, Montreal, Quebec, Canada Isdore Chola Shamputa Department of Microbiology, Institute of Tropical Medicine, Antwerpen, Belgium Ian M. Smith Office of the Director–General, World Health Organization, Geneva, Switzerland Melvin Spigelman Research and Development, Global Alliance for TB Drug Development, New York, New York, U.S.A. Sergio Spinaci Global Malaria Programme, World Health Organization, HIV/AIDS, Tuberculosis and Malaria Cluster, Geneva, Switzerland Jeffrey R. Starke Pediatrics Section of Infectious Diseases, Baylor College of Medicine and Ben Taub General Hospital, Houston, Texas, U.S.A. Roberto Tapia-Conyer Subsecretariat of Prevention and Control of Diseases, Mexican Secretariat of Health, Mexico City, Mexico Mukund Uplekar Stop TB Department, World Health Organization, Geneva, Switzerland Richard Urbanczik Tuberculosis Consultants Panel, World Health Organization/International Union Against Tuberculosis and Lung Disease, Scho¨mberg, Germany

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Contributors

Armand Van Deun Department of Microbiology, Institute of Tropical Medicine, Antwerpen, Belgium Jeroen van Gorkom The Netherlands

KNCV Tuberculosis Foundation, The Hague,

Jaap Veen Head Unit Europe, KNCV Tuberculosis Foundation, The Hague, The Netherlands Suzanne Verver Head Unit Europe, KNCV Tuberculosis Foundation, The Hague, The Netherlands Ve´ronique Vincent Stop TB Department, World Health Organization, Geneva, Switzerland Diana E. C. Weil Stop TB Department, World Health Organization, Geneva, Switzerland Virginia G. Williams International Union Against Tuberculosis and Lung Disease, Paris, France Jean Woo Department of Community and Family Medicine, Division of Geriatrics, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, and School of Public Health, Prince of Wales Hospital, Shatin, Hong Kong, China Samuel C. Woolwine Division of Infectious Diseases, Department of Medicine, Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A. Douglas Young CMMI, Department of Infectious Diseases and Microbiology, Imperial College London, London, U.K. Richard Zaleskis Regional Office for Europe, TB Unit, World Health Organization, Copenhagen, Denmark Noureddine Zidouni Algiers, Algeria

Faculty of Medicine, University of Algiers,

Matteo Zignol Stop TB Department, World Health Organization, Geneva, Switzerland Alimuddin Zumla Windeyer Institute of Medical Sciences, Centre for Infectious Diseases and International Health, University College London, Royal Free and University College London Medical School, London, U.K.

Contents

Introduction Claude Lenfant . . . . iii Historical Background Lee B. Reichman and Earl S. Hershfield . . . . v Preface . . . . vii Acknowledgments . . . . xi Contributors . . . . xiii PART A SECTION I: BASIC ASPECTS OF TUBERCULOSIS 1. The Global Tuberculosis Epidemic: Scale, Dynamics, and Prospects for Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Christopher Dye I. Introduction . . . . 1 II. Global and Regional TB Epidemics: Scale and Dynamics . . . . 2 III. Tuberculosis Control . . . . 6 IV. Chemotherapy and the DOTS Strategy . . . . 8 V. Implementation and Impact of DOTS, 1991 to 2005 . . . . 10 VI. Prospects for Tuberculosis Control, 2006 to 2015 and Beyond . . . . 12 VII. Conclusion . . . . 21 References . . . . 25

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2. Bacteriology of Tuberculosis . . . . . . . . . . . . . . . . . . . . . . Fadila Boulahbal and Leonid Heifets I. Mycobacterium tuberculosis Complex . . . . 29 II. Bacterial Populations in Patients . . . . 32 III. Bacteriological Diagnosis of Tuberculosis . . . . 33 IV. Methods for Mycobacterium tuberculosis Identification . . . . 35 V. Detection of Drug Resistance . . . . 38 References . . . . 42

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3. Genomics and Evolution of Tubercle Bacille . . . . . . . . . . . 47 Ve´ronique Vincent, Maria-Cristina Gutie´rrez, and Roland Brosch I. Introduction . . . . 47 II. The Genome Sequence and Biology of Mycobacterium tuberculosis . . . . 48 III. Comparative Genomics and Evolution Within the Mycobacterium tuberculosis Complex . . . . 51 IV. Evolution of Mycobacterium bovis BCG . . . . 52 V. Population Structure and Clonal Evolution of the Mycobacterium tuberculosis Complex . . . . 54 VI. Ecotypes Within the Mycobacterium tuberculosis Complex . . . . 56 VII. Mycobacterium prototuberculosis: The Progenitor of the Mycobacterium tuberculosis Complex Orphan Clone . . . . 57 VIII. Conclusion . . . . 59 References . . . . 60 4. Epidemiology of Tuberculosis . . . . . . . . . . . . . . . . . . . . . Jacqueline S. Coberly and George W. Comstock I. Introduction . . . . 65 II. Etiologic Epidemiology . . . . 66 III. Administrative Epidemiology . . . . 79 IV. Conclusion . . . . 92 References . . . . 92 5. Overview of the Pathogenesis of Tuberculosis from a Cellular and Molecular Perspective . . . . . . . . . . . . . . . Samuel C. Woolwine and William R. Bishai I. Introduction . . . . 101 II. Infection . . . . 103

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III. IV. V. VI.

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Host Response . . . . 106 Cavitary Tuberculosis . . . . 109 Latent Tuberculosis . . . . 110 Conclusion . . . . 111 References . . . . 112

6. The Human Host: Immunology and Susceptibility . . . . . . 117 S. K. Schwander and Jerrold J. Ellner I. Introduction . . . . 117 II. The Natural History of Mycobacterium tuberculosis Infection in Humans . . . . 118 III. Human Immunity to Mycobacterium tuberculosis . . . . 119 IV. Susceptibility to Mycobacterium tuberculosis Infection and Tuberculosis Development . . . . 133 V. Resistance to Mycobacterium tuberculosis Infection . . . . 138 References . . . . 140 SECTION II: CLINICAL TUBERCULOSIS 7. Diagnosis of Pulmonary and Extrapulmonary Tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155 Phung K. Lam, Philip A. LoBue, Sharon Perry, and Antonino Catanzaro I. Introduction . . . . 155 II. Medical History and Physical Examination . . . . 156 III. The Tuberculin Skin Test . . . . 156 IV. Interferon Release Assays . . . . 157 V. Chest Radiography . . . . 158 VI. Respiratory Specimen Sampling: AFB Smear and Culture . . . . 159 VII. Culture-Negative Pulmonary Tuberculosis . . . . 160 VIII. Extrapulmonary Tuberculosis . . . . 160 IX. Clinical Use of Diagnostic Tests: Comparing Sensitivity and Specificity to PPV and NPV . . . . 160 X. Using Newer Diagnostic Tests: Incorporating Clinical Suspicion of Tuberculosis . . . . 161 XI. Newer Diagnostic Tests: NAA Assays . . . . 164

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XII. A Proposed Diagnostic Algorithm for the Diagnosis of TB Using Clinical Suspicion of TB with NAA Testing . . . . 166 XIII. Creating New Diagnostic Tests Based on Older Technology: Serodiagnosis by Immunoassays . . . . 168 XIV. Conclusion . . . . 171 References . . . . 172 8. Treatment of Tuberculosis . . . . . . . . . . . . . . . . . . . . . . 183 Philip C. Hopewell I. Tuberculosis Treatment as a Public Health Measure . . . . 183 II. History of Antituberculosis Chemotherapy . . . . 184 III. Antituberculosis Drugs . . . . 185 IV. Promoting Adherence to Treatment . . . . 195 V. Current Treatment Regimens . . . . 196 VI. Treatment in Special Situations . . . . 201 VII. Adjunctive Treatments for Pulmonary Tuberculosis . . . . 204 VIII. Extrapulmonary Tuberculosis . . . . 205 IX. New Drugs for Tuberculosis . . . . 209 References . . . . 210 9. Diagnosis of Latent Tuberculosis Infection . . . . . . . . . . . Dick Menzies and T. Mark Doherty I. Tuberculin Skin Testing . . . . 215 II. Chest X-ray (for Diagnosis of Tuberculosis Infection) . . . . 242 III. Interferon-g Release Assays . . . . 243 IV. Conclusions . . . . 248 Glossary . . . . 250 References . . . . 251

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10. Treatment of Latent Tuberculosis Infection . . . . . . . . . . David L. Cohn and Wafaa M. El-Sadr I. Introduction . . . . 265 II. Efficacy of Treatment of LTBI . . . . 266

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III. Safety and Tolerability of Treatment of LTBI . . . . 279 IV. Treatment of LTBI in Special Populations . . . . 286 V. Recommendations for the Treatment of LTBI . . . . 288 VI. Programmatic and Other Issues Related to the Treatment of LTBI . . . . 292 VII. Future Directions . . . . 296 VIII. Conclusions . . . . 297 References . . . . 297 11. Childhood Tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . 307 Flor M. Munoz and Jeffrey R. Starke I. Introduction . . . . 307 II. Epidemiology . . . . 309 III. Pathogenesis . . . . 314 IV. Clinical Forms of Pediatric Tuberculosis . . . . 316 V. Diagnosis of Tuberculosis in Children . . . . 325 VI. Treatment . . . . 329 VII. Summary . . . . 336 References . . . . 336 12. Tuberculosis in the Elderly . . . . . . . . . . . . . . . . . . . . . . 345 Peter D. O. Davies, Jean Woo, and John Moore-Gillon I. Introduction . . . . 345 II. The Aging Population . . . . 346 III. Epidemiology . . . . 346 IV. Decline in Immunocompetence with Increasing Age . . . . 348 V. Tuberculosis in Special Situations . . . . 351 VI. Clinical Presentation . . . . 353 VII. Mortality . . . . 354 VIII. Human Immunodeficiency Virus Infection . . . . 356 IX. Diagnosis . . . . 357 X. Treatment . . . . 358 XI. Preventive Therapy . . . . 361 XII. Case Reports . . . . 362 XIII. Conclusions . . . . 366 References . . . . 366

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13. Tuberculosis–HIV Coinfection: Epidemiology, Clinical Aspects, and Interventions . . . . . . . . . . . . . . . . Kathleen R. Page, Peter Godfrey-Faussett, and Richard E. Chaisson I. Introduction . . . . 371 II. Risk of Tuberculosis in Persons with HIV Infection . . . . 372 III. Prevalence of HIV Infection Among Patients with Tuberculosis . . . . 374 IV. Influence of HIV Infection on the Pathogenesis of Tuberculosis . . . . 375 V. Influence of Tuberculosis on the Course of HIV Infection . . . . 377 VI. Diagnosis of Tuberculosis Infection and Disease . . . . 378 VII. Treatment of Tuberculosis in Patients with HIV . . . . 385 VIII. Tuberculosis and HIV in Children . . . . 392 IX. Tuberculosis Caused by Multidrug-Resistant Organisms . . . . 394 X. Treatment of Latent Tuberculosis Infection . . . . 396 XI. Programs and Interventions . . . . 399 References . . . . 404 14. Diagnosis and Treatment of Multidrug-Resistant Tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Michael Leonard Rich I. Introduction . . . . 417 II. History . . . . 417 III. Mechanisms of Resistance . . . . 418 IV. Cross-Resistance . . . . 419 V. Pathogenicity, Transmissibility, and Drug Resistance . . . . 419 VI. Preventing the Evolution and Transmission of Drug Resistance . . . . 422 VII. Multidrug-Resistant Tuberculosis Diagnosis . . . . 424 VIII. Multidrug-Resistant Tuberculosis Treatment . . . . 427

371

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IX. Drug-Resistant Tuberculosis and HIV (and Other Immunosuppressive States) . . . . 445 X. Factors Associated with Good Treatment Outcomes . . . . 447 XI. Summary . . . . 448 References . . . . 449 15. Surgical Treatment of Pulmonary Tuberculosis . . . . . . . . Mikhail I. Perelman I. Historical Background . . . . 459 II. Indications for Surgery . . . . 462 III. Contraindications . . . . 467 IV. Types of Operation . . . . 468 V. Conclusion . . . . 479 References . . . . 480

459

SECTION III: CONTROL OF TUBERCULOSIS—BASIC PRINCIPLES AND TOOLS 16. History of Tuberculosis Control . . . . . . . . . . . . . . . . . . 483 John A. Sbarbaro and Sergio Spinaci I. Introduction . . . . 483 II. Compulsory Isolation and the Beginnings of TB Control in the United States . . . . 484 III. The Origins of the Tuberculosis Clinic . . . . 484 IV. The Impact of Effective Chemotherapy . . . . 485 V. Nonadherence and the Introduction of Directly Observed Treatment . . . . 486 VI. Preventive Treatment: Expanding the Role of Chemotherapy in the United States . . . . 487 VII. The Tuberculin Skin Test . . . . 488 VIII. Tuberculosis Control in Europe . . . . 489 IX. Tuberculosis Control in Developing Countries . . . . 491 X. Advancing the Goals of Tuberculosis Control . . . . 493 XI. The Impact of Social Trends upon TB Control . . . . 495 XII. Conclusion . . . . 496 References . . . . 497

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17. Tuberculosis Control Interventions: A Stepwise Approach . . . . . . . . . . . . . . . . . . . . . . . . . . Antonio Pio I. Concepts of Tuberculosis Control, Elimination, and Eradication . . . . 501 II. Overview of Tuberculosis Control Interventions . . . . 502 III. The Global Stop TB Strategy . . . . 502 IV. Case Management Intervention . . . . 504 V. Case Management Impact on the Risk of Infection . . . . 504 VI. Case Management Impact on Morbidity Incidence . . . . 505 VII. Case Management Impact on Case Fatality and Mortality . . . . 506 VIII. Specific Tuberculosis-Control Interventions Other than Case Management . . . . 507 IX. Bacille Calmette–Gue´rin Immunization . . . . 507 X. Chemoprophylaxis . . . . 507 XI. Nonspecific Tuberculosis-Control Interventions . . . . 509 XII. A Stepwise Approach to Implementation of Tuberculosis-Control Interventions . . . . 510 XIII. Summary . . . . 517 References . . . . 517

501

18. The Laboratory Network in Tuberculosis Control in High-Prevalence Countries . . . . . . . . . . . . . . . . . . . . 521 Adalbert Laszlo, Isabel N. de Kantor, and Richard Urbanczik I. The Concept of Diagnosis in Tuberculosis Control . . . . 521 II. Diagnosis as a Strategy of the NTP . . . . 523 III. TB Laboratory Network Technical Profile . . . . 525 IV. TB Laboratory Network Organizational Profile . . . . 525 V. Resources of the NTP Laboratory Network . . . . 527 VI. Management of Laboratory Supplies . . . . 530 VII. Training and Human Resource Development . . . . 531 VIII. Quality Assurance in the Laboratory Network . . . . 534 IX. Evaluation . . . . 537 References . . . . 539

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19. BCG Vaccines: History, Efficacy, and Policies . . . . . . . . Anne Fanning and Mark FitzGerald I. Introduction . . . . 541 II. History of Bacille Calmette Gue´rin Development . . . . 541 III. Vaccine Efficacy Trials . . . . 542 IV. Global Immunization Practices . . . . 548 V. World Health Organization Bacille Calmette Gue´rin Policy . . . . 549 VI. Hope for Future Vaccines . . . . 551 References . . . . 552

541

20. The Role of Contact Tracing in Low- and High-Prevalence Countries . . . . . . . . . . . . . . . . . . . . . . Sue C. Etkind and Jaap Veen I. Introduction . . . . 555 II. Definitions . . . . 556 III. Contact-Tracing Objectives . . . . 557 IV. Contact Tracing in Low-Prevalence Countries . . . . 558 V. Contact Tracing in High-Prevalence Countries . . . . 568 VI. New Technologies . . . . 574 VII. Summary . . . . 576 References . . . . 577

555

21. Managing Tuberculosis Patients: The Centrality of Nurses . . . . . . . . . . . . . . . . . . . . . . . 583 Virginia G. Williams, Chantelle Allen, and Sirinapha Jittimanee I. Introduction . . . . 583 II. Role of Nurses in Tuberculosis Control . . . . 586 III. Conclusion . . . . 595 References . . . . 595 22. Involving Community Members in Tuberculosis Care and Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . 597 Dermot Maher, Jeroen van Gorkom, and Francis Adatu-Engwau I. Introduction . . . . 597 II. Definition of Terms . . . . 598 III. Background . . . . 599

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IV. Review of Published Experience . . . . 601 V. Principles of Community Contribution to Tuberculosis Care as Part of NTP Activities . . . . 606 VI. The Future . . . . 611 References . . . . 613 23. Molecular Epidemiology: Its Role in the Control of Tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . 617 Marcel A. Behr and Kevin Schwartzman I. Introduction . . . . 617 II. IS6110-Based RFLP . . . . 618 III. Spoligotyping . . . . 627 IV. Mycobacterial Interspersed Repetitive Units—Variable Number of Tandem Repeats . . . . 629 V. Molecular Epidemiology in Suspected Outbreaks . . . . 631 VI. Community-Level Studies . . . . 633 VII. Concluding Thoughts and Future Directions . . . . 642 References . . . . 644 24. Economic and Financial Aspects of Global Tuberculosis Control . . . . . . . . . . . . . . . . . . . . . . . . . . 649 Katherine Floyd I. Introduction . . . . 649 II. Overview of Economic and Financial Analyses Related to TB Control Undertaken in Recent Years . . . . 654 III. Major Results from Two Recent Cost-Effectiveness Studies . . . . 665 IV. Recent Trends in Financing of TB Control and Projected Needs for the Decade 2006–2015 . . . . 671 V. What New Work Is Needed in the Next 5 to 10 Years? . . . . 677 References . . . . 680 25. Advancing and Advocating Tuberculosis Control Globally Through the Stop Tuberculosis Partnership . . . . . . . . . . . Petra I. Heitkamp and Marcos A. Espinal Fuentes I. Introduction . . . . 685 II. Role of Partnerships and Advocacy . . . . 685

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III. Advocacy, Communication, and Social Mobilization . . . . 687 IV. The Stop Tuberculosis Partnership . . . . 690 V. Characteristics of a Successful Partnership . . . . 694 VI. Conclusion . . . . 701 References . . . . 701 26. The Global Drug Facility: A Revolution in Tuberculosis Control . . . . . . . . . . . . . . . . . . . . . . . . Virginia C. Arnold and Ian M. Smith I. Introduction . . . . 705 II. History of the GDF . . . . 706 III. Operating Mechanisms of the GDF . . . . 707 IV. Achievements . . . . 708 V. Future Challenges and Opportunities . . . . 711 VI. Conclusion . . . . 713 References . . . . 714

705

Index . . . . I-1 PART B SECTION IV: CONTROL OF TUBERCULOSIS—TAILORING TUBERCULOSIS CONTROL 27. Fundamentals of Tuberculosis Control: The DOTS Strategy . . . . . . . . . . . . . . . . . . . . . . . . . . 717 Fabio Luelmo, Leopold Blanc, and Donald A. Enarson I. Introduction . . . . 717 II. Principles of Tuberculosis Control . . . . 718 III. A Strategy Called DOTS . . . . 719 IV. How the DOTS Strategy Has Been Expanded: From the London Meeting to the Global DOTS Expansion Plan . . . . 720 V. The Expanded DOTS Framework for Effective Tuberculosis Control . . . . 721 VI. The Success of the DOTS Strategy Well Applied . . . . 724 VII. Threats to Progress in the Fight Against Tuberculosis and the Way Forward . . . . 726 References . . . . 727

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28. Tuberculosis Control in the Countries of Eastern Europe and the Former Soviet Union . . . . . . . . . . . . . . . . . . . . . . . . . . 731 Malgorzata Grzemska and Richard Zaleskis I. Introduction . . . . 731 II. Historical Review of TB Control in the Countries of Eastern Europe and the Former Soviet Union . . . . 732 III. Epidemiology . . . . 733 IV. Adaptation to the International Standards . . . . 736 V. Applying International Standards . . . . 737 VI. Policy Development with Examples from Countries . . . . 738 VII. Challenges . . . . 739 VIII. Conclusions . . . . 743 References . . . . 743 29. Tuberculosis Control in Low-Prevalence Countries of Europe . . . . . . . . . . . . . . . . . . . . . . . . . . . Giovanni Battista Migliori and Rosella Centis I. The Framework for Tuberculosis Control: An Evolving Strategy . . . . 747 II. Definitions . . . . 749 III. Context: New Challenges for Tuberculosis Control in Low-Incidence Countries . . . . 750 IV. Aims of the Elimination Strategy . . . . 755 V. Approach to Control and Eliminate Tuberculosis . . . . 755 VI. Prerequisites to Implementation of the European Framework . . . . 758 VII. Conclusions . . . . 763 References . . . . 764

747

30. Tuberculosis in the United States: Toward Elimination? . . . . . . . . . . . . . . . . . . . . . . . . . . 767 Michael F. Iademarco and Kenneth G. Castro I. Introduction . . . . 767 II. Factors Associated with the Tuberculosis Epidemic in the United States . . . . 768 III. The Response to the Epidemic and Associated Reversal in Trend . . . . 769

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IV. The Choice Between Elimination and Stagnation: Another Cycle of Neglect? . . . . 775 V. The Way Forward . . . . 776 VI. Summary . . . . 783 References . . . . 784 31. Tuberculosis Transmission and Infection Control in Congregate Settings . . . . . . . . . . . . . . . . . . . . . . . . . Edward A. Nardell and Kevin P. Fennelly I. Introduction . . . . 793 II. Tuberculosis Transmission . . . . 796 III. TB Infection Control in Low-Prevalence, Resource-Rich Settings . . . . 803 IV. High-Risk, Resource-Limited Settings . . . . 811 V. TB Infection Control in Prisons . . . . 815 VI. Summary . . . . 816 References . . . . 817

793

32. Tuberculosis Drug Resistance in the World . . . . . . . . . . . 823 Franc¸oise Portaels, Leen Rigouts, Isdore Chola Shamputa, Armand Van Deun, and Mohamed Abdel Aziz I. Introduction . . . . 823 II. Extent of the Worldwide Drug Resistance Problem . . . . 825 III. Drug-Resistance Surveillance . . . . 832 IV. Causes of (Multi)drug Resistance and Risk Factors for Its Development . . . . 834 V. Role of the Laboratory Activities in Drug-Resistance Surveillance . . . . 838 References . . . . 840 33. Programmatic Control of Multidrug-Resistant Tuberculosis 845 Peter Cegielski, Kai Blo¨ndal-Vink, Kitty Lambregts-van Weezenbeek, and Ernesto Jaramillo I. Background and Introduction . . . . 845 II. Drug-Resistant TB: Definitions and Program Implications . . . . 847 III. Etiology of Drug Resistance and Program Implications . . . . 850 IV. Epidemiology of Drug-Resistant Tuberculosis . . . . 851 V. The Global Response to Multidrug-Resistant Tuberculosis . . . . 855

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VI. The Framework for Multidrug-Resistant Tuberculosis Control . . . . 858 VII. Emerging Issues in Multidrug-Resistant Tuberculosis Control Programs . . . . 861 VIII. Summary and Conclusions . . . . 864 References . . . . 865 34. Tuberculosis Control and Migration . . . . . . . . . . . . . . . . Suzanne Verver and Jaap Veen I. Introduction . . . . 869 II. History of Migration of TB . . . . 870 III. Epidemiology . . . . 872 IV. Contribution of Migration to Transmission in the Host Country . . . . 884 V. Interventions . . . . 885 VI. Legal Aspects of TB Control Among Immigrants . . . . 895 VII. Epilogue . . . . 895 References . . . . 896

869

35. Tuberculosis Control in Refugee and Displaced Populations . . . . . . . . . . . . . . . . . . . . . . 907 Michelle Gayer and Ma´ire A. Connolly I. Introduction . . . . 907 II. The Changing Context of Conflict Situations . . . . 908 III. Risk Factors . . . . 908 IV. Burden of TB . . . . 909 V. Constraints to Implementing TB Control Programs for Refugee and Displaced Populations . . . . 911 VI. Management of TB in Refugee and Displaced Populations . . . . 914 VII. TB Control Successes in Refugee and Displaced Populations . . . . 915 VIII. Challenges for the Future . . . . 916 IX. Conclusions . . . . 917 References . . . . 918 36. Tuberculosis Control in Prisons . . . . . . . . . . . . . . . . . . . Michael E. Kimerling I. Introduction: Two Sides of the Wall . . . . 921 II. Access to Adequate TB Care and Human Rights in Prisons . . . . 922

921

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III. Prisons as Special Communities . . . . 923 IV. Epidemiology of TB in Prisons: The Convergence of Risk Groups and a Disproportionate Burden of Disease . . . . 923 V. The Revolving Door of Prisons and Links to the General Community . . . . 928 VI. Establishing DOTS Programs in Prisons . . . . 930 VII. Conclusions and Challenges Ahead . . . . 944 References . . . . 945 37. Tuberculosis Control in Mines . . . . . . . . . . . . . . . . . . . Gavin J. Churchyard and Elizabeth L. Corbett I. Introduction . . . . 949 II. Epidemiology . . . . 950 III. Tuberculosis Control . . . . 957 IV. Conclusion . . . . 960 References . . . . 961

949

SECTION V: NEW CHALLENGES FOR A NEW CENTURY 38. Programmatic Management of Human Immunodeficiency Virus–Associated Tuberculosis . . . . . . . . . . . . . . . . . . . 967 Anthony D. Harries and Paul Nunn I. Introduction . . . . 967 II. Global Burden of TB and HIV Infection . . . . 967 III. Current Interaction Between Tuberculosis and AIDS Programs . . . . 968 IV. Strategic Work to Decrease the Burden of TB–HIV . . . . 972 V. Principles, Policies, and Guidelines for Implementing Collaborative TB–HIV Activities . . . . 972 VI. General Overview of Initiatives to Scale Up Antiretroviral Treatment in Resource-Poor Countries . . . . 977 VII. TB as an Entry Point to Antiretroviral Therapy: Benefits and Risks for TB Control . . . . 979 References . . . . 980 39. Engaging Private Providers in Tuberculosis Control: Public–Private Mix for DOTS . . . . . . . . . . . . . . . . . . . Mukund Uplekar and Knut Lo¨nnroth I. Introduction . . . . 985 II. Global Assessment . . . . 986

985

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III. What Makes Public–Private Mix for DOTS Work? . . . . 989 IV. Evidence Base . . . . 994 V. Economic Analysis . . . . 998 VI. Scaling Up Public–Private Mix for DOTS . . . . 999 VII. Public–Private Mix for DOTS and the Millennium Development Goals . . . . 1001 References . . . . 1002 40. Controlling Tuberculosis in Large Metropolitan Settings . . . . . . . . . . . . . . . . . . . . . . . . . 1005 Knut Lo¨nnroth, Matteo Zignol, and Mukund Uplekar I. Introduction . . . . 1005 II. Rapid Urbanization and Sprawling Slums . . . . 1006 III. Urban TB Epidemiology . . . . 1007 IV. Major Barriers to TB Control in Large Cities . . . . 1010 V. Two Examples of TB Control in Large Cities . . . . 1013 VI. A Provisional Framework for TB Control in Large Cities . . . . 1020 References . . . . 1024 41. Health Education and Social Mobilization in Tuberculosis Control . . . . . . . . . . . . . . . . . . . . . . . . . . 1029 Roberto Tapia-Conyer and Ernesto Jaramillo I. Introduction . . . . 1029 II. Health Education in TB Control . . . . 1030 III. Social Mobilization in TB Control . . . . 1032 IV. Promoting Social Mobilization: The Experience of the National TB Control Program of Mexico . . . . 1035 V. The Impact of Social Mobilization . . . . 1037 References . . . . 1038 42. Workforce Constraints in Tuberculosis Control . . . . . . . . 1041 Gijs Elzinga, Gilles Dussault, and Jose´ I. Figueroa I. Introduction . . . . 1041 II. Global Tuberculosis Control and Health Workforce Constraints . . . . 1041 III. Human Resources for Health Constraints and Tuberculosis Control Targets . . . . 1042

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IV. Positioning Tuberculosis Programs Within the Health System . . . . 1045 V. Strategies and Policies Required . . . . 1049 VI. Conclusions . . . . 1055 References . . . . 1057 43. The Practical Approach to Lung Health Strategy for Integrated Respiratory Care . . . . . . . . . . . . . . . . . . . . . 1059 Salah-Eddine Ottmani and Jaouad Mahjour I. Introduction . . . . 1059 II. Burden of Respiratory Illnesses in Populations . . . . 1060 III. Demand of Care for and Management of TB and Other Respiratory Illnesses in PHC Settings . . . . 1061 IV. Objectives of the PAL Strategy . . . . 1064 V. Components of the PAL Strategy . . . . 1065 VI. Adaptation of the PAL Strategy . . . . 1066 VII. Steps to Introduce the PAL Strategy in Countries . . . . 1067 VIII. Preliminary Results from Country Experiences . . . . 1075 IX. Perspectives of the PAL Strategy . . . . 1078 X. Conclusion . . . . 1079 References . . . . 1080 44. The Responsibilities of Medical and Nursing Schools in Tuberculosis Care and Control in Countries with Medium and High Tuberculosis Incidence . . . . . . . . . . . . 1083 Pierre Chaulet and Noureddine Zidouni I. Introduction . . . . 1083 II. The Social Responsibility of Training Institutes . . . . 1084 III. Limitations of the Traditional Approach to the Teaching of TB . . . . 1084 IV. Introducing Innovative Teaching Techniques in TB Control . . . . 1085 V. Basic Training for Health-Care Workers . . . . 1087 VI. Training of Trainers . . . . 1090 VII. Participation in Continuous Training . . . . 1093

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VIII. Building Partnerships to Assess the Impact of Training on the Performance of National Programs . . . . 1093 IX. Enhancing the Quality of Training and Stemming the Outflow of Trained Staff . . . . 1094 References . . . . 1094 45. Tuberculosis in the Poverty Alleviation Agenda . . . . . . . . 1097 Christy L. Hanson, Diana E. C. Weil, and Katherine Floyd I. Introduction . . . . 1097 II. Associations Between TB and Poverty . . . . 1099 III. TB Control and the Poverty-Reduction Agenda . . . . 1106 IV. Conclusions . . . . 1110 References . . . . 1111 SECTION VI: BUILDING THE FUTURE 46. New Diagnostics for Tuberculosis: An Essential Element for Global Control and Elimination . . . . . . . . . . . . . . . . . . . 1115 Mark D. Perkins and Richard J. O’Brien I. Introduction . . . . 1115 II. The Need for Improved Diagnostics . . . . 1116 III. Obstacles to TB Diagnostic Development . . . . 1118 IV. TB Diagnostic Priorities . . . . 1120 V. Characteristics of Needed Tests . . . . 1122 VI. TB Diagnostics Currently in the Development Pipeline . . . . 1122 VII. Public–Private Partnerships and a Development Strategy . . . . 1128 VIII. Conclusion . . . . 1130 References . . . . 1130 47. New Drugs for Tuberculosis . . . . . . . . . . . . . . . . . . . . . 1135 Ann Ginsberg and Melvin Spigelman I. Introduction . . . . 1135 II. Treatment of Active Tuberculosis . . . . 1135 III. Treatment for MDR-TB . . . . 1136 IV. Treatment of Active TB in Individuals Infected with HIV . . . . 1137

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V. Treatment of Latent TB . . . . 1137 VI. The Global Alliance for TB Drug Development . . . . 1137 VII. The Drug Development Process . . . . 1138 VIII. The Emerging Global Tuberculosis Drug Portfolio . . . . 1139 IX. Future Prospects in TB Drug Development . . . . 1148 References . . . . 1149 48. The Future of Tuberculosis Vaccinology . . . . . . . . . . . . . 1153 Ruth Griffin and Douglas Young I. The TB Vaccine Challenge: To Improve on Bacille Calmette–Gue´rin . . . . 1153 II. The Genome and New Vaccine Candidates . . . . 1155 III. Clinical Trials . . . . 1161 References . . . . 1164 49. Research Priorities in Tuberculosis . . . . . . . . . . . . . . . . 1169 Philip Onyebujoh, William Rodriguez, and Alimuddin Zumla I. Background and Introduction . . . . 1169 II. Specific TB Research Priority Areas . . . . 1176 References . . . . 1223 50. The New Stop TB Strategy of WHO: Reaching Global Targets . . . . . . . . . . . . . . . . . . . . . . . 1227 Mukund Uplekar, Diana E. C. Weil, and Mario C. Raviglione I. Introduction . . . . 1227 II. Challenges and Opportunities . . . . 1228 III. Goals and Targets . . . . 1230 IV. Components of the Stop TB Strategy . . . . 1232 V. Measuring Global Progress and Impact . . . . 1241 VI. Conclusion . . . . 1243 References . . . . 1244 Index . . . . I-1

SECTION I: BASIC ASPECTS OF TUBERCULOSIS

1 The Global Tuberculosis Epidemic: Scale, Dynamics, and Prospects for Control

CHRISTOPHER DYE Stop TB Department, World Health Organization, Geneva, Switzerland

I. Introduction Drugs that can cure most tuberculosis (TB) patients have been available since the 1950s, yet TB remains the world’s second most important cause of death from an infectious agent, after the human immunodeficiency virus (HIV) (1). TB control is high on the international public health agenda, not just because of the enormous burden of the disease, but also because short-course chemotherapy is recognized to be among the most cost effective of all health interventions (2–4). This evidence has been central to the global promotion of the DOTS strategy, the package of measures combining best practices in the diagnosis and treatment of patients with active TB, in which direct observation during treatment is a key element (5,6). This chapter provides an update on epidemiological burden and trends, and an overview of the documented and potential impact of DOTS as the principal method of control. But the scope of the discussion is intended to be broader in two respects. First, to contain the TB epidemic, and to show that it has been contained, requires strong, quantitative epidemiology. Epidemiological methods are needed, not only to measure the size and direction of the TB epidemic, but also to explain what is measured. 1

2

Dye

Second, the DOTS strategy as originally formulated may not be sufficient on its own to bring TB under control and drive the disease toward elimination. Numerous regional variations in TB epidemiology, and in the organization of health care, mean that the core DOTS strategy needs to be enhanced in different ways in different parts of the world. In sub-Saharan Africa, a huge proliferation of TB patients is associated with the spread of HIV infection. Countries of the former Soviet Union have especially high rates of drug resistance, a problem undoubtedly exacerbated by the deterioration of health and health care during the 1990s. In Asia, a relatively high proportion of TB patients first seek help from private practitioners rather than from the public health system, which underlines the importance of forming links between the two. On top of this, multimillion-dollar initiatives were launched around the turn of the millennium to develop better diagnostics, drugs, and vaccines, operating under the umbrella of the Stop TB Partnership (8). Some of the products of this new research, especially a new high-efficacy vaccine, could stimulate changes to the way in which TB control is done. II. Global and Regional TB Epidemics: Scale and Dynamics Based on surveys of the prevalence of infection and disease, on assessments of the performance of surveillance systems, and on death registrations, there were an estimated 8.9 million new cases of TB in 2004, fewer than half of which were reported to public health authorities and World Health Organization (WHO). Approximately 3.9 million cases were sputum-smear positive, the most infectious form of the disease (5,8,9). The WHO African region has the highest estimated incidence rate (356 per 100,000 population per year), but the majority of TB patients live in the most populous countries of Asia: Bangladesh, China, India, Indonesia, and Pakistan together account for half the new cases arising each year (Fig. 1). About 80% of new cases arising each year occur in the 22 top-ranking countries. TB is predominantly a disease of adult men. In regions where the transmission of Mycobacterium tuberculosis has been stable or increasing for many years, the incidence rate is relatively high among infants and young adults, and most cases are due to recent infection or reinfection. As transmission falls, the caseload shifts to older adults, and a higher proportion of cases come from the reactivation of latent infection. Therefore, in the countries of Western Europe and North America that now have low incidence rates, indigenous TB patients tend to be elderly, whereas patients who are immigrants from high-incidence countries tend to be young adults. Allowing for the difficulties of diagnosing childhood TB, estimation exercises indicate that there are relatively few cases among 0 to 14 year olds, even in areas of high transmission (18% of all new cases in Africa in 2004, but only 4% in the established market economies). In 2004, countries reported 1.4 million sputum-smear TB cases among men, but only 775,000 among women. In some instances, women have poorer

The Global Tuberculosis Epidemic

3

Figure 1 Distribution of TB in the world in 2004. Maps show (A) the estimated numbers of new TB cases (all forms) by country, and (B) the incidence per 100,000 population. Source: From Ref. 5.

access to diagnostic facilities (10), but the broader pattern also reflects real epidemiological differences between the sexes: although there is some evidence that young adult women (15–44 years) are more likely than men to develop active TB following infection, this effect is typically outweighed by the much higher exposure and infection rates among adult men (11–14). Although the TB incidence rate appears to be growing slowly in the world as a whole, incidence rates have been steady or falling for at least two decades in the Southeast Asia and Western Pacific Regions, and in Western and Central Europe, North and Latin America, and the Middle

4

Figure 2 (Caption on facing page )

Dye

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East (as judged from trends in case notifications; Fig. 2). The global increase is attributable to the striking proliferation of cases in countries of Eastern Europe (mainly the former Soviet Union) since 1990 and in subSaharan Africa (regions with high and low rates of HIV infection) since the mid-1980s. However, trends in case reports suggest that the rate of increase in both regions has slowed significantly since the mid-1990s, and the incidence in Eastern Europe may now be in decline (5,6). The downturn in case notifications in Eastern Europe is clear in data from Russia, Belarus, and the Baltic States of Estonia, Latvia, and Lithuania, whereas incidence rates appear still to be increasing in the central Asian republics of Kazakhstan, Tajikistan, and Uzbekistan (5). Summing up the figures obtained across the nine regions depicted in Figure 2 gives the global trend in incidence; the case rate per capita was increasing most quickly at 1.5% per year in 1995, but, because of the dynamics in Africa and Eastern Europe, has since been decelerating. The continued increase in TB incidence rate worldwide from 2004 onwards is entirely due to the increase in Africa. The resurgence of TB in Eastern European countries can be explained by economic decline and the failure of TB control and other health services since 1991 (15). Based on periodic surveys, more than 10% of new TB cases in Estonia, Latvia, and some parts of the Russia are multidrug-resistant (MDR) TB, i.e., resistant to at least isoniazid and rifampicin, the two most effective antituberculosis drugs (16,17). Drug resistance is likely to be a by-product of the events that led to TB resurgence in these countries, not the primary cause of it, for three reasons. First, resistance is generated initially by inadequate treatment due, for example, to interruption of the treatment schedule, the use of low-quality drugs, or the use of high-quality drugs at low dosage. Second, resistance tends to build up over many years, even though there was a sudden increase in TB incidence in Eastern European countries after 1991. And third, although formal calculations have not been done, resistance rates are probably too low to attribute all of the

Figure 2 (Figure on facing page) Trajectories of the tuberculosis epidemic for nine epidemiologically different regions of the world. Points mark trends in incidence rates, derived from case notifications for 1990–2004. The two panels separate regions with estimated incidence rates (A) above or (B) below the global average in 1990 (heavy line). Groupings of countries are based on the WHO regions of Africa (subdivided into two regions comprising those countries with high HIV-infection rates, more than or equal to 4% of patients aged 15 to 49 years, in 2004, and those with low rates of HIV infection, less then 4%), Central Europe, Eastern Europe (former Soviet countries plus Bulgaria and Romania), Eastern Mediterranean, Established Market Economies [all 30 Organization for Economic Cooperation and Development (OECD)] countries, except Mexico, Slovakia, and Turkey, plus Singapore, Latin America, Southeast Asia, and Western Pacific. The countries in each region are listed in full elsewhere. Source: Adapted from Ref. 6.

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increase in caseload to excess transmission from treatment failures. While parts of Eastern Europe are clearly hotspots for MDR-TB, only 4–6% of TB cases arising each year (new and previously treated) are estimated to be MDR (18,19) though the frequency among previously treated cases is higher. Much of the recent increase in global TB incidence can be explained by the spread of HIV in Africa (5,6,9). Globally, an estimated 13% of new adult tuberculosis cases were infected with HIV in 2004, but there was marked variation among regions—from 33% in sub-Saharan Africa to 1.4% in the Western Pacific Region. HIV infection rates in TB patients have so far remained below 1% in Bangladesh, China, Indonesia, and Pakistan. In African populations with higher rates of HIV infection, a higher proportion of TB patients are women 15 to 24 years (5,9). Across Africa, the rise in the number of TB cases is slowing (though this may not be true in every country), perhaps because HIV infection rates are also beginning to stabilize or fall (20), and perhaps also because TB surveillance systems have been overloaded by patients. HIV has probably had a smaller effect on TB prevalence than on incidence because the duration of TB among HIVinfected patients is relatively short, with a rapid onset of severe illness and a marked reduction in life expectancy (21). In places where HIV infection rates are high in the general population, they are even higher among TB patients; estimates for 2004 exceeded 50% in Botswana, Malawi, South Africa, Zambia, and Zimbabwe, among other countries. Approximately 1.7 million people died of tuberculosis in 2004, including 248,000 patients who were coinfected with HIV (6,9). Although these are usually reported as AIDS deaths under the International Classification of Diseases-10 and by WHO, TB control programs need to know the total number of TB deaths, whatever the underlying cause. Because few countries with high burdens of TB compile reliable statistics on the cause of death, the global and regional trends in TB deaths are uncertain. However, recent assessments based on modeling have suggested that the global TB mortality rate began to fall around year 2000, after growing during the 1990s (5,6).

III. Tuberculosis Control The methods of TB control are to prevent infection, to stop progression from infection to active disease, and to treat active disease. Roughly, 100 million infants (more than 80% of the annual cohort) are vaccinated each year with bacille Calmette–Gue´rin (BCG), and the effect of this vaccine is mainly to prevent serious forms of disease in children—meningitis and miliary TB. The most complete analysis of effectiveness to date suggests that BCG given to children worldwide in 2002 will have prevented approximately 30,000 cases of childhood meningitis and about 11,500 cases of miliary TB during their first five years, or 1 case for every 3400 and 9300 vaccinations, respectively (22). The protective efficacy against pulmonary tuberculosis in adults is highly variable, and often very low (23).

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Individuals at high risk of TB who have a positive tuberculin skin test but not active disease (e.g., associates of active cases, especially children, and immigrants to low-incidence countries) can be offered preventive therapy (also called treatment of latent TB infection), most commonly with the relatively safe and inexpensive drug, isoniazid (isoniazid preventive therapy, IPT). Randomized, controlled, clinical trials have shown that 12 months of daily isoniazid gives 25% to 92% protection against developing active TB (range of point estimates),but towards the upper end of this range when patients adhere fully to the treatment regimen (Chapter 10). However, IPT is not widely used, mainly because compliance with long-term daily treatment tends to be poor among healthy people—a relatively high risk of TB among people carrying latent infections is usually still a low risk in absolute terms. The exceptionally high risk of TB among people coinfected with M. tuberculosis and HIV is a reason for encouraging wider use of IPT, especially in Africa. Among the control methods that are possible with current technology, only the treatment of active disease has so far been implemented and shown to be effective on a large scale. The cornerstone of TB control at the start of the 21st century is the prompt treatment of active cases with short-course chemotherapy using first-line drugs that are administered via the DOTS strategy with targets framed by the United Nations Millennium Development Goals (MDGs) (Table 1) (5,6). Because of the importance of treating active TB, now and for the foreseeable future, the following discussion focuses on chemotherapy, delivered via the DOTS strategy and its extensions. Table 1 Goals, Targets, and Indicators for Tuberculosis Control Millennium Development Goal 6 Combat HIV/AIDS, malaria and other diseases Target 8: To have halted by 2015 and begun to reverse the incidence of malaria and other major diseases Indicator 23: Prevalence and death rates associated with TB Indicator 24: Proportion of TB cases detected and cured under DOTS (the basis of the WHO recommended Stop TB Strategy) Stop TB Partnership targets By 2005: At least 70% of people with sputum-smear positive TB will be diagnosed (i.e., under the DOTS strategy), and at least 85% cured. These are targets set by the World Health Assembly of WHO By 2015: The global burden of TB (prevalence and death rates) will be reduced by 50% relative to 1990 levels. This means reducing prevalence to approximately 150 per 100,000 or lower and deaths to approximately 15 per 100,000 per year or lower by 2015 (including TB cases coinfected with HIV). The number of people dying from TB in 2015 should be less than approximately one million, including those coinfected with HIV By 2050: The global incidence of TB will be less than one case per million population per year Source: From Ref. 24.

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The core DOTS strategy has five elements: political commitment, diagnosis primarily by sputum-smear microscopy among patients attending health facilities, short-course chemotherapy with effective case management (including direct observation), a regular supply of quality-assured anti-TB drugs, and systematic monitoring to evaluate the outcomes for every patient started on treatment. Standard short-course chemotherapy can cure more than 90% of new, drug-susceptible tuberculosis cases, and high cure rates are a prerequisite for expanding case finding (25,26). Although the DOTS strategy aims primarily to provide free treatment for smear-positive patients, most DOTS programs also treat smear-negative patients, often without a fee. DOTS is increasingly being used as the basis for more complex interventions, for example, where rates of drug resistance or HIV infection are high, as reflected in connection with the Stop TB Strategy (27) (Table 2). The internationally agreed targets for TB control, embraced by the United Nations MDGs, are to detect 70% of sputum-smear–positive cases and successfully treat 85% of such cases by the end of 2005 (Table 1). Mathematical modeling (based mainly on European and North American data) suggests that the incidence rate of TB will decline at 5% to 10% per year when these targets are met, even though this represents a treatment success among all infectious cases of only 60% (25,26,28). These expectations do not, however, allow for the complications associated with HIV coinfection and drug resistance. For example, the impact of DOTS will be less than that suggested above when HIV is spreading through a population. Nor do the anticipated reductions in TB incidence account for changes in risk attributable to factors such as air pollution (29,30), tobacco smoke (31,32), diabetes (33–35), malnutrition and undernutrition (36), and alcohol abuse (37). In principle, TB incidence could be forced down more quickly than seen in Europe and North America, by as much as 30% per year, if new cases could be found soon enough to eliminate transmission. In general, the decline is faster when a larger fraction of cases arises from recent infection (i.e., in areas where transmission rates have recently been high) and slower where there is a large backlog of asymptomatic (latent) infection, and where rates of reactivation are higher among latently infected people. These facts explain why it should be easier to control epidemic than endemic disease: during an outbreak in an area that previously had little TB, the reservoir of latent infection is small, and most new cases come from recent infection. In practice, the best results in the control of endemic TB by chemotherapy (largely) have been achieved in native communities (Inuit and others) of Alaska, Canada, and Greenland, where the incidence rate was reduced by 13% to 18% annually from the early 1950s (26). Over a much wider area in Western Europe, TB declined at 7% to 10% per year after drugs became available during the 1950s, though the incidence rate was already falling at 4% to 5% per year before chemotherapy.

Global Plan to Stop TB, 2006–2015 Budget for specific activities including Increased case detection and treatment success toward and beyond target levels Enhanced advocacy, communication, and social mobilization Strengthened laboratory services for microscopy, culture, and DST Improved case management including directly observed treatment and patient support to increase adherence and chance of cure, and to lower risk of acquiring drug resistance Regular supply of high-quality drugs; improvement of drug management capacity Technical assistance, including monitoring and evaluation Contributing to case finding, treatment success, and TB prevention TB/HIV control including active TB case finding among HIV-infected people, treatment of latent infection for HIV-infected people without active TB, antiretroviral therapy, and cotrimoxazole preventive therapy; MDR-TB management including expanded DST and treatment with second-line drug regimens Investment in staff, infrastructure, health information, and management, oriented to TB but more widely applicable; investment in syndromic management of adult respiratory disease Improved links between public, non-governmental, and private health care systems Community TB care; advocacy, communication, and social mobilization New diagnostics and drags (new vaccine not expected before 2015)

Abbreviations: DST, drug susceptibility testing; MDR-TB, multidrug-resistant TB.

Engage all care providers Empower patients and communities Enable and promote research

Contribute to health system strengthening

Drug supply Monitoring and impact evaluation Additional components Address TB/HIV, multidrug resistant TB (MDR-TB) and other challenges

Principal components DOTS expansion and enhancement Political commitment Case detection through bacteriology Standardized treatment, with supervision and patient support

Stop TB Strategy

Table 2 Elements of the Global Plan to Stop TB, 2006–2015, Underpinned by the Revised Stop TB Strategy of WHO

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The long-term aim of TB control is to eliminate all new cases [defined as an incidence less than one case per million population per year (24,38)], but cutting prevalence and death rates are arguably more important in the short term. About 86% of the burden of TB, as measured in terms of disabilityadjusted life years lost, is due to premature death rather than illness, and prevalence and mortality can be reduced faster than incidence in chemotherapy programs. For example, the TB death rate among the Alaskan Inuit population dropped by an average of 30% per year in the period 1950–1970. V. Implementation and Impact of DOTS, 1991 to 2005 A. Case Detection

More than 21 million TB patients were diagnosed and treated in DOTS programs between 1994 and 2004. Despite this mounting total, only 53% of all estimated new smear-positive cases were reported by DOTS programs to WHO in 2004, with much variation between regions of the world (Fig. 3A). The case detection rate in DOTS programs has been accelerating globally. The recent improvement in case finding has been due mostly to rapid implementation in India, where detection increased from 1.7% in 1998 to 57% in 2004, and in China, where detection increased from 30% in 2002 to 63% in 2004. In 2004, almost all (91%) TB cases reported to WHO were reported by DOTS programs. Because very few of the undetected TB patients were reported elsewhere in the public health system, DOTS programs must seek other sources of patients in order to reach the 70% target for detection. Among these sources are private practitioners, and public hospitals that have not traditionally been linked to TB clinics (39). B. Treatment Success

Many of the 183 national DOTS programs in existence by the end of 2004 have shown that they can successfully treat a high proportion of patients. The average treatment success among 1.7 million smear-positive patients in the 2003 DOTS cohort was 82%, not far below the 85% target (Fig. 4). Concealed by this high proportion of successful treatments are poorer results in Africa, Eastern Europe, and in the established market economies (Fig. 3). In the African countries most affected by HIV (Africa—high HIV), 7% of patients died during treatment, and 21% were lost to follow-up (defaulted, transferred to other treatment centers, or not evaluated). In the established market economies, the death rate was higher than in any other region (10%), because a large proportion of patients are elderly. In Eastern Europe, where rates of drug resistance are relatively high, 9% of patients failed to respond to treatment and 6% died during treatment. C. Incidence, Prevalence, and Mortality

Although the decline in TB has almost certainly been accelerated by good chemotherapy programs in countries such as Chile, Cuba, and Uruguay, there have been only few recent, unequivocal demonstrations of impact in

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Figure 3 Case detection and treatment failure rates reported by DOTS programs at the end of 2004. (A) Smear-positive case detection rates in 2004 for the nine regions defined in Figure 2. (B) Adverse outcomes of treatment in the 2003 DOTS cohort, for each of the nine regions defined in Figure 2. Source: From Ref. 5.

high-burden countries. Two persuasive examples come from Morocco and Peru. Between 1994 and 2000, the incidence of pulmonary TB among Moroccan children up to four years of age fell by more than 10% per year, suggesting that the risk of infection was falling at least as quickly (Ministry of Health Morocco, unpublished data). Moreover, average age of TB cases has been rising for over 20 years in Morocco. And yet the overall reduction in pulmonary TB was only 4% per year, in part because of the large reservoir of infection in adults. DOTS was launched in Peru in 1991, and high rates of case detection and cure appear to have pushed down the incidence rate of pulmonary TB by 6% per year (40). For epidemic TB, as a result of aggressive intervention following an outbreak in New York City, the number of MDRTB cases fell by over 40% per year (41).

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Figure 4 Progress toward the targets of 70% smear-positive case detection by DOTS programs (filled points, heavy lines) and 85% treatment success (open points, light lines). Points show the measured progress in smear-positive case detection from 1995 to 2004 and treatment success for the 1994 to 2003 cohorts. Lines project changes to 2015 according to Global Plan scenarios 2 (dashed) and 3 (continuous) for improved TB control (case detection by DOTS programs is zero in scenario 1, so treatment success does not apply).

Indirect assessments of the effect of DOTS suggest that 70% of the TB deaths expected in the absence of DOTS were averted in Peru between 1991 and 2000, and more than half the TB deaths expected in the absence of DOTS are prevented each year in DOTS-served provinces of China (40,42). There have been few direct measures of the reduction in TB prevalence over time, but surveys done in China in 1990 and 2000 showed a 32% [95% confidence limits, 9% to 51%] reduction in the prevalence per capita of all forms of TB in DOTS areas, as compared with the change in the prevalence in other parts of the country (43). Preliminary findings from a 2004 national survey in Indonesia indicate that the per capita prevalence of smear-positive TB was threefold lower than in surveys carried out around 1979 and 1982 (Ministry of Health, Indonesia; WHO, unpublished data) (44,45). But not all of this reduction can be attributed to the DOTS program, or even to the direct effects of chemotherapy. VI. Prospects for Tuberculosis Control, 2006 to 2015 and Beyond The prospects for TB control over the next 10 years, implementation and impact, have been set out in the Global Plan to Stop TB, 2006–2015 (46). The Global Plan imagines three scenarios: Scenario 1: No DOTS. This assumes that the strategy was never introduced in any region, so chemotherapy would continue in the same way as it was pre-DOTS, with variable rates of case detection and typically

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lower rates of cure. This gives a baseline against which to compare the gains that have already been made under DOTS, and which might be made in future. Scenario 2: Sustained DOTS. Case detection and treatment success both increase until 2005, and then remain steady until 2015 (Fig. 4). Approximately, 50 million patients would be treated under DOTS between 2006 and 2015, as compared with 21 million in the previous decade, 1996–2005. Scenario 3: Enhanced DOTS. Case detection and treatment success continue to increase beyond 2005, up to 2015 (Fig. 4). As in scenario 2, roughly 50 million patients would be treated between 2006 and 2015 (a higher proportion of patients treated sooner means that, as a result of reduced transmission, there are fewer patients later; Table 3). To reach high rates of case detection and cure requires various additions to the basic DOTS strategy, including community-based care, a syndromic approach to diagnosing and treating TB among other respiratory conditions, and improved collaboration between public and private health sectors. To improve the management of drug-resistant disease, more patients will be given drug sensitivity tests, and around 800,000 MDR-TB patients will be treated with regimens including second-line drugs (Table 3, Fig. 5A). HIV testing and counselling will be provided to 29 million TB patients, and antiretroviral therapy (ART) and cotrimoxazole preventive therapy offered to 3.2 million (Fig. 5B). Approximately 200 million people infected with HIV will be screened for TB, and 24 million will be offered IPT. Analyses carried out for the Global Plan investigate the impact of these additions to DOTS used in varying combinations, and implemented at different rates, in seven endemic regions of the world (i.e., excluding established market economies and Central Europe). The potential impact of scenario 3, as compared with scenarios 1 and 2, has been evaluated with a mathematical transmission model describing, as in previous models (27,47–49), how the planned interventions determine incidence, prevalence, and death rates through time. Model calculations show that scenarios 2 and 3 should both satisfy MDG target 8 ‘‘to have halted and begun to reverse incidence,’’ globally (Fig. 6) and in each of the seven regions (Fig. 7). In fact, the annual incidence of new cases is expected to be in decline well before 2015, even under scenario 2. Ambitious plans for the South-East Asia and Western Pacific regions are reflected in the relatively rapid declines in incidence expected by 2015 (7–9% per year). Even with these rates of decline in Asia, TB incidence would still exceed 10 per 100,000 globally in 2050, which is 100 times greater than the target for TB elimination. The targets of halving prevalence and death rates between 1990 and 2015 are more challenging. Projections suggest that these targets can be met globally with full implementation of the enhanced DOTS strategy (scenario 3, Fig. 6), but not in Africa or Eastern Europe (Fig. 8A). Based on the calculated rate of decline in mortality from 2006 to 2015 in the African countries most affected by HIV (Africa—high HIV), the target death rate (Text continues on page 18.)

DOTS expansion Total number of new ssþ patients treated in DOTS programs (millions) Case detection rate (%) Total number of new ssþ patients successfully treated in DOTS programs (millions) Treatment success rate (%) Total number of new ss-/extra-pulmonary patients treated in DOTS programs (millions) Percentage of new ss-/extra-pulmonary patients treated in DOTS programs Management of drug resistance Total number of detected MDR-TB patients that are treated in DOTS-Plus programs (millions) Percentage of detected MDR-TB patients that are treated in DOTS-Plus programs TB/HIV Total number of PLWHA attending HIV services screened for TB (millions) 2.2 (2.8) 79% 1.9 (2.2) 86% 3.0 (3.9) 77%

0.09 (0.14) 64%

23 (23)

64% 1.8 (2.1) 86% 3.0 (4.6) 67%

0.02 (0.12) 17%

11 (18)

2010

2.1 (3.3)

2006

26 (26)

100%

0.11(0.11)

84%

89% 2.7 (3.2)

82% 1.6 (1.8)

1.8 (2.2)

2015

209 (225)

62%

0.8 (1.3)

77%

81% 30 (39)

78% 17 (21)

21 (27)

2006–2015

Interventions with current technologya

Table 3 Interventions and New Technology to Be Introduced Under the Global Plan to Stop TB, 2006–2015

NA

0.01c

26%

80% 12 (46)b

32% 9 (11)

12 (37.5)b

1996–2005 comparison

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100% 2.6 (35) 7% 3.2 (3.8) 84% 0.3 (0.6) 50%

61% 1.2 (30) 4% 2.5 (3.4) 74% 0.2 (0.5) 40%

57%

0.4 (0.7)

85%

8% 2.9 (3.4)

100% 3.1 (40)

52%

3.2 (6.1)

81%

7% 29 (36)

93% 24 (354)

NA

NA

NA

Numbers in parentheses indicate the denominator. For DOTS expansion it is the number of new TB cases. For DOTS-Plus it is the total number of detected MDR-TB cases. For PLWHA screened for TB, it is the total number of PLWHA. For PLWHA-offered IPT, it is all PLWHA. For TB patients, HIV tested and counseled, it is TB patients treated under DOTS covered by TB/HIV activities. For TB patients enrolled in ART, it is TB/HIV–positive patients known to be eligible for ART. b Assumes values for 2004 and 2005 as for 2003 as published in the Global Plan. c Refers to number of patients approved by WHO’s Green Light Committee from 2000–2004. d HIV services include testing and counseling and HIV treatment and care services. Abbreviations: ART, antiretroviral therapy; IPT, izoniazid preventive therapy; PLWHA, persons living with HIV/AIDS; MDR-TB, multidrug-resistant TB; NA, data not available, but likely to be very low; SSþ, sputum smear-positive TB; SS
, sputum smear-negative TB. Source: From Ref. 42.

a

Percentage of PLWHA screened for TBd Total number of newly diagnosed and eligible PLWHA offered IPT (millions) Percentage of PLWHA offered IPT Total number of TB patients in DOTS programs, HIV tested, and counseled (millions) Percentage of TB patients treated in DOTS programs, HIV tested, and counseled Total number of TB patients (HIV positive and eligible) in DOTS programs enrolled on ART (millions) Percentage of TB patients (HIV positive and eligible) in DOTS programs enrolled an ART

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Figure 5 Expected numbers of people and patients to be treated in components of the Global Plan to Stop TB, 2006–2015, (scenario 3) related to the management of DOTS plus for the management of MDR-TB (A, B) and to the joint management of TB and HIV/AIDS (C, D, logarithmic scale). Numbers of people and patients are summed by region (A, C) and year (B, D). MDR-TB patients are detected by procedures including drug sensitivity testing. In the context of TB/HIV, testing and counseling is with respect to HIV infection. Abbreviations: PLWHA, persons living with HIV/AIDS; ART, antiretroviral therapy; IPT, izoniazid preventive therapy; MDR-TB, multidrug resistant tuberculosis.

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Figure 6 Expected changes in tuberculosis incidence, prevalence, and deaths from 1990 to 2015, assuming full implementation of the Global Plan to Stop TB, 2006–2015. Changes are expressed as rates (upper row) and numbers (lower row, millions), for scenarios 1 (dotted line), 2 (light continuous line), and 3 (heavy continuous line), and with reference to the targets of halving prevalence and death rates between 1990 and 2015 (horizontal dashed lines).

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Figure 7 Expected annual changes in TB incidence rate by 2015 (measured as the difference between 2014 and 2015), assuming full implementation of the Global Plan to Stop TB, 2006–2015 in seven regions of the world.

would not be reached before 2025. If the rate of decline in mortality slows, as it has in Europe and North America, then the target will be reached later than 2025. In Eastern Europe, but not in Africa, prevalence rates are also expected to remain high compared with 1990 levels. In Eastern Europe, a relatively high proportion of patients have chronic TB, which is commonly MDR. In Africa, patients who are infected with HIV do not suffer from TB for long; their illness typically progresses quickly, and they either are cured or die (21). This bleak outlook for TB control in Africa and Eastern Europe arises in large part from the choice of 1990 as the MDG reference year. In that year, TB incidence rates in these two regions were close to their lowest levels for at least half a century, and most of the recent rise in incidence happened during the 1990s. Although the epidemiology of the recent past is not ignored, the impact of Global Plan in the near future is more relevant here. The same projections also show that, over the 10 years from 2006 to 2015, the impact of the enhanced DOTS strategy, assuming full implementation, would be almost as great in Africa and Eastern Europe as in other regions of the world: a reasonable goal in all regions would be to halve prevalence and death rates between 2005 and 2015 (Fig. 8). To that end, the implementation of the enhanced DOTS strategy will be especially important in Africa and Eastern Europe, where the incremental benefits of enhanced DOTS (scenario 3) compared with sustained DOTS (scenario 2) are greatest. Indeed, the proportional reduction in TB cases under scenario 3 (as compared with scenario 2) would be greater in Eastern Europe than any other region (Fig. 9A). The proportional reduction in deaths would be greatest in Africa (high-HIV countries) and Eastern Europe (Fig. 9B). In other regions of the world, a higher proportion of the benefits to be obtained over the next 10 years come from sustaining what has been achieved over the past 10 years, and TB epidemiology in these other regions, notably

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Figure 8 Expected reductions in prevalence and death rates by 2015, as compared with the estimated rates in (A) Millennium Development Goals baseline year 1990, or (B) with the rates in 2005. Although targets for halving prevalence and death rates between 1990 and 2015 (bars < 0.5) are unlikely to be reached in Africa and Eastern Europe (A), the impact of the Global Plan to Stop TB, 2006–2015 is not expected to be much less in these two regions during the period 2006–2015 (B).

Asia, governs the global trend (Fig. 6). Thus, enhanced DOTS (scenario 3), as compared with sustained DOTS (scenario 2), would save only 2.7 million deaths globally over the next decade. But if scenario 3 is considered to be the logical extension of the program of global DOTS expansion that began in the early 1990s, then enhanced DOTS will save 13.7 million deaths between 2006 and 2015 (compared with scenario 1). In continuing this program of

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Figure 9 (A) TB cases and (B) deaths that would be saved through the implementation of the Global Plan to Stop TB, 2006–2015 (comparing scenarios 2 and 3), for seven regions separately and combined. Bars show the percentage of cases and deaths saved; numbers over the bars are millions of cases and deaths saved by scenario 3 in comparison with scenarios 1 (open bars) and 2 (solid bars).

DOTS expansion, most cases and deaths saved will be in the Southeast Asian and Western Pacific regions (Fig. 9). Two outcomes of the analyses for Africa and Eastern Europe are not visible in the summary statistics (Figs. 6–9). First, while expanding DOTS

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Figure 10 Expected changes in the incidence rate of TB in region ‘‘Africa—high HIV’’ under the Global Plan to Stop TB, 2006–2015 (scenario 3; heavy line), and the different trends in incidence among people with (light line) and without HIV infection (dotted line).

programs are not expected to bring down the overall incidence of TB in eastern and southern Africa (Africa—high HIV) before 2005, the incidence in the HIV-negative population has been, according to model calculations, in continuous decline since 1990 (Fig. 10). Data, rather than models, provide some evidence of a similar decline in the HIV-negative population in Malawi (50,51). Second, DOTS-plus programs using second-line drug regimens in Eastern Europe are expected to reduce deaths from MDR-TB more quickly than the TB death rate overall (so the percentage of TB deaths due to MDR-TB falls; Fig. 11). The incidence of MDR-TB cases has fallen faster than the incidence of all TB in Hong Kong (52), Republic of Korea (53), and Mexico (54), but it is not yet known whether treatment with second-line drugs can disproportionately reduce MDR-TB deaths on a large scale.

VII. Conclusion Although countries of the former Soviet Union suffered big increases in TB incidence during the 1990s, there are strong signs in some, notably Russia, that incidence began falling again at the turn of the millennium. The increase of TB in Africa appears to be slowing, although case reports to 2004 give no indication of when the incidence will peak. In other regions of the world, most importantly in Asia where the majority of new TB patients are found

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Figure 11 Expected changes in the TB death rate in Eastern Europe among all cases (heavy line) and among those with MDR-TB (light line), and the percentage of deaths due to MDR-TB (dotted line, right axis). Abbreviation: MDR, multidrug resistant.

each year, TB continued to decline through the 1990s, albeit slowly. TB incidence was probably still increasing slowly in 2005 throughout the world, whereas the number of deaths may already have begun to fall. These epidemiological trends have undoubtedly been influenced by chemotherapy, which has existed in most countries in some form since the 1950s. But drug treatment delivered via DOTS programs will have had a measurable impact only in countries that achieved high coverage by the mid-1990s. Although there is a great deal of circumstantial evidence that chemotherapy programs can drive TB incidence downwards, more direct, recent demonstrations of the impact of DOTS are restricted to a few countries such as Peru (reduced incidence) and China (reduced prevalence). DOTS programs are likely to have an impact in populations with high rates of HIV infection and MDR-TB, but the evidence remains equivocal. To evaluate the full impact of the DOTS strategy and its extensions, much more effort needs to be given to measurement. The effects of largescale public health programs, such as DOTS, can never be assessed under experimental conditions, but periodic population-based surveys of the prevalence of active disease and infection will show trends, which could be attributable to progress in TB control. TB deaths need to be counted more frequently and more accurately, either as a component of general cause-ofdeath surveys or through systems of routine death registration. The evidence from surveys of prevalence and mortality should be supplemented by fuller

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analyses of the vast body of surveillance data that is routinely collected by national control programs (following the example of Peru). The MDG framework has highlighted the importance of measuring epidemiological impact and, by including TB prevalence and deaths as indicators, has added momentum to the process of evaluation. Although data are being gathered from all these sources, planning for TB control over the next decade and beyond must be done with the evidence at hand. The Global Plan to Stop TB, 2006–2015 has been developed by asking what methods of TB control would be needed, and at what rate they must be implemented, in order to reverse the rise in incidence, and to halve TB prevalence and death rates between 1990 and 2015. The mathematical models used to assess the impact of different control scenarios are heavily influenced by the experiences of Europe and North America since the 1950s; they may omit some important but unknown features of TB epidemiology that now apply in Asia, Africa, or the Americas, such as the changing risks associated with tobacco smoking, air pollution, nutritional disorders, urban crowding, and other factors. With these qualifications, the calculations made for the Global Plan suggest that enhanced DOTS (scenario 3), if fully implemented, would bring down TB incidence long before 2015 (satisfying MDG target 8), although not fast enough to reach the 2050 target for elimination (less than one case per million population). Enhanced DOTS should also, by 2015, halve prevalence and death rates worldwide, and in all major endemic regions except Africa and Eastern Europe. Although Africa and Eastern Europe cannot quickly regain all the ground lost since 1990, the impact of enhanced DOTS over the period 2006–2015 is expected to be almost as big in these two regions as in other regions of the world. Scenario 3 would prevent 2.7 million deaths in comparison with scenario 2 (sustained DOTS), and fewer than one million people would die from TB in 2015. In the larger picture, considering enhanced DOTS as an extension of the project to expand DOTS worldwide since the 1990s, nearly 14 million deaths would be prevented between 2006 and 2015 (comparing scenarios 1 and 3). By 2015, enhanced DOTS should begin to make incremental gains over sustained DOTS that will grow larger in the years beyond. These forecasts are certainly not precise; rather they are intended to be broadly indicative of what can and cannot be achieved, regionally and globally, by implementing the Global Plan over the next 10 years. To do as much as planned, enhanced DOTS must successfully adapt the basic package of care so that it can move beyond the limits of public notification systems. This means forging better links between DOTS programs and other, nonparticipating public clinics and hospitals. It also means engaging medical services in prisons and the armed forces, private clinicians, nongovernmental organizations, mission hospitals, and clinics in the corporate sector. Besides encouraging all medical practitioners to adopt the basic package of care (55–57), DOTS programs must participate in the expansion of health services to serve populations where no

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professional health care is yet available. For example, half the population of Ethiopia has no access to health services and therefore no access to TB diagnosis and treatment. To do better than planned, especially in Africa and Eastern Europe, would require one or more of the following: higher rates of case detection and cure, for smear-positive and smear-negative patients and for those with MDR-TB, achieved in part through active case finding; more widespread use of drug sensitivity testing and second-line drug regimens; more rapid distribution of ART and cotrimoxazole for patients infected with HIV; greater use of preventive therapy for people with and without HIV coinfections; and faster reductions in HIV incidence. Some of these gains could be made more easily with new technology,as proposed in the Global Plan (Table 4). Improved TB diagnostics will probably be the first to reach field application (58). A new drug could improve cure rates by shortening the duration of treatment to one or two months, by increasing treatment success among patients with MDR-TB,

Table 4 Development of New Technology for Tuberculosis Control, as Described in the Global Plan to Stop TB, 2006–2015 By 2000 Vaccines

Drugs

Diagnostics

By 2010

By 2015

Four phase III efficacy Nine candidates in phase II trials; at least trials carried out. One safe, effective, two vaccines in phase licensed vaccine IIb or proof of concept trials by 2003; available by 2015 beginning of phase III trials 27 new compounds One to two new drugs Seven new drugs registered for TB in the TB pipeline registered for TB indication; regimen indication; treatment revolutionized: shortened to 3–4 mo clinical testing of drugs that can shorten treatment to 1–2 mo Predictive test for Rapid culture for case Point of care: rapid LTBI in culture; improved detection and DST demonstration microscopy; phage in demonstration phase detection (þDST); phase and simplified NAAT introduced

Three candidates in phase I trials by end 2005

Abbreviations: DST, drug susceptibility testing; NAAT, nucleic acid amplification test; LTBI, latent tuberculosis infection. Source: From Ref. 46.

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or by reducing the frequency of relapse among patients coinfected with HIV (59). There is no guarantee that a new vaccine will be available before 2015, or that it will have high efficacy against pulmonary TB (60). But if such a vaccine can be made, mass immunization could change the approach to TB control, shifting the emphasis from cure to prevention. Whatever the technological developments, they need to find field application urgently, not just to accelerate progress toward the MDGs, but to provide any hope that TB can be eliminated by 2050. Acknowledgments I thank Bernadette Bourdin, Katherine Floyd, Mehran Hosseini, Knut Lonnroth, Dermot Maher, Eva Nathanson, Andrea Pantoja, Alasdair Reid, and Catherine Watt who helped to compile information and data for this chapter. References 1. World Health Organization. The World Health Report 2004: Changing History. Geneva: World Health Organization, 2004. 2. Jamison DT, Mosley WH, Meashem AR, Bobadilla JL, eds. Disease Control Priorities in Developing Countries. New York: Oxford University Press for the World Bank, 1993. 3. de Jonghe E, Murray CJ, Chum HJ, Nyangulu DS, Salomao A, Styblo K. Costeffectiveness of chemotherapy for sputum smear-positive pulmonary tuberculosis in Malawi, Mozambique and Tanzania. Int J Health Plann Manage 1994; 9:151–181. 4. Murray CJL, De Jonghe E, Chum HJ, Nyangulu DS, Salomao A, Styblo K. Cost effectiveness of chemotherapy for pulmonary tuberculosis in three sub-Saharan African countries. Lancet 1991; 338:1305–1308. 5. World Health Organization. Global Tuberculosis Control: Surveillance, Planning, Financing. Geneva: World Health Organization, 2006:362. 6. Dye C, Watt CJ, Bleed DM, Hosseini SM, Raviglione MC. Evolution of tuberculosis control and prospects for reducing tuberculosis incidence, prevalence, and deaths globally. J Am Med Assoc 2005; 293:2767–2775. 7. www.stoptb.org. 8. Dye C, Scheele S, Dolin P, Pathania V, Raviglione MC. Global burden of tuberculosis: estimated incidence, prevalence, and mortality by country. WHO Global Surveillance and Monitoring Project. J Am Med Assoc 1999; 282:677–686. 9. Corbett EL, Watt CJ, Walker N, et al. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med 2003; 163: 1009–1021. 10. Hudelson P. Gender differentials in tuberculosis: the role of socio-economic and cultural factors. Tuberc Lung Dis 1996; 77:391–400. 11. Borgdorff MW, Nagelkerke NJ, Dye C, Nunn P. Gender and tuberculosis: a comparison of prevalence surveys with notification data to explore sex differences in case detection. Int J Tuberc Lung Dis 2000; 4:123–132. 12. Hamid Salim A, Declercq E, Van Deun A, Saki KAR. Gender differences in tuberculosis: a prevalence survey done in Bangladesh. Int J Tuberc Lung Dis 2004; 8: 952–957. 13. Radhakrishna S, Frieden TR, Subramani R. Association of initial tuberculin sensitivity, age and sex with the incidence of tuberculosis in south India: a 15-year follow-up. Int J Tuberc Lung Dis 2003; 7:1083–1091.

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14. Rieder HL. Epidemiologic Basis of Tuberculosis Control. 1st ed. Paris: International Union Against Tuberculosis and Lung Disease, 1999:1–162. 15. Shilova MV, Dye C. The resurgence of tuberculosis in Russia. Philos Trans R Soc Lond B Biol Sci 2001; 356:1069–1075. 16. Espinal MA, Laszlo A, Simonsen L, et al. Global trends in resistance to antituberculosis drugs. N Engl J Med 2001; 344:1294–1303. 17. World Health Organization IUATALD. Anti-Tuberculosis Drug Resistance in the World: Third Global Report. WHO/IUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance. Geneva: World Health Organization, 2004:299. 18. Dye C, Espinal MA, Watt CJ, Mbiaga C, Williams BG. Worldwide incidence of multidrug-resistant tuberculosis. J Infect Dis 2002; 185:1197–1202. 19. Zignol M, Hosseini MH, Wright A, et al. Global Incidence of Multidrug-Resistant Tuberculosis. J Infect Dis. In Press. 20. Asamoah-Odei E, Garcia Calleja JM, Boerma JT. HIV prevalence and trends in subSaharan Africa: no decline and large subregional differences. Lancet 2004; 364:35–40. 21. Corbett EL, Charalambous S, Moloi VM, et al. Human immunodeficiency virus and the prevalence of undiagnosed tuberculosis in African gold miners. Am J Respir Crit Care Med 2004; 170:673–679. 22. Trunz BB, Fine P, Dye C. Effect of BCG vaccination on childhood tuberculous meningitis and miliary tuberculosis worldwide: a meta-analysis and assessment of cost-effectiveness. Lancet 2006; 367:1173–1180. 23. Rieder HL. BCG vaccines. In: Davies PDO, ed. Clinical Tuberculosis. London: Arnold, 2003:337–353. 24. Dye C, Maher D, Weil D, Espinal M, Raviglione M. Targets for global tuberculosis control. Int J Tuberc Lung Dis 2006; 10:460–462. 25. Styblo K, Bumgarner JR. Tuberculosis can be controlled with existing technologies: evidence. Tuberc Surveill Res Unit Prog Rep 1991; 2:60–72. 26. Styblo K. Epidemiology of Tuberculosis. 2nd ed. The Hague: Royal Netherlands Tuberculosis Association (KNCV), 1991:1–136. 27. Raviglione MC, Uplekar MW. WHO’s new stop TB strategy. Lancet 2006; 367: 952–955. 28. Dye C, Garnett GP, Sleeman K, Williams BG. Prospects for worldwide tuberculosis control under the WHO DOTS strategy. Lancet 1998; 352:1886–1891. 29. Smith KR, Mehta S. The burden of disease from indoor air pollution in developing countries: comparison of estimates. Int J Hyg Environ Health 2003; 206:279–289. 30. Baris E, Ezzati M. Should interventions to reduce respirable pollutants be linked to tuberculosis control programmes? Br Med J 2004; 329:1090–1093. 31. Kolappan C, Gopi PG. Tobacco smoking and pulmonary tuberculosis. Thorax 2002; 57:964–966. 32. Gajalakshmi V, Peto R, Kanaka TS, Jha P. Smoking and mortality from tuberculosis and other diseases in India: retrospective study of 43000 adult male deaths and 35000 controls. Lancet 2003; 362:507–515. 33. Kim SJ, Hong YP, Lew WJ, Yang SC, Lee EG. Incidence of pulmonary tuberculosis among diabetics. Tuberc Lung Dis 1995; 76:529–533. 34. Ponce de Leon A. Tuberculosis and diabetes in southern Mexico. Diabetes Care 2004; 27:1584–1590. 35. Olmos P, Donoso J, Rojas N, et al. Tuberculosis and diabetes mellitus: a longitudinalretrospective study in a teaching hospital. Revista Med Chile 1989; 117:979–983. 36. Cegielski JP, McMurray DN. The relationship between malnutrition and tuberculosis: evidence from studies in humans and experimental animals. Int J Tuberc Lung Dis 2004; 8:286–298.

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37. Coetzee N, Yach D, Joubert G. Crowding and alcohol abuse as risk factors for tuberculosis in the Mamre population. Results of a case-control study. S Afr Med J 1988; 74:352–354. 38. Institute of Medicine. Ending Neglect: The Elimination of Tuberculosis in the United States. Washington, D.C.: Institute of Medicine, 2000. 39. World Health Organization. Public-Private Mix for DOTS. Global progress. Report of the second meeting of the PPM subgroup for DOTS Expansion. WHO/HTM/TB/ 2004.338. 40. Suarez PG, Watt CJ, Alarcon E, et al. The dynamics of tuberculosis in response to 10 years of intensive control effort in Peru. J Infect Dis 2001; 184:473–478. 41. Frieden TR, Fujiwara PI, Washko RM, Hamburg MA. Tuberculosis in New York City—turning the tide. N Engl J Med 1995; 333:229–233. 42. Stop TB partnership and World Health Organization. The Global Plan to Stop TB, 2006–2015. 2006 TB Partnership:Geneva. 43. China Tuberculosis Control Collaboration. The effect of tuberculosis control in China. Lancet 2004; 364:417–422. 44. Aditama TY. Prevalence of tuberculosis in Indonesia, Singapore, Brunei Darussalam, and the Philippines. Tubercle 1991; 72:255–260. 45. Ministry of Health-Republic of Indonesia. Tuberculosis survey in Indonesia, 2004. National Institute of Health Research and Development, Ministry of Health, Jakarta Indonesia 2005:99. 46. Stop TB Partnership and World Health Organization. The Global Plan to Stop TB, 2006–2015. 2006. Stop TB Partnership:Geneva. 47. Blower SM, McLean AR, Porco TC, et al. The intrinsic transmission dynamics of tuberculosis epidemics. Nat Med 1995; 1:815–821. 48. Dye C, Williams BG. Criteria for the control of drug-resistant tuberculosis. Proc Natl Acad Sci USA 2000; 97:8180–8185. 49. Dye C, Espinal MA. Will tuberculosis become resistant to all antibiotics? Proc R Soc London B 2001; 268:45–52. 50. Glynn JR, Crampin AC, Ngwira BM, et al. Trends in tuberculosis and the influence of HIV infection in northern Malawi, 1988–2001. AIDS 2004; 18:1459–1463. 51. Borgdorff MW, Corbett EL, DeCock KM. Trends in tuberculosis and the influence of HIV infection in northern Malawi, 1988–2001. AIDS 2004; 18:1465–1467. 52. Kam KM, Yip CW. Surveillance of Mycobacterium tuberculosis drug resistance in Hong Kong, 1986–1999, after the implementation of directly observed treatment. Int J Tuberc Lung Dis 2001; 5:815–823. 53. Hong YP, Kim SJ, Bai JY, Lew WJ, Lee EG. Twenty-year trend of chronic excretors of tubercle bacilli based on the nationwide tuberculosis prevalence surveys in Korea, 1975–1995. Int J Tuberc Lung Dis 2000; 4:911–919. 54. DeRiemer K, Garcia-Garcia L, Bobadilla-del-Valle M, et al. Does DOTS work in populations with drug-resistant tuberculosis? Lancet 2005; 365:1239–1245. 55. Elzinga G, Raviglione MC, Maher D. Scale up: meeting targets in global tuberculosis control. Lancet 2004; 363:814–819. 56. UN Millennium Project. Investing in strategies to reverse the global incidence of TB. Task Force on HIV/AIDS, Malaria, TB, and Access to Essential Medicines. London: Earthscan, 2005. 57. Stop TB Partnership. Report on the Meeting of the Second ad hoc Committee on the TB Epidemic. Geneva: World Health Organization, 2004:17. 58. www.finddiagnostics.org. 59. www.tballiance.org. 60. www.aeras.org.

2 Bacteriology of Tuberculosis

FADILA BOULAHBAL

LEONID HEIFETS

Mycobacteriology, National Reference TB Laboratory, Institut Pasteur d’Alge´rie, Alger, Alge´rie

Mycobacteriology Clinical Reference Laboratory, National Jewish Medical and Research Center, Denver, Colorado, U.S.A.

I. Mycobacterium tuberculosis Complex A. Taxonomy

The genus Mycobacterium is the only genus in the family of Mycobacteriaceae, which, along with six families of Actinomycetes, belongs to the order of Actinomycetales. The taxonomy and nomenclature of the genus Mycobacterium within this order has been addressed in special reviews (1–4). Hundreds of species of this genus, usually called nontuberculous mycobacteria (NTM) or mycobacteria other than tubercle bacilli, can be found in the environment (water, soil, etc.), and about 60 or 70 of them have been identified (or suspected) as potential human pathogens (5). The elucidation of new mycobacterial species is currently based on a molecular approach, which relies on the definition of species-specific nucleotide sequences, particularly within the hypervariable regions (termed A and B) of the 16S ribosomal DNA molecule. Mycobacterium tuberculosis (complex) and Mycobacterium leprae are known as the only mycobacteria that are not found in the environment, and the only pathogens in this genus transmissible from person to person. The generic term ‘‘tubercle bacilli’’ incorporates at least five species belonging to a group termed the M. tuberculosis complex: M. tuberculosis, Mycobacterium bovis, 29

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Mycobacterium africanum, Mycobacterium canettii, and Mycobacterium microti. The first four of these species are definite human pathogens that can cause tuberculosis (TB), and a few cases of disease in humans caused by M. microti have also been reported. Recently, two additional species have been suggested: Mycobacterium caprae (6) and Mycobacterium pinnipedii (7). bacille Calmette–Gue´rin (BCG), an attenuated M. bovis subspecies, can be found in diagnostic specimens in cases where BCG is used for bladder cancer therapy, or results after BCG vaccination in a disseminated infection (for example, in HIV-positive individuals) or in the so-called ‘‘cold abscesses.’’ BCG is not transmissible from person to person. B. Common Features of the Genus Mycobacterium

1.

2.

3.

4.

5.

6.

7.

Due to the high content of lipids in their cell wall, all mycobacteria are acid-fast bacteria (AFB), which means that special efforts are required to make the dyes penetrate through the bacterial cell wall, and it is difficult to decolorize them with acid–alcohol after they are stained. Mycobacteria are gram-positive rods 1 to 4 mm long and 0.3 to 0.6 mm in diameter; because of their acid fastness they may be seen as clear rod-shaped zones in smears stained by the Gram method. Mycobacteria have a high lipid content in the outer layer of the cell wall, which includes glycolipids and esters of fatty acids with fatty alcohols; one of the water-soluble glycolipids (mycosides), known as ‘‘cord factor,’’ is considered to be related to the virulence of tubercle bacilli. Mycolic acid of the cell wall is considered one of the specific features of this family of bacteria, although this fatty acid can also be found in cell walls of some genuses of aerobic Actinomycetes (Nocardia, Gordonia, Tsukamurella, Rhodococcus, etc.) and in most species of the genus Corynebacterium. Most of the pathogenic mycobacterial species are fastidious with regard to culture conditions. M. tuberculosis will only grow on specially designed culture media, with optimal temperature conditions limited to 35 C to 37 C, optimal pH of 6.4 to 7.4, and the presence of CO2 in the atmosphere for some media. Some species, such as Mycobacterium haemophilum, Mycobacterium ulcerans, Mycobacterium avium spp. paratuberculosis, and Mycobacterium genavense are particularly fastidious. Mycobacteria grow slowly in culture media (generation time for M. tuberculosis is from 12–20 hours), and the colonies do not become visible on solid media before two to three weeks of cultivation; however, a group of mycobacteria called ‘‘rapid-growers’’ may produce visible colonies after only a few days of cultivation. Most of the mycobacterial species are strict aerobes; some M. bovis isolates may grow in an oxygen-reduced atmosphere.

Bacteriology of Tuberculosis 8.

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Members of M. tuberculosis complex, M. avium complex, and a number of other pathogenic mycobacteria are considered facultative intracellular parasites (in macrophages); it is possible that long periods of persistence of the tubercle bacilli in individuals with latent TB may be related to their intracellular survival.

C. Genetics: Typing

The sequencing of the M. tuberculosis (strain H37Rv) genome has been completed (8), indicating that it contains about 4000 genes that encode proteins and about 50 genes that encode RNA other than mRNA. An unusual feature, when compared with other bacteria, is the large number of genes (250) that encode enzymes for the metabolism of fatty acids. Progress in the molecular biology of mycobacteria is essential not only for the current knowledge on the biology of these organisms, but also for practical solutions related to issues such as the development of new rapid methods for diagnosis and detection of drug resistance, as well as for better differentiation between various species (9). Molecular biology tools are also useful for application in modern ‘‘molecular epidemiology’’ (see Chapter 23). This new discipline is based on molecular typing methods of M. tuberculosis strains, or DNA fingerprinting. The DNA-based methods replaced various phenotype characteristics (such as drug susceptibility or resistance patterns and phage typing) used in the past to distinguish between different strains or clinical isolates and for cluster analysis of outbreaks. One of the DNAbased methods, restriction fragment length polymorphism (RFLP) pattern analysis, is based on analysis of strain divergence within the same species in restriction sites (identified by restriction enzymes), leading to changes in the length of fragments between genomes (10). Description of the repetitive insertion sequence IS6110 in M. tuberculosis (11) led to the establishment of the IS6110 RFLP technology, which became the most widely used genotyping method for investigating TB outbreaks (12–15). This technology has been standardized for broad application (16) and is now available in regional laboratories assigned by the Centers for Disease Control and Prevention (CDC) for the evaluation of M. tuberculosis isolates obtained from TB patients in the United States. Other methods of DNA fingerprinting usually employ polymerase chain reaction (PCR), such as spoligotyping, PCR for IS6110 and for other genetic loci, as well as whole-genome fingerprinting. These methods have certain advantages and disadvantages compared with the more traditional IS6110 RFLP analysis in regard to the level of sensitivity of the assay, turnaround time of the report, labor intensity, and cost (17–21). It is important to stress that all these methods require a high level of technical competency in both laboratory procedures and interpretation of results. Therefore, implementation of genotyping procedures should be considered only for large and well-equipped TB laboratories that already have all basic techniques in their arsenal and provide service to a large population of TB patients.

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For more details on the biology of mycobacteria, particularly on the genetics and physiology of M. tuberculosis, please refer to other chapters of this publication and to special reviews in the monograph recently published by the American Society for Microbiology (22). II. Bacterial Populations in Patients A. Latent Tuberculosis Infection

Various aspects of latent tuberculosis infection (LTBI) have been addressed in a recent comprehensive review (23). According to the information presented in this review, the probability of an individual becoming infected with tubercle bacilli depends on a number of factors such as closeness and duration of exposure, the degree of infectiousness of the source (number of bacteria excreted in sputum, involvement of larynx, type of inflammation, and ability to produce aerosols by coughing), actual size of the inhaled infectious dose, ability of the bacterial strain to survive and multiply within the host (so-called fitness of the organism), and the immunological status of the host. It is estimated that only about 10% of infected immunocompetent individuals will develop the active disease during their lifetime. The usual event after infection is the development of a LTBI, which is defined as a clinical condition without clinical or radiological signs of active disease, and is manifested only by a positive tuberculin skin test (23). Persons with LTBI may harbor viable tubercle bacilli for many years in a state of relative dormancy, or rather, as currently defined, in a state of nonreplicating persistence (NRP). This rather descriptive term indicates that the tubercle bacilli are not replicating, with no reference made to the mechanism behind this phenomenon (24). Factors that may induce NRP include depletion of nutrients, shifts in pH, accumulation of growth-inhibiting products, and depletion of oxygen. Extensive research using various in vitro and in vivo models indicates that NRP is associated with certain genetic changes in the physiology of tubercle bacilli. Annually, about one-third, or about 2.5 million, of all new cases of active TB in the world result from activation from LTBI, while the remaining 4 to 6 million cases result from new infection (23). Treatment of LTBI and the mechanism of the NRP status of tubercle bacilli remain among the most important topics of modern TB research. B. Bacterial Population in Patients with Active Tuberculosis

The bacterial population in patients with active TB is quite heterogeneous. It consists of at least four subpopulations: actively metabolizing and relatively rapidly growing bacteria, semidormant bacteria whose growth is partially inhibited by the low pH of the early acute inflammation sites, semidormant bacteria that have occasional short spurts of metabolism in locations other than those with low pH, and bacteria in a dormant state (25,26). Recognition of this diversity is essential to designing appropriate treatment regimens that include drugs active against these subpopulations. The relative sizes of these subpopulations change during the course of the

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disease, and their proportions alter under the effect of drugs implemented for therapy. In addition, the structure of the patient’s bacterial population may be modified by the development of drug resistance. III. Bacteriological Diagnosis of Tuberculosis A. Smear Examination

The bacteriological diagnosis of TB is most commonly based on examination of sputum specimens (smear examination, culture isolation, molecular methods, etc.). Depending on the site of infection, other specimens include various body fluids (pleural, cerebrospinal, synovial, etc.), blood, lymph nodes, and other biopsy specimens. Sputum smear examination for AFB detection is the method most widely used for the provisional diagnosis of pulmonary TB. There are several technical options for this diagnostic tool. The most traditional among them (especially in countries with low resources) is a direct sputum smear stained by the Ziehl–Neelsen method and examined under light microscopy. The sensitivity of this method is limited: the results can be positive if the specimen contains no less than 104 AFB/mL of sputum, with variations depending on the skill of the technologists. Higher sensitivity, perhaps 10-fold greater, compared with the direct method examined after Ziehl– Neelsen stain, can be achieved when a sputum specimen is concentrated and examined after a fluorescent acid-fast stain (for example, with auramine O). Unfortunately, the feasibility of this approach is limited in most laboratories of low-income countries by lack of resources, expertise, and maintenance capabilities. Patients with positive smear results are considered to be the most infectious, and, therefore, their detection in the community is one of the priorities set by World Health Organization (WHO) for TB programs. According to the WHO standards, a definitive TB case is defined as ‘‘a patient who is culture-positive for M. tuberculosis complex’’ (27). The same definition also applies to patients with two AFB-positive sputum smears in countries where the culture isolation procedure is not available (27). It is now well established that AFB smear examination detects no more than 50% of all culture-positive adult patients with pulmonary TB (28). According to a study employing molecular epidemiology methods, the remaining smear-negative (culture-positive) patients represented a source of infection for 17% of all new cases. This conclusion was reached in a situation (in San Francisco) where all the smear-negative patients were detected and treated. It is not clear what role such patients may play as a source of infection when they are undetected and untreated. It is recommended by WHO to expand the methods for bacteriological diagnosis of TB beyond smear examination where resources allow (29). B. Culture Isolation

Detailed protocols for culture isolation, including descriptions of various culture media, methods for processing of the specimens, their applicability

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in different settings, as well as the advantages and disadvantages of different methods, can be found in technical manuals, handbooks, and special reviews (29–32). According to these descriptions, culture isolation of tubercle bacilli from patients’ specimens with subsequent identification procedures is a ‘‘gold standard’’ for the definitive diagnosis of TB. Culture is not only more sensitive than smear examination, but also allows identification of the mycobacterial species and determination of the drug susceptibility pattern of the isolate. The major obstacles to the broad application of culture isolation are the necessity for decontamination of specimens from nonsterile sites, cost, need for appropriate biosafety conditions, and expensive modern technology for rapid detection of mycobacteria in cultures. Processing specimens for cultivation involves aerosol-generating procedures such as homogenization and centrifugation. Therefore, culture isolation should not be considered in laboratories that do not have aerosol-contained centrifuges and other safe equipment and supplies. Besides more complete and accurate diagnosis, culture isolation and subsequent or concurrent drug susceptibility testing (DST) are important for making decisions on suitable therapy, but only if the laboratory reports are timely enough to be useful for adjustment of the treatment regimen. Isolation of the tubercle bacilli on the egg-based culture media most often used around the world [such as Lo¨wenstein-Jensen (L-J)] usually takes four to five weeks, but may take up to eight weeks. Visible colonies of M. tuberculosis can be detected on agar-based media after only two to four weeks of cultivation for most of the isolates, but may take up to six weeks. Even faster detection of growth (one to two weeks for most isolates) can be achieved in automated or semiautomated systems employing liquid selective media, such as BACTEC-460 and -960 (Becton Dickinson, Sparks, Maryland, U.S.A.), BacT/Alert (Biomerieux, Inc., Durham, North Carolina, U.S.A.), and ESP (Trek Diagnostics, Westlake, Ohio, U.S.A.). Each of the liquid medium systems has certain advantages and disadvantages, and the decision for preference is usually made depending on the specific conditions of the laboratory. In most countries, mycobacterial isolation is based on the inoculation of an egg-based medium with homogenized or decontaminated and concentrated sputum specimens, and the methods used for decontamination may vary in different laboratories (29–31). In some countries, it is recommended to use more than one medium for culture isolation. In the United States, it is mandatory to use a combination of solid and liquid media, including an option of combining up to four units of the medium. Detailed protocols on these and other procedures can be found in special reviews and laboratory manuals (29–32). In conclusion, we should stress that culture isolation has obvious advantages over the direct smear examination in regard to the more complete detection of all new TB patients in the community and an opportunity, when combined with DST, for early identification of patients with drug resistance. Nevertheless, so far, direct smear examination remains the only affordable tool for detection of most of the infectious patients in

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low-income countries. Insufficient resources for proper equipment and a safe and efficient laboratory environment, lack of well-trained technical personnel, and general infrastructure problems, limit the use of culture isolation in these countries. Implementation of culture isolation, when resources become available, should be done in a stepwise manner, leaving to the end introduction of the most attractive (and most expensive) rapid methods, such as liquid media systems and molecular methods described below. Among the less expensive solid media, the egg-based (for example, L-J) media are more familiar to most laboratories in the world, and, therefore, the easiest to implement first. Subsequently or simultaneously, the agar-based medium (7H10/7H11) should be considered, because it has an advantage over L-J slants for earlier detection of colonies due to the medium transparency, especially when used in Petri dishes. The disadvantage of the 7H10/7H11 agar medium is that it contains an expensive and difficult to standardize nutrient supplement, oleate-albumin-dextrosecatalase (OADC), and cultivation is required in a 5% to 10% CO2 atmosphere. For future development, the use of a new formulation of agar medium can be considered (33): in this medium OADC is replaced with an animal serum, and CO2 incubators are not required. This medium can be even less expensive than an egg-based medium, especially when used for DST. IV. Methods for Mycobacterium tuberculosis Identification Differentiation of M. tuberculosis complex from other mycobacteria represents an important public health issue, particularly in countries with a high prevalence of diseases caused by NTM. The next step is the determination of the species among the members of M. tuberculosis complex, which in practice usually involves differentiation between M. tuberculosis and M. bovis. A. Conventional Identification Tests

Isolation of M. tuberculosis requires incubation at 35 C to 37 C, while no growth appears at 25 C, 32 C, or 42 C. The buff-colored colonies are always nonpigmented and have a rough, dry surface with irregular edges, and often have a wrinkled surface. It is typical to find serpentine cording in smears made from a broth culture. Results of four tests, with cultures from any medium, may be used for final identification of M. tuberculosis and its differentiation from M. bovis. Identification of M. tuberculosis is based on the following results: positive niacin production, positive nitrate reduction, resistance to 5 mg/mL of thiophen-2-carboxylic acid hydrazide (TCH), and positive pyrazinamidase test. The results of these four tests (30,32,34,35) are reversed for M. bovis. The niacin test can be negative for some M. tuberculosis strains, especially those resistant to isoniazid; this test is more reliable when performed with an L-J culture. The pyrazinamidase test with M. tuberculosis can be negative if the patient has been treated with

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pyrazinamide (PZA) and resistance to this agent has developed. In addition, false-negative results with any of these tests may appear due to (quite common) deviations from the prescribed technique. The Niacin Test

Formerly, this test was relied upon for identification of M. tuberculosis, but rapid methods described below have greatly reduced its value. Laboratories that still use this and other conventional identification methods should be aware that the niacin test can be positive with some mycobacterial species other than M. tuberculosis, such as Mycobacterium simiae, some BCG strains, and some rapidly growing mycobacteria. Many laboratories use three- to four-week-old cultures grown on Middlebrook 7H10 or 7H11 agar, and the test works well in most cases. However, some M. tuberculosis strains do not produce a sufficient amount of niacin on this medium for detection. The frequency of these false-negative results can be decreased if the agar medium is enriched with L-asparagine (0.25%) or its potassium salt (0.1%). False-negative results can be almost completely eliminated by using sixweek-old or older cultures on L-J medium. This can serve as a backup if results with the agar-grown culture after three weeks of cultivation are negative. The presence of some contaminants in the culture may cause false-positive results, so it is necessary to confirm the purity of the culture by examining a smear stained by the Ziehl–Neelsen method. The test is based on detection of niacin in the medium, not in the bacteria. In cases of confluent growth, it is therefore necessary to pierce through the bacterial growth with a pipette to expose the medium. Nitrate Reduction Test

Nitrate reduction test is the second most important conventional test for identifying M. tuberculosis, and particularly for differentiating it from M. bovis. Besides M. tuberculosis, other species (Mycobacterium kansasii, Mycobacterium szulgai, Mycobacterium flavescens, Mycobacterium fortuitum, Mycobacterium terrae, Mycobacterium triviale, Mycobacterium phlei, Mycobacterium smegmatis, and Mycobacterium vaccae) produce nitrate reductase. The test is negative with M. bovis but it can be weakly positive with some BCG strains. The Pyrazinamidase Test

The pyrazinamidase test detects the presence of the enzyme that converts PZA to pyrazinoic acid. Pyrazinamidase can be found in cultures of M. tuberculosis strains susceptible to PZA, but PZA-resistant M. tuberculosis strains do not possess detectable amounts of the enzyme. All M. bovis strains, including BCG, are resistant to PZA, and the organisms show negative results in the pyrazinamidase test. Positive results of these tests confirm M. tuberculosis, while negative results suggest the presence of M. bovis. One must be alert to negative reactions with M. tuberculosis strains resistant to PZA that were isolated from patients previously treated with this drug. M. africanum is susceptible to PZA and is positive in the pyrazinamidase test.

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The Test for Susceptibility to Thiophen-2-Carboxylic Acid Hydrazide

The test for susceptibility to TCH is especially useful for differentiation between M. bovis and the multidrug-resistant strains of M. tuberculosis, because these strains can produce negative results in the three other differentiation tests described above. Only M. bovis strains (including BCG) are susceptible to 1.0 and 5.0 mg of TCH/mL incorporated into Middlebrook 7H10/7H11 agar medium, or in a similar test using L-J medium. B. Rapid Methods

The most widely used rapid identification procedures include cell-wall lipid (mycolic acid) analyses by high-performance liquid chromatography (HPLC), nucleic acid probes, and amplification procedures with raw specimens. In addition, a nucleic acid sequencing test, currently used in only a few laboratories, may have potential for wider use in the future. High-Performance Liquid Chromatography Procedure

This technique is now available in almost all TB laboratories in the United States (36–38). The mycolic acids extracted from mycobacterial cells are converted to esters and subjected to chromatographic separation to detect the characteristic patterns associated with various mycobacterial species. The analysis is based on a comparison of retention time of the peaks and their height ratios. The recent review on HPLC in mycobacteriology describes 63 chromatographic patterns representative of 73 known mycobacterial species (36). Introduction of fluorescence detection instead of ultraviolet spectrophotometry made the method much more sensitive, so that the AFB-positive broth cultures can be used instead of a large harvest from solid media (37), but the sensitivity of this method for detection of mycobacteria directly in sputum specimens remains insufficient to rely upon. More details on cell-wall lipid analysis methods can be found in the reviews (36–38). Nucleic Acid Probes

The AccuProbe technology (Gen-Probe, San Diego, California, U.S.A.) is commercially available for identification of the M. tuberculosis complex, M. avium complex, M. avium, M. intracellulare, M. kansasii, and M. gordonae. The test employs chemiluminescent acridinium ester–labeled single-stranded DNA probe complementary to the rDNA of the target bacteria. The association of the two strands forms a stable hybrid, and chemiluminescence is developed by the addition of hydrogen peroxide and is measured in a luminometer (39). The test can be performed with a culture grown either on solid or in liquid media. With most of the clinical isolates, it takes a minimum of three weeks on 7H11 agar plates and about 10 days in liquid media to achieve growth sufficient for this test. If the test with the M. tuberculosis complex probe is positive, the results are reported as M. tuberculosis complex, because this probe does not distinguish between

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M. tuberculosis and other members of the complex. This type of report is sufficient for timely public health actions and appropriate treatment decisions. Amplification Procedures

The concept of amplification of discrete fragments of bacterial DNA or RNA opened a new opportunity for making the nucleic acid probe hybridization method (described above) highly sensitive, leading to the idea of detection and identification of mycobacteria (particularly M. tuberculosis) directly in the patient’s specimen. A number of amplification systems have been developed recently, both ‘‘in-house’’ assays and commercial systems (40–43). The most popular among them are PCR and Gen-Probe amplified Mycobacterium tuberculosis Direct (MTD) test. The appeal of the amplification methods is their high sensitivity, allowing detection of only a few bacterial cells in a raw specimen, which means that diagnosis of TB can be completed in a few days or perhaps hours after arrival of a specimen in the laboratory. The techniques are very expensive and should be used in addition to other methods when their use is fully justified. To avoid false-positive results, these methods should not be used in patients who have had a history of TB. Other shortcomings are related mainly to the low sensitivity of these methods for smear-negative (culture-positive) sputum specimens—only 70% or less. The primary reason for using any of the amplification systems is to provide rapid differentiation between M. tuberculosis and NTM in a smear-positive sputum specimen, so that necessary actions, including a patient’s isolation and treatment, can be carried out without delay. The insufficient sensitivity and specificity of the new methods for smear-negative sputum specimens suggests the use of amplification techniques for broth cultures at the earliest possible detection of growth in addition to and/or instead of a test with raw specimens (41). C. Nucleic Acid Sequencing

Hypervariable regions of the 16S rRNA molecule have been found to be useful in the identification of mycobacterial species (44–46). The identification is based on comparison of the isolate with known sequences. Among the disadvantages of this procedure is the high cost, insufficient standardization of the method, and limited availability of libraries of mycobacterial species. Nevertheless, in the near future, this procedure could prove valuable to the reference laboratories dealing with a substantial number of NTM. At the same time, other less costly rapid methods may have advantages for the specific purpose of differentiating between M. tuberculosis and NTM. V. Detection of Drug Resistance A. General Concepts

Correct implementation of effectively supervised therapy programs is indispensable to the prevention of epidemics of drug-resistant TB. In addition, DST, especially in new patients, can be an effective tool in parts of the world

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where an increase in prevalence of multidrug-resistant TB (MDR-TB) is already taking place. Unfortunately, this measure can only be applied in laboratories that perform cultivation of tubercle bacilli, and have sufficient resources, expertise, and an appropriate biosafety environment. Therefore, in many countries, detection of patients with drug resistance is based on a rather empirical approach. Drug resistance, particularly multidrug resistance, is suspected in patients who fail to respond to the standard treatment regimen. In such cases, an alternative treatment regimen is administered on the assumption that the patient’s isolate is resistant to the first-line drugs. In countries that have TB laboratories with limited capabilities, specimens are often submitted to the laboratory for DST only if the patient fails to respond to the initial standard treatment regimen. Either of these options can be unsafe and costly: there is danger for individual patients who may receive inappropriate treatment, and extra cost for society because of the prolonged period during which a patient with MDR-TB is infectious. Management of patients with MDR-TB can be much more expensive than the cost of DST of the initial isolates from all new patients. Therefore, when resources become available, development of an appropriate laboratory system in countries with growing rates of drug resistance should be among the priorities of national programs (29). In the meantime, systematically conducted epidemiological surveys to evaluate the dynamics of drug resistance prevalence in different countries are recommended for identification of problematic areas and proper adjustment of the local TB control programs (47). The DST system is most likely to be affordable if it is based on direct delivery of raw specimens to a central mycobacteriology laboratory that has a large operational volume and well-trained personnel, and is properly equipped. Unfortunately, this option is currently difficult to implement in large lowincome countries with underdeveloped general infrastructure. The classical definition of a drug-resistant strain of M. tuberculosis is that it is significantly different by the degree of susceptibility from a wild strain that has never come into contact with the drug (48,49). The drug concentrations to distinguish susceptible and resistant strains (so-called ‘‘critical concentrations’’) should be somewhere between the highest minimal inhibitory concentration (MIC) found among the wild strains and the lowest MIC found among the isolates considered resistant. Progress in molecular biology may provide a new definition of drug resistance, but may also raise new questions to be addressed, especially considering that resistance to some drugs has more than one genetic mechanism responsible for low and high levels of resistance (50,51). Different methods for M. tuberculosis DST, as well as their advantages and disadvantages, have been previously discussed in detail (52–55). The main requirement for a DST is the ability to distinguish between susceptible and resistant M. tuberculosis strains, which can be reliably achieved by the traditional strategy based on cultivation. Newer molecular biology– based methods for the detection of mutations associated with drug resistance offer several advantages over the conventional phenotypic method,

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including: (i) possible availability of the results in a matter of hours or days, (ii) better reproducibility, especially in cases of low degree of resistance, and (iii) ability to work with poorly growing and/or mixed cultures. On the other hand, classical phenotypic methods, which involve culturing mycobacteria in the presence of drugs under standardized conditions to detect inhibition of growth, offer several advantages; these methods are less expensive, which makes them more affordable in resource-limited settings. B. Testing on Solid Media

Drug susceptibility methods based on mycobacterial cultivation on solid media, either egg or agar based, can be performed as a direct or indirect test. In the direct test, a set of drug-containing and drug-free media is inoculated directly with a concentrated specimen. An indirect test is the inoculation of the media with a pure culture, and it is classically performed with a bacterial suspension made from growth on solid media (L-J, or 7H10 or 7H11 agar). However, a 7H9 broth culture can also be used as an inoculum when it is grown within five to eight days up to the turbidity of a McFarland Standard No. 1 (about 108 CFU/mL). An advantage of the direct over the indirect test is that the results are available sooner and better represent the patient’s original bacterial population. If the results of the direct test are not valid because there is insufficient or excessive growth in drug-free controls, or there is heavy contamination, the test must be repeated with a pure culture, i.e., as an indirect test. Three methods were originally suggested by the WHO panel for starch-free L-J medium: (i) the proportion method, (ii) the resistance ratio method, and (iii) the absolute concentration method (48,49). The option of using agar medium instead of L-J is little known in laboratories outside the United States. More details on these and other techniques can be found in the CDC manual (30) and other publications (52–55). An advantage of performing tests on agar plates is that the final results can be reported within three weeks instead of four to six weeks or more, as is necessary when using the L-J medium. According to the practices of the TB laboratories in the United States, three weeks of total turnaround time for a direct test on agar plates provides an advantage over the indirect test, which requires initial isolation followed by a susceptibility procedure, with a total turnaround time of six weeks on agar medium and 10 to 12 weeks on L-J medium for most isolates. A significant disadvantage of this method is that cultivation on 7H10 or 7H11 agar requires an incubator that can provide 5% to 10% CO2. This problem can be addressed with use of the new agar medium (33). C. Indirect Test in Liquid Medium: BACTEC-460 Method

New automated liquid medium systems (MB/BacT, MGIT-960, ESP, etc.) were introduced recently, but most of the experience has been accumulated by using the radiometric BACTEC-460 system. Technology for liquid media systems other than BACTEC-460 is based on similar principles and can be found in appropriate manufacturer’s inserts. The 7H12 broth in 12B

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vials (4.0 mL in each) is composed of 7H9 broth base, casein hydrolysate, bovine serum albumin, catalase, and 14C-fatty acid. Consumption of the 14 C-substrate by the growing bacteria results in release of the 14CO2, the amount of which is expressed by the instrument as a growth index (GI) on a scale of 0 to 999. In the presence of an antimicrobial agent, susceptibility is detected by the inhibition of daily GI increases (56–58). The major advantage of this technique is the ability to detect growth, and its inhibition earlier than by other means. An indirect DST in this system usually required an average of 9.3 days (58). The overall mean time for primary isolation plus indirect testing was 18 days in a cooperative study by five institutions (56). The major disadvantage of the BACTEC-460 system is the problem of disposing large volumes of radioactive materials (12B vials), even though radioactivity is very low. Another disadvantage is the cost, which is much higher than for solid media, but is less expensive than the newer nonradioactive liquid medium systems mentioned above. Technical details on use of the BACTEC-460 system can be found in published reviews and in the manufacturer’s manuals. D. A Test in Mycobacterial Growth Indicator Tubes

The nonradioactive automated BACTEC-960 system with mycobacterial growth indicator tubes from Becton Dickinson is another option for performing an indirect test in a liquid medium with five first-line drugs. Comparison of this method with the BACTEC-460 system (59), as well as with the agar proportion method, indicates that this new method is quite promising. Further studies in different laboratory settings with a large number of clinical isolates will probably be required before this method is considered as reliable as the proportion method on solid media or the BACTEC-460 method. E. Molecular Approaches

Molecular biology–based methods can be divided into two categories: phenotypic and genotypic. In view of the current limitations for their worldwide applicability, only a very basic listing of these methods is provided here; readers may find more detailed descriptions in special reviews (54,60–63). Phenotypic Methods

New phenotypic methods, as well as the traditional phenotypic cultivation methods addressed above, target detection of drug resistance regardless of its genetic basis. Unlike the traditional techniques, new methods employ molecular indicators of changes in bacterial metabolic activity related to the development of drug resistance. The following procedures can be classified in this category: bioluminescence assay of adenosine triphosphate (64), some colorimetric techniques (65,66), flow cytometry (67,68), quantitation of mycobacterial antigens in agglutination with beads coated with polyclonal antibodies (69), luciferase reporter phages test (70,71), and phage-based assays (72,73). Among other suggestions is the so-called microscopic observation drug susceptibility (74–76).

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These methods are based on current knowledge regarding mutations in specific genes responsible for resistance to different antimicrobial agents (50,51): isoniazid—katG, inhA, kasA, cpM; rifampicin—rpoB; streptomycin—rpsL; ethambutol—group emb; PZA—pncA; and quinolones—gyrA and gyrB. The usual first step in most of the genotypic methods for detection of drug resistance is amplification of the corresponding DNA segments. With this approach, there is a tendency to perform the test with the raw specimen, which may provide the main advantage of such methods—minimizing the turnaround time. Development of these methods and their specifics has been addressed in a number of reviews (50,51,54,55,60,77,78). Most attention has been given in these reviews to the following methods: automated DNA sequencing, PCR single-strand confirmation polymorphism, PCR-heteroduplex formation, and Line Probe Assay. Oligonucleotide ligation assay using DNA microchips is a new, rapidly developing approach (79,80). Another new suggestion is based on the combined use of two microassays for detection of resistance to rifampicin and isoniazid (81). All these and other novel methods represent an obvious interest for future development of methods for rapid detection of drug resistance, but before any of them is introduced for routine use in a clinical laboratory, their justification should be based on sensitivity and specificity analyses in comparison with the most advanced conventional methods (for example, direct test on solid media), total turnaround time, total cost (including labor), cost-effectiveness analyses, and proper qualification of the laboratory. It is important that such methods, at least initially, are introduced in addition to, not instead of, the well-standardized conventional protocols. References 1. Goodfellow M, Wayne LG. Taxonomy and nomenclature. In: Ratledge C, Stanford J, eds. The Biology of the Mycobacteria. 1. 1. London, England: Academic Press Inc., Ltd., 1982:471–521. 2. Woods GL, Washington JA. Mycobacteria other than Mycobacterium tuberculosis: review of microbiologic and clinical aspects. Rev Infect Dis 1987; 9:275–294. 3. Goodfellow M, Magee JG. Taxonomy of mycobacteria. In: Gangadharam PRJ, Jenkins PA, eds. Mycobacteria: Basic Aspects. New York, New York: Chapman and Hall (International Thomson Publishing), 1998:1–71. 4. Tortoli E. Impact of genotypic studies on mycobacterial taxonomy: the new mycobacteria of 1990s. Clin Microbiol Rev 2003; 16:319–354. 5. Heifets L. Mycobacterial infections caused by nontuberculous mycobacteria (NTM). Semin Resp Crit Care Med 2004; 25(3):283–295. 6. Aranaz A, Cousins D, Mateos A, Domonguez L. Evaluation of M. tuberculosis subsp. caprae to species rank as M. caprae comp. nov. sp. Int J Syst Evol Microbiol 2003; 53:1785–1789. 7. Cousins DV, Bastida R, Cataldi A, et al. Tuberculosis in seals caused by a novel member of Mycobacterium tuberculosis complex: M. pinnipedii sp. nov. Int J Syst Evol Microbiol 2003; 53:1305–1314.

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8. Cole ST, Brosch R, Parkhill J, et al. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 1998; 393:537–544. 9. Cole ST. Comparative mycobacterial genomics as a tool for drug target and antigen discovery. Eur Respir J 2002; 20:78S–86S. 10. Tenover TC, Arbet RD, Goering V, et al. Interpreting chromosomal DNA restriction pattern produced by pulsed-field gel electrophoresis criteria for bacterial strain typing. J Clin Microbiol 1995; 33:2233–2239. 11. Thierry D, Cave MD, Eisenach KD, et al. IS6110, an IS-like element of M. tuberculosis complex. Nucleic Acids Res 1990; 18:188. 12. Poulet S, Cole ST. Characterization of the highly abundant polymorphic GC-richrepetitive sequence (PGRS) present in M. tuberculosis. Arch Microbiol 1995; 163: 87–95. 13. van Soolingen D. Molecular epidemiology of tuberculosis and other mycobacterial infections: main methodologies and achievements. J Intern Med 2001; 349:1–26. 14. Small PM, Hopewell PC, Singh S, et al. The epidemiology of tuberculosis in San Francisco: a population-based study using conventional and molecular methods. N Engl J Med 1994; 330:1703–1709. 15. DeRiemer K, Daley CL. Tuberculosis transmission based on molecular epidemiologic research. Sem Resp Crit Care Med 2004; 25(3):297–306. 16. van Embden JD, Cave MD, Crawford JT, et al. Strain identification of M. tuberculosis by DNA fingerprinting: recommendations for a standardized methodology. J Clin Microbiol 1993; 31:406–409. 17. Groenen PM, Bunschoten AE, van Soolingen D, van Embden JD. Nature of DNA polymorphism in the direct repeat cluster of M. tuberculosis: application for strain differentiation by novel typing method. Mol Microbiol 1993; 10:1057–1065. 18. Haas WH, Butler WR, Woodley CL, Crawford JT. Mixed-linker polymerase chain reaction: a new method for fingerprinting of M. tuberculosis complex isolates. J Clin Microbiol 1993; 31:1293–1298. 19. Kato-Maeda M, Rhee JT, Gingeras TR, et al. Comparing genomes within the species of M. tuberculosis. Genome Res 2001; 11:547–554. 20. Kremer K, van Soolingen D, Frothingham R, et al. Comparison of methods based on different molecular epidemiological markers for typing complex strains: inter-laboratory study of discriminatory power and reproducibility. J Clin Microbiol 1999; 37:2607–2618. 21. Supply P, Lesjean S, Savine E, et al. Automated high throughout genotyping for study of global epidemiology of M. tuberculosis based on mycobacterial interspersed repetitive units. J Clin Microbiol 2001; 39:3563–3571. 22. Cole ST, Eisenach KD, McMurray DN, Jackobs WR, eds. Tuberculosis and the Tubercle Bacilli. Washington, DC: ASM Press, 2005. 23. Nuermberger E, Bishai WR, Grosset JH. Latent tuberculosis infection. Sem Resp Crit Care Med 2004; 25(3):317–336. 24. Wayne LG, Sohaskay CD. Nonreplicating persistence of M. tuberculosis. Annu Rev Microbiol 2001; 55:139–163. 25. Mitchison DA. The action of antituberculosis drugs in shout-course chemotherapy. Tubercle 1985; 66:219–225. 26. Mitchison DA. Role of individual drugs in the chemotherapy of tuberculosis. Int J Tuberc Lung Dis 2000; 4:796–806. 27. Harries A, Maher D, Graham S. TB/HIV: a Clinical Manual. 2d ed. Geneva: World Health Organization, 2004. 28. Behr MA, Warren SA, Salamon H, et al. Transmission of M. tuberculosis from patients smear-negative for acid-fast bacilli. Lancet 1999; 353:444–449.

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29. World Health Organization. An Expanded DOTS Framework for Effective Tuberculosis Control. Geneva: WHO/CDS/TB/2002.297, 2002. 30. Kent PT, Kubica JP. Public Health Mycobacteriology: a Guide for the level III Laboratory. Atlanta: Center for Disease Control, 1985. 31. Hall GS. Primary processing of specimens, and isolation and cultivation of mycobacteria. Clin Lab Med 1996; 16(3):551–568. 32. Heifets L, Desmond E. Clinical mycobacteriology (tuberculosis) laboratory: services and methods (Chapter 4). In: Cole ST, Eisenach K, McMurray DN, Jackobs WR, eds. Tuberculosis and Tubercle Bacilli. Washington, DC: ASM Press, 2005:49–69. 33. Heifets L, Sanchez T. New agar medium for mycobacteria (HSTB). US Patent 6,579,694 B2; June 17, 2003. 34. Witebsky FG, Kruczak-Filipov P. Identification of mycobacteria by conventional methods. Clin Lab Med 1996; 16:569–602. 35. Heifets L, Jenkins PA. Speciation of mycobacteria in clinical laboratories. In: Gangadharam PRJ, Jenkins PA, eds. Mycobacteria: Basic Aspects. Vol. 1. New York: Chapman & Hall, 1998:308–350. 36. Butler WR, Guthertz LS. Mycolic acid analysis by high-performance liquid chromatography for identification of Mycobacterium species. Clin Microbiol Rev 2001; 14(4):704–726. 37. Jost KC Jr., Dunbar DF, Barth SS, Headley VL, Elliot LB. 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 1995; 33:1270–1277. 38. Roberts GD, Bo¨ttger EC, Stockman L. Rapid methods for the identification of mycobacterial species. Clin Lab Med 1996; 16:603–616. 39. Arnold LJ, Hammond PW, Wiese WA, Nelson NC. Assay formats involving acridinium-ester-labeled DNA probes. Clin Chem 1989; 35:1588–1594. 40. Eisenach KD, Sifford MD, Cave MD, Bates JH, Crawford JT. Detection of Mycobacterium tuberculosis in sputum samples using polymerase chain reaction. Am Rev Resp Dis 1991; 144:1160–1163. 41. Forbes BA, Hicks KES. Direct detection of Mycobacterium tuberculosis in respiratory specimens in a clinical laboratory by polymerase chain reaction. J Clin Microbiol 1993; 31:1688–1694. 42. Shinnick TM, Jonas V. Molecular approach to the diagnosis of tuberculosis. In: Bloom BR, ed. Tuberculosis: Pathogenesis, Protection, and Control. Washington, DC: ASM Press, 1994:517–530. 43. Desmond E, Loretz K. Use of the Gen-Probe amplified Mycobacterium tuberculosis direct test for early detection of Mycobacterium tuberculosis in BACTEC 12B medium. J Clin Microbiol 2001; 39(5):1993–1995. 44. Rogall T, Flohr T, Bo¨ttger EC. Differentiation of Mycobacterium species by direct sequencing of amplified DNA. J Gen Microbiol 1990; 136:1915–1920. 45. Kirschner P, Springer B, Vogel U. Genotypic identification of mycobacteria by nucleic acid sequence determination: report of a two-year experience in a clinical laboratory. J Clin Microbiol 1993; 31:2882–2889. 46. Kirschner P, Meier A, Bo¨ttger EC. Genotypic identification and detection of mycobacteria facing novel and uncultured pathogens. In: Pershing DH, Tenover F, White TJ, eds. Diagnostic Molecular Microbiology. Washington, DC: American Society for Microbiology, 1993:173–190. 47. Espinal MA, Laszlo A, Simonsen L, et al. Global trends in resistance to tuberculosis drugs. N Engl J Med 2001; 344:1294–1303.

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48. Canetti G, Fox W, Khomenko A, et al. Advances in techniques of testing mycobacterial drug sensitivity and the use of sensitivity tests in tuberculosis control programs. Bull World Health Org 1969; 41:21–43. 49. Canetti G, Froman S, Grosset J, et al. Mycobacteria: laboratory methods for testing drug sensitivity and resistance. Bull World Health Org 1963; 29:565–578. 50. Telenti A. Genetics of drug resistance in tuberculosis. Clin Chest Med 1997; 18: 55–64. 51. Takiff HE. The molecular mechanisms of drug resistance in M. tuberculosis (Chapter 6). In: Bastian I, Portaels F, eds. Multi-drug Resistant Tuberculosis. The Netherlands: Kluwer Academic Publishers, 2000:77–114. 52. Heifets L. Drug susceptibility tests in the management of chemotherapy of tuberculosis (Chapter 3). In: Heifets LB, ed. Drug Susceptibility in the Chemotherapy of Mycobacterial Infections. Boca Raton, FL: CRC Press, 1991:89–121. 53. Heifets L. Drug susceptibility testing in mycobacteriology. Clin Lab Med 1996; 16:641–656. 54. Heifets L, Cangelosi GA. Drug susceptibility testing of Mycobacterium tuberculosis—a neglected problem at the turn of the century. Int J Tuberc Lung Dis 1999; 3(7): 1–18. 55. Parsons LM, Somoskovi A, Urbanchzik R, Salfinger M. Laboratory diagnostic aspects of drug resistant tuberculosis. Front Biosci 2004; 9:2086–2115. 56. Roberts G, Goodman NL, Heifets L, et al. Evaluation of the BACTEC radiometric method for recovery of mycobacteria and drug susceptibility testing of M. tuberculosis from acid-fast smear-positive specimens. J Clin Microbiol 1983; 18:689–696. 57. Siddiqi SH, Libonati JP, Middlebrook G. Evaluation of rapid radiometric method for drug susceptibility testing of M. tuberculosis. J Clin Microbiol 1981; 13: 908–912. 58. Heifets L. Rapid automated method (BACTEC system) in clinical mycobacteriology. Sem Respir Med 1986; 1(4):242–249. 59. Bemer PF, Palicova S, Rusch-Gerdes H, et al. Multicenter evaluation of fully automated BACTEC Mycobacteria Growth Indicator Tube 960 system for susceptibility testing of Mycobacterium tuberculosis. J Clin Microbiol 2002; 40(1):150–154. 60. Palomino JC. Novel rapid antimicrobial susceptibility tests for M. tuberculosis (Chapter 9). In: Bastian I, Portaels F, eds. Multi-drug Resistant Tuberculosis. The Netherlands: Kluwer Academic Publishers, 2000:145–162. 61. Ramaswamy S, Musser JM. Molecular genetic basis of antimicrobial agent resistance in M. tuberculosis. Tuberc Lung Dis 1998; 79:3–29. 62. Zhang A, Telenti A. Genetics of drug resistance in M. tuberculosis. In: Hatfull GF, Jacobs WR, eds. Molecular Genetics of Mycobacteria. Washington, DC: ASM Press, 2000:225–254. 63. Telenti A, Tenover FC. Genetic methods for detecting bacterial resistance genes. In: Lewis K, Salyers AA, Taber HW, Wax RG, eds. Bacterial Resistance to Antimicrobials. New York: Marcel Dekker, Inc., 2002:239–264. 64. Nillson LE, Hoffner SE, Ansehn S. Rapid susceptibility testing of M. tuberculosis by luminescence assay of mycobacterial ATP. Antimicrob Agents Chemother 1988; 32:1208–1212. 65. Franzblau SG, Witzig RS, McLaughlin JC, et al. Rapid, low-technology MIC determination with clinical M. tuberculosis isolates by using the microplate alamar blue assay. J Clin Microbiol 1998; 36:362–366. 66. Palomino JC, Portaels F. Simple procedure for drug susceptibility testing of M. tuberculosis using a commercial colorimetric assay. Eur J Clin Microbiol Infect Dis 1999; 18:380–383.

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67. Kirk SM, Schell RF, Moore AV, et al. Flow cytometric testing of susceptibility of M. tuberculosis isolates to ethambutol, isoniazid, and rifampin in 24 hours. J Clin Microbiol 1998; 36:1568–1573. 68. Moore AV, Kirk SM, Callister SM, et al. Safe determination of susceptibility of M. tuberculosis to antimicrobial agents by flow cytometry. J Clin Microbiol 1999; 37:479–483. 69. Drowart A, Cambasso CL, Huygen K, et al. Detection of rifampicin and isoniazid resistance of M. tuberculosis by particle counting immunoassay (PACIA). Int J Tuberc Lung Dis 1997; 1:284–288. 70. Jacobs W Jr., Barletta WR, Bloom BR Jr., et al. Rapid assessment of drug susceptibilities of M. tuberculosis by means of luciferase reporter phages. Science 1993; 260:819–822. 71. Riska PF, Su Y, Bardarov S, et al. Rapid film-based determination of antibiotic susceptibilities of M. tuberculosis strains by using a luciferase reporter phage and the Bronx box. J Clin Microbiol 1999; 37:1144–1149. 72. Wilson SM, al-Suwaidi Z, McNerney R, et al. Evaluation of a new rapid bacteriophage-based method for the drug susceptibility testing of Mycobacterium tuberculosis. Nat Med 1997; 3:465–468. 73. Albert H, Trollip AP, Mole RJ, et al. Rapid indication of multidrug-resistant tuberculosis from liquid cultures using FASTPlaque TB-RIFTM, a manual phage-based test. Int J Tuberc Lung Dis 2002; 6:523–528. 74. Caviedes L, Lee TS, Gilman RH, et al. Rapid, efficient detection and drug susceptibility testing of M. tuberculosis in sputum by microscopic observation if broth cultures. J Clin Microbiol 2000; 38:1203–1208. 75. Park WG, Bishai WR, Chaisson RE, Dorman SE. Performance of microscopic observation drug susceptibility assay in drug susceptibility for M. tuberculosis. J Clin Microbiol 2002; 40:4750–4752. 76. Moor DAJ, Mendoza D, Gilman RH, et al. Microscopic observation drug susceptibility assay, a rapid, reliable diagnostic test for multidrug-resistant tuberculosis in resource-poor setting. J Clin Microbiol 2004; 42(10):4432–4437. 77. Alcaide F, Telenti A. Molecular techniques in the diagnosis of drug-resistant tuberculosis. Ann Acad Med 1997; 26:647–650. 78. Drobniewski FA, Wilson SM. The rapid diagnosis of isoniazid and rifampicin resistance in M. tuberculosis—a molecular story. J Med Microbiol 1997; 47:189–196. 79. Michailovich V, Lapa S, Gryadunov D, et al. Identification of rifampin-resistant M. tuberculosis strains by hybridization, PCR, and ligase detection reaction on oligonucleotide microchips. J Clin Microbiol 2001; 39:2531–2540. 80. Deng J-Y, Zhang X-E, Lu H-B, et al. Multiplex detection of mutations in clinical isolates of rifampin-resistant M. tuberculosis by short oligonucleotide ligation assay on DNA chips. J Clin Microbiol 2004; 42(10):4850–4852. 81. Nikolayevsky V, Brown T, Balabanova Y, et al. Detection of mutations associated with isoniazid and rifampin resistance in M. tuberculosis isolates from Samara region, Russian Federation. J Clin Microbiol 2004; 42(10):4498–4502.

3 Genomics and Evolution of Tubercle Bacille

VE´RONIQUE VINCENT

MARIA-CRISTINA GUTIE´RREZ

Stop TB Department, World Health Organization, Geneva, Switzerland

Laboratoire de Re´fe´rence des Mycobacte´ries, Institut Pasteur, Paris, France

ROLAND BROSCH Unite´ de Ge´ne´tique Mole´culaire Bacte´rienne, Institut Pasteur, Paris, France

I. Introduction Soon after the discovery of the bacterial agent of tuberculosis by Robert Koch in 1888, Lehmann and Neumann formally described Mycobacterium tuberculosis (1). By the early 1900s, culture techniques and bacteriological tests allowed the differentiation of M. tuberculosis from Mycobacterium bovis by growth rate, colonial morphology, biochemical characteristics, and behavior in experimental animals (2). According to the same criteria, Mycobacterium microti and Mycobacterium africanum were identified in the 1950s and in the 1970s, respectively. Moreover, serial passages of a M. bovis strain over 13 years on potato slices soaked in ox bile and glycerol led Calmette and Gue´rin to the selection of a strain that lost its virulence and was used for human vaccine purposes, beginning from 1921. DNA/DNA hybridization studies showed a high level of genomic relatedness among the above bacille, indicating that they all belong to a single species (3). Sequence analyses confirmed these data, showing that tubercle bacille share great genetic similarity, seen by homology at the DNA level of greater than 99% (4–6). However, some particular genetic and phenotypic characteristics based mainly on different host preferences have led researchers to maintain 47

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the traditional species names, and to create additional ones. The M. tuberculosis complex now encompasses M. tuberculosis, M. bovis, M. africanum (7), M. microti (8), Mycobacterium pinnipedii (9), and Mycobacterium caprae (10). In this chapter, the additional agent of tuberculosis, Mycobacterium canettii (11), is not included in the designation ‘‘M. tuberculosis complex’’ and will be discussed separately. II. The Genome Sequence and Biology of Mycobacterium tuberculosis Until a few years ago, M. tuberculosis was called the ‘‘genetically intractable organism’’ (12). With the development of genome sequencing, a growing body of information became available in the last 10 years. Genomics, the systematic analysis of the complete genome by means of DNA sequencing and bioinformatics, generates complete data sets of genes, proteins, and antigens, allows in vitro reconstruction of evolution, and provides rich biological, evolutionary, and medical knowledge. Five complete genome sequences of pathogenic mycobacteria have been published (two for M. tuberculosis, one for M. bovis, one for Mycobacterium leprae, and one for Mycobacterium paratuberculosis) (6,13–16), and several other mycobacterial sequencing projects [Mycobacterium abscessus, Mycobacterium avium, M. bovis bacille Calmette–Gue´rin (BCG), Mycobacterium marinum, M. microti, Mycobacterium smegmatis, and Mycobacterium ulcerans] are either in the finishing phase or have been completed, awaiting publication (17). The M. tuberculosis H37Rv genome consists of 4,411,532 base pairs (bp) containing approximately 4000 genes encoding proteins and 50 genes encoding RNAs (15,18,19). Similarly to other prokaryotes, a 91% potential coding capacity and gene density of one gene for 1.1 kb are found. The genome sequence highlighted several characteristics of the biology of M. tuberculosis. 1.

M. tuberculosis differs radically from other bacteria in that at least 8% of its coding capacity is dedicated to lipid metabolism. The genome reveals more genes encoding potential lipid biosynthetic activities than there are known products in in vitro–grown tubercle bacille, thus raising the intriguing possibility that many more novel lipids and polyketides remain to be found. Moreover, numerous genes and proteins associated with lipolytic functions seem to enable M. tuberculosis to degrade exogenous lipids and sterols from host tissues. Support for this proposal is available because Wheeler et al. have reported that mycobacteria obtained from infectedtissuescanavidlydegradeexogenouslipidsandcontribute to energy metabolism (20,21). In addition to the classical b-oxidation cycle catalyzed by the multifunctional FadA/FadB proteins, the genome sequence suggests that alternative lipid oxidation pathways may well exist. A striking level of redundancy in

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lipid metabolic genes was apparent in the M. tuberculosis H37Rv genome, with 36 fadD alleles encoding acyl-CoA synthase, 36 fadE genes encoding acyl-CoA dehydrogenase, and 21 echA genes encoding enoyl-CoA hydratase/isomerase (15). The apparent redundancy in lipid enzymes may, however, need to be readdressed in light of the recent work on the fadD genes. Gokhale and coworkers have shown that some of the fadD alleles do not encode fatty acyl-CoA ligases, but instead code for a new class of fatty acyl-AMP ligases that are linked to a proximal pks gene encoding a unique polyketide synthase (22). It is therefore possible that the apparent redundancy in lipid enzymes hides novel enzyme activities. As another example, the genome comparison of M. tuberculosis H37Rv and the more distantly related Corynebacterium glutamicum has greatly helped to identify the gene encoding the condensase, which is responsible for the final condensation step in mycolic acid biosynthesis. Although M. tuberculosis harbors several pks genes encoding various polyketide synthases, C. glutamicum only shows one pks gene ortholog of pks13. Because both mycobacteria and corynebacteria produce mycolic acids, Pks13 that contains the four catalytic domains theoretically required for the condensation reaction was selected as the candidate condensase. These predictions were then experimentally confirmed. Because mycobacteria, in contrast to corynebacteria, are not viable without mycolic acids, Pks13 is also a promising target for the development of new antimycobacterial drugs (23). In addition to electron transport chains using oxidative phosphorylation, components of several anaerobic electron-transport chains were identified. The dual presence of these energy-generation systems allows M. tuberculosis to adapt its metabolism to environmental changes, actively growing in an oxygen-rich lung cavity on the one hand or surviving in oxygen-poor tissues or granulomas on the other. An operon, narGHJI, is present for the formation of nitrate reductase, which allows utilization of nitrate as a terminal electron acceptor. Immunodeficient mice infected with a narG mutant of M. bovis BCG developed smaller granulomas than those infected with the wild BCG type, and presented no clinical signs of disease after more than 200 days (24). It therefore appears that the ability to respire anaerobically contributes to virulence. It is also noteworthy that one of the classical microbiological methods to differentiate M. bovis from M. tuberculosis is based on nitrate, reductase activity. M. tuberculosis reduces nitrate to nitrite, whereas M. bovis performs this reduction very poorly. Bange and coworkers have also shown that this defect in nitrate reductase activity is due to a point mutation in the promoter of the M. bovis narGHIJ cluster (24).

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4.

5.

Almost 3.4% of the genome is composed of insertion sequences (IS) and phages. Some of these IS elements are highly similar to those encountered in other actinomycetes, suggesting that horizontal transfers occurred in nature when the ancestor of M. tuberculosis lived in soil and shared its ecological niche with other bacteria. Moreover, IS6110, the most abundant element, which varies in copy number from 0 to 23 in M. tuberculosis, plays an important role in genome plasticity of individual strains, causing either inactivation of genes by insertion of the IS element or deletion of chromosomal fragments in the size range of several kilobases by homologous recombination of two adjacent IS6110 elements (25,26). The phospholipase encoding genes plcA-D genes are hotspots of IS6110 integration (27). The M. tuberculosis sequence presents large gene families, the PE and PPE families, encoding nearly 10% of the coding sequence and comprising 100 and 67 members, respectively. Members of these families share a conserved N-terminal domain with the characteristic motifs ProGlu (PE) or ProProGlu (PPE), whereas the C-terminal segment varies in length and sequence. These proteins are cell-wall associated and surface exposed. The two multigene families have a significant higher genetic variability compared with the genome as a whole (6). They may represent the principal source of antigenic variation and interfere with immune responses by inhibiting antigen processing (15). Disruption of the gene encoding a PE protein leads to a marked reduction of bacterial clumping, suggesting that this protein may mediate cell–cell adhesion and altered phagocytosis by macrophages (28). Another PE protein can bind fibronectin and could mediate bacterial interaction with host cells (29,30). Several characteristics can be considered to contribute to the slow growth rate of the tubercle bacille. (i) M. tuberculosis, like the other slow-growing mycobacteria, has only a single copy of the genes coding for the ribosomal RNAs, whereas most bacteria have several copies of these genes (31). (ii) This single ribosomal RNA operon is located unusually at 1500 kb from the origin of replication, unlike most bacteria which have several copies of this operon close to the origin of replication to exploit the gene-dosage effect obtained during replication. (iii) Genes are evenly distributed along the two DNA strands and 59% of the genes are transcribed with the same polarity as the replication fork. By contrast, a high percentage of genes located on the leading replication strand are thought to be associated with higher gene-expression levels, because replication and transcription act with the same polarity (15).

In addition to the H37Rv type strain, another M. tuberculosis strain has also been fully sequenced. The strain CDC1551 is a clinical, highly

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transmissible strain and was the cause of an outbreak in a rural area of the United States (32). The strain induces a strong immunologic response by the host and is less virulent than strain H37Rv in animal models (33). Its genome sequence is nearly identical to that of H37Rv but slightly smaller at 4,403,836 bp (6,34). The M. bovis strain AF2122/97, isolated from a cow in the United Kingdom, has a genome nearly 70 kb smaller than those of the M. tuberculosis strains at 4,435,492 bp (13,35). The main reason for this size difference is the absence of several previously identified regions from the genome of M. bovis, described in more detail below. The number of about 2400 single nucleotide polymorphisms (SNPs) between M. bovis and M. tuberculosis corresponds to approximately twice as many point mutations than the number of SNP between the two sequenced M. tuberculosis strains. Several of these SNPs may have important consequences for the biology of the organism as shown by a SNP causing one of the key in vitro differences between M. bovis and M. tuberculosis, which is a requirement for pyruvate when glycerol is the sole carbon source. Strikingly, the genome sequence of M. bovis revealed that the gene encoding pyruvate kinase activity, pykA, contains a SNP that affects binding of the Mg2þ cofactor. As such, M. bovis glycolytic intermediates are blocked from feeding into oxidative metabolism, meaning that in vivo M. bovis must rely on amino acids or fatty acids as a carbon source for energy metabolism. The same SNP is also responsible for the classical phenotypic difference between the ‘‘eugonic’’ growth of M. tuberculosis on media containing glycerol, compared to the small ‘‘dysgonic’’ colonies produced by M. bovis on the same media (36). III. Comparative Genomics and Evolution Within the Mycobacterium tuberculosis Complex The availability of several genomes from members of the M. tuberculosis complex now allows genome-wide comparisons to be employed at the nucleotide level. However, larger polymorphisms between tubercle bacille were first identified by subtractive hybridization, bacterial artificial chromosome (BAC) arrays, and microarrays (37–39). By these methods, regions of differences (RDs) have been identified as being absent from M. bovis BCG but present in M. tuberculosis. The presence or absence of these RD regions was analyzed in a large set of strains and gave rise to a scheme of the phylogenetic lineages within members of the M. tuberculosis complex (40). Sequencing of the flanking regions of the different RD regions—and particularly of RD9, which is present in full length in M. tuberculosis and absent from M. africanum, M. microti, M. bovis, M. pinnipedii, and M. caprae— revealed that most of the deletions had occurred within coding regions, exactly at the same sites, indicating firstly that the involved genetic events were deletions in the M. africanum–M. bovis lineage and not insertions into M. tuberculosis. Secondly, the identity of the junction sequences in various members of the M. tuberculosis complex from different hosts and geographical locations suggested that the deletions did not occur independently in the

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individual strains of the M. tuberculosis complex, but resulted from successive, irreversible genetic events in common progenitor strains, which were then inherited from daughter strains. M. bovis has lost these RD regions corresponding in total to approximately 70 kb, which are still present in M. tuberculosis. This logically excludes M. bovis as the ancestor of M. tuberculosis. In addition, except for one region (TbD1), which is present in M. bovis but absent from most tested M. tuberculosis strains, M. bovis did not contain any additional genomic material compared to M. tuberculosis. Thirdly, the members of the M. tuberculosis complex show a clonal population structure, with very little or no recent horizontal transfer as discussed below (41). Taken together, these results refute the previous hypothesis on the origin of human tuberculosis, suggesting that humans acquired tuberculosis through milk consumption in the era of domestication of cattle. This hypothesis was consistent with the large host range of M. bovis and the restricted human one of M. tuberculosis, and implied that M. tuberculosis evolved from the bovine bacille by adaptation from the bovine to the human host. The present hypothesis suggests that M. tuberculosis and M. bovis derived from a common ancestor, which resembled M. tuberculosis and could well have been a human pathogen already (40). It is also interesting that the DNA of tubercle bacille amplified from a North American Pleistocene extinct bison (dated 17,000 years) showed a genetic profile based on the DR region that resembled M. africanum or M. tuberculosis more closely than it resembeled M. bovis (42). For the M. tuberculosis lineage, presence or absence of the M. tuberculosis–specific TbD1 divides strains into ancestral M. tuberculosis strains, which still harbor the TbD1 region, and the modern strains, which have lost it. In the evolutionary pathway drawn by RDs, the loss of RD9 corresponds to a major divergence leading to a main lineage encompassing M. africanum and all the tubercle bacille that have animals as preferential hosts. Successive deletions, some species specific, led to M. microti, M. pinnipedii, M. caprae, M. bovis and eventually M. bovis BCG (Table 1). Thus, the RD analysis provides a useful molecular tool for the rapid and unambiguous identification of the various members of the M. tuberculosis complex (Table 1). These markers are in very good agreement with other genetic markers, such as for example, the pncA SNP, which is responsible for the natural resistance of M. bovis strains to the antituberculosis drug pyrazinamide. All tested M. bovis strains that showed the characteristic pncA SNP also lacked the RD4 region. Therefore, rapid polymerase chain reaction (PCR) screening for absence of RD4, using internal and flanking primers of the RD4 region, may be a useful additional procedure for identification of clinical isolates. IV. Evolution of Mycobacterium bovis BCG The use of genomic deletion analysis in strains of M. bovis BCG allowed the reconstruction of the BCG genealogy (45). It has to be remembered that early after the development of the vaccine, Calmette and Gue´rin distributed

Nitrate reductase þ – – V þ – – –

Niacin þ – – V – þ – –

– – þ þ þ

þ þ – – – – – – – –

þ þ

þ –

– –

PZA –

Pyruvate –

þ

TCH

þ þ þ þ þ

– –

þ

RD4

– þ – – –

– –

þ

RD9

þ þ þ – þ

– –

þ

RD12

RDpind

RDcanb RDmicc

RD1

TbD1a

RD specific

Note: The phenotypic tests include niacin production, presence of nitrate reductase, growth on TCH, growth stimulated by pyruvate, and growth in the presence of PZA. The genotypic characteristics consist of the presence (þ) or absence (
) of regions RD4, RD9, and RD12. a TbD1 region is absent from ‘‘modern’’ M. tuberculosis only and present in all members of the MTBC (40). b RDcan corresponds to a region specifically absent from M. canettii that only partially overlaps RD12 (40). c RDmic corresponds to a region specifically absent from M. microti that only partially overlaps RD1 (40). d RDpin corresponds to a region specifically absent from M. pinnipedii that only partially overlaps RD2 (40). Abbreviations: PZA, pyrazinamide; RD, regions of difference; V, variable; TCH, thiophen-2-carboxylic acid hydrazide. Source: From Refs. 8, 11, 37, 40, 43, and 44.

Mycobacterium tuberculosis Mycobacterium bovis Mycobacterium bovis bacille Calmette–Gue´rin Mycobacterium africanum Mycobacterium canettii Mycobacterium microti Mycobacterium caprae Mycobacterium pinnipedii

Strain

Table 1 Phenotypic and Genotypic Characteristics of the Mycobacterium tuberculosis Complex Members

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the BCG strain throughout the world for local vaccine production. Preparation of seed lots was performed only in the 1960s, and approximately 1000 passages were carried out in vaccine production centers. Local manufacturers also distributed cultures of the strain to other vaccine producers. This history explains the present diversity of BCG strains, which differ by phenotypic features, mycolic acid content, antigenic proteins as well as virulence and protective efficacy in mouse models (45,46). Because the vaccines never reverted to virulent strains, genetic changes that occurred during the attenuation process have permanently disabled BCG from causing tuberculosis in immunocompetent individuals. Comparative genomics of various BCG vaccines identified 10 genomic deletions that mark the molecular evolution of BCG daughter strains (39). Deletions specific for some BCG strains, which may contribute to the spectrum of protective immunity, as well as deletions shared by all BCG strains, which are likely to account for the attenuation of the vaccine, have been identified. The RD1 region is deleted in all BCG strains. This region encodes for two immunodominant, exported proteins in M. tuberculosis. Animal models infected with recombinant BCG vaccines expressing the two proteins, ESAT-6 and CFP10, showed that the presence of the RD1 region is simultaneously associated with increased virulence in immunocompromised hosts and with improved protection in immunocompetent hosts. The RD1 region is therefore an interesting target for second-generation vaccine candidates, combining the safety of the BCG vaccine with an improved protection against tuberculosis (47).

V. Population Structure and Clonal Evolution of the Mycobacterium tuberculosis Complex Even before genome sequences were available, Musser and coworkers stressed that SNPs were rare among tubercle bacille. Their pioneering studies on 26 structural genes totalling 2 Mb showed that the level of allelic variation in M. tuberculosis is 2000 times less than in Borrelia burgdorferi and 600 times less than in Neisseria meningitidis (48). The authors proposed the hypothesis that M. tuberculosis was evolutionarily young and had only recently spread globally. The availability of the three genome sequences confirmed these results and established that SNPs account for less than 0.2% of the differences between the two M. tuberculosis genomes and less than 0.05% of the differences between M. bovis and the two M. tuberculosis strains. Genomic studies were conducted on large number of strains to elucidate the structure of the M. tuberculosis population. Studies have investigated SNPs based on a set of structural genes (49,50) or at a genome-wide scale (51–53); large genomic deletions on microarrays or membranes (54–56); or the variability generated by intergenic sequences such as the mycobacterial interspersed repetitive units (MIRUs). MIRUs occur as tandem repeats between genes in operons and vary according to their copy number (41,57). Results showed significant linkage disequilibrium corresponding to nonrandom association

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of genomic polymorphism at different chromosomal loci, which were consistent with a highly clonal population structure of M. tuberculosis, where no lateral gene transfer, i.e., recombination of chromosomal sequences between strains was detectable (41). Based on the SNP of the katG and gyrA genes, Musser and coworkers identified three genetic groups: a large one (group 1) comprising all bacille of the M. tuberculosis complex and two other groups (groups 2 and 3) corresponding to M. tuberculosis sensu stricto (48). This first attempt to differentiate genetic groups among the tubercle bacille was confirmed and enriched by the RD classification (40). All strains of genetic groups 2 and 3 belong to ‘‘modern’’ M. tuberculosis strains as defined by the deletion of the TbD1 region. The polymorphism of a specific molecular marker identified only in the M. tuberculosis complex and not in other mycobacteria, the DR locus, has been used to define genotype families within the M. tuberculosis complex (58,59). The direct repeat (DR) region consists of a single locus characterized by 36-bp direct repeats interspersed by polymorphic spacer regions. It belongs to the family of Clustered Regularly Interspaced Short Palindromic Repeats identified in prokaryotic genomes (60). One of the most successful M. tuberculosis genotype families is the ‘‘Beijing’’ family first identified in China, which spread to other countries of the region and emerged in other parts of the world, specially in the former Soviet Union and in the West (61), and was recently found in Africa (62). The ‘‘Beijing’’ family was the focus of specific interest and studies because strains of this family show particular virulence and are often associated with frequent resistance to several antituberculosis drugs. The ‘‘W’’ strains, involved in an outbreak of more than 250 patients with multidrug-resistant M. tuberculosis in the United States, belong to the ‘‘Beijing’’ family (63). Molecular markers described above (DR locus, MIRUs, IS6110, RD, and/or SNP analysis) all contribute to identify genetic lineages within the two main agents of tuberculosis—M. tuberculosis and M. bovis. Because the population structure is clonal and the occurrence of horizontal gene transfer is rare, starting from a common ancestor, each phylogenetic lineage evolves independently from others (40). This peculiar population structure of the M. tuberculosis complex has important implications in public health because distinct lineages may differ in phenotypes such as virulence, transmissibility, ability to reactivate, and host-specific association. Interestingly, the role of lipids in the pathogenesis of M. tuberculosis has been recently revisited. Some M. tuberculosis strains, such as the 210 (Beijing type) strain, produce a particular phenolic glycolipid (PGL), whereas most M. tuberculosis strains do not. The absence of the PGL has been associated with a deletion of 7 bp that introduces a frameshift in the pks15/1 gene (64) found in strains belonging to the genetic group 2 or 3 (65), as defined by Sreevatsan et al. (48). The synthesis of this PGL molecule is correlated with a decrease in the production of proinflammatory cytokines by host immune cells (66). This finding could explain in part the

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hypervirulent phenotype observed for strains from the Beijing family (33,67) and the stability of the associated phenotype due to a specific deletion (64). VI. Ecotypes Within the Mycobacterium tuberculosis Complex For the M. bovis lineage, host preference has been demonstrated with the description of genetic clades prevalent in voles (M. microti), goats (M. caprae), sea lions, and fur seals (M. pinnipedii), and in artiodactyls (antelopes, oryx, etc.) (68). These observations led Smith et al. to propose the application of the ecotype concept to the M. tuberculosis complex. According to Cohan’s model of bacterial speciation (69), adaptation of a strain to a new niche corresponds to the emergence of a new ecotype that becomes immune to diversity. In other words, strains adapted to one host are less prone to infect another host. In the evolutionary scheme of Brosch et al. (Fig. 1), the lineage that encompasses animal-pathogen tubercle bacille may be seen as a series of host-adapted clades that follow the Cohan’s ecotype concept. M. microti, M. pinnipedii, and M. caprae have distinct host preference, and their evolution is related to specific SNPs and genomic deletions (40,71). They can be considered as ecotypes although further division within these groups is possible. The specific adaptation to a host and maladaptation to others is illustrated by the historical rabbit infection model used to differentiate M. tuberculosis

Figure 1 Scheme of the evolutionary pathway of the tubercle bacille. Source: Adapted from Refs. 40, 70.

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from M. bovis. In this animal, lesions due to M. tuberculosis regress over time and those due to M. bovis lead to pulmonary cavities. Whereas M. bovis has been regarded as a generalist and M. tuberculosis as a restricted human pathogen, Smith et al. stress that the ecotype concept applied to the M. tuberculosis complex should lead to new research insights in the identification of authentic ecotypes and the investigation of genetic differences associated with host specificity (68). This issue has already been addressed in a study led by P. Small, specifically designed to determine whether distinct strains of M. tuberculosis infect different human populations and whether associations between host and pathogen are stable despite global traffic in large cosmopolitan cities (55). The study supports the expected results from the theory of population genetics and shows highly stable association between host and pathogen populations. Recently, Gagneux et al. expanded these results and showed that M. tuberculosis lineages were more prone to spread in sympatric than in allopatric patient populations. These observations suggest that, similarly to M. bovis clades adapted to specific animal hosts, M. tuberculosis genetic lineages have adapted to specific human host populations and are maladapted to others (72). VII. Mycobacterium prototuberculosis: The Progenitor of the Mycobacterium tuberculosis Complex Orphan Clone The M. tuberculosis complex (as defined in this chapter, encompassing the species M. tuberculosis, M. africanum, M. microti, M. caprae, M. pinnipedii, and M. bovis) represents one of the most extreme examples of genetic homogeneity with about 0.01% to 0.03% synonymous nucleotide variations in their genomes. In comparison, the synonymous nucleotide variation is close to 6% and 12% in bacterial species such as N. meningitidis and Escherichia coli, respectively. No significant trace of horizontal genetic exchange has been detected among members of the complex. These data indicate that the M. tuberculosis complex is evolutionarily young and corresponds to a clone that had recently spread globally, roughly 15,000 to 20,000 years ago (48). However, the clone remained an orphan, with no identified progenitor species. Similarly, other main human pathogens such as Salmonella enteritica serotype Typhi and Yersinia pestis consist of single clones of recent emergence. These clones have evolved from well-known progenitor species, Yersinia pseudotuberculosis and S. enteritica, respectively. The progenitor of M. tuberculosis has been elucidated recently (70). In the evolutionary scheme based on deletion analysis (Fig. 1), Brosch et al. indicated that M. canetti presented all the genomic regions deleted in the members of the M. tuberculosis complex (40). M. canetti strains are rare strains that present an unusual smooth colony type. Although the first smooth colony of a tubercle bacille had been described in the 1970s by G. Canetti, only few isolates with this unusual phenotype had been isolated worldwide (11). Recently, a collection of 37 smooth strains was investigated

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(70). Strains were isolated from tuberculous patients, mostly immunocompetent patients who were living in or had lived in Djibouti, East Africa. Genetic data, based on the molecular markers usually used for the M. tuberculosis complex, on 16S rDNA sequencing and on the analysis of polymorphism within six housekeeping genes totalling 3387 nucleotides, showed that the smooth bacille do not all correspond to M. canetti but define eight distinct genetic clusters (Fig. 2). All these groups and the M. tuberculosis complex share the same 16S rRNA sequence and form a single mycobacterial species. However, the synonymous nucleotide variation within the smooth tubercle bacille was much higher than in the M. tuberculosis complex alone but interestingly in the range of other bacterial species. In addition, the housekeeping genes display mosaic structures, providing direct evidence of intragenic recombination within the smooth

Figure 2 Split decomposition analysis of the concatenated sequences of the six housekeeping genes of the eight genetic groups of smooth tubercle bacille (A to I) and of those of the Mycobacterium tuberculosis complex. Groups A and C/D correspond to the previous formal description of Mycobacterium canetti. The nodes represent strains and are depicted as small squares (smooth tubercle bacille) or small circles (MTBC members). The scale bar represents Hamming distance. Abbreviation: MTBC, Mycobacterium tuberculosis complex. Source: Adapted from Refs. 11, 70.

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strains. The sequences of these housekeeping genes in the M. tuberculosis complex appear as a patchwork of sequences from different smooth groups. The M. tuberculosis genome therefore appears to be a composite assembly of smooth bacille genomic fragments resulting from ancient horizontal DNA exchanges. In other words, the M. tuberculosis complex is only a clone of the larger tubercle bacille species defined by the smooth strains. Knowledge of this ancient history contributes to explain the extraordinary adaptation of the M. tuberculosis complex to mammals, because genetic exchange is known to play a crucial role in the adaptation of pathogens to their hosts (70). Assuming the same hypothesis to estimate the age of the M. tuberculosis clone of 35,000 years, the minimal time needed to accumulate the observed amount of synonymous divergence in the smooth strains is between 2.6 and 2.8 million years (70). Instead of having a recent origin as previously thought, tuberculosis could be much older than the plague, typhoid fever, or malaria, and might have affected early hominids. It is fascinating that the history of the tubercle bacille may mirror the history of the human species, with a common birthplace in East Africa, where hominids were present three million years ago. It is also striking that the diversity found in smooth strains, all originating from Djibouti, and the homogeneity retrieved in the globally spread M. tuberculosis complex, are reminiscent of the distribution of human populations with the highest genetic distance found in Africa. These findings suggest that tubercle bacille emerged in Africa where they diversified and a successful clone expanded and spread globally, possibly carried by the waves of human migration out of Africa. The long interaction lasting almost three million years between the tubercle bacille and hominids may explain the successful persistence of the bacille in the human host with the sophisticated protection conferred by granulomas, which both protect living bacteria and isolate them from their host for decades, as long as the immune system is not impaired. VIII. Conclusion The investigation of smooth bacille and the description of M. prototuberculosis, the progenitor of the M. tuberculosis complex clone, suggest that the tubercle bacille are much more ancient than previously thought. Tubercle bacille could have been present in early hominids as long as three million years ago. The human–chimpanzee divergence is estimated to have occurred between five and seven million years ago (73). It is noteworthy that comparative genomics of the chimpanzee and human genomes showed that among the most rapidly evolving genes is the gene for granulysin, a protein which directly kills extracellular M. tuberculosis, alters the membrane integrity of the bacille, and contributes to immunity against intracellular pathogens (74). The description of M. prototuberculosis opens new avenues of research for a better understanding of the successful expansion of M. tuberculosis. Comparative genomics and proteomics of smooth tubercle bacille, which disclose an extensive polymorphism and are confined to a limited geographical area, and

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classical tubercle bacille will contribute to elucidate the global expansion of the M. tuberculosis clone. Moreover, the identification of genetic families and the concept of ecotypes applied to the M. tuberculosis complex and its animal as well as human hosts have profound implications for tuberculosis control and specifically for the development of new vaccines. The variety of M. tuberculosis genotypes and host–pathogen adaptation should be considered in relation to the design and evaluation of vaccine candidates. References 1. Lehmann KB, Neumann R. Atlas und Grundriss der Bakteriologie und Lehrbuch der speziellen bakteriologischen Diagnostik. 1st ed. Munchen, 1896. 2. Smith T. A comparative study of bovine tubercle bacilli and of human bacilli from sputum. J Exp Med 1898; 3:451–511. 3. Imaeda T. Deoxyribonucleic acid relatedness among selected strains of Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium bovis BCG, Mycobacterium microti, and Mycobacterium africanum. Int J Syst Bacteriol 1985; 35:147–150. 4. Brosch R, Gordon SV, Pym A, Eiglmeier K, Garnier T, Cole ST. Comparative genomics of the mycobacteria. Int J Med Microbiol 2000; 290(2):143–152. 5. Gordon SV, Eiglmeier K, Garnier T, et al. Genomics of Mycobacterium bovis. Tuberculosis 2001; 81(1/2):157–163. 6. Fleischmann RD, Alland D, Eisen JA, et al. Whole-genome comparison of Mycobacterium tuberculosis clinical and laboratory strains. J Bacteriol 2002; 184(19): 5479–5490. 7. Niemann S, Kubica T, Bange FC, et al. The species Mycobacterium africanum in the light of new molecular markers. J Clin Microbiol 2004; 42(9):3958–3962. 8. van Soolingen D, van der Zanden AG, de Haas PE, et al. Diagnosis of Mycobacterium microti infections among humans by using novel genetic markers. J Clin Microbiol 1998; 36(7):1840–1845. 9. Cousins DV, Bastida R, Cataldi A, et al. Tuberculosis in seals caused by a novel member of the Mycobacterium tuberculosis complex: Mycobacterium pinnipedii sp. nov. Int J Syst Evol Microbiol 2003; 53(Pt 5):1305–1314. 10. Aranaz A, Cousins D, Mateos A, Dominguez L. Elevation of Mycobacterium tuberculosis subsp. caprae Aranaz et al. 1999 to species rank as Mycobacterium caprae comb. nov., sp. nov. Int J Syst Evol Microbiol 2003; 53(Pt 6):1785–1789. 11. van Soolingen D, Hoogenboezem T, de Haas PE, et al. A novel pathogenic taxon of the Mycobacterium tuberculosis complex, Canetti: characterization of an exceptional isolate from Africa. Int J Syst Bacteriol 1997; 47(4):1236–1245. 12. Jacobs WR. Mycobacterium tuberculosis: a once genetically intractable organism. In: Hatfall GF, Jacobs WR, eds. Molecular Genetics of Mycobacteria. Washington, DC: American Society for Microbiology, 2000:1–16. 13. Garnier T, Eiglmeier K, Camus JC, et al. The complete genome sequence of Mycobacterium bovis. Proc Natl Acad Sci U.S.A. 2003; 100(13):7877–7882. 14. Li L, Bannantine JP, Zhang Q, et al. The complete genome sequence of Mycobacterium avium subspecies paratuberculosis. Proc Natl Acad Sci U.S.A. 2005; 102(35): 12344–12349. 15. Cole ST, Brosch R, Parkhill J, et al. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 1998; 393:537–544. 16. Cole ST, Eiglmeier K, Parkhill J, et al. Massive gene decay in the leprosy bacillus. Nature 2001; 409(6823):1007–1011. 17. http://www.genomesonline.org/

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18. Camus JC, Pryor MJ, Medigue C, Cole ST. Re-annotation of the genome sequence of Mycobacterium tuberculosis H37Rv. Microbiology 2002; 148(Pt 10):2967–2973. 19. http://genolist.pasteur.fr/TubercuList/ 20. Wheeler PR, Bulmer K, Ratledge C. Enzymes for biosynthesis de novo and elongation of fatty acids in mycobacteria grown in host cells: is Mycobacterium leprae competent in fatty acid biosynthesis? J Gen Microbiol 1990; 136(1):211–217. 21. Wheeler PR, Bulmer K, Ratledge C. Fatty acid oxidation and the beta-oxidation complex in Mycobacterium leprae and two axenically cultivable mycobacteria that are pathogens. J Gen Microbiol 1991; 137(4):885–893. 22. Trivedi OA, Arora P, Sridharan V, Tickoo R, Mohanty D, Gokhale RS. Enzymic activation and transfer of fatty acids as acyl-adenylates in mycobacteria. Nature 2004; 428(6981):441–445. 23. Portevin D, De Sousa-D’Auria C, Houssin C, et al. A polyketide synthase catalyzes the last condensation step of mycolic acid biosynthesis in mycobacteria and related organisms. Proc Natl Acad Sci USA 2004; 101(1):314–319. 24. Stermann M, Sedlacek L, Maass S, Bange FC. A promoter mutation causes differential nitrate reductase activity of Mycobacterium tuberculosis and Mycobacterium bovis. J Bacteriol 2004; 186(9):2856–2861. 25. Brosch R, Gordon SV, Eiglmeier K, et al. Genomics, biology, and evolution of the Mycobacterium tuberculosis complex. In: Hatfull GF, Jacobs WR, eds. Molecular Genetics of Mycobacteria. Washington, DC: ASM Press, 2000:19–36. 26. Ho TB, Robertson BD, Taylor GM, Shaw RJ, Young DB. Comparison of Mycobacterium tuberculosis genomes reveals frequent deletions in a 20 kb variable region in clinical isolates. Yeast 2000; 17(4):272–282. 27. Vera-Cabrera L, Hernandez-Vera MA, Welsh O, Johnson WM, Castro-Garza J. Phospholipase region of Mycobacterium tuberculosis is a preferential locus for IS6110 transposition. J Clin Microbiol 2001; 39(10):3499–3504. 28. Brennan MJ, Delogu G, Chen Y, et al. Evidence that mycobacterial PE-PGRS proteins are cell surface constituents that influence interactions with other cells. Infect Immun 2001; 69(12):7326–7333. 29. Singh KK, Zhang X, Patibandla AS, Chien P Jr., Laal S. Antigens of Mycobacterium tuberculosis expressed during preclinical tuberculosis: serological immunodominance of proteins with repetitive amino acid sequences. Infect Immun 2001; 69(6):4185– 4191. 30. Espitia C, Laclette JP, Mondragon-Palomino M, et al. The PE-PGRS glycine-rich proteins of Mycobacterium tuberculosis: a new family of fibronectin-binding proteins? \questMicrobiology1999; 145ðPt12Þ : 3487 3495: 31. Bercovier H, Kafri O, Sela S. Mycobacteria possess a surprisingly small number of ribosomal RNA genes in relation to the size of their genome. Biochem Biophys Res Commun 1986; 136:1136–1141. 32. Valway SE, Sanchez MP, Shinnick TF, et al. An outbreak involving extensive transmission of a virulent strain of Mycobacterium tuberculosis. N Engl J Med 1998; 338(10):633–639. 33. Manca C, Tsenova L, Bergtold A, et al. Virulence of a Mycobacterium tuberculosis clinical isolate in mice is determined by failure to induce Th1 type immunity and is associated with induction of INF-alpha/beta. Proc Natl Acad Sci USA 2001; 98:5752–5757. 34. http://www.tigr.org 35. http://genolist.pasteur.fr/BoviList/ 36. Keating LA, Wheeler PR, Mansoor H, et al. The pyruvate requirement of some members of the Mycobacterium tuberculosis complex is due to an inactive pyruvate kinase: implications for in vivo growth. Mol Microbiol 2005; 56(1):163–174.

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37. Gordon SV, Brosch R, Billault A, Garnier T, Eiglmeier K, Cole ST. Identification of variable regions in the genomes of tubercle bacilli using bacterial artificial chromosome arrays. Mol Microbiol 1999; 32(3):643–655. 38. Mahairas GG, Sabo PJ, Hickey MJ, Singh DC, Stover CK. Molecular analysis of genetic differences between Mycobacterium bovis BCG and virulent M. bovis. J Bacteriol 1996; 178(5):1274–1282. 39. Behr MA, Wilson MA, Gill WP, et al. Comparative genomics of BCG vaccines by whole-genome DNA microarray. Science 1999; 284(5419):1520–1523. 40. Brosch R, Gordon SV, Marmiesse M, et al. A new evolutionary scenario for the Mycobacterium tuberculosis complex. Proc Natl Acad Sci USA 2002; 99(6): 3684–3689. 41. Supply P, Warren RM, Banuls AL, et al. Linkage disequilibrium between mini satellite loci supports clonal evolution of Mycobacterium tuberculosis in a high tuberculosis incidence area. Mol Microbiol 2003; 47(2):529–538. 42. Rothschild BM, Martin LD, Lev G, et al. Mycobacterium tuberculosis complex DNA from an extinct bison dated 17,000 years before the present. Clin Infect Dis 2001; 33(3):305–311. 43. Aranaz A, Liebana E, Gomez-Mampaso E, et al. Mycobacterium tuberculosis subsp. caprae subsp. nov.: a taxonomic study of a new member of the Mycobacterium tuberculosis complex isolated from goats in Spain. Int J Syst Bacteriol 1999; 49: 1263–1273. 44. Espinosa de los Monteros LE, Galan JC, Gutierrez M, et al. Allele-specific PCR method based on pncA and oxyR sequences for distinguishing Mycobacterium bovis from Mycobacterium tuberculosis: intraspecific M. bovis pncA sequence polymorphism. J Clin Microbiol 1998; 36(1):239–242. 45. Brosch R, Behr MA. Comparative genomics and evolution of Mycobacterium bovis BCG. In: Cole ST, Eisenach KD, McMurray DN, Jacobs WR, eds. Tuberculosis and the Tubercle Bacilli. Washington, DC: American Society for Microbiology, 2005:155–164. 46. Behr MA, Small PM. A historical and molecular phylogeny of BCG strains. Vaccine 1999; 17(7–8):915–922. 47. Brodin P, de Jonge MI, Majlessi L, et al. Functional analysis of early secreted antigenic target-6, the dominant T-cell antigen of Mycobacterium tuberculosis, reveals key residues involved in secretion, complex formation, virulence, and immunogenicity. J Biol Chem 2005; 280(40):33,953–33,959. 48. Sreevatsan S, Pan X, Stockbauer KE, et al. Restricted structural gene polymorphism in the Mycobacterium tuberculosis complex indicates evolutionarily recent global dissemination. Proc Natl Acad Sci USA 1997; 94(18):9869–9874. 49. Baker L, Brown T, Maiden MC, Drobniewski F. Silent nucleotide polymorphisms and a phylogeny for Mycobacterium tuberculosis. Emerg Infect Dis 2004; 10(9):1568–1577. 50. Filliol I, Motiwala AS, Cavatore M, et al. Global phylogeny of Mycobacterium tuberculosis based on single nucleotide polymorphism (SNP) analysis: insights into tuberculosis evolution, phylogenetic accuracy of other DNA fingerprinting systems, and recommendations for a minimal standard SNP set. J Bacteriol 2006; 188(2): 759–772. 51. Alland D, Whittam TS, Murray MB, et al. Modeling bacterial evolution with comparative-genome-based marker systems: application to Mycobacterium tuberculosis evolution and pathogenesis. J Bacteriol 2003; 185(11):3392–3399. 52. Gutacker MM, Mathema B, Soini H, et al. Single-nucleotide polymorphism-based population genetic analysis of Mycobacterium tuberculosis strains from 4 geographic sites. J Infect Dis 2006; 193(1):121–128.

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53. Gutacker MM, Smoot JC, Migliaccio CA, et al. Genome-wide analysis of synonymous single nucleotide polymorphisms in Mycobacterium tuberculosis complex organisms: resolution of genetic relationships among closely related microbial strains. Genetics 2002; 162(4):1533–1543. 54. Goguet de la Salmoniere YO, Kim CC, Tsolaki AG, Pym AS, Siegrist MS, Small PM. High-throughput method for detecting genomic-deletion polymorphisms. J Clin Microbiol 2004; 42(7):2913–2918. 55. Hirsh AE, Tsolaki AG, DeRiemer K, Feldman MW, Small PM. Stable association between strains of Mycobacterium tuberculosis and their human host populations. Proc Natl Acad Sci USA 2004; 101(14):4871–4876. 56. Tsolaki AG, Hirsh AE, DeRiemer K, et al. Functional and evolutionary genomics of Mycobacterium tuberculosis: insights from genomic deletions in 100 strains. Proc Natl Acad Sci USA 2004; 101(14):4865–4870. 57. Supply P, Magdalena J, Himpens S, Locht C. Identification of novel intergenic repetitive units in a mycobacterial two-component system operon. Mol Microbiol 1997; 26(5):991–1003. 58. Kremer K, van Soolingen D, Frothingham R, et al. 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 Microbiol 1999; 37(8):2607–2618. 59. Sola C, Filliol I, Gutierrez MC, Mokrousov I, Vincent V, Rastogi N. Spoligotype database of Mycobacterium tuberculosis: biogeographic distribution of shared types and epidemiologic and phylogenetic perspectives. Emerg Infect Dis 2001; 7(3): 390–396. 60. Gordon SV, Supply P. Repetitive DNA in the Mycobacterium tuberculosis complex. In: Cole ST, Eisenach K, McMurray D, Jacobs WR Jr., eds. Tuberculosis and the Tubercle Bacillus. Washington: American Society for Microbiology Press, 2005:191–202. 61. Glynn JR, Whiteley J, Bifani PJ, Kremer K, van Soolingen D. Worldwide occurrence of Beijing/W strains of Mycobacterium tuberculosis: a systematic review. Emerg Infect Dis 2002; 8(8):843–849. 62. Glynn JR, Crampin AC, Traore H, et al. Mycobacterium tuberculosis Beijing genotype, northern Malawi. Emerg Infect Dis 2005; 11(1):150–153. 63. Bifani PJ, Plikaytis BB, Kapur V, et al. Origin and interstate spread of a New York City multidrug-resistant Mycobacterium tuberculosis clone family. JAMA 1996; 275(6):452–457. 64. Constant P, Perez E, Malaga W, et al. Role of the pks15/1 gene in the biosynthesis of phenolglycolipids in the Mycobacterium tuberculosis complex. Evidence that all strains synthesize glycosylated p-hydroxybenzoic methly esters and that strains devoid of phenolglycolipids harbor a frameshift mutation in the pks15/1 gene. J Biol Chem 2002; 277(41):38,148–38,158. 65. Marmiesse M, Brodin P, Buchrieser C, et al. Macro-array and bioinformatic analyses reveal mycobacterial ‘core’ genes, variation in the ESAT-6 gene family and new phylogenetic markers for the Mycobacterium tuberculosis complex. Microbiology 2004; 150(Pt 2):483–496. 66. Reed MB, Domenech P, Manca C, et al. A glycolipid of hypervirulent tuberculosis strains that inhibits the innate immune response. Nature 2004; 431(7004):84–87. 67. Lopez B, Aguilar D, Orozco H, et al. A marked difference in pathogenesis and immune response induced by different Mycobacterium tuberculosis genotypes. Clin Exp Immunol 2003; 133(1):30–37. 68. Smith NH, Kremer K, Inwald J, et al. Ecotypes of the Mycobacterium tuberculosis complex. J Theor Biol 2006; 239:220–225. 69. Cohan FM. What are bacterial species? Annu Rev Microbiol 2002; 56:457–487.

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4 Epidemiology of Tuberculosis

JACQUELINE S. COBERLY and GEORGE W. COMSTOCK Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, Maryland, U.S.A.

I. Introduction Tuberculosis (TB) remains a leading contender for the dubious distinction of being the most important plague of mankind. The World Health Organization (WHO) estimated that in 2003, 8.8 million people developed TB, of whom 3.9 million had so many tubercle bacille in their sputum that the bacille could be identified by simple microscopy, and that there were 1.7 million deaths due to TB (1). In 2003, the incidence of TB was stable or falling in five of six WHO regions. The exception was the African region (AFR). Incidence was increasing in this region, especially in areas with high human immunodeficiency virus (HIV) prevalence rates (1), enough so that the global incidence of TB continued to increase at about 1% per year. Accentuating the impact of TB on the world’s well-being is its concentration among young adults throughout most of the developing world, and its airborne spread from person to person, especially to household members. TB has been exacting a toll for many centuries. Of particular interest from an epidemiologic point of view is the reported frequency of skeletal lesions suggestive of TB among pre-Columbian populations of North America (2). Although such lesions were occasionally noted in skeletons of 65

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the Late Woodland peoples (800–1050 A.D.), their successors, the Mississippians, had a much higher frequency of TB-like bony lesions, associated with their coming together in larger and relatively permanent settlements. That TB and crowding go together is now so generally accepted that the reason(s) for the association is (are) rarely considered. Is it solely because crowding increases the risk of becoming infected if infectious cases are present? Is it because there is something associated with crowding, which makes it more likely that an infected person will develop tuberculous disease? Is it some combination of these sets of risks? Answers to questions like these comprise the ‘‘etiologic epidemiology’’ of TB. This chapter will first address ‘‘etiologic epidemiology’’ by reviewing what is known about risk factors for becoming infected with tubercle bacille, then risk factors for developing disease given that infection has occurred, and finally risk factors for relapse following apparent cure or spontaneous healing of the disease. ‘‘Administrative epidemiology’’ will then be reviewed. This aspect of epidemiology deals with the occurrence of TB based on routine reporting or special surveys. These data are vital for public health administrators who must know the distribution of cases by time, place, and personal characteristics regardless of what caused these distributions. II. Etiologic Epidemiology A. Risk of Becoming Infected with Tubercle Bacille Causes of Tuberculous Infection

Three related organisms—Mycobacterium tuberculosis, M. africanum, and M. bovis—are the necessary causes of TB. M. tuberculosis is by far the most common. M. africanum is rarely found outside of northwestern Africa, and disease due to M. bovis is limited in developed countries by widespread pasteurization of milk and in the developing world by the low consumption of milk along with the practice of boiling much that is consumed. Mycobacterium canettii and M. microti have recently been found to be genetically related to the tubercle bacille and have been included in the group on this basis. M. microti generally causes disease in rodents, but has been linked retrospectively to infections in llamas, ferrets, and cats. It has also been implicated as the cause of pulmonary TB in a small number of humans (3,4). M. canettii appears to be strictly a human pathogen. The probability of having been infected with one of the tubercle bacille can be assessed by the size of induration caused by the tuberculin test and more recently by various blood tests. However, these new tests have not had the rigorous long-term evaluation accorded the tuberculin test (see Chapters 7 and 46). Risk of Infection by Time and Place

The reported incidence of TB in the United States declined at an average rate of 5.9% per year for several decades until 1985. The case rate then rose

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from 9.3 per 100,000 in 1985 to a high of 10.5 in 1992 when it began to decline steadily (5,6). The now familiar increase in the mid-1980s was caused by the advent of HIV/AIDS and was mirrored in populations worldwide; however, the initial decline in incidence seen until the 1980s has also been duplicated in many countries as they develop economically. The causes of this type of decline are undoubtedly similar around the world and examination of the well-documented decline in the United States is instructive. The best estimate of the decrease in the risk of becoming infected for residents of the United States still comes from the extensive and carefully standardized tuberculin testing of Navy recruits (7,8). Among white males aged 17 to 21 years, the proportion of positive reactors fell from 6.6% in 1949 to 1951 to 3.1% in 1967 to 1968. Subsequent testing on a routine basis showed the prevalence of positive reactors among all recruits to be 1.5% from 1980 to 1986 and to have risen to 2.5% in 1990 (9). Although the mean age of recruits had probably changed little since 1950, the two later study populations included sizeable proportions of nonwhites who, in the earlier study, had much higher proportions of infected people than the white recruits. In addition, the positive reactors throughout this entire period undoubtedly included some who were infected with nontuberculous mycobacteria (NTM) and not with M. tuberculosis. Correcting for this mixture of infections led to an estimate that only 1.4% of the white male recruits tested in 1968 had been infected with M. tuberculosis (8). Very little is known about the prevalence of positive tuberculin reactions among adults in the United States. The only data that might be considered representative of the total adult population comes from the first Health and Nutrition Examination Survey in 1971 to 1972. Among 1494 adults aged 25 to 74 years, 16.1% were classified as reactors (10). The likelihood of having been infected among household contacts of infectious cases of TB has also declined with time, at least in the United States (11). In Williamson County, Tennessee, U.S., in the period 1931 to 1955, 67% of household contacts aged five to nine years were positive tuberculin reactors. In a large study of contacts in 1958, this proportion was 48%. In 1996, only 17.7% of children under the age of 15 years, who were household contacts of pulmonary TB cases, were positive tuberculin reactors (12). In 2003, the risk of becoming infected was falling throughout the world except in Africa, where rates were increasing (1,13). Reasonably good estimates can be obtained in countries where there are enough children and young adults who have not been vaccinated with bacille Calmette– Gue´rin (BCG) to allow the risk to be estimated (14,15). For example, in the Netherlands, the risk of becoming infected was 0.5% per year in 1950 and only 0.02% in 1971. In contrast, several African countries had an estimated risk of becoming infected of 3.0% per year in 1950, with only a slight increase during the next 20 years. Recent findings have been reported from Cambodia and Orissa State of Eastern India (16,17). Among children five to nine years of age in Cambodia, the average risk of infection in 1995 was estimated to be 1.0% in Phnom Penh and 0.75% in the provinces. In

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Orissa State during 2002 to 2003, the average annual risk of infection was 2.5% in urban areas and 1.6% in rural areas. The most dramatic decrease in the risk of infection was documented among the Inuit residents of the Yukon and Kuskokwim River deltas in Alaska (18). In 1949 to 1951, 62% of children aged zero to six years were infected with tubercle bacille, equivalent to an average annual risk of becoming infected of approximately 25% per year. An intensive program of case-finding and treatment, supplemented by isoniazid preventive therapy, was instituted. By 1963 to 1964, only 2.4% were infected, and in 1969 to 1970, there were only two reactors among 1535 tested children in this age group. Personal Risk Factors for Acquiring Infections Degree of Contact and Intensity of Exposure

Because TB is a communicable disease primarily spread by the airborne route, it is not surprising that the risk of an uninfected person becoming infected is strongly associated with the probability of coming in contact with someone with infectious TB, the closeness or intimacy of that contact, its duration, and the degree of infectiousness of the case. Crowding increases both the likelihood of coming into contact with a case and the closeness of the contact. In the U.S. Navy recruit testing program, the prevalence of positive tuberculin reactions among white males aged 17 to 21 years who were lifetime residents of metropolitan areas was 4.2% compared to 2.8% among lifetime residents of farms (7). The associations of infection risk with closeness of contact, with factors related to race, and with the degree of infectiousness of the source case are shown in Table 1 (19). In the Canadian provinces of British Columbia and Saskatchewan, Indian contacts were more likely to have been infected than whites, probably because Indian households were more crowded. For both Indians and whites, infection risk was greater if the contact was Table 1 Age-Adjusteda Percentages of Positive Tuberculin Reactors Among White and Indian Children Aged 0–14 Years in British Columbia and Saskatchewan by Sputum Status of Source Case, 1966–1971 Race and closeness of tuberculosis contact Indian children (%) Sputum status of source case Positive smear Positive culture only Negative culture a

White children (%)

Intimate (n ¼ 1012)

Casual (n ¼ 619)

Intimate (n ¼ 1873)

Casual (n ¼ 3031)

44.7 27.7 25.7

37.4 15.6 18.7

34.7 8.9 7.2

10.1 2.4 3.3

Adjusted to age distribution of total study population aged 0–14 years. Source: From Ref. 19.

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intimate (household associates or partners) than if it was casual (other friends, fellow employees). If sputum of the source case contained so many tubercle bacille that they were demonstrable by microscopic examination of a stained sputum smear, the risk of infecting a contact was also greatly increased. In this population, there was only equivocal evidence that cases with positive sputum cultures were more infectious than those with negative cultures. In other populations, the infectiousness of cases with positive sputum cultures was appreciably greater than those with negative cultures (20). Other characteristics of the source case are related to the prevalence of positive tuberculin reactions among children who are household contacts (19). The extent of pulmonary involvement was strongly associated with infectivity: 62% of contacts of cases with far advanced disease were reactors compared to only 16% reactors among contacts to minimal cases. Also related to the risk of infection was cough frequency, which decreased appreciably during the first week of chemotherapy. Similar findings were noted in a study in Mysore State, India (21). Duration of Exposure

Duration of exposure is important in comparing the infectiousness of TB with that of other communicable diseases. Although an occasional tuberculous patient can be as infectious as a child with measles (22), in most instances, the proportion of exposed contacts who become infected with tubercle bacille is much lower than the risk of infection from cases of other acute communicable diseases. When the duration of exposure is taken into account, the average TB patient has a low degree of infectiousness per unit of time. Virulence of Organism

It has been known for some time that strains of M. tuberculosis from different parts of the world show considerable variation in their virulence in guinea pigs (23). Isoniazid-resistant organisms also have decreased virulence in guinea pigs (24). Until recently, however, the possibility of strain resistance has not been seriously considered in the pathogenesis or epidemiology of human TB. During 1994 to 1996, 21 cases of TB developed in a small rural community in the midwestern part of the United States (25). Investigation of the outbreak showed an unusually high rate of infection among contacts of the source case. Of the 42 identified and tested contacts of the source case, 37 (88.1%) were positive reactors, and 8 (21.6%) of the reactors had documented tuberculin conversions. High proportions of the contacts of the index case were also tuberculin reactors and converters. Environmental investigations revealed no explanation for these high infection rates. The strain of tubercle bacille responsible for the outbreak was initially reported to be more virulent than the standard virulent Erdman strain. However, subsequent laboratory investigations did not confirm this finding (26). The high proportion of infections could also have resulted from chance (27). Whether or not M. tuberculosis varies in its virulence for humans remains uncertain.

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Foreign Residence

There is little evidence that a period of foreign residence is associated with an important risk of infection for people born in the United States. Navy recruits who had lived abroad at a time when TB was common even in many developed countries were only slightly more likely to be tuberculin reactors than lifetime residents of the United States (7). At least some of the difference must have resulted from BCG vaccinations received in the foreign country. The fact that the excess risk was so low is probably attributable to the lifestyle of most expatriate U.S. citizens, most of whose exposures must have occurred in public places and have been very short in duration. Age

There is some evidence that the risk of acquiring infections increases with age during the period from infancy to early adult life (28), probably because of increasingly numerous contacts with other people. Although tuberculin sensitivity, once acquired as a result of infection with tubercle bacille, persists for many years, the prevalence of positive tuberculin reactions tends to level off around 50 to 60 years of age. In some populations, there is even a decreased prevalence in older ages, possibly because the infecting bacille in some people had died out at an early age. Sex and Race

In nearly all populations around the world, adult males are more likely to have been infected than females, again probably reflecting their opportunity for more and varied contacts in most societies (29). This sex difference was clearly illustrated in a large tuberculin-testing program among New York City school employees (30,31). The prevalence of positive reactors was also higher among nonwhites than whites. Socioeconomic Status

In the New York City study, the prevalence of positive tuberculin reactors decreased steadily with increasing socioeconomic status of their neighborhood. In the highest socioeconomic areas, the frequency of reactors was similar among whites and nonwhites (26,27). Among high school students in Washington County, Maryland, U.S.A., large tuberculin reactions typical of those resulting from tuberculous infection were much more common among students living in crowded, inadequate housing (32). Chemotherapy of Source Case

Effective chemotherapy of the source case appears to reduce infectiousness rapidly, perhaps even more rapidly than is indicated by results of sputum examinations (22,33,34). Although isoniazid-resistant organisms have reduced virulence for guinea pigs, there is no indication that drug resistance per se has any effect on infectiousness for humans (35). However, when source cases with drug-resistant organisms had a history of prior and probably ineffective treatment, their contacts were at increased risk of being

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infected. It is likely that this increased risk resulted from the long duration of exposure that is associated with multiple episodes of treatment. Institutionalization

Both voluntary and involuntary confinement in two types of institutions has been shown to be associated with an increased risk of becoming infected with tubercle bacille. In a survey of nursing homes in Arkansas, it was found that the risk of becoming a positive tuberculin reactor was 3.5% per year even if there had been no recognized TB cases in the home within the previous three years (36). Periodic tuberculin testing in an elderly population in poor health can be misleading in individuals because of the relatively high degree of instability of the tuberculin reaction in such people (37). Using the two-step procedure at the time of initial testing will help identify many of the conversions that are due to ‘‘boosting’’ (anamnestic reaction), which might otherwise be subsequently classified as new infections (37–39). Identification of new TB infections among people in long-term correctional institutions also faces the problem of differentiating new infections from boosted reactions. This problem can be minimized by the use of two-step testing at the initial examination (39,40). A conversion from a negative to a positive test within a ‘‘week or two’’ interval in two-step testing is highly likely to be a boosted reaction. A subsequent conversion at a semiannual or annual retest among people negative to the second of the two tests should be considered as evidence of a new infection. Repeated tuberculin testing in state prisons in two states showed conversion rates from a negative to a positive tuberculin test of 6.3% and 9% per year (41,42). Since then, TB has been recognized as a serious threat because of gross overcrowding in correctional institutions and the ease of airborne spread of infection (40,41). A growing problem concerns TB transmission in shelters for the homeless. The presence of an untreated infectious case of TB in these often crowded, poorly ventilated buildings confers a considerable risk of infection on the other clients and the shelter personnel (43). Intrinsic Susceptibility

A review of the foregoing shows that the known determinants of becoming infected are extrinsic to the exposed person or, in other words, environmental. Whether or not there is also an intrinsic risk factor is still uncertain. In one study, blacks were more likely to become positive tuberculin reactors than whites, when exposed similarly in nursing homes and prisons (44). However, a careful study of a primary school outbreak found no difference in infection rates among white and black children similarly exposed to an infectious physical education teacher (45). At present, the issue of intrinsic susceptibility to infection remains unsettled, kept alive by the fact that individuals do differ in almost all characteristics and by anecdotal reports of people who are still negative tuberculin reactors after a lifetime of caring for TB patients.

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Relatively few studies have been able to investigate the factors that influence whether or not an infected person will develop TB. Although most of them were done 25 or more years ago, the relative risks are still likely to be relevant. Reinfection

For the past 100 years, there have been many discussions and opinions about the relative importance of exogenous reinfection and endogenous reactivation in the development of clinical TB following the initial infection with M. tuberculosis (46). With the ability to genotype tubercle bacille, it is now clear that reinfection from a new source case can occur. However, it is still uncertain how often reinfection is responsible for the development of manifest disease. In any case, it is likely that the risks of being exposed to possible reinfection are similar to the risks of first becoming infected, as reviewed in the previous section. Time and Place

The change in risk of disease occurring after infection is not known with respect to calendar time. There are, however, some data showing that the risk of disease is highest shortly after receipt of infection and that it declines thereafter. Findings from a controlled trial of isoniazid prophylaxis among contacts of active TB cases and a trial among hospitalized psychiatric patients can be combined to yield a reasonable estimate (47). In these two trials, 1472 people allocated to the placebo regimen converted from a negative to a positive tuberculin reaction at some time within the first study year. Of the 29 new cases that developed during a seven-year follow-up period, 64% occurred during the first year, the year in which they became reactors, 22% developed during the next three years, and 13% during the last three years. In South India, the risk of developing TB was 2.6% within the first year after tuberculin conversion, and only 0.5% during the next three years (48). Incidence of TB among tuberculin reactors varies by place, probably related to the intensity of exposure. Among 265,488 tuberculin reactors with negative chest radiographs who participated in a mass campaign in 1950 to 1952 in Denmark (exclusive of Copenhagen), the average annual incidence over the next 12 years was 29 per 100,000 (49). At the other extreme was the Inuit population in the Yukon-Kuskokwim delta of Alaska, where the average annual incidence rate from 1957 to 1964 was over 500 per 100,000 people with initially negative chest radiographs, virtually all of whom were tuberculin reactors (50). In Denmark, in the 1960s, rural tuberculin reactors 15 to 44 years of age had a risk of subsequently developing TB, which was only 60% of the risk for their urban counterparts (49). Personal Characteristics Age

Among TB contacts in British Columbia and Saskatchewan, Canada, who had positive tuberculin reactions, the frequency of active TB discovered

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during a six-month period following diagnosis of the index case decreased with increasing age of the contacts (19). A similar pattern by age was observed in South India (48). The higher risk among younger contacts may have resulted in part from the fact that a higher proportion of infections among young people are likely to have been recent. The incidence of TB among tuberculin reactors by age was investigated as a by-product of a controlled trial of BCG vaccination in Puerto Rico (51). Among 82,269 tuberculin reactors aged 1 to 18 years, who were followed for 18 to 20 years, 1400 cases of TB were identified. As shown in Figure 1, there were two peaks of incidence. One occurred among children in the one- to four-year-old age group, probably reflecting the fact that these infections must have been recent. The second peak occurred during late adolescence and early adult life and was experienced by all birth cohorts as they passed through this period of life. A similar peak was noted among British adolescents, although at a slightly lower age (53). The cause of increased incidence at this age, even for people infected in early childhood, is unknown. The risk among older adults is not well established, but all evidence points to the persistence of at least a low risk of developing TB during the lifetime of infected people. For this reason, life expectancy is a major determinant of the lifetime risk of developing TB among tuberculin reactors. Sex

In seven studies that reported sex- and age-specific incidence rates among positive tuberculin reactors, rates for females were higher during their childbearing ages than the rates for males; at older ages, rates were higher in

Figure 1 Incidence of tuberculosis among Puerto Rican children who were reactors to tuberculin, by age when tuberculosis was first diagnosed. Source: From Ref. 52.

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males (29). An exception to this pattern occurred in the large BCG trial in the Chengleput area of South India (54). Among people with tuberculin reactions of 12 mm or larger, males had higher incidence rates than females at all ages. Findings from a directly observed treatment program in another area of South India confirm the excess risk among infected males (55). Prevalence of positive reactors was only 20% higher among males, whereas the attack rate of tuberculous disease was 6.5 times greater among males. Race

Race per se appears to have little influence on the risk of disease once infection has occurred. Case rates were not significantly different among black and white reactors in Georgia and Alabama (56), nor among Navy recruits (57). As can be seen in Table 2, Indian and white reactors in Canada also had similar rates when age, intimacy of contact, and infectiousness of source case had been controlled (19). Dosage of Infection

The findings shown in Table 2 also bear on the relationship of dosage of infection to the risk of developing TB (19). All the subjects in this study were tuberculin reactors and can be considered to have been infected. Because the risk of disease was greatest among those exposed to the most infectious cases and among those with the closest contact, the conclusion seems inescapable that people infected with larger numbers of tubercle bacille are at greater risk than those infected with smaller numbers of organisms. A study in Mysore State, India, also showed that among contacts who were strongly positive tuberculin reactors, development of pulmonary disease was most likely among those with the most intense exposure, i.e., the contacts most likely to have received larger doses of infection (58).

Table 2 Age-Adjusteda Prevalence of Active Tuberculosis Among Infected Tuberculosis Contacts in British Columbia and Saskatchewan by Race, Type of Contact, and Sputum Status of Source Case, 1966–1971 Prevalence (%) Indian contacts Sputum status of source case Positive smear Positive culture only Negative culture a

White contacts

Intimate (n ¼ 352)

Casual (n ¼ 169)

Intimate (n ¼ 412)

Casual (n ¼ 216)

14.4 5.1 3

10 3.9 0

14 5 2.3

8.2 6.2 0

Adjusted to age distribution of total study population aged 0–14 years. Source: From Ref. 19.

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Size of Tuberculin Reaction

It has been known for several decades that infections with NTM often cause tuberculin sensitivity but rarely result in disease, and also that crossreactions to tuberculin caused by these organisms are usually smaller than those caused by M. tuberculosis (59). Consequently, it is not surprising that where nontuberculous mycobacterial infections are present, small tuberculin reactions are less likely to be caused by infections with tubercle bacille, and hence are less likely to be associated with a risk of subsequent disease than larger reactions. The importance of this risk was illustrated by a study of Puerto Rican children (52). Children with reactions measuring 16 mm or more in diameter to one tuberculin unit of a purified tuberculin had a subsequent risk of tuberculous disease, more than five times greater than children with reactions of 6 to 10 mm, following a test with 10 tuberculin units of a purified tuberculin. The prognostic importance of this widely available risk factor has recently been recognized in recommended standards for TB control (60). Immunosuppression

The fact that the great majority of people do not develop TB after they have been infected indicates the ability of the normal immune system to hold the infecting organisms in abeyance or even, in some instances, eradicate them. Treatment with immunosuppressive agents can upset this balance, as can infection with HIV. TB is reported to be rampant in populations throughout the world who have dual infections with both the tubercle bacille and HIV. An early illustration of the enormous magnitude of this risk was afforded by a longitudinal study among intravenous drug users in New York City (61). No cases of TB were observed among 298 reactors who were HIV negative, compared to eight among 215 HIV-positive people. Seven of the eight TB cases occurred among 36 who were known to have been positive tuberculin reactors but who had not received isoniazid chemoprophylaxis, an average annual case rate on the order of approximately 8000 per 100,000. The temporary loss of tuberculin sensitivity following measles has also been equated with immunosuppression, and hence increased susceptibility to activation of a latent tuberculous infection. However, a careful review of the pertinent literature failed to substantiate this belief (62). Relative Weight

Among the few benefits of being overweight is its association with protection against TB. Among white male recruits with positive tuberculin reactions and negative chest radiographs on entry to the Navy, those who were 10% or more underweight were 3.4 times more likely to develop TB than those who were 10% or more overweight (63). Genetics

Genetic factors clearly play some role in the development of TB in humans, but the extent of the role is unclear. Lurie has shown that there is some

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genetic basis for resistance to TB in rabbits (64), and a variety of evidence suggests the same is true for humans. In a tragic accident in 1926, 249 infants in Lubeck, Germany were vaccinated with live M. tuberculosis instead of BCG vaccine. All 249 developed TB, although the severity of the illness varied widely; 76 infants died. None of the infants had been previously vaccinated with BCG, none were old enough to have developed natural acquired immunity, and all received the same dose of mycobacteria. The variation in their response to the infection may be partially due to nutritional status and other factors, but some must have been due to differences in innate susceptibility to TB (65,66). When TB was introduced for the first time in the Qu’Appelle Indians in the late 19th century, 10% of the population died annually from the disease. Half of the families in the community died out within two generations, but the annual TB death rate in the remaining population dropped to only 0.2% (67). A similar scenario occurred when TB was introduced to the Yanomami Indians in the Amazon (68). These scenarios appear to show the development of population immunity to TB where intrinsically more susceptible people die from infection, leaving only those genetically more capable of surviving infection. Perhaps the strongest evidence that genetics plays a role in development of disease comes from twin studies, which examine the incidence of disease in pairs of twins. When both twins in a pair develop a disease, they are called concordant; they are discordant when only one of the twins is diseased. If genetics plays no role in a disease, monozygotic and dizygotic twin pairs should have similar concordance rates. If genetics is important, then concordance should be higher in monozygotic twins because they have identical genomes. Several twin studies have shown that the concordance for TB is roughly two times higher in monozygotic twins even when data was adjusted for the effects of sex, age, infectivity of the index case, type of TB, and years of contact (69–71). Although environment must play a role in the development of disease in twin pairs, it seems clear that monozygotic twins are at greater risk of disease. There have been other types of studies suggesting a genetic component in TB. In a well-done study by Overfield and Klauber, the prevalence of a positive tuberculin response and active TB was correlated with ABO and MN blood types in a random sample of Alaskan Eskimos with a very high TB infection rate. The authors reported that people with blood type AB and B were three times more likely to have moderate to severe TB compared to people with blood type O and A (72). There also appears to be some correlation between development of TB and histocompatibility types (73). Several studies have also shown that specific genetic polymorphisms may be associated with TB. Allelic variation in the gene nramp-1 was associated with TB in a case–control study in the Gambia (74). Another study from Cambodia identified a specific HLADQ haplotype associated with TB (75). Interferon-cR1 deficiency has also been shown to be associated with increased susceptibility to TB in a study of French children who developed disseminated BCG after vaccination.

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A few children with no underlying immune defect had a specific autosomal recessive mutation in the gene coding for interferon c-R1 (65,76,77). Studies have also suggested that several other genes or chromosome regions may effect susceptibility to TB, and research continues in this area (65). Smoking

Although a link between smoking and TB has been long been postulated, the evidence supporting the association has been lacking until recently. A 2003 study in India showed that male smokers were three times more likely to report a history of TB than nonsmokers (78). A prospective study in Hong Kong also examined the incidence of TB in smokers and nonsmokers and found that the incidence was highest in current smokers (735/100,000), lowest in never smokers (174/100,000), and intermediate in ex-smokers (427/100,000). The trend was significant (p < 0.001) and persisted after adjustment for multiple factors. In addition, current smokers who developed TB smoked more cigarettes than those who did not (13.43 cigarettes per day vs. 7.87, p ¼ 0.01), and a significant dose response was observed (79). A study in Kuwait suggests that smoking may delay sputum conversion in some people receiving treatment (80). Although the mechanics of the smoking–TB association have not been explained, some have suggested that iron-loading of pulmonary macrophages secondary to smoking may damage the cells and make them more susceptible to infection with the tubercle bacille (81). Socioeconomic Status

There is almost no evidence about the relationship of social and economic factors to the development of tuberculous disease among tuberculin reactors. In Muscogee County, Georgia, U.S.A., the incidence of TB among reactors during the period 1950 to 1962 showed no association with the quality of their housing, as recorded in a private census in 1946 (56). This held true for both whites and blacks. There are no data on reactors living under conditions of extreme deprivation, although anecdotal evidence indicates a high risk. C. Risk of Reactivation of Disease

The third risk to be considered in etiologic epidemiology is relapse, namely the risk of developing active disease following spontaneous or therapeutically associated ‘‘cure.’’ Relatively little is known about these risks, except for those related to chemotherapy. Adherence to Chemotherapy

Chemotherapy has made an almost miraculous improvement in the prognosis of people who develop TB. Conscientious adherence to an appropriate regimen even in the earlier days of chemotherapy came close to guaranteeing a lasting cure (82). It is not surprising, therefore, that poor compliance with therapy is a major risk factor not only for treatment failure, but also for relapse after apparent cure (83–85). The presence of drug-resistant tubercle bacille is also an important risk factor for relapse. In 12 controlled trials of short-course chemotherapy, patients with bacille resistant to

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streptomycin or isoniazid were much more likely to relapse than patients with bacille sensitive to these drugs (86). Even though completion of an appropriate regimen comes close to guaranteeing a cure (60), close is not perfection. As one example, among 582 patients who completed a six-month regimen with isoniazid and rifampicin throughout and pyrazinamide plus either ethambutol or streptomycin for the first two months and who were followed for five years, the relapse rate during this period was 3.4% (87). Expressed as a percentage, this appears low, but it is equivalent to an average annual rate of 680 per 100,000. Life-table reanalysis of the data from the U.S. Public Health Service (USPHS) TB short-course chemotherapy trial 21 showed a relapse rate of approximately 600 per 100,000 per year for the two regimens combined (88). Time

The risk of relapse by calendar time has clearly been influenced by the markedly reduced risk following the introduction of chemotherapy. In Denmark, after the introduction of isoniazid into the therapeutic regimen, the relapse rate fell from nearly 13% to 6% (89). The risk of relapse by time following completion of therapy has also been influenced by the introduction of antibiotic chemotherapy. Prior to its introduction, relapse was most likely to occur shortly after treatment stopped (90,91); after chemotherapy was introduced, relapses were less likely during the year or two following adequate treatment (88,91). Longterm risk after adequate chemotherapy is not known. Age, Sex, and Race

Relapse rates by age do not show a consistent pattern. In untreated people whose disease was judged to be inactive or fibrotic at the time of diagnosis, reactivation was less likely with increasing age (91,92). Among people whose disease became inactive after treatment, relapse rates went up with age in Denmark (67), and showed no significant trend with age in India (93). There was a tendency for relapse rates to be somewhat higher in males than females (89,92,93), although not in all populations (94). Reactivation rates were more common among Canadian Indians than other Canadians (95) and, in the state of Georgia, more common among blacks than whites (90). Socioeconomic Status

Among blacks in Georgia, degree of skin pigmentation was not related to the risk of relapse, suggesting that socioeconomic factors might be more important than race per se (90). Another indication that socioeconomic factors might play a role came from a geographic comparison of relapse rates in Denmark (89). Relapse rates among residents of Copenhagen were higher than among people living in the more rural areas of Denmark. Extent of Disease

In Georgia and in Europe, reactivation in untreated people was much more likely among people with extensive fibrotic disease than among those with

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only minimal lesions (90,96). A similar finding was reported among previously treated patients in Wisconsin and South Africa (83,97). III. Administrative Epidemiology Information on TB morbidity and mortality is voluminous compared to that available for etiological epidemiology. Even so, most of it is based on official reports and can be related only to time, place, race, sex, and age. Hard data on other factors are sparse. The available information on many aspects of administrative epidemiology is included in other chapters of this volume. A. Time and Place

The risk of TB infection varies widely around the world. It is stable or falling throughout in five of the six WHO regions. Rates are lowest and continue to drop in developed and more affluent developing countries in Latin America and Eastern Europe. Incidence is stabilizing in Asia, although the sheer size of the population means there are millions of cases in the region. Rates in Africa continue to rise, however, particularly in areas with high HIV prevalence, although the rate of increase is slowing in some countries (1). In the United States, reported incidence declined at an average rate of 5.9% per year for several decades until 1985 (Fig. 2) (5). The case rate then rose from 9.3 per 100,000 in 1985 to a high of 10.5 in 1992. Since then, the case rate has fallen steadily to 5.1 in 2003 (6).

Figure 2 Number of tuberculosis cases and deaths, United States, 1953 to 2003, all ages, all types. Source: From Refs. 5, 6.

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The so-called resurgence of TB from 1985 to 1992 was far from uniform among U.S. states and cities, with marked variation in case rate changes both during and after the resurgence period (98). Seven states—California, Nevada, New Jersey, New York, Texas, Utah, and Washington—showed average annual increases of 4% to 17% during the period 1984 to 1991. Rates for the rest of the country showed a slight decline throughout this entire period. Most Western European countries and Canada showed a slowing of the previous decline in TB rates after 1985, and some even showed slight increases. A notable exception was Finland, where the decrease in case rates accelerated after 1985. Various factors have been suggested as the cause of the resurgence in the United States (99). These include HIV infection, poverty, homelessness, drug abuse, immigration, and, usually last, decreased funds for TB control. The only one of these factors to have changed in a favorable direction since 1985, however, was the considerable increase in TB control funds during the 1990s, which led to a revitalization of TB control activities in critical areas (100). The WHO collects and reports global TB incidence data annually. Although reporting to WHO is voluntary, nearly all countries in the world comply by reporting the number of new TB cases of all types, the number of new smear-positive cases, and age and sex information for smear-positive cases, as well as information on the status of their TB control program (101). The quality of the incidence data reported to WHO varies. To compensate for these differences, WHO reports both the number of cases reported by each country (case notifications) and an estimated number of TB cases, which is a standardized adjustment of the case notifications based on countryspecific information (102). There are considerable differences between the number of case notifications and number of estimated cases in some instances (Table 3), generally due to undercounting of incident disease. For comparison across countries or between WHO world regions, therefore, the estimated incidence is preferable. WHO presents data annually by geographic regions of the world (101). Although convenient and logical, in some of the six regions, there are countries with very different risks of TB. This confuses the epidemiologic picture somewhat, but the WHO regions are the only available source of standardized global information. Among the WHO regions, the absolute burden of TB as measured by the number of cases is greatest in the Southeast Asian region (SEAR), but the rate of disease is highest in the AFR. Either way, the SEAR and AFR together accounted for more than 60% of incident cases in the world in 2004 (1). The rates of disease in the East Mediterranean region (EMR) and the Western Pacific region (WPR) are also high, but only about onethird of the rate seen in AFR. The number of cases and rate of disease are lowest in the Americas and European region (EUR), which are dominated by the more developed countries of the world. Figures 3 and 4 show trends in case notification rates collected by WHO for 1982 to 2002 for different world populations. The notification

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Table 3 Number of Notified and Estimated Tuberculosis Cases (All Types), Cumulative Incidence, and Estimated Rate of Tuberculosis, All Types, Worldwide and by World Health Organization Region, 2002 Number of cases

Estimated annual rate (per 100,000)

WHO region

Notified

Estimated

Ratio of estimated to notified

AFR Americas EMR EUR SEAR WPR

992,054 233,648 188,458 373,497 1,487,985 806,112

2,354,000 370,000 622,000 472,000 2,890,000 2,090,000

2.37 1.58 3.30 1.26 1.94 2.59

350 43 124 54 182 122

Global

4,081,754

8,707,000

2.13

141

Abbreviations: AFR, African region; EMR, East Mediterranean region; EUR, European region; SEAR, Southeast Asian region; WPR, Western Pacific region. Source: From Ref. 101.

rates in the figure are expressed relative to an arbitrary standard of 100 in 1990 to emphasize time trends. The error bars show the 95% confidence interval of the standardized rates. Countries included in the graphs were considered representative of countries within the region for the time period specified. Increases observed in notification rates in the late 1990s in some areas may be due to improvements in TB control programs rather than true increases in disease rates, but, in general, the standardized notification rates shown accurately reflect changes in disease trends in the populations (101). In the established market economies and Central Europe, notification rates dropped fairly steadily over the time period, except for the 1985-to1992 period, mentioned earlier, which is visible here as a flattening of the trend line around 1990. Similarly, rates in the EMR and Latin America appear to have been dropping steadily. In the SEAR, the trend is less clear, but, since 1996, notification rates have been dropping steadily. Declines seen in the WPR between 1990 and 1996 have been lost, and the trend in notification rates has flattened. In Eastern European countries, case and death rates from TB have historically been higher than in Western Europe, but were declining in most of the countries through 1992 (103). After that, notification rates climbed steadily until 2001 when they were roughly double the rate seen 20 years earlier. Revised data from 2004 show that rates peaked in 2001 and have been falling since then (1). Notification trends in Africa vary by HIV prevalence. In high-prevalence areas, notification rates continue to increase as they have since the mid-1980s, although the increase in some countries has been mitigated by effective TB control activities (103,104). In low-prevalence countries, a previously flat trend began increasing at the turn of the 20th century.

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Figure 3 Trends in tuberculosis case notification rates, all types, for selected countries and world regions, 1981 to 2002. Established market economies: Australia, Austria, Belgium, Canada, Czech Rep., Denmark, Finland, France, Germany, Greece, Iceland, Ireland, Japan, Luxembourg, Netherlands, New Zealand, Norway, Portugal, Singapore, Spain, Sweden, Switzerland, United Kingdom, United States. Central Europe: Albania, Croatia, Cyprus, Hungary, Poland, Serbia and Montenegro, Slovakia, Slovenia, Turkey. Latin America: Argentina, Bolivia, Brazil, Chile, Cuba, Dominican Republic, El Salvador, Guatemala, Guyana, Honduras, Jamaica, Nicaragua, Paraguay, Peru, Puerto Rico, Uruguay, Venezuela. Eastern Mediterranean: Iran, Jordan, Lebanon, Morocco, Oman, Qatar, Saudi Arabia, Syria, Tunisia. Pacific: China Hong Kong, SAR, China Macao SAR, Lao People’s Democratic Republic, Malaysia, Republic of Korea, Vietnam. SE Asia: Bhutan, India, Maldives. Source: From Ref. 101.

TB is more common in large cities than in rural areas (97,103). In the United States, in 2002, metropolitan statistical areas with populations greater than 500,000 had 77% of the new cases, for a case rate of 6.3/ 100,000. In the less populous areas, the rate was only 3.0/100,000. Forty-nine percent of the 3142 U.S. counties reported no cases in 1998; most were located in the northern plains and Rocky Mountain areas (84).

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Figure 4 Trends in tuberculosis case notification rates, all types, for Africa and Eastern Europe, 1981 to 2002. Africa–low HIV: Algeria, Benin, Comoros, Ghana, Guinea, Madagascar, Mali, Mauritania, Mauritius. Africa–high HIV: Botswana, Coˆte d’Ivoire, Democratic Republic of Congo, Kenya, Lesotho, Malawi, Uganda, UR Tanzania, Zambia, Zimbabwe. Eastern Europe: Armenia, Bulgaria, Estonia, Kazakhstan, Kyrgyzstan, Latvia, Lithuania, Republic of Moldova, Romania, Russian Federation, Tajikistan, Turkmenistan, Ukraine, Uzbekistan. Source: From Ref. 101.

The same situation is also seen in other parts of the world, even highly endemic areas. In Orissa State, India, the prevalence of TB in children residing in urban areas was 60% higher than the risk of those living in rural areas (16). Similarly, the estimated annual risk of TB infection from 1955 through 1995 was consistently higher in Phnom Penh, Cambodia, than it was in the surrounding provinces (17). Not all of the considerable geographic differences can be explained by stage of economic development, immigration, or prevalence of HIV infections. Case rates within the original European community varied from 7.4 to 31.9 per 100,000 in 1983; among six members of the Eastern Bloc, the range was 20.3 to 72.8 (105). In 2002, Iceland had the lowest estimated rate of TB in Europe, 3.0/100,000, with Sweden and Norway close behind at 3.0 and 5.0/100,000, respectively (81). Rates in England and Wales ranged from 3.1 in Anglia to 37.0 per 100,000 in some boroughs of London in 1983 (106), while among the 50 U.S. states, the case rate in 2003 ranged from 0.8/100,000 in Wyoming to 14.0/100,000 in Washington, DC (104). Unfortunately, interpretation of geographic variations is more difficult than generally recognized. Within the United States in 1992, the percentage of

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pulmonary cases not bacteriologically confirmed varied from 0% to 35.4% among states with 25 or more reported cases (107). Considerable variations between nations in both the extent and nature of cases of pulmonary TB have also been recorded (108). Influx of immigrants from an area where the prevalence of TB is high has also affected temporal trends adversely, especially in industrialized countries. An early experience was reported from British Columbia, Canada. TB case rates had been declining from 1970 to 1985, except for the city of Vancouver (109). On investigation, it was found that the failure of the rates to decline in Vancouver was selective immigration into the poorer areas of the city of a group of high risk, socially disadvantaged immigrants. In the United States, the proportion of cases from abroad increased from 29% in 1993 to 53% in 2003 (103). Perhaps the heaviest burden of immigration has fallen on Israel, where more than a million immigrants, mostly from high-prevalence countries, were admitted during 1990 to 2000 (110). By adapting TB control procedures to the problems and needs of immigrants, Israel has had considerable success in controlling TB among them, with no evidence to date that there has been significant spread of disease to the host population. Genotyping has cast considerable light on the risks of TB among immigrants. In New York City, genotyping indicated that reactivation of latent TB infection was the cause of most cases among the foreign-born, whereas among US-born people, many cases were due to recent transmission (111). A large study in Hamburg, Germany, also concluded on the basis of molecular and epidemiologic investigations that recent transmission was not important among immigrants (112). Spoligotyping of tubercle bacille from Swedish cases indicated that only 14% were due to recent transmission and that the strains of tubercle bacille among immigrants corresponded closely with the countries from which the immigrant cases had come (113). The results of genotyping 1100 isolates from 11 countries also showed that tubercle bacille tended to have characteristics that were unique to the country from which they were obtained (114). B. Age, Race, and Sex

The number of reported TB cases per 100,000 population for 1989 through 2002 by ethnic group for the United States is shown in Figure 5 (5,103,107). All ethnic groups are currently showing a downward trend in TB rates. The trend began about 1992 for Hispanics, blacks, and whites; 1995 for Asian/ Pacific Islanders; and in 1994 for American Indian/Alaskan Natives. In the United States, in 2002, case rates were low in infancy and decreased somewhat during early childhood (5). After puberty, they showed a generally steady increase with age (Fig. 6). For all ethnic groups, rates among females are lower than among males. TB case rates for whites are the lowest at all ages, and Asian/Pacific Islanders are the highest. Rates among blacks, Hispanics, and American Indian/Alaskan natives are intermediate.

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Figure 5 Reported tuberculosis rates per 100,000 by race/ethnicity group, United States, 1989 to 2002 (up to 1993, Hispanics are also included in one of the other groups). Source: From Ref. 103.

Figure 6 Tuberculosis case rates, United States, 1996, by race/ethnicity and age groups. Abbreviations: A, American Indian/Alaska native; A/P, Asian/Pacific Islander; H, Hispanic; B, black, non-Hispanic; W, white, non-Hispanic; M, male; F, female. Source: From Ref. 76.

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Figure 7 Number of smear-positive cases of tuberculosis per 100,000 population in the World Health Organization Americas, East Mediterranean, and European regions by age and sex, 2002. Abbreviations: AMR, American region; EMR, East Mediterranean region; EUR, European region; M, male; F, female. Source: From Ref. 81.

Smear-positive TB notification rates by age, sex, and WHO world region are shown in Figures 7 and 8. Among women in five of the six WHO regions of the world, rates start low in infancy, climb to a peak at 25 to 35 years of age (101), and then decline or flatten with increasing age. In the EMR, the rates also begin low but then continue to rise with increasing age. In high-prevalence areas such as the AFR and SEAR, the

Figure 8 Number of smear-positive cases of tuberculosis per 100,000 population in the World Health Organization Southeast Asia, Western Pacific, and African regions by age and sex, 2002. Abbreviations: AFR, African region; SEAR, Southeast Asian region; WPR, Western Pacific region; M, male; F, female. Source: From Ref. 101.

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increase between 14 and 35 years of age is much steeper than that seen in low incidence areas. The pattern is not quite so clear in men across the six regions. In all regions, rates start low and rise into early adulthood. In the Americas, EUR, and AFR, the rates increase to a peak at 25 to 45 years and then decline or remain roughly level with increasing age. The pattern is similar in the SEAR but the peak is delayed until 55 to 64 years of age. In contrast, in the WPR and EMR, the rates of smear-positive disease continue to increase throughout life. Figures 7 and 8 also show that age- and sex-specific curves of smearpositive notification rates throughout the world fit one of two patterns. In the most common one, the curves are similarly shaped and smear-positive TB rates are lower in women at all ages. This is the pattern seen in five of the six WHO regions. The pattern in the AFR is different, however. The curves for males and females still parallel each other in shape but the rates in females are higher from birth through 24 years of age and then lower than males throughout the rest of life. However, Figures 7 and 8 can be misleading. Examination of case-specific age/sex rates for individual countries shows that there are some countries in each region of the world, except the EUR, in which the rates are greater in women than men from birth through 24 years of age. This is obscured on a region-wide level because the first pattern predominates in all but the AFR. C. Socioeconomic Status and Nutrition

The association of TB with poor socioeconomic status has long been noted (7,99,115). Decades ago, homeless men in New York City were found to have high rates of TB (115) and a similar excess was noted among unmarried men living in central Copenhagen (116). The situation is no different today. In the United States, in 2002, 56% of new TB cases occurred in people who had been unemployed for more than 24 months and 6% in the homeless (103,117). The situation in the United States and some other developed countries is aggravated by an increase in the number of homeless people and the continued high frequency of TB among them (117,118). Further aggravation in more developed countries comes from the tendency of poor immigrants to crowd into large cities (119,120). Initially, their TB risk reflects the prevalence of the disease in their native countries and, although the risk decreases with their duration of stay in their adopted homes (109,121,122), they still produce foci of infection in areas with otherwise low rates of TB (119). Even in highly endemic areas such as Hong Kong, more TB cases reside in rooming houses or one-room apartments than in more luxurious accommodations (123,124). Interestingly, the reverse situation can be found in some developing countries. In Sabah, Malaysia, the rate of TB in native-born Malaysians is higher than in immigrants from the Philippines and Indonesia, even though overall rates in those countries are higher. In this case, it may be that immigrants are wealthier than native-born Malaysians and have had a lower risk of disease within their home country (125).

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Based on a survey from 29 states in 1984 to 1985, occupational status was strongly associated with TB case rates (126). Executives and professionals had the lowest rates, and laborers, farm workers, and household servants had the highest rates. Health-care workers had rates of TB about the same as that of the general population, except for higher rates among inhalation therapists, nursing aides, orderlies, and attendants. An interesting exception to the inverse association of TB with occupational status was the higher-than-expected rate among funeral directors. A recent study showed that funeral home employees who performed embalming were twice as likely to have been infected with tubercle bacille as other employees (127). Historically, moderate to severe malnutrition has also been linked to the development of TB, although the available supporting evidence in humans is limited. The best evidence suggesting a link comes from the first National Health and Nutrition Examination, in which a representative cross section of U.S. adults were followed longitudinally for more than 10 years. Individuals with body mass index or upper arm circumference in the lowest decile of the population had a 6- to 10-fold increased risk of TB after controlling for other known risk factors (128). A more recent study in Malawi also shows that the severe pulmonary TB is more common in people with lower body mass index and fat mass (129). There is also a suggestion that certain micronutrients may effect TB infection. In a study in India, people with TB had lower levels of serum vitamin A than did controls (130). D. Institutional Living

Because poverty is associated with both crime and TB, it is not surprising that TB is often a problem among inmates of correctional institutions. Various surveys have estimated that the frequency of TB is increasing among such populations and that it is three to six times higher than expected from rates in the general population (131). TB among people living and working in nursing homes and other facilities providing long-term medical care has only recently been recognized as a problem (36). A survey of 29 states suggested that the case rate for patients was approximately 50% higher and the rate among employees was three times higher than expected from the rates in similar age sex groups in the general population (36,131). E. Special Medical Situations

A variety of medical conditions are associated with TB. Although these risk factors are presumably limited to people already infected with M. tuberculosis, studies to substantiate this presumption are few and rarely definitive. By far, the most important is immunosuppression, particularly that resulting from infection with the HIV (129,132). Other causes of immunosuppression also accompanied by an increased TB risk include treatment with immunosuppressive drugs, including prolonged adrenocorticosteroid therapy, some hematologic and reticuloendothelial diseases such as leukemia and lymphoma, and end-stage renal disease and renal transplantation (133).

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Silicosis has long been linked with TB, so much so that silico TB is an accepted disease entity. Although the causal nature of this association is largely based on uncontrolled reports, silica dust has long been known to have an adverse effect on TB in animals (134). Diabetes, too, has long been accepted as a risk factor for TB (135). Two studies in the 1950s indicated that the prevalence among diabetics was approximately four times that in a comparable general population and that the risk was greatest among those with severe diabetes (136,137). Alcoholism and drug addiction are also associated with TB, although it is not clear whether these diseases increase susceptibility to TB or whether conditions conducive to substance abuse are similar to those leading to TB. In any case, alcoholism was well known to physicians in TB sanatoria, because 10% to 30% of patients were reported to be alcoholics (7). Current surveys also show a high prevalence of TB among alcoholics and drug addicts (138). Smoking has also been implicated as a risk factor for TB. In a historical cohort study among elderly people in Hong Kong, annual TB case rates per 100,000 were 174 among never smokers, 427 among ex-smokers, and 735 among current smokers (79). The trend persisted after adjustment for possible confounders, including alcohol intake. F. Infection with HIV

The immune deficiency characteristic of HIV infection increases both the risk of acquiring new TB infection and the risk of developing disease once infected. Add to that the fact that HIV infection is most prevalent in the areas of the world where TB incidence is highest and the outcome is a massive coepidemic of TB and HIV infection centered in sub-Saharan Africa and Asia. The greatly increased risk of clinical TB among people infected with M. tuberculosis and HIV has been clearly demonstrated in this country and abroad (61,132,139). Only in the study by Selwyn et al. (61) is it clear that new tuberculous infection was not the major contributor to the increased risk. In recent years, there have been frequent reports of localized outbreaks (clusters) of TB cases among groups at high risk of developing TB. Many of these people were known to be HIV-positive. In these clusters, a very high proportion of cases were found to have tubercle bacille with the same restriction fragment-length polymorphism pattern, strongly suggesting that all cases came from a single source, probably recent (140,141). In these cluster situations, it is reasonable to believe that there was a high risk of becoming infected and, consequently, a high attack rate of tuberculous disease. Only in populations with a low risk of becoming infected is it reasonable to assume that most HIV-associated TB is the result of reactivation of latent infection. Two features distinguish the epidemiology of HIV-associated TB. First is the speed with which clinical disease becomes manifest following exposure. In two outbreaks among HIV-infected people, attack rates of

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16.7% and 29.4% were observed within somewhat less than a two-year period (142,143). For comparison, during the first two years of observation of HIV-negative household contacts admitted to the placebo arm of an isoniazid prophylaxis trial, only 1.3% of 6608 initially positive reactors and 2.2% of 867 tuberculin converters developed TB (47). The likelihood of developing manifest TB depends on the stage of the HIV infection. Most cases of TB are recognized at about the same time that other AIDS-defining conditions occur; the majority of the remaining cases occur somewhat prior to that time (144). The other feature is that HIV-related TB under usual circumstances appears to be somewhat less infectious than TB not associated with HIV infection (145). Although this decreased infectiousness might appear to be related to the tendency for HIV-infected people to have noncavitary and extrapulmonary disease, the decreased risk of infection persisted after allowing for these and other conditions considered to be related to infectiousness. G. Genetic Susceptibility

In the 19th century, it was commonly believed that TB was a hereditary disease (146). In the early part of the 20th century, Karl Pearson and Raymond Pearl each attempted to disentangle the hereditary and environmental factors that led to the familial concentration of TB (135)—investigations that were continued in the Williamson County Tuberculosis Study by Puffer (147). Subsequent studies of monozygotic and dizygotic twins indicated that some degree of susceptibility was inherited (71). Because of these indications of genetic susceptibility, investigators have looked for associations of TB with various genetic markers. Among the Inuits in Alaska, TB was more prevalent among people with blood groups B and AB than among those with blood groups O or A (72). Although various human leukocyte antigen types have also been suspected of playing a role in TB susceptibility, no consistent associations have been found (148,149). H. Nontuberculous Mycobacterial Infections

It has long been known that NTM are common in the environment, residing in water, soil, and a variety of animals and plants (135). Their global distribution had not been systematically studied until recently, however. In 1996, members of the Bacteriology and Immunology Section of the International Union Against Tuberculosis and Lung Disease formed a working group to collect systematic data on NTM isolated in laboratories around the world and have confirmed a number of conjectures with previously limited support. The most basic point is that the number of NTMs isolated from people increased steadily from 1976 to 1996, probably because of improved laboratory techniques and the advent of the HIV pandemic. The working group also identified the five most commonly isolated NTMs and discovered that the geographic distribution of NTM species is constantly changing and that new species are constantly emerging. For example, Mycobacterium

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xenopi was first isolated in 1980 in Spain, but by 1996, it was the third most common NTM isolated from people, although the rate of isolation varies considerably in the countries studied. There is also considerable geographic variation of chromogenic and nonchromogenic NTM species (150). In a series of experiments unlikely to be rivaled in size and sophistication, Palmer and Long showed that infections with a variety of mycobacteria increased the resistance of guinea pigs against TB (151). Evidence of protection was also found among British adolescents who reacted only to the 100 TU (the standard measurement unit for PPD tuberculin) dose of tuberculin and U.S. Navy recruits who reacted to antigens prepared from Mycobacterium avium-intracellulare or Mycobacterium scrofulaceum but not to the intermediate dose of purified-protein derivative (PPD)-tuberculin (152,153). These findings were not confirmed in a large study in Puerto Rico (51), although it is possible that the nonreactors to the strong dose of tuberculin were like some of Palmer’s guinea pigs that showed some evidence of protection even after failing to develop hypersensitivity after two injections of NTM. Although the question is unsettled, there is a strong possibility that human infections with NTM do confer some protection against TB. I. Psychosocial Stress

Although medical scientists are often hesitant to study the possible effects of mind on the body, there have been persistent hints in the TB literature that psychological, social, and economic stresses have an adverse effect on TB (154–156). Stress is a common thread running throughout the risk factors of poverty, homelessness, marital disruption, institutionalization, and substance abuse. A study that controlled for many other risk factors involved Navy recruits (57). White, black, and Filipino recruits who were tuberculin reactors on entry to the Navy had very similar housing, diet, and income during the first four years of their enlistment. Case rates among white and black reactors decreased during this period; case rates among Filipino reactors increased, possibly because of stresses associated with separation from families and with being a small minority with few social supports. J. Multidrug-Resistant Tuberculosis

Multiple drug resistance, currently defined as resistance to at least isoniazid and rifampicin, has become a major problem in many areas throughout the world (157). Although multiple drug–resistant tubercle bacille have been involved in many outbreaks of TB during the past decade or two, there is at present no evidence that their virulence differs from that of susceptible organisms. Rather, their association with outbreaks appears to be due largely to the situations in which outbreaks occur, namely people at high risk because of immunosuppression, crowding, homelessness, drug abuse, and/or poverty, especially in circumstances where chemotherapeutic regimens are poorly administered or accepted, often because of inadequate TB control programs. Understanding of the global distribution of multidrug-resistant tuberculosis (MDR-TB) is limited by a lack of systematic information. WHO and

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the International Union Against Tuberculosis and Lung Disease founded the Global Project on Anti-tuberculosis Drug Resistance Surveillance in 1994 and have sought to collect representative global data. Unfortunately, the project covers only 60 regions of the world and may not include data from all parts of a given country (158,159). Thus, although their data suggest that MDR-TB rates are 1% or less of all cases in most industrialized nations, there are conflicting reports that suggest much higher rates in at least some parts of some industrialized nations such as the Baltic and some countries of the former Soviet Union (159). In addition, information is very limited from parts of Asia and Africa where TB incidence is highest. Modeling of available data suggests that 250,000 to 500,000 new cases of MDR-TB occur globally each year (159). There are also numerous reports that detail foci of MDR-TB infection in select cities and populations (160–164), but a clearer understanding of the global distribution of MDR-TB remains elusive. IV. Conclusion Although this review of risk factors seems lengthy, it should be noted that much of the information rests on relatively few studies and that some of the most important ones were performed 30 to 40 years ago. Of concern is the current risk of disease following tuberculous infection in a variety of populations. Some way of reliably identifying people who continue to harbor tubercle bacille after having been infected would allow TB control efforts to be much more sharply focused on the seedbed of disease. Even small and individually nondefinitive studies of these and other risk factors would be helpful if they all pointed to the same conclusion. Increased knowledge of current risks of infection and subsequent disease could help greatly in efforts to bring TB back under control and, in developed countries, could even lead to its elimination. References 1. WHO Stop TB Programme. Global Tuberculosis Control, WHO Report 2005. World Health Organization, Geneva, 2005. 2. Buikstra JE, Cook DC. Pre-Columbian tuberculosis in West-Central Illinois: prehistoric disease in biocultural perspective. In: Buikstra JE, ed. Prehistoric Tuberculosis in the Americas. Evanston, IL: Northwestern University Archeological Program, 1981:115–139. 3. Pfyffer G, Auckenthaler R, van Embden JDA, van Soolingen D. Mycobacterium canettii, the smooth variant of M. tuberculosis, isolated from a Swiss patient exposed in Africa. Emerg Infect Dis 1998; 4(4):631–634. 4. Niemann S, Richter E, Dalugge-Tamm H, et al. Two cases of Mycobacterium microti-derived tuberculosis in HIV-negative immunocompetent patients. Emerg Infect Dis 2000; 6(5):539–542. 5. CDC. Reported Tuberculosis in the United States, 2002. Atlanta, GA: US Department of Health and Human Services, CDC, September 2003.

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94. Chan-Yeung M, Galbraith JD, Schulson N, Brown A, Grzybowski S. Reactivation of inactive tuberculosis in northern Canada. Am Rev Respir Dis 1971; 104: 861–865. 95. Nakielna EM, Cragg R, Grzybowski S. Lifelong follow-up of inactive tuberculosis: its value and limitations. Am Rev Respir Dis 1975; 112:765–772. 96. International Union against Tuberculosis Committee on Prophylaxis. Efficacy of various durations of isoniazid preventive therapy for tuberculosis: five years of follow-up in the IUAT trial. Bull WHO 1982; 60:555–564. 97. Cowie RL, Langton ME, Becklake MR. Pulmonary tuberculosis in South African gold miners. Am Rev Respir Dis 1989; 139:1086–1089. 98. Comstock GW. Variability of tuberculosis trends in a time of resurgence. Clin Infect Dis 1994; 19:1015–1022. 99. Brudney K, Dobkin J. Resurgent tuberculosis in New York City. Human immunodeficiency virus, homelessness, and the decline of tuberculosis control programs. Am Rev Respir Dis 1991; 144:745–749. 100. U.S. Congress, Office of Technology Assessment. The Continuing Challenge of Tuberculosis, OTA-H-574. Washington, DC: U.S. Government Printing Office, 1993. 101. World Health Organization. Global tuberculosis control: surveillance, planning, financing. WHO Report 2004, Geneva, Switzerland, ISBN 92 4 156264 1. 102. Dye C, Scheele S, Dolin P, Pathania V, Raviglione MC. Global burden of tuberculosis estimated incidence, prevalence and mortality by country. JAMA 1999; 282:677–686. 103. CDC. Reported Tuberculosis in the United States, 2003. Atlanta, GA: U.S. Department of Health and Human Services, CDC, September 2004. 104. CDC. Reported Tuberculosis in the United States, 1998. Atlanta, GA: U.S. Department of Health and Human Services, CDC, September 1999. 105. Tala E. Registration of tuberculosis in Europe. Bull Int Union Tuberc Lung Dis 1987; 62(1–2):74–76. 106. Medical Research Council Tuberculosis and Chest Diseases Unit. The geographical distribution of tuberculosis notifications in a national survey of England and Wales in 1983. Tubercle 1986; 67:163–178. 107. Centers for Disease Control and Prevention. Reported Tuberculosis in the United States, 1993. Atlanta: Public Health Service, 1994. 108. Horwitz O, Comstock GW. What is a case of tuberculosis? The tuberculosis case spectrum in eight countries evaluated from 1235 case histories and roentgenograms. Int J Epidemiol 1973; 2:145–152. 109. Enarson DA, Wang JS, Grzybowski S. Case-finding in the elimination phase of tuberculosis: tuberculosis in displaced people. Bull IUATLD 1990; 65(2–3):71–72. 110. Chemtob D, Leventhal A, Weller-Ravell D. Screening and management of tuberculosis in immigrants: the challenge beyond professional competence. Int J Tuberc Lung Dis 2003; 7:959–966. 111. Geng E, Kreiswirth B, Driver C, et al. Changes in the transmission of tuberculosis in New York City from 1990 to 1999. N Engl J Med 2002; 246:1453–1459. 112. Diel R, Rusch-Gerdes S, Nieman S. Molecular epidemiology of tuberculosis among immigrants in Hamburg, Germany. J Clin Microbiol 2004; 42:2952–2966. 113. Brudey K, Gordon M, Mostrom P, et al. Molecular epidemiology of Mycobacterium tuberculosis in Western Sweden. J Clin Microbiol 2004; 42:3046–3051. 114. Ahmed N, Alam M, Rao KR, et al. Molecular genotyping of a large, multicentric collection of tubercle bacilli indicates geographical partitioning of strain variation and has implications for global epidemiology of Mycobacterium tuberculosis. J Clin Microbiol 2004; 42:3240–3247.

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115. Chaves AD, Robins AB, Abeles H. Tuberculosis case finding among homeless men in New York City. Am Rev Respir Dis 1961; 84:900–901. 116. Horwitz O. Tuberculosis risk and marital status. Am Rev Respir Dis 1971; 104: 22–31. 117. Von Ville P, Holtzhauer F, Long T, et al. Tuberculosis among residents of shelters for the homeless—Ohio, 1990. Morb Mortal Wkly Rep 1991; 40:869–877. 118. Lukacs J, Tubak V, Mester J, et al. Conventional and molecular epidemiology of tuberculosis in homeless patients in Budapest, Hungary. J Clin Microbiol 2004; 42:5931–5934. 119. Faggiano F, Vigna-Taglianti FD, Versino E, Bugiani M. Tuberculosis incidence in Turin, Italy, 1973–1999. Int J Tuberc Lung Dis 2004; 8(2):171–179. 120. Froggatt K. Tuberculosis: spatial and demographic incidence in Bradford, 1980– 1982. J Epidemiol Commun Health 1985; 39:20–26. 121. Centers for Disease Control. Tuberculosis among Asians/Pacific Islanders— United States, 1985. Morb Mortal Wkly Rep 1987; 36:331–334. 122. Sutherland I, Springett VH, Nunn AJ. Changes in tuberculosis notification rates in ethnic groups in England between 1971 and 1978/79. Tubercle 1984; 65:83–91. 123. Noland CM, Elarth AM. Tuberculosis in a cohort of Southeast Asian refugees. A five-year surveillance study. Am Rev Respir Dis 1988; 137:805–809. 124. Leung CC, Yew WW, Tam CM, et al. Socio-economic factors and tuberculosis: a district-based ecological analysis in Hong Kong. Int J Tuberc Lung Dis 2004; 8: 958–964. 125. Dony JF, Ahmad J, Tiong YK. Epidemiology of tuberculosis and leprosy, Sabah, Malaysia. Tuberculosis 2004; 84:8–18. 126. McKenna MT, Hutton M, Cauthen G, Onorato IM. The association between occupation and tuberculosis. A population-based survey. Am J Respir Crit Care Med 1996; 154:587–593. 127. Gershon RRM, Vlahov D, Escamilla-Cejudo JA, et al. Tuberculosis risk in funeral home employees. J Occup Environ Med 1998; 40:497–503. 128. Cegielski JP, McMurray DN. The relationship between malnutrition and tuberculosis: evidence from studies in humans and experimental animals. Int J Tuberc Lung Dis 2004; 8:286–298. 129. Van Lettow M, Kumwenda JJ, Harries AD, et al. Malnutrition and severity of lung disease in adults with pulmonary tuberculosis in Malawi. Int J Tuberc Lung Dis 2004; 8(2):211–217. 130. Ramachandran G, Santha T, Garg R, et al. Vitamin A levels in sputum-positive pulmonary tuberculosis patients in comparison with household contacts and health ‘normals’. Int J Tuberc Lung Dis 2004; 8(9):1130–1133. 131. Hutton MD, Cauthen GM, Bloch AB. Results of a 29-state survey of tuberculosis in nursing homes and correctional facilities. Public Health Rep 1993; 108: 305–314. 132. Braun MM, Badi N, Ryder RW, et al. A retrospective cohort study of the risk of tuberculosis among women of childbearing age with HIV infection in Zaire. Am Rev Respir Dis 1991; 143:501–504. 133. Klote MM, Agodoa LY, Abbott K. Mycobacterium tuberculosis infection incidence in hospitalized renal transplant patients in the United States, 1998–2000. Am J Transplant 2004; 4:1523–1528. 134. Snider DE Jr. The relationship between tuberculosis and silicosis. Am Rev Respir Dis 1978; 118:455–460. 135. Pinner M. Pulmonary Tuberculosis in the Adult. In: Its Fundamental Aspects. Springfield, IL: Charles C Thomas, 1945:190.

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136. Boucot KR, Dillon ES, Cooper DA, Meier P, Richardson R. Tuberculosis among diabetics. The Philadelphia survey. Am Rev Respir Dis 1952; 65(No. 1, Part 2):1–50. 137. Oscarsson PN, Silwer H II. Incidence of pulmonary tuberculosis among diabetics. Search among diabetics in the county of Kristianstad. Acta Med Scand 1958; 161(suppl 335):23–48. 138. Friedman LN, Sullivan GM, Bevilaqua RP, Loscos R. Tuberculosis screening in alcoholics and drug addicts. Am Rev Respir Dis 1987; 136:1188–1192. 139. Allen S, Batungwanayo J, Kerlikowske K, et al. Two-year incidence of tuberculosis in cohorts of HIV-infected and uninfected urban Rwandan women. Am Rev Respir Dis 1992; 146:1439–1444. 140. Genewein A, Telenti A, Bernasconi C, et al. Molecular approach to identifying route of transmission of tuberculosis in the community. Lancet 1993; 342:841–844. 141. Small PM, Hopewell PC, Singh SP, et al. The epidemiology of tuberculosis in San Francisco. A population-based study using conventional and molecular methods. N Engl J Med 1994; 330:1703–1709. 142. Dooley SW, Villarino ME, Lawrence M, et al. Nosocomial transmission of tuberculosis in a hospital unit for HIV-infected patients. JAMA 1992; 267:2632–2635. 143. Daley CL, Schechter GF, Rutherford GW. Tuberculosis outbreak among people in a residential facility for HIV-infected people—San Francisco. Morb Mortal Wkly Rep 1991; 40:649–652. 144. Rieder HL, Cauthen GM, Bloch AB, et al. Tuberculosis and acquired immunodeficiency syndrome—Florida. Arch Intern Med 1989; 149:1268–1273. 145. Cauthen GM, Dooley SW, Onorato IM, et al. Transmission of Mycobacterium tuberculosis from tuberculosis patients with HIV infection or AIDS. Am J Epidemiol 1996; 144:69–77. 146. Daniel T. Captain of death. In: The Story of Tuberculosis. Rochester: University of Rochester Press, 1997:69–76. 147. Puffer RR. Familial Susceptibility to Tuberculosis. In: Its Importance as a Public Health Problem. Cambridge, MA: Harvard University Press, 1944. 148. Hwang C-H, Khan S, Ende N, Mangura BT, Reichman LB, Chou J. The HLA-A, -B, and -DR phenotypes and tuberculosis. Am Rev Respir Dis 1985; 132:382–385. 149. Hawkins BR, Higgins DA, Chan SL, Lowrie DB, Mitchison DA, Girling DJ. HLA typing in the Hong Kong Chest Service/British Medical Research Council study of factors associated with the breakdown to active tuberculosis of inactive pulmonary lesions. Am Rev Respir Dis 1988; 138:1616–1621. 150. Martin-Casabona N, Bahrmand AR, Bennedsen J, et al., Spanish Group for Non-tuberculosis Mycobacteria. Non-tuberculosis mycobacteria: patterns of isolation. A multi-country retrospective survey. Int J Tuberc Lung Dis 2004; 8(10): 1186–1193. 151. Palmer CE, Long MW. Effects of infection with atypical mycobacteria on BCG vaccination and tuberculosis. Am Rev Respir Dis 1966; 94:553–568. 152. Hart PDA, Sutherland I. 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 1977; 2:293–295. 153. Edwards LB, Acquaviva FA, Livesay VT. Identification of tuberculous infected. Dual tests and density of reaction. Am Rev Respir Dis 1973; 108:1334–1339. 154. Downes J, Price CR. The importance of family problems in the control of tuberculosis. Milbank Memorial Fund Quart 1942; 20:7–22. 155. Hendricks CM. Psychosomatic aspects of tuberculosis. In: Hayes EW, ed. The Fundamentals of Pulmonary Tuberculosis and Its Complications. Springfield, IL: Charles C Thomas, 1949:233–244.

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156. Holmes TH. Multidiscipline studies of tuberculosis. In: Sparer PJ, ed. Personality, Stress and Tuberculosis. New York: International Universities Press, 1956. 157. Cohn DL, Bustreo F, Raviglione MC. Drug-resistant tuberculosis: review of the worldwide situation and the WHO/IUATLD Global Surveillance Project. International Union Against Tuberculosis and Lung Disease. Clin Infect Dis 1997; 24(suppl 1):S121–S130. 158. Drobniewski F, Balabanova Y, Coker R. Clinical features, diagnosis, and management of multiple drug-resistant tuberculosis since 2002. Curr Opin Pulmonary Med 2004; 10:211–217. 159. WHO: Anti-tuberculosis Drug Resistance in the World. Report No. 2: Prevalence and Trends. Geneva: WHO, 2000. 160. Kruuner A, Hoffner SE, Silastu H, et al. Spread of drug-resistant pulmonary tuberculosis in Estonia. J Clin Microbiol 2001, 39:3339–3345. 161. Toungoussova S, Caugant DA, Sandven P, et al. Drug resistance of M. tuberculosis strains isolated from patients with pulmonary tuberculosis in Archangels, Russia. Int J Tuberc Lung Dis 2002; 6:406–414. 162. Drobniewski F, Balabanova Y, Ruddy M, et al. Rifampin and multiple drug resistant tuberculosis in the Russian civilian and prison sectors-dominance of the Beijing strain family. Emerg Infect Dis 2002; 8:1320–1326. 163. Almeida D, Rodrigues C, Udwadia ZF, et al. Incidence of multidrug-resistant tuberculosis in urban and rural India and implications for prevention. Clin Infect Dis 2003; 36:e152–e154. 164. Shemyakin IG, Stepanshina VN, Ivanov IY, et al. Characterization of drugresistant isolates of Mycobacterium tuberculosis derived from Russian inmates. Int J Tuberc Lung Dis 2004; 8:1994–1203.

5 Overview of the Pathogenesis of Tuberculosis from a Cellular and Molecular Perspective

SAMUEL C. WOOLWINE and WILLIAM R. BISHAI Division of Infectious Diseases, Department of Medicine, Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A.

I. Introduction Mycobacterium tuberculosis, the cause of human tuberculosis (TB), has been a scourge of humanity throughout recorded history. Even today, this bacille claims 2 to 3 million lives per year, remains one of the leading causes of death among the infectious diseases (1), and is the leading killer of people with AIDS (2). Human TB is a multistage disease. Any rational approach to TB control must be based upon the pathogenic processes at work during these stages. The pathogenic process begins with the inhalation of infectious aerosols. Bacille lodging in the alveoli are engulfed by the alveolar macrophage (AM) and, if able to survive this initial encounter with the innate immune system, begin a period of logarithmic growth, doubling every 24 hours until the macrophage bursts to release the bacterial progeny. New macrophages attracted to the site engulf these bacille and the cycle continues. The bacille may spread from the initial lesion via the lymphatic and/or circulatory systems to other parts of the body. After three weeks, the host develops specific immunity to the bacille. The resulting M. tuberculosis–specific lymphocytes migrate to the site of 101

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infection, surrounding and activating the macrophages there. As the cellular infiltration continues, the center of the cell mass, or granuloma, becomes caseous and necrotic (Fig. 1). In the majority of cases, the immunocompetent human is able to arrest the growth of the bacille within the primary lesion with little or no signs of illness. The initial lesion, which eventually resolves or calcifies, may still harbor viable bacille, in which case the host is said to harbor latent TB infection (LTBI, see below). However, in about 10% of infected individuals (3–7), the disease progresses during the initial weeks or months after infection, and

Figure 1 The histopathology of caseous necrosis in rabbit pulmonary tubercles five weeks following infection with Mycobacterium bovis. (A) A caseous center (hematoxylin and eosin staining) revealing disintegrating epithelioid macrophages at the center and a rim of basophilic mononuclear cells and early capillary formation on the periphery. (B) Same caseous center (acid-fast stain) showing the relative paucity of acid-fast bacille in rabbit tubercles at five weeks. (C) Multinucleated (Langhans) giant cell in rabbit lung tissues at five weeks (hematoxylin and eosin staining). (D) Acid-fast staining and high power (400
) view of a peripheral region of a five-week-old caseous rabbit tubercle showing several acid-fast bacille and some weakly acid-fast debris from destroyed bacille. Source: Courtesy of M. Yoder, Johns Hopkins University, Baltimore, Maryland, U.S.A.

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Figure 2 (A) Whole lungs from a nonsensitized New Zealand White (outbred) rabbit infected transthoracically with 108 colony forming units of Mycobacterium bovis in paraffin–lanolin according to the method of Yamamura revealing a large tuberculous lesion 3 cm in diameter. (B) Incision reveals an early cavitary lesion containing thick partially liquefied caseous material. Source: Courtesy of M. Yoder, Johns Hopkins University, Baltimore, Maryland, U.S.A.

the patient develops the typical symptoms of active (or progressive) primary TB: cough, fever, lethargy, and weight loss. In some cases, the granuloma becomes quite large and the caseous material liquefies, a phenomenon referred to as cavitary TB (see below and Fig. 2). This phenomenon is more commonly seen in cases of reactivation of latent TB. If the wall of the cavity erodes into an airway, the patient may become highly infectious as the liquefied contents of the cavity are expelled by coughing. Both caseous granulomas and cavities are devoid of blood supply, impairing both the immune system’s ability to fight the infection as well as the clinician’s attempts to treat the disease chemotherapeutically. The progression of TB from infection to either containment of disease or demise of the host has been well characterized anatomically. Although the molecular mechanisms responsible for many aspects of TB pathogenesis remain unknown, progress has been made in recent years on a number of fronts. This chapter will follow the typical course of the disease through its various stages and describe what is known regarding the molecular processes involved. II. Infection Although M. tuberculosis can infect by atypical routes and manifest in a number of anatomic sites, this pathogen is acquired in the overwhelming majority of cases by aerosol inhalation. The classic experiments of Wells and Riley (8–11) investigating the mechanics of airborne TB transmission have been revisited after more than 40 years in a recent study by Fennelly et al. (12), demonstrating that a large proportion of viable tubercle bacille expelled by coughing are contained in droplets less than 5 mm in size,

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consistent with the predictions made by the earlier investigators. Such infectious droplets, being small enough to reach the alveolus, allow the bacille to avoid the mucociliary clearance mechanisms of the airways. Once in the alveolus, the bacille is engulfed by the AM. AMs are continually ingesting inhaled particulates and as a result are usually in a partially activated state, depending on the nature of the particulates and the mechanism by which the material is ingested (e.g., with or without opsonization, specific receptors involved, etc.) (13,14). Phagocytosis by an insufficiently activated AM allows the bacille to avoid being killed and to begin a phase of exponential replication. That the AM actually contributes to productive M. tuberculosis infection is suggested by the observation that selective depletion of AMs from mice by using liposomeencapsulated dichloromethylene diphosphonate, which induces apoptosis of AMs, prior to and shortly after infection with M. tuberculosis resulted in 100% survival of the mice at 150 days following infection, compared to 60% survival with liposome treatment alone (15). Thus, ironically, the unactivated macrophage is used by the pathogen as a site for intracellular multiplication, and apoptosis of infected macrophages may be an antibacterial host defense mechanism. A few in vitro studies have suggested that M. tuberculosis might be capable of invading respiratory epithelial cells (16–19). Sato et al. reported that approximately 10% of the bacille observed by electron microscopy in lung sections (from mice intravenously infected with 5
107 organisms) were located inside type II alveolar cells at two days postinfection, with the remaining 90% contained within macrophages or neutrophils (20). At 14 days postinfection, few if any mycobacteria were observed within type II alveolar cells. Because most natural infections result from the successful aerosol implantation of one or a few bacille, the relevance of bacillary uptake by respiratory epithelial cells remains to be substantiated. A. Macrophage Receptors

A great deal of effort has gone into investigating the molecular interactions leading to phagocytosis of M. tuberculosis by the macrophage. A number of macrophage cell–surface molecules have been shown to bind to and promote internalization of M. tuberculosis, including multiple complement receptors (CR1, CR3, and CR4), mannose receptor, CD14, immunoglobulin G Fcc receptor, and scavenger receptors (21–26). The mechanism by which phagocytosis occurs may influence subsequent cytoplasmic events, thus M. tuberculosis may have evolved mechanisms to promote its uptake via specific pathways to avoid intracellular killing. Selectively blocking individual phagocytic pathways with antibody or competitive ligands does not seem to have an appreciable effect on M. tuberculosis survival or growth in macrophages (26). However, opsonization of M. tuberculosis with specific antibody results in antibody receptor–mediated phagocytosis and subsequent killing of the bacille after phagosome–lysosome fusion (21), whereas the bacille is able to prevent phagosome–lysosome fusion otherwise (27). For example,

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one study found that coating the bacille with monoclonal antibody to arabinomannan prior to infection had a protective effect in mice (28). B. Survival Within the Macrophage

Perhaps more articles have been published on mycobacterial survival within the macrophage than on any other aspect of TB pathogenesis. Ever since the observation that macrophage phagosomes containing M. tuberculosis fail to fuse with lysosomes (the normal fate of ingested bacteria) (27), investigators have attempted to unravel the underlying mechanisms of M. tuberculosis intracellular survival. The mycobacterial phagosome has recently been reviewed in great depth by Vergne et al. (29). Whereas the interior of the phagosome ordinarily becomes more acidic as it progresses down the endosomal/lysosomal pathway, phagosomes containing M. tuberculosis and other pathogenic mycobacteria do not completely acidify (30,31). This reduced acidification has been attributed to failure of the M. tuberculosis phagosome to accumulate vesicular proton– adenosine triphosphatase (ATPase) (30). Consistent with the observation that M. tuberculosis–containing phagosomes do not fuse with lysosomes (27), such phagosomes are also lacking in mature lysosomal hydrolases and other lysosomal markers (32–36). C. Calcium Signaling and Phagosome Maturation

The mechanism responsible for phagosome maturation arrest has been the subject of intense investigation in recent years. Deretic and coworkers have performed extensive characterization of the molecules involved in vesicle trafficking and whether or not these molecules localize normally in M. tuberculosis–infected cells (37–42). Chief among their findings were the aberrant accumulation of Rab5 and failure to acquire Rab7 on the mycobacterial phagosome (41). Rab5 and Rab7 are small guanosine triphosphate (GTP)-binding proteins involved in vesicular trafficking, being markers of early and late endosomes, respectively. GTP-binding proteins bind to GTP, thereby becoming activated for interaction with and/or regulation of other specific proteins. The GTP-binding protein also hydrolyzes the GTP to guanylnucleoside diphosphate (GDP), thus reverting to an inactive form until the GDP is exchanged for GTP once again. In this way, GTP hydrolysis acts as a molecular timer for protein activation. Following up on the observed block at the Rab5/Rab7 stage, Fratti et al. discovered that early endosomal autoantigen 1 (EEA1), a Rab5regulated protein involved in endosome docking and fusion (43), failed to localize to M. tuberculosis phagosomes (39). EEA1 also interacts with phosphatidylinositol-3-phosphate (PI3P) (44), generated from membrane phosphatidylinositol (PI) by another protein, hVPS34, a PI kinase (45). This interaction helps to localize EEA1 to the phagosome membrane (44). Vergne et al. showed that hVPS34 interacts with the Ca2þ-binding protein calmodulin in a Ca2þ-dependent manner (46). These findings intersect with another line of study by Malik et al. demonstrating that M. tuberculosis

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blocks the intracellular rise in Ca2þ associated with phagocytosis and that the Ca2þ/calmodulin pathway contributes to phagosome–lysosome fusion (47,48). These observations have collectively led to a model (Fig. 3) in which M. tuberculosis prevents phagosome maturation by blocking the increase of intracellular Ca2þ. Lower intracellular Ca2þ, in turn, prevents the Ca2þ/calmodulin-dependent activation of the PI kinase hVPS34, and thus no PI3P is generated on the phagosome membrane to recruit and retain EEA1 (29). It has recently been shown that the M. tuberculosis cell wall glycolipid lipoarabinomannan (LAM) inhibits intracellular increases in Ca2þ (46). It appears that the M. tuberculosis–dependent blocking of Ca2þ elevation occurs via inhibition of host cell sphingosine kinase (49), which has been shown to link a number of cell surface receptors to a rise in cytosolic Ca2þ (50,51). One observation that is not explained by this model is the inability of heat- or radiation-killed M. tuberculosis to inhibit the Ca2þ spike (47). This result seems to be at odds with the aforementioned ability of purified LAM to inhibit Ca2þ increase in the macrophage (46), as dead M. tuberculosis would still contain LAM. This may suggest that the active secretion or release of LAM from the cell wall of M. tuberculosis requires bacterial viability. The failure to synthesize PI3P on the phagosomal membrane would explain many observations regarding the mycobacterial phagosome, including its failure to acquire the vesicular proton-ATPase and lysosomal hydrolases (cathepsins) normally delivered to the phagosome by vesicles of the trans-Golgi network (Fig. 3) (29,32,35). III. Host Response A. The Dendritic Cell

If successful in preventing phagosome–lysosome fusion, the bacille replicates within the macrophage, filling the cell with its progeny until the macrophage ruptures to release its microbial cache. These bacille are in turn engulfed by the more immature monocyte-derived macrophages recruited to the area by chemoattractants such as complement components, bacterial products, and cytokines released by the infected host cell (52). Some of these secondarily infected host cells are dendritic cells (DCs) that migrate to the draining lymph nodes to initiate the onset of the adaptive immune response (53,54). DCs are derived from the monocyte/macrophage lineage and function as effective scavengers that phagocytose, process, and present antigens to T-lymphocytes, a necessary event in the development of cellmediated as well as humoral immunity. A growing body of literature suggests that M. tuberculosis interferes with DC function. Infection of blood monocytes with M. tuberculosis prevents their subsequent interferon-a–induced differentiation into DCs (55). It has also been discovered that the DC-specific intercellular adhesion molecule–grabbing nonintegrin (DC-SIGN) binds to LAM, a prominent glycolipid on the surface of M. tuberculosis (56). DC-SIGN has been

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Figure 3 A model for phagosome maturation arrest caused by Mycobacterium tuberculosis. Lipoarabinomannan from the mycobacterial cell wall prevents the normal rise in intracellular Ca2þ associated with phagocytosis. This in turn prevents the calcium/calmodulin activation of hVPS34 and its subsequent generation of PI3P. PI3P synthesized from the phagosome membrane phosphatidylinositol ordinarily serves to recruit both Rab5 and early endosomal autoantigen 1, which interact with syntaxin-6 on the membrane of vesicles from the trans Golgi network carrying molecules such as cathepsins and the vesicular proton–ATPase. Abbreviations: LAM, lipoarabinomannan; LBC, phagosome containing latex bead; MPC, phagosome containing M. tuberculosis; PI3P, phosphatidylinositol-3-phosphate; CaM, calcium/ calmodulin; PI, phosphatidylinositol; TGN, trans Golgi network; ATPase, adenosine triphosphatase; EEA1, early endosomal autoantigen 1; GDI, guanosine nucleotide dissociation inhibitor. Source: From Ref. 29.

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found to bind to surface molecules of a number of bacterial, parasitic, and viral pathogens, notably HIV-1 and -2, Ebola virus, and Dengue virus (57). The binding of LAM to DC-SIGN has been shown to inhibit both lipopolysaccharide-induced secretion of interleukin (IL)-12 and Mycobacterium bovis bacille Calmette–Gue´rin (BCG)-mediated DC maturation (56). LAM–DC–SIGN interaction also stimulates secretion of the anti-inflammatory cytokine IL-10 (56). Whether or not the effects of M. tuberculosis on DC function play a role in TB pathogenesis, the fact remains that TB patients do develop specific cell-mediated immunity (CMI) and delayed-type hypersensitivity (DTH). Therefore, it stands to reason that either impairment of DC function by M. tuberculosis does not occur in vivo (or at least not to the extent of preventing an adaptive immune response), or that other antigen-presenting cells (e.g., macrophages) must play a role in T-cell activation and proliferation, or both. B. Granuloma Formation

The rabbit model of TB, pioneered by Lurie and Dannenberg, has provided a wealth of information regarding the histopathologic changes that occur following aerosol infection with M. tuberculosis. Following ingestion of M. tuberculosis by the AM and the initial replication within this cell, the resulting bacille are taken up by the newly arriving macrophages derived from blood monocytes. By two weeks postinfection, infected macrophages at the center of the lesion have acquired an epithelioid morphology. As these cells die, they provide the raw material for the process of caseation necrosis. The periphery of the lesion consists largely of activated macrophages and neutrophils. At four weeks postinfection, the number of mature macrophages seen at the periphery of the caseous lesion has increased. Multinucleated giant cells (Langhans cells, see Fig. 1) are often seen by this time, formed by the fusion of activated macrophages. In addition, M. tuberculosis–specific lymphocytes have appeared and surrounded the lesion, along with plasma cells and fibroblasts. The onslaught of the immune response has by this time destroyed a large proportion of the bacille, and by six weeks the rare remaining bacille are typically found at the edge of the caseous center of the lesion, surrounded by a zone of activated macrophages. Eight weeks following infection, the lesion consists of a caseous necrotic core, surrounded by lymphocytes and a few remaining macrophages. Few if any viable bacille may be present at this time. These lesions may range in size from 1 to 5 mm (58,59). C. Cell-Mediated Immunity vs. Delayed-Type Hypersensitivity

Dannenberg has made a distinction between mechanisms of macrophageactivating CMI and tissue-damaging DTH (60). In this dual mechanism model, CMI is described as an immunologic mechanism in which macrophages are activated by antigen-specific T-cells, thereby acquiring an enhanced ability to destroy bacille they have ingested. DTH, on the other hand, is viewed as a separate phenomenon whereby bacille-laden macrophages are themselves destroyed, along with some surrounding tissue, resulting in

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caseous necrosis. Both CMI and DTH occur within the environment of the granuloma after the onset of adaptive immunity. If the host produces effective CMI, the macrophages attracted to the site of infection become highly activated and surround the existing lesion, engulfing and destroying any bacille that have been released from dying cells or from the periphery of the caseous center of the granuloma. In this way, the infection is contained and the spread of caseous necrosis is prevented. However, in hosts that fail to mount effective CMI, the incoming macrophages are insufficiently activated and become parasitized by the bacille, serving as reservoirs for further bacterial replication until they are destroyed by the tissue-damaging DTH response. In this way, more lung tissue is destroyed as the caseous lesion grows larger. Although the operational distinction between CMI and DTH is useful in terms of understanding the pathology of the disease, it should be noted that experimental evidence for immunologically distinct mechanisms of CMI and DTH has yet to be conclusively demonstrated. Perhaps a more fundamental way of viewing CMI and DTH as defined above is that these processes represent opposing blades of a double-edged sword: the more effective the immune response at killing or halting replication of the bacille, the less collateral tissue damage occurs and vice versa. IV. Cavitary Tuberculosis In some cases, the caseous lesion becomes quite large and transforms into a liquid-filled cavity. Unfortunately, little is known regarding the process of liquefaction at the molecular level. As more tissue surrounding the cavity is destroyed by caseous necrosis, the cavity expands. The bacille multiply to high numbers within the liquefied cavity, and if the cavity erodes into the wall of an adjacent blood vessel, the patient may become seeded throughout the body with tubercle bacille. On the other hand, if the cavity ruptures into an airway, the fluid is expelled as an infectious aerosol when the patient coughs. Thus cavitary TB is one of the most important manifestations of the disease from the perspective of transmission. As with the process of granuloma formation, the rabbit has provided an excellent model for studying the development of cavitary TB. Whereas the rabbit is usually able to contain and even clear infection with M. tuberculosis, infection with M. bovis leads to progressive disease. Cavitation in the rabbit is often seen 8 to 12 weeks following infection or reinfection with M. bovis (61–63). Yamamura et al. developed a rabbit model of cavitary TB following direct injection of bacille or bacterial extracts into the lung through the chest wall (64,65). These investigators found that previous exposure of the rabbit to heat-killed M. bovis by subcutaneous injection greatly increased the frequency of cavity formation upon subsequent infection. In fact, Yamamura observed that transthoracic injection of even heat-killed bacille led to cavitation in 40% to 85% of sensitized rabbits, but failed to do so in na€
ve animals. Therefore, the process of cavitation seems to be purely a host response phenomenon. Immunosuppressive agents (6-mecaptopurine and

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azathioprine) were found to reduce the occurrence of cavity formation in sensitized rabbits (66). This finding is consistent with the more current observation that TB patients with advanced HIV infection are less likely to develop cavitary disease (67). V. Latent Tuberculosis Of those who become infected with M. tuberculosis, about 10% will progress to active primary disease. The roughly 90% of individuals (3–7) who contain the infection within the initial lesion may still harbor viable bacille, a condition referred to as LTBI (5). They are at risk for developing secondary (or reactivation) TB, which may manifest as pulmonary or extrapulmonary disease. In the immunocompetent host, the lifetime risk of developing reactivation disease is usually estimated to be 5% to 10%. There is good evidence that the use of various immunosuppressive drugs increases the risk of reactivation substantially. Tumor necrosis factor-a inhibitors such as infliximab, etanercept, and adalimumab are associated with an increased incidence of TB, usually within the first months of administration (68–71). Advanced HIV infection has been calculated to increase the relative risk of reactivation TB 10-fold compared to non–HIV-infected patients with LTBI (72). Given that M. tuberculosis can persist for years in the human host before recrudescence of active disease, it follows that either the replication of the bacille must drastically slow or even cease, or that host bactericidal mechanisms must keep pace with the growth of the bacille. In fact, this is typically observed in the murine model of TB: after a period of around three weeks of exponential growth of M. tuberculosis following inoculation of the mouse, the bacillary burden plateaus. This change in the rate of bacterial growth coincides with the onset of specific immunity. Although one might at first conclude this represents ‘‘latency,’’ there are important differences between the condition of the mice and that of humans with LTBI. First, the mice continue to harbor high titers of bacille in their lungs. Second, the mice eventually succumb to the disease, specifically to the loss of airspace in the lungs as a result of progressive inflammatory infiltration. Unfortunately, there are still no truly adequate animal models for LTBI, although the rabbit model shows great promise. Rabbits infected with M. tuberculosis form the caseous lesions typical of human TB pathology, and, like most humans, are often able to contain the disease such that no cultivable bacille are recovered from lung homogenates of these animals. If these animals harbor latent bacille, it may be possible to precipitate reactivation TB through the use of immunosuppressive agents. A. In Vitro Models of Latency

In vitro models in which M. tuberculosis halts replication, yet remains viable, have been developed to better study the bacterial physiology in LTBI. One of these models, developed by Wayne, is based on the gradual depletion of oxygen from exponentially growing cultures (73). Given the

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avascular nature of the caseous lesion, and the fact that hypoxia results in a nonreplicating yet viable state, the Wayne model seems to represent a logical hypothesis to explain the change in bacillary metabolism in LTBI. Wayne and coworkers found specific enzyme activities that were induced upon transition to the hypoxic state. Specifically, glycine dehydrogenase activity catalyzing the reductive amination of glyoxylate to glycine was significantly increased (74). The production of glycine in this reaction is coupled to the oxidation of NADH to NADþ, and it has been postulated that this regeneration of NADþ allows the bacille to complete the current cycle of DNA replication and achieve an orderly metabolic shutdown (74). Boon et al. subsequently used the Wayne model to study protein changes in M. bovis BCG and found that four proteins were significantly induced (75). Two of these are proteins of unknown function. The third protein, HspX (Acr), belongs to a family of proteins known as chaperones. Chaperones assist in the proper folding (or refolding) of other proteins either during synthesis or after they have become misfolded due to heat shock or chemical stress. The fourth protein, DosR, is a transcriptional regulator that activates the expression of many genes, including hspX, in response to hypoxic conditions (76). More recently, whole-genome expression profiling of M. tuberculosis identified a host of genes induced in response to hypoxic conditions, including dosR, hspX, and several genes involved in diverse metabolic pathways, many of which were subsequently found to be regulated by DosR (76). Several genes found to be induced by hypoxia were also found to be induced by low levels of nitric oxide, a potent antibacterial molecule implicated in the defense against M. tuberculosis (77). Among these genes were dosR, hspX, nrdZ (ribonucleotide reductase class II), narX (fused nitrate reductase), narK2 (nitrite extrusion protein), ctpF (cation transport ATPase), and fdxA (ferredoxin). Another in vitro model that maintains bacterial viability in a state of nonreplication is nutrient starvation. Using whole-genome expression profiling, Betts et al. identified several hundred genes that were induced during nutrient limitation. Among these were hspX, discussed above, and four genes (sigB, sigE, sigF, and sigD) belonging to the sigma factor family (78). Sigma factors are components of the bacterial RNA polymerase, which confer gene target specificity to the polymerase; i.e., it is the sigma factor that determines which genes a given molecule of RNA polymerase will recognize and express. Although these genomic studies have identified many genes and metabolic pathways involved in response to starvation or hypoxia, the actual molecular mechanisms by which tubercle bacille enter a latent state have yet to be elucidated. In fact, it is still not known whether these in vitro conditions truly represent the bacterial physiology at work in LTBI. VI. Conclusion What, then, does biomedical science have to offer to the fight against TB? One might argue that an effective vaccine would be a beneficial tool.

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However, roughly 90% of individuals infected with TB are able to contain the infection, and in spite of this successful immune response, many of these individuals are unable to completely eradicate the organism from the body. Effective vaccination schemes, hence, will need to protect newborns from infection, and ideally also protect adults with LTBI from the risk of reactivation. Because reactivation of LTBI most often occurs in the context of a weakened immune system, these goals remain daunting challenges. New drugs active against the tubercle bacille are perhaps the most desperately needed weapons in the war on TB. Our current arsenal of drugs contains both bactericidal and sterilizing antibiotics, which work both against active TB and as secondary prevention in patients with LTBI. It is likely that the new anti-TB drugs may also have dual applicability for these two therapeutic needs. Safe, short-course, effective therapy against latent infection is certainly a high priority for successful TB control. In fact, bacille with latent-state physiology may comprise a significant percentage of the bacillary population even during active disease, and may be one reason why such long treatment regimens are required. As more information is gathered on the survival mechanisms of M. tuberculosis within the macrophage and during latent infection, new targets for drug intervention may be realized. Clearly it will take a concerted effort on the part of scientists, physicians, and other health care workers, as well as political leaders, to continue making progress against one of the most successful bacterial killers the world has ever known. References 1. Dye C, Scheele S, Dolin P, Pathania V, Raviglione M. Consensus statement. Global burden of tuberculosis: estimated incidence, prevalence, and mortality by country. WHO global surveillance and monitoring project. J Am Med Assoc 1999; 282:677–686. 2. Hopewell P, Chaisson R. Tuberculosis and human immunodeficiency virus infection. In: Reichman L, Hershfield E, eds. Tuberculosis: A Comprehensive International Approach. 2nd ed. New York: Marcel Dekker, Inc., 2000:525–552. 3. Ferebee S. Controlled chemoprophylaxis trials in tuberculosis: a general review. Adv Tuberc Res 1969; 17:28–106. 4. Grzybowski S, Barnett G, Styblo K. Contacts of cases of active pulmonary tuberculosis. Bull Int Union Tuberc 1975; 50:90–106. 5. Nuermberger E, Bishai W, Grosset J. Latent tuberculosis infection. Semin Respir Crit Care Med 2004; 25:317–336. 6. Sutherland I. Recent studies in the epidemiology of tuberculosis, based on the risk of being infected with tubercle bacilli. Adv Tuberc Res 1976; 19:1–63. 7. Sutherland I. The Ten-Year Incidence of Clinical Tuberculosis Following ‘‘Conversion’’ in 2550 Individuals Aged 14 to 19 Years. TSTRU Progress Report. The Hague: KNCV, 1968. 8. Riley R, Mills C, Nyka W, et al. Aerial dissemination of pulmonary tuberculosis: a two year study of contagion in a tuberculosis ward. Am J Hyg 1959; 70:185–196. 9. Wells W. On air-borne infection. II: Droplets and droplet nuclei. Am J Hyg 1934; 20:611–618.

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10. Wells W, Lurie M. Experimental airborne disease: quantitative natural respiratory contagion of tuberculosis. Am J Hyg 1941; 34:21–40. 11. Wells W, Ratcliffe H, Crumb C. On the mechanics of droplet nuclei infection. II: Quantitative experimental air-borne tuberculosis in rabbits. Am J Hyg 1948; 47:11–28. 12. Fennelly K, Martyny J, Fulton K, Orme I, Cave D, Heifets L. Cough-generated aerosols of Mycobacterium tuberculosis. Am J Respir Crit Care Med 2004; 169: 604–609. 13. Brown D, Donaldson K, Borm P, et al. Calcium and ROS-mediated activation of transcription factors and TNF-a cytokine gene expression in macrophages exposed to ultrafine particles. Am J Physiol Lung Cell Mol Physiol 2004; 286:L344–L353. 14. Kobzik L, Huang S, Paulauskis J, Godleski J. Particle opsonization and lung macrophage cytokine response. J Immunol 1993; 151:2753–2759. 15. Leemans J, Juffermans N, Florquin S, et al. Depletion of alveolar macrophages exerts protective effects in pulmonary tuberculosis in mice. J Immunol 2001; 166: 4604–4611. 16. Reddy V, Hayworth D. Interaction of Mycobacterium tuberculosis with human respiratory epithelial cells (HEp-2). Tuberculosis 2002; 82:31–36. 17. Mehta P, King C, White E, Murtagh J, Quinn F. Comparison of in vitro models for the study of Mycobacterium tuberculosis invasion and intracellular replication. Infect Immun 1996; 64:2673–2679. 18. Bermudez L, Goodman J. Mycobacterium tuberculosis invades and replicates within type II alveolar cells. Infect Immun 1996; 64:1400–1406. 19. Bermudez L, Sangari F, Kolonoski P, Petrofsky M, Goodman J. The efficiency of the translocation of Mycobacterium tuberculosis across a bilayer of epithelial and endothelial cells as a model of the alveolar wall is a consequence of transport within mononuclear phagocytes and invasion of alveolar epithelial cells. Infect Immun 2002; 70:140–146. 20. Sato K, Tomioka H, Shimizu T, Gonda T, Ota F, Sano C. Type II alveolar cells play roles in macrophage-mediated host innate resistance to pulmonary mycobacterial infections by producing proinflammatory cytokines. J Infect Dis 2002; 185:1139– 1147. 21. Armstrong J, Hart P. Phagosome-lysosome interactions in cultured macrophages infected with virulent tubercle bacilli. Reversal of the usual nonfusion pattern and observations on bacterial survival. J Exp Med 1975; 142:1–16. 22. Ernst J. Macrophage receptors for Mycobacterium tuberculosis. Infect Immun 1998; 66:1277–1281. 23. Peterson P, Gekker G, Hu S, et al. CD14 receptor-mediated uptake of nonopsonized Mycobacterium tuberculosis by human microglia. Infect Immun 1995; 63: 1598–1602. 24. Schlesinger L. Macrophage phagocytosis of virulent but not attenuated strains of Mycobacterium tuberculosis is mediated by mannose receptors in addition to complement receptors. J Immunol 1993; 150:2920–2930. 25. Schlesinger L, Bellinger-Kawahara C, Payne N, Horwitz M. Phagocytosis of Mycobacterium tuberculosis is mediated by human monocyte complement receptors and complement component C3. J Immunol 1990; 144:2771–2780. 26. Zimmerli S, Edwards S, Ernst J. Selective receptor blockade during phagocytosis does not alter the survival and growth of Mycobacterium tuberculosis in human macrophages. Am J Respir Cell Mol Biol 1996; 15:760–770. 27. Armstrong J, Hart P. Response of cultured macrophages to Mycobacterium tuberculosis, with observations on fusion of lysosomes with phagosomes. J Exp Med 1971; 134:713–740.

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28. Teitelbaum R, Glatman-Freedman A, Chen B, et al. A mAb recognizing a surface antigen of Mycobacterium tuberculosis enhances host survival. Proc Natl Acad Sci USA 1998; 95:15688–15693. 29. Vergne I, Chua J, Singh S, Deretic V. Cell biology of Mycobacterium tuberculosis phagosome. Annu Rev Cell Dev Biol 2004; 20:367–394. 30. Sturgill-Koszycki S, Schlesinger P, Chakraborty P, et al. Lack of acidification in mycobacterium phagosomes produced by exclusion of the vesicular proton-ATPase. Science 1994; 263:678–681. 31. Crowle A, Dahl R, Ross E, May M. Evidence that vesicles containing living virulent M. tuberculosis or M. avium in cultured human macrophages are not acidic. Infect Immun 1991; 59:1823–1831. 32. Sturgill-Koszycki S, Schaible U, Russell D. Mycobacterium-containing phagosomes are accessible to early endosomes and reflect a transitional state in normal phagosome biogenesis. EMBO J 1996; 15:6960–6968. 33. Barker L, George K, Falkow S, Small P. Differential trafficking of live and dead Mycobacterium marinum organisms in macrophages. Infect Immun 1997; 65:1497–1504. 34. Clemens D, Horwitz M. Characterization of the Mycobacterium tuberculosis phagosome and evidence that phagosomal maturation is inhibited. J Exp Med 1995; 181:257–270. 35. Fratti R, Chua J, Vergne I, Deretic V. Mycobacterium tuberculosis glycosylated phosphatidylinositol causes phagosome maturation arrest. Proc Natl Acad Sci USA 2003; 100:5437–5442. 36. Xu S, Cooper A, Sturgill-Koszycki S, et al. Intracellular trafficking in Mycobacterium tuberculosis and Mycobacterium avium-infected macrophages. J Immunol 1994; 153:2568–2578. 37. Fratti RA, Chua J, Deretic V. Induction of p38 mitogen-activated protein kinase reduces early endosome autoantigen 1 (EEA1) recruitment to phagosomal membranes. J Biol Chem 2003; 278:46961–46967. 38. Fratti RA, Chua J, Deretic V. Cellubrevin alterations and Mycobacterium tuberculosis phagosome maturation arrest. J Biol Chem 2002; 277:17320–17326. 39. Fratti RA, Backer JM, Gruenberg J, Corvera S, Deretic V. Role of phosphatidylinositol 3-kinase and Rab5 effectors in phagosomal biogenesis and mycobacterial phagosome maturation arrest. J Cell Biol 2001; 154:631–644. 40. Fratti RA, Vergne I, Chua J, Skidmore J, Deretic V. Regulators of membrane trafficking and Mycobacterium tuberculosis phagosome maturation block. Electrophoresis 2000; 21:3378–3385. 41. Via LE, Deretic D, Ulmer RJ, Hibler NS, Huber LA, Deretic V. Arrest of mycobacterial phagosome maturation is caused by a block in vesicle fusion between stages controlled by rab5 and rab7. J Biol Chem 1997; 272:13326–13331. 42. Deretic V, Via LE, Fratti RA, Deretic D. Mycobacterial phagosome maturation, rab proteins, and intracellular trafficking. Electrophoresis 1997; 18:2542–2547. 43. Christoforidis S, McBride HM, Burgoyne RD, Zerial M. The Rab5 effector EEA1 is a core component of endosome docking. Nature 1999; 397:621–625. 44. Simonsen A, Lippe R, Christoforidis S, et al. EEA1 links PI(3)K function to Rab5 regulation of endosome fusion. Nature 1998; 394:494–498. 45. Christoforidis S, Miaczynska M, Ashman K, et al. Phosphatidylinositol-3-OH kinases are Rab5 effectors. Nat Cell Biol 1999; 1:249–252. 46. Vergne I, Chua J, Deretic V. Tuberculosis toxin blocking phagosome maturation inhibits a novel Ca2þ/Calmodulin-PI3K hVPS34 cascade. J Exp Med 2003; 198:653–659. 47. Malik ZA, Denning GM, Kusner DJ. Inhibition of Ca(2þ) signaling by Mycobacterium tuberculosis is associated with reduced phagosome-lysosome fusion and increased survival within human macrophages. J Exp Med 2000; 191:287–302.

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48. Malik ZA, Iyer SS, Kusner DJ. Mycobacterium tuberculosis phagosomes exhibit altered calmodulin-dependent signal transduction: contribution to inhibition of phagosome-lysosome fusion and intracellular survival in human macrophages. J Immunol 2001; 166:3392–3401. 49. Malik ZA, Thompson CR, Hashimi S, Porter B, Iyer SS, Kusner DJ. Cutting edge: Mycobacterium tuberculosis blocks Ca2þ signaling and phagosome maturation in human macrophages via specific inhibition of sphingosine kinase. J Immunol 2003; 170:2811–2815. 50. Spiegel S, Milstien S. Sphingosine 1-phosphate, a key cell signalling molecule. J Biol Chem 2002; 277:25851–25854. 51. Melendez A, Floto R, Gillooly D, Harnett M, Allen J. FccRI coupling to phospholipase D initiates sphingosine kinase-mediated calcium mobilization and vesicular trafficking. J Biol Chem 1998; 273:9393–9402. 52. Sadek M, Sada E, Toossi Z, Schwander S, Rich E. Chemokines induced by infection of mononuclear phagocytes with mycobacteria and present in lung alveoli during active pulmonary tuberculosis. Am J Respir Cell Mol Biol 1998; 19:513–521. 53. Jiao X, Lo-Man R, Guermonprez P, et al. Dendritic cells are host cells for mycobacteria in vivo that trigger innate and acquired immunity. J Immunol 2002; 168: 1294–1301. 54. Marino S, Pawar S, Fuller C, Reinhart T, Flynn J, Kirschner D. Dendritic cell trafficking and antigen presentation in the human immune response to Mycobacterium tuberculosis. J Immunol 2004; 173:494–506. 55. Mariotti S, Teloni R, Iona E, et al. Mycobacterium tuberculosis diverts alpha interferon-induced monocyte differentiation from dendritic cells into immunoprivileged macrophage-like host cells. Infect Immun 2004; 72:4385–4392. 56. Geijtenbeek T, van Vliet S, Koppel E, et al. Mycobacteria target DC-SIGN to suppress dendritic cell function. J Exp Med 2003; 197:7–17. 57. van Kyook Y, Geijtenbeek T. DC-SIGN: escape mechanism for pathogens. Nat Rev Immunol 2003; 3:697–709. 58. Lurie M. Resistance to Tuberculosis. Cambridge: Harvard University Press, 1964. 59. Lurie M. The correlation between the histological changes and the fate of living tubercle bacilli in the organs of tuberculous rabbits. J Exp Med 1932; 55: 31–54. 60. Dannenberg AM Jr. Roles of cytotoxic delayed-type hypersensitivity and macrophageactivating cell-mediated immunity in the pathogenesis of tuberculosis. Immunobiology 1994; 191:461–473. 61. Dannenberg AM Jr. Pathogenesis of pulmonary Mycobacterium bovis infection: basic principles established by the rabbit model. Tuberculosis 2001; 81:87–96. 62. Lurie M. The fate of tubercle bacilli in the organs of reinfected rabbits. J Exp Med 1929; 50:747. 63. Lurie M. A correlation between the histological changes and the fate of living tubercle bacilli in the organs of reinfected rabbits. J Exp Med 1933; 57:181. 64. Yamamura Y. The pathogenesis of tuberculous cavities. Adv Tuberc Res 1958; 9: 13–37. 65. Yamamura Y, Yasaka S, Yamaguchi M, et al. Studies of the experimental tuberculosis cavity: the experimental formulation of the tuberculous cavity in the rabbit lung. Med J Osaka Univ 1954; 5:187–197. 66. Yamamura Y, Ogawa Y, Yamagata H. Prevention of tuberculous cavity formation by immunosuppressive drugs. Am Rev Respir Dis 1968; 98:720. 67. Lucas S, Nelson A. Pathogenesis of tuberculosis in human immunodeficiency virusinfected people. In: Bloom B, ed. Tuberculosis: Pathogenesis, Protection and Control. Washington, DC: American Society for Microbiology, 1994:503–513.

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68. Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 2001; 345:1098–1104. 69. Tuberculosis associated with blocking agents against tumor necrosis factor-alpha— California, 2002–2003. Morb Mortal Wkly Rep 2004; 53:683–686. 70. Wallis RS, Broder MS, Wong JY, Hanson ME, Beenhouwer DO. Granulomatous infectious diseases associated with tumor necrosis factor antagonists. Clin Infect Dis 2004; 38:1261–1265. 71. Wallis R, Broder M, Wong J, Beenhouwer D. Granulomatous infections due to tumor necrosis factor blockade: correction. Clin Infect Dis 2004; 39:1254–1255. 72. Horsburgh CR Jr. Priorities for the treatment of latent tuberculosis infection in the United States. N Engl J Med 2004; 350:2060–2067. 73. Wayne L, Sohaskey C. Nonreplicating persistence of Mycobacterium tuberculosis. Annu Rev Microbiol 2001; 55:139–163. 74. Wayne L, Lin K. Glyoxylate metabolism and adaptation of Mycobacterium tuberculosis to survival under anaerobic conditions. Infect Immun 1982; 37:1042–1049. 75. Boon C, Li R, Qi R, Dick T. Proteins of Mycobacterium bovis BCG induced in the Wayne dormancy model. J Bacteriol 2001; 183:2672–2676. 76. Park H, Guinn K, Harrell M, et al. Rv3133c/dosR is a transcription factor that mediates the hypoxic response of Mycobacterium tuberculosis. Mol Microbiol 2003; 48:833–843. 77. Voskuil M, Schnappinger D, Visconti K, et al. Inhibition of respiration by nitric oxide induces a Mycobacterium tuberculosis dormancy program. J Exp Med 2003; 198:705– 713. 78. Betts J, Lukey P, Robb L, McAdam R, Duncan K. Evaluation of a nutrient starvation model of Mycobacterium tuberculosis persistence by gene and protein expression profiling. Mol Microbiol 2002; 43:717–731.

6 The Human Host: Immunology and Susceptibility

S. K. SCHWANDER and JERROLD J. ELLNER Department of Medicine and Ruy V. Lourenco Center for the Study of Emerging and Reemerging Pathogens, UMDNJ—New Jersey Medical School, Newark, New Jersey, U.S.A.

I. Introduction Epidemiological evidence suggests that protective immunity against Mycobacterium tuberculosis exists in most exposed humans. The proportion of nonimmunocompromised individuals who undergo primary infection or reactivation disease following M. tuberculosis infection is low. Only 5% to 10% of M. tuberculosis–infected individuals develop tuberculosis (TB) disease during their lifetime (Fig. 1) (1,2). The study of human immunity to M. tuberculosis infection is critical to the understanding of the mechanisms that contain the initial tuberculous focus and maintain clinical latency. Such studies validate basic concepts established in animal models and are required because differences are apparent between experimental models in cell function, effector molecules, and disease expression. Immunological markers of protection in humans also serve as desirable end points for the study of new antituberculous vaccines and new vaccine delivery strategies and as readouts for adjuvant immunotherapies.

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Figure 1 Hypothetical model of the natural history of Mycobacterium tuberculosis infection in humans. Abbreviations: IFN-c, interferon gamma-c; M. tb, Mycobacterium tuberculosis; TST, tuberculin skin test.

II. The Natural History of Mycobacterium tuberculosis Infection in Humans Infection with M. tuberculosis in most instances occurs by inhalation of droplet nuclei (1–5 mm) that contain the infectious bacteria and are aerosolized from the lung tissue of TB patients (3–6) by respiratory maneuvers such as coughing or speaking. Droplet nuclei are deposited in the terminal airspaces and the initial site of exposure is most often in the lower and middle lobes due to the higher ventilation of these lung regions. Most latently, M. tuberculosis–infected individuals do not develop active TB. M. tuberculosis infection in such persons is typically accompanied only by the development of a positive tuberculin skin test (TST) or M. tuberculosis antigen–specific lymphocyte proliferation or interferon gamma (IFN-c) production in vitro. The risk of developing active TB is greatest in the first two years following infection and is associated with more intense exposure to M. tuberculosis. It is higher for persons infected through contact with an index sputum smear-positive TB case (7). The age at the time of M. tuberculosis infection is also important. Persons who become infected in infancy, adolescence, or old age are more likely to progress to active TB. Overall, 5% to 10% of immunocompetent persons develop active TB during their lifetime. A. Primary Tuberculosis

The vast majority of immunocompetent persons develop an effective immune response against M. tuberculosis and contain the primary infection,

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leaving only small, calcified parenchymal scars (Ghon complex). Following primary infection, immunocompetent persons develop specific acquired resistance to reinfection. This specific acquired resistance (also called adaptive or memory immunity) is long lasting, possibly due to low-level endogenous bacterial replication or, in high prevalence areas, repeated exogenous exposure. B. Progressive Primary Tuberculosis

Persons who fail to develop specific acquired immune responses following primary M. tuberculosis infection may develop progressive primary TB. This form of disease is most common in young children, the immunocompromised, and the elderly. Miliary or meningeal disease may result after widespread hematogenous dissemination of M. tuberculosis. The clinical presentation is frequently cryptic with nonspecific symptoms such as malaise and fatigue or fever of unknown origin (8). Progressive primary disease in young adults presents with fever, productive cough, night sweats, weight loss, and upper lobe cavitary lesions, which can be reliably distinguished from reactivation TB only when recent TST conversion has been documented (9). C. Reactivation (Postprimary) Tuberculosis

The risk of developing progressive primary or reactivation TB following infection with M. tuberculosis is increased in immunocompromised persons; the degree of risk varies with the underlying disease impairing host defenses. The lungs are the most common sites of reactivation TB. Chronic productive cough with mucopurulent sputum of greater than three weeks’ duration, night sweats, weight loss, and anorexia are the most frequent complaints. Forty percent to 60% of patients are afebrile at presentation. The onset of symptoms is usually insidious. About one-fifth of patients with reactivation TB have no pulmonary symptoms and the diagnosis is detected on a routine chest radiograph (10). In areas of high TB prevalence, exogenous reinfection may occur and progress to active disease. III. Human Immunity to Mycobacterium tuberculosis Progression of M. tuberculosis infection to primary or reactivation TB has in the past been interpreted as a function of the extent and efficiency of protective human immunity against M. tuberculosis. However, there is increasing evidence for a complex mutual interplay of host and pathogen biology and for a major role of M. tuberculosis isolates in triggering a variety of host responses. Much of the current knowledge of human immunity to M. tuberculosis is derived from studies of blood cells because they are most accessible. Blood provides the source of cells that are recruited to and compartmentalized at the inflammatory focus and form the building blocks of the granulomatous tissue reaction. Studies in healthy household contacts (HHC) of TB patients provide a model of protective immunity, and correlates of immunity established here may guide in the development of

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new vaccination approaches. Pulmonary TB in the adult represents a good model to delineate pathogenesis, immunopathology, and concomitants of reactivation disease and to test concepts concerning immunotherapy. With increasing attention to TB, a great deal now is known about the human immune response in infection and disease. The observations should be placed in the context of the natural history of M. tuberculosis infection (Fig. 1). Several themes emerge. In exposed household contacts and individuals with latent infection, innate and acquired immune mechanisms prevent the establishment of infection and progression to disease. Stimulation of Toll-like receptors (TLR) on monocytes (MN), alveolar macrophages (AM), and dendritic cells (DC) by M. tuberculosis and its constituents is a key component of innate immunity. Specific acquired resistance and ‘‘protective immunity’’ are characterized by a predominant T helper 1 (TH1) response (with production of interleukin [IL]-2), and IFN-c and suppression of T helper 2 (TH2) responses (with production of IL-4, IL-5, and IL-13). It has become clear that the initial interaction of M. tuberculosis with antigen-presenting cells (APC) may be the crucial event that determines the balance between TH1 and TH2 immunity and the effectiveness of the immune response. Further, genetic and acquired factors (e.g., helminthic infection and atopy) may modify this balance. The eventual ‘‘breakdown’’ of clinically latent foci of M. tuberculosis infection may result from immunosuppression, aging, comorbidities (diabetes mellitus), or unknown factors and culminates in reactivation disease. Deciphering the immune response in the presence of disease is complex and findings related to pathogenesis may be confounded by disease-related factors (fever, weight loss, etc.). The systemic immune response during TB is dominated by immunosuppression. This may avert the deleterious effects of systemic immune activation (i.e., septic shock). This specialized form of immunosuppression has as a downside: susceptibility to progression of exogenous reinfection to active disease. This, in fact, has been recognized recently in patients from high-prevalence areas, who were shown to frequently become exogenously reinfected. The local immune response in active TB shows unregulated immune activation with an abundance of inflammatory mediators demonstrable in the blood, bronchoalveolar lavage fluid, pleural fluid, and sputum. Some of these mediators are immunosuppressive or proapoptotic. They disappear early during the course of TB chemotherapy. Immune activation is a dominant finding in studies of bronchoalveolar lavage cells (BAC) from radiographically involved lungs of TB patients. The occurrence of high local levels of potentially protective cytokines such as IFN-c concomitant to active disease suggests that the response to these cytokines may be blocked. A. Cell-Mediated Immunity

There is general consensus that cell-mediated immunity (CMI) is the primary host defense mechanism against intracellular pathogens such as M. tuberculosis

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(Fig. 2). M. tuberculosis is taken up by phagocytic antigen–presenting MN, macrophages (MØ), DC, and epithelial cells. M. tuberculosis is taken up by MN and MØ through binding to complement and/or mannose receptors (11,12) and by DC through binding to a C-type lectin DC-specific intercellular adhesion molecule-3–grabbing nonintegrin (DC-SIGN) (13–17). In their role as APC, MN, MØ, and DC process mycobacterial antigens and present them bound to the major histocompatibility complex (MHC) class I or II molecules or to T-cells, primarily CD4 T-cells and CD8 T-cells, or through unconventional [CD1b, CD1c, CD1d (18–22)] or undefined receptors to double-negative (Valpha24þCD4
CD8
) T-cells and natural killer T (NKT) cells or to gamma delta (cd) T-cells, respectively. The relative contribution of the various T-cell or natural killer (NK) populations to the control of M. tuberculosis infection in humans may vary by infection site, involved organ, and natural history of the M. tuberculosis infection. Clearly, T-cells play a central role in host defense and mucosal immunity against M. tuberculosis. The balance of receptor expression, receptor signaling, and cytokine production by APC (MØ, MN and DC) determines

Figure 2 Active immune surveillance by Mycobacterium tuberculosis–specific CD4 and CD8 T cells and the presence of interferon gamma and tumor necrosis factor alpha are required to control latent M. tuberculosis infection.

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whether or not the T-cell will differentiate along the TH1 or TH2 pathway. Activated CD4þ T-cells can differentiate into TH1 or TH2 cells that secrete specific subsets of cytokines. The TH1 cell product of greatest relevance to M. tuberculosis immunity is IFN-c, the predominant activator of MØ and MN (23,24), whereas TH2 cells principally produce IL-4, IL-5, and IL-13. IL-10 from TH2 cells, naturally occurring CD4þ T regulatory cells (Tregs), CD8 T-cells, MØ and DC, and transforming growth factor beta (TGF-b) (from TH3 cells) provide immune regulation via inhibition of both TH1 and TH2 responses. Following M. tuberculosis infection, effector T-cells are stimulated. M. tuberculosis antigen–specific memory T-cells are subsequently generated. These memory T-cells can be distinguished into T effector memory (TEM) and T central memory (TCM) cells. TEM cells are found predominantly in peripheral tissue and at sites of inflammation where they exhibit rapid effector function. TCM cells reside predominantly in lymphoid organs and cannot be immediately activated. Upon exposure to M. tuberculosis, reinfection or vaccination TCM are thought to rapidly expand and differentiate to resupply the effector T-cell pool at peripheral sites. Specific surface markers distinguish the two memory cell types (TEM: CCR7lo, CD62Llo, CD69hi; TCM: CCR7hi, CD62Lhi, CD69lo, CD27hi) (25–27). IFN-c regulates a host of genes that are involved in direct bactericidal effects against M. tuberculosis, and antigen processing and generation of reactive nitrogen intermediates (RNI). The evidence for a central role of IFN-c in M. tuberculosis immunity derived from IFN-c knockout mice, which fail to produce RNI, and succumb rapidly to the experimental infection with M. tuberculosis (28,29). In children with hereditary IFN-c receptor deficiencies (30,31), there is progression and uncontrolled dissemination of mycobacterial infections. As the role of external addition of recombinant human (rh) IFN-c to the control of mycobacterial growth in in vitro studies remains controversial (32–34) and therapeutic administration of rhIFN-c (in patients with multidrug-resistant TB) resulted, at best, in transitory therapeutic benefits only (35), much remains uncertain about the expression of IFN-c–dependent protective immunity in humans. Monocytes and Macrophages

Nitric oxide is the primary product of inducible nitric oxide synthase (iNOS, NOS2 isoform) expressed by MN and MØ and can kill M. tuberculosis at low concentrations. The relevance of nitric oxide in human protective immunity against M. tuberculosis has accumulated slowly. Nitric oxide is released from M. tuberculosis–infected blood MN (36,37), AM (38–41), and respiratory epithelial cells (42,43) and is increased in exhaled air of TB patients (44). iNOS is present in TB lung granulomata and expressed in combination with eNOS in MØ and multinucleated cells in the inflammatory zone and the surrounding lung tissue and is significantly elevated in granulomatous tissue from TB patients relative to control tissue (45). Nitric oxide production as determined by expression of iNOS mRNA can be triggered in human AM

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by bacille Calmette–Gue´rin (BCG) (46) and confers antimycobacterial activity against M. tuberculosis (37,40) and BCG (46). However, there is a large interindividual variability in nitric oxide production from AM following M. tuberculosis infection, which correlates with intracellular growth inhibition of M. tuberculosis by AM (40). Increased generation of nitric oxide by AM (38,39) or MN (36) from TB patients amplifies the synthesis of proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-c) (36,38) and IL-1 (38), in an autoregulatory manner. Conversely, the release of RNI in human cells is triggered by IFN-c, TNF-a, and IL-1R (37) and mycobacterial components such as lipoarabinomannan and M. tuberculosis 19 kDa lipoprotein (47). Studies in the murine system also suggest that RNI production may be mediated by the interaction of pathogens with TLR and the downstream cytoplasmic adapter protein myeloid differentiation primary response gene 88 (myD88) (48). MN and MØ [including AM (49)] can undergo apoptosis following intracellular infection with M. tuberculosis. Apoptosis of these phagocytes upon M. tuberculosis infection may present a protective immune response that averts the release of intracellular components and the spread of mycobacterial infection by sequestering the pathogens within apoptotic bodies (50,51). More recently, transcriptional responses of MN and MØ to M. tuberculosis infection have been studied using high-density DNA microarrays. These comprehensive assessments of gene expression patterns provide the possibility of elucidating the complex cross talk between M. tuberculosis and host cells and to identify the genes involved in host pathogen responses that so far remained elusive. Initial studies of the MN transscriptome during M. tuberculosis infection indicate that M. tuberculosis interferes with the human MØ activation program (52). MØ infected with M. tuberculosis upregulate many nuclear factor kappa B (NF-jB) members, receptors for chemokines, and ILs and downregulate molecules necessary to respond to the immunosuppressive cytokine TGF-b. Induction of IL-12 also was significantly depressed after infection with M. tuberculosis, which may enhance the survival of M. tuberculosis (52). Dendritic Cells

The differentiation of na€
ve T-cells to effector TH1 and TH2 subtypes is greatly influenced by APC and thus also by DC. The understanding of the role of DC in the immune regulation, production of cytokines, and growth control of M. tuberculosis during M. tuberculosis infection is evolving. DC phagocytose particulate antigens including M. tuberculosis are the most potent APC for the activation of CD4 T-cells and CD8 T-cells in both primary and recall immune responses (53). DC maturation is induced by microbial lipopeptides that stimulate DC via TLR2 (54). DC are present in the respiratory tract (55), constitute 1% of epithelial cells in the airways, and are found peripherally in the human lung as far distally as the alveolar septa (56). Infection of human MN–derived DC with live M. tuberculosis

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induces expression on their surfaces of costimulatory signals (CD54, CD40, and B7.1) as well as of MHC class I molecules (57). Human MN–derived DC infected with M. tuberculosis secrete TNF-a, IL-1, IL-12 (57), IL-6, IL-10, IFN-a (58), and IFN-b (59); however, their capacity to control the growth of M. tuberculosis growth is inferior to that of MØ (60). The presence or function of DC in ex vivo pulmonary material from TB patients or HHC has not been assessed to date. CD4 T-Cells

CD4 T-cells are critical to adaptive CMI in adults (61–64) and children (32). MHC class II–restricted CD4 T-cells are the predominant source of IFN-c and IL-2 and are critical for the induction of delayed type hypersensitivity responses during M. tuberculosis infection and the development and maintenance of CD8 cytotoxic T-lymphocyte (CTL) responses (65). CD4 T-cells are directly involved in inhibiting M. tuberculosis growth in human MN (33). The predominant importance of CD4 T-cells in M. tuberculosis immunity is apparent during HIV-1 infection. The reduction of CD4 T-cell numbers and function confers the greatest known risk for the reactivation of latent and progression of primary M. tuberculosis infection to active TB disease. The increased risk that a clinically latent focus will reactivate during HIV-1 infecion (5–10% per year) indicates that active immunologic surveillance involving CD4 T-cells is required to maintain latency. It further indicates that ‘‘latency’’ is a misnomer because there is a dynamic balance between bacterial replication and host immune response at the infectious site(s). CD8 T-Cells

MHC class I–restricted CD8 T-cells were first shown in the murine model to be components of protective immunity against infection with Mycobacterium bovis BCG (66) and M. tuberculosis (67–69). Evidence is evolving that CD8 T-cells may have a role in human M. tuberculosis immunity (41,70–75) both as effector T-cells and as CTL. Human CD8 T-cells are reactive to several M. tuberculosis antigens including early secretory antigenic target 6, antigen (Ag) 85A, Ag85B, 38 kDa protein, heat shock protein 65, and 19 kDa lipoprotein (76–79). CTL that are primarily CD8 T-cells play an essential role in the lysis of M. tuberculosis–infected target cells (67–70). CD8 CTL lyse M. tuberculosis infected MØ via a Fas-independent granule exocytosis pathway (72,80–82) and via a Fas–FasL interaction (83) that results in the apoptotic death of M. tuberculosis–infected target cells. Alveolar CD4 T-cells and CD8 T-cells confer cytotoxic activity against M. tuberculosis–infected MØ from healthy individuals (71), suggesting that either or both of these cell types that are present in the alveoli during active TB (84) could act as CTL in the lung. Cytotoxic products of CTL, granulysin, perforin, and granzymes, are the effector molecules released by CD8 and CD4 CTL upon interaction with M. tuberculosis–infected target cells (22,72). Human peripheral CD8 effector T-cells also contribute to the production of IFN-c (41,85,86) and TNF-a upon stimulation with M. tuberculosis (41,86).

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The overlap in function of T-cell populations suggests that events that impact on their presence and differentiation at local sites of bacterial replication may determine their specific role in acquired resistance. Natural Killer Cells

Unconventional cells are of increasing interest in human M. tuberculosis immunity because of their potential roles in local innate immunity and the induction of adaptive immune responses. NK cells coregulate human CD8 T-cell effector function against M. tuberculosis (lysis of M. tuberculosis– infected target cells), which depends on the release of IFN-c by NK cells and of IL-15 and IL-18 by MN (87). Direct NK-mediated killing of M. tuberculosis in vitro occurs early (within 24 hours) and requires direct cell-to-cell contact (88). NK cells are activated by MN-derived immature DC in the presence of M. tuberculosis or IFN-c and reciprocally enhance DC maturation and IL-12 production (89). Human NKT cells are a unique subset of T-cells, are non–MHCrestricted, and recognize the nonclassical APC molecule, CD1d, which is expressed on human MN–derived cells (90). NKT cells secrete IFN-c and IL-13 and have bactericidal effects that appear to be mediated by granulysin (22,90). Gamma/Delta T-Cells (c/dT-Cells)

Human T-cells with a cd rather than the usual ab T-cell receptor are called cdT-cells and account for less than 10% of T-cells in blood and in the lung and respond to stimulation with unusual, nonpeptide phosphoantigens from M. tuberculosis (91,92). Non–peptide-reactive cd T-cells are only found in humans. cd T-cells proliferate in response to whole M. tuberculosis, are unrestricted by MHC class I or II molecules (93), are competent cytotoxic effector cells, and recognize the antigen that is presented by both AM (94) and MØ (91). cd T-cells contribute to M. tuberculosis immunity by producing IFN-c, granulocyte macrophage colony-stimulating factor (GM-CSF), IL-3, and TNF-a, and thus by activating MØ to eliminate M. tuberculosis (92,95). A subgroup of human cd T-cells that is activated by M. tuberculosis and recognizes mycobacterial nonpeptide phosphoantigens is Vc9Vd2þ (91,92). Proportions of Vc9Vd2þ cells are decreased in blood and lung cells from TB patients (96), probably as a consequence of M. tuberculosis– triggered apoptotic death (97). BCG vaccination expands and activates this cell population to provide helper functions for M. tuberculosis–specific CD4 T-cells and CD8 T-cells (98). These findings suggest a role for cd T-cells in the protective immune response to M. tuberculosis infection and one that may be expressed in the respiratory epithelium. Regulatory T-Cells

Several control and regulatory immune mechanisms prevent and minimize tissue damage from autoreactive and overexuberant immune responses to pathogens (99,100). Naturally occurring Tregs have recently been shown to be crucial elements of the regulation of immune responses by suppressing

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self-reactive T-cells and preventing ‘‘collateral’’ damage from pathogendirected protective immune responses by antigen-reactive T-cells (99). The suppressive function of Tregs depends critically on cell–cell interaction (101) and can involve the action of IL-10 (Tr1 cells), cytotoxic T-lymphocyte– associated protein (CTLA-4), or TGF-b (TH3 cells) (100). Major Tregs subsets are naturally occurring CD4 T-cells that express high levels of the IL-2 receptor alpha chain CD25 (CD4þCD25þ Tregs) and produce IL-10 and TGF-b. Murine Tregs express TLR (102) and can be activated in vitro by lipopolysaccharide (LPS), suggesting that Tregs can be stimulated by components of M. tuberculosis. Increased IL-10 levels have been detected in patients with advanced TB. Patients with TB, who lack TST reactivity to purified protein derivative (PPD) and often have a poor clinical outcome, are characterized by IL-10 production (not IFN-c production) from constitutively IL-10–producing T-cells (103). IL-10–producing Tregs inhibit T-cell responses to M. tuberculosis antigens (103,104). Reciprocally, neutralizing antibodies to IL-10 in in vitro–stimulated peripheral blood mononuclear cells (PBMC) from HIV-1–infected and HIV-1–negative TB patients were shown to increase IFN-c production by enhancing IL-12 production from MN (105). IL-10–producing Tregs, thus, may play a major role in limiting human immune responses to M. tuberculosis. High-level expression of CD25 and expression of the DNA-binding transcription factor Foxp3 (a master control gene for Tregs development) are functional markers for the identification of natural CD4þ Tregs. However, as stable phenotypic markers for unequivocal identification of human Tregs are still unidentified, the exact role of Tregs in human immunity to M. tuberculosis is evolving. Tregs may turn out to be of major importance in human immunity against M. tuberculosis as the balance between effector T-cells and Tregs at sites of infection may determine the pathogen survival in the presence of protective host immunity. Suppression of immune responses by enhancing Tregs function or boosting of immunity by suppressing Tregs function may become a future immunomodulating means of great therapeutic promise (101,106). B. Humoral Immunity

The prevailing view has been that humoral immunity has little or no impact on the course of M. tuberculosis infection. This may not be accurate. There is evidence in the murine model that arabinomannan-specific antibodies alter the course of (M. tuberculosis) infection and increase survival (107). Further, the presence of antibodies against M. tuberculosis liparabinomannan (LAM) is associated with resistance to dissemination of disease in children (108). Antibodies also may play a pathogenic role during adult TB by enhancing proinflammatory and by blocking downregulatory cytokines. PPD-specific immunoglobulin (Ig) G1 antibodies augment secretion of TNF-a (109,110) and IL-6 and IL-10 (110) by PPD-stimulated MN from patients with TB. Absorption of IgG1 removed the augmenting activity for TNF-a and IL-6 and increased, rather than decreased, IL-10 secretion. The role

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of antibodies during the initial encounter between M. tuberculosis and host cells in the alveolar spaces, prevention of M. tuberculosis dissemination, and induction of anti–M. tuberculosis antibodies following vaccination are important areas of active research (111). C. Systemic Immunity in Tuberculosis

MN of TB patients (112) depress PPD-stimulated lymphocyte transformation (112–114) and production of TH1-type cytokines IL-2 and IFN-c (115–117) selectively. This, in part, accounts for the decreased responsiveness of blood T-cells during TB (112). TGF-b and IL-10 are important MN and MØ, as well as T-cell–derived mediators of cytokine-mediated suppression (116,118,119). In vitro depletion of adherent cells (120) and the use of neutralizing anti– TGF-b antibodies (116) normalize lymphocyte proliferation in response to PPD and significantly increase PPD-stimulated production of IFN-c in TB patients. IL-10 inhibition has a similar effect on IFN-c production. The recent description of Tregs that may produce IL-10 or TGF-b requires reexamination of the cellular source of these cytokines in active TB. Blood MN from patients with active TB are activated as determined by the release of cytokines (112,114) and expression of markers of activation such as Fcc receptor type I and III and human leukocyte antigen (HLA)-DR on their cell surface (121). The antigen specificity of suppression in TB is due to the fact that blood MN primed in situ are restimulated in vitro with M. tuberculosis constituents to overproduce immunosuppressive cytokines. For example, M. tuberculosis cell wall lipoglycans and culture filtrate proteins directly stimulate MN to produce cytokines including TNF-a (122) and TGF-b (123). MN-dependent T-cell suppression is associated with negative TST responses in patients with TB. Apoptosis (124) of M. tuberculosis antigen–specific T-cells and compartmentalization of antigen-specific T-cells to the sites of inflammation (typically the alveolar and pleural spaces) contribute to decreased immune responses in the peripheral blood. In longitudinal studies of immune responses during and following antituberculous therapy, TGF-b and IL-10 responses normalize by three months, whereas IFN-c production remained depressed for at least 12 months. The protracted primary T-cell defect in IFN-c production may be due to apoptosis that occurs in the course of active disease (119). The uncontrolled immune activation in the course of active TB is associated with high levels of cytokines in plasma, sputum, bronchoalveolar lavage (BAL), and pleural fluid. These inflammatory markers disappear rapidly during the course of treatment. They may well contribute to programmed cell death and the protracted primary defect in T-cell function in pulmonary TB. D. Lung Immunity in Tuberculosis

Studies of local lung immunity at the entry site of aerosolized M. tuberculosis provide a window into the fundamental biologic interactions at the interface of M. tuberculosis with the human host. The interplay of activating

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and suppressing immune mechanisms determines whether M. tuberculosis infection remains in latency and confinement or whether TB disease will develop. The epidemiological evidence of resistance to M. tuberculosis infection despite aerogenic exposure suggests that the study of local innate and adaptive immune mechanisms against M. tuberculosis may reveal correlates of human protective immunity. The Granulomatous Tissue Response

Granulomatous tissue reactions are the pathologic hallmark of TB. By immunohistochemistry, TB granulomas comprise MN, MØ, and T-cells. The latter mostly are CD4 T-cells and CD8 T-cells. Granuloma formation in human TB is associated with the expression of characteristic cytokine profiles. By reverse transcriptase PCR (RT-PCR) from biopsy material of granulomatous TB lymph nodes, IFN-c, IL-12 (p40), IL-1b, TNF-c, GMCSF, and lymphotoxin-b (LT-b) production are increased twofold (IL-1b) to 19-fold (IFN-c) compared to control biopsy material from patients with carcinomas or chronic organizing pneumonias (125). mRNA of TH2 cytokines (IL-4, IL-5) is detectable in only one-half of the studied TB granulomas (126). Interestingly, levels of GM-CSF expression are tightly linked to the intensity of the granulomatous response, and GM-CSF is present in epitheloid cells and lymphocytes surrounding granulomatous lesions (125). Levels of TNF-a and LT-b mRNA correlate negatively with the extent of caseous necrosis present in TB lesions (125). In a study of surgically removed lung granulomas from five TB patients, employing in situ hybridization with riboprobes, detectable levels of IFN-c and TNF-a mRNA were found in all and IL-4 mRNA in three of five subjects. Two patients with granulomas exhibited IFN-c but not IL-4 cytokine production, expressed low levels of TNF-a, and presented with more necrotic lesions than did the three TB patients positive for both IFN-c and IL-4. Lung granuloma MØ from TB patients also express TGF-b, which may interfere with antimycobacterial mechanisms and effective granuloma formation (127). Granulomas in TB are simultaneously present in multiple stages of maturity that correlate with different patterns of cytokine mRNA expression. Newer, less mature granulomas exhibit IFN-c and TNF-a but no IL-4; intermediate granulomas exhibit IFN-c, TNF-a, and IL-4 and mature granulomas show greater expression of TNF-a, intermediate amounts of IL-4, and little IFN-c. TNF-a appears to correlate positively with IL-4 gene expression and negatively with the presence of caseous necrosis. Cells stained with the myeloid marker CD68, probably MØ, show mRNA production for IFN-c and IL-4 (128). The latter observation coincides with the finding that AM from patients with TB (129) and in vitro M. tuberculosis–infected AM express IFN-c mRNA (130). The granulomatous tissue reactions depend on the regulation of apoptosis. Initiation of apoptosis requires death-inducing signals such as lack of survival factors, metabolic supplies, binding to death signal–transmitting receptors, etc. (131). Members of the TNF-a superfamilies of TNF-aR

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and TNF-a-ligands are involved in the control of such apoptotic processes during granuloma formation. TNF-a induces apoptosis of M. tuberculosis– infected AM (49,132), favoring formation of caseating granulomas. Pleural Fluid Cells

Tuberculous pleuritis is most common in primary TB and usually resolves spontaneously (133,134). Immune responses occurring in the pleural spaces therefore probably represent protective immunity that controls multiplication of M. tuberculosis. Compartmentalization of PPD-specific immune cells in TB was first described in pleural effusion cells on the basis of increased antigen-specific DNA synthesis (120,135–137) as compared to autologous blood cells. TH1 cytokine responses are increased and CD4 T-cells with a memory phenotype (CD45RA
) accumulate locally (124,138,139) with increased frequencies of cells responding to PPD (120,137). These cells express multiple homing receptors such as CD11a, CC chemokine receptor 5 (CCR5), and CXC chemokine receptor (CXCR) 3 (139). Pleural fluid cells also produce increased concentrations of cytokines in comparison with autologous blood cells. IFN-c (49,140–144) and TNF-a production by pleural fluid cells is increased both constitutively (124,141–143,145) and in response to stimulation with protein–peptidoglycan complex, lipoarabinomannan (138), and M. tuberculosis Erdman (141). The increases in IFN-c production are paralleled by increases in IL-6 (146), free IL-12p40, and heterodimeric IL-12, both constitutively and when stimulated with heat-killed M. tuberculosis (147). Pleural effusion cells from TB patients also showed increased production of IL-10 (141) and of TGF-b (148). IL-10 and TGF-b might play a role in limiting the inflammation in this compartment (149). Levels of IFN-c and the proapoptotic molecules TNF-a, FasL, and Fas are increased in pleural fluid from TB patients relative to plasma (124). Spontaneous apoptosis of CD4 T-cells and non-CD4 T-cells is increased in pleural TB, suggesting that immune activation and loss of antigen-responsive T-cells may occur concomitantly, favoring persistence of M. tuberculosis infection (124). In HIV-1– seronegative pleural TB, vigorous immune responses usually are associated with negative M. tuberculosis cultures. In HIV-1–seropositive pleural TB, M. tuberculosis cultures most often are positive. Therefore, the finding that levels of IFN-c (as well as the proapoptotic molecules and apoptosis) are increased further in HIV-1–seropositive pleural TB is suggestive of a block in the protective response to IFN-c (150). Bronchoalveolar Cells

Bronchoalveolar cells (BAC) obtained by BAL permit the study of localized immunoregulatory functions during TB and in M. tuberculosis–exposed but healthy subjects. BAC provide insights into immunologic compartmentalization and are thought to reflect processes in the granulomatous tissue that is adjacent to the bronchoalveolar spaces. The procedure generally samples approximately one million alveoli, the walls of which contain the granulomas. In health, BAC are composed of 90% to 95% AM and 5% to 10% alveolar lymphocytes (AL), with occasional neutrophils and eosinophils.

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The most prominent finding of BAL studies in TB patients is a compartmentalized pulmonary immune response. Unstimulated total BAC in TB contain increased numbers of cells expressing IFN-c (129,151,152) and IL-12 mRNA (152) but not IL-4 or IL-5 mRNA (129,152) and release increased amounts of IL-1b, IL-6, and TNF-a (153). Spontaneous TNF-a secretion in AM is associated with reduced in vitro M. tuberculosis growth in normal AM (154). BAC in pulmonary TB are also characterized by an alveolitis of ab T-cell receptor–bearing AL that are activated as manifested by HLA-DR and CD69 membrane expression (84). Upon challenge with PPD, these BAC produce a TH1 type cytokine host response (155). Compartmentalization of mycobacterial antigen-specific responses to the lung in TB is due, in part, to recruitment of T-cells from the blood to the lungs, as well as mycobacterial antigen–specific expansion in situ. Recruitment of M. tuberculosis–specific cells to the lung compartments is mediated by chemokines with lymphocyte chemotactic activity such as that conferred by Regulated on Activation, Normal T-cell Expressed and Secreted (RANTES), IL-8, and MN chemoattractant protein-1 (MCP-1). These chemokines, among others, are increased in the BAL fluid of patients with pulmonary TB (156,157). Recent studies in a bronchoscopic challenge model of TST-positive healthy subjects showed induction of IFN-c–inducible protein 10 (IP-10) and monokine induced by IFN-c (Mig) and presence of resident CD45ROþ memory cells after PPD challenge in the lungs. The PPD-specific AL were predominantly CD4þ T-cells that produce IFN-c (158). There is evidence for a role of CTL in CMI against M. tuberculosis in the human lungs. Alveolar and blood CD4 T-cells and CD8 T-cells express M. tuberculosis antigen–specific CTL activity when stimulated by M. tuberculosis–infected AM from healthy TST-positive donors (71). Mycobacterial antigen-pulsed AM are targets of blood CTL activity but are significantly more resistant to cytotoxicity than antigen-pulsed autologous blood MN (71). The findings that both CD4 T-cells and CD8 T-cells are present and increased in number and activated in alveoli during active pulmonary TB (84) suggest that either or both of these cell types could function as antigen-specific CTL in the lung during disease. As mediators of innate and adaptive immune responses, AM contribute to the production of cytokines and of chemokines that facilitate the recruitment of lymphocytes and MN. About 20% of AM are immature and possibly recently recruited from the blood during active TB (84). M. tuberculosis–infected AM release TNF-a, IL-1, IL-6, IL-12, IL-15, IL-18 (153,159–161), GM-CSF, and deactivating cytokines IL-10 and TGF-b (161,162). Expression of IFN-c mRNA from AM of TB patients ex vivo (129) and production of IFN-c from AM upon in vitro infection with M. tuberculosis (130) have also been observed. Upon in vitro infection with M. tuberculosis, AM release RANTES, MCP-1, macrophage inflammatory protein (MIP)-1a, and IL-8 (157,163) in amounts that may vary depending on the virulence of the infecting M. tuberculosis strain (163).

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AM (as well as DC and MN) express the recently described TLR. Qualitative and quantitative differences in the protein expression of these TLR have profound implications on the modulation of both innate and adaptive immunity, e.g., by mediating TNF-a, IL-1, and IL-6 and killing M. tuberculosis (164) and probably RNI production (48). Innate resistance against M. tuberculosis is thought to be critically dependent on the engagement of three of the known 13 TLR on macrophages (TLR2, 4, and 9). TLR2 agonists include a variety of bacterial cell wall components, such as peptidoglycan as well as lipoarabinomannan, which is a major cell wall–associated glycolipid derived from M. tuberculosis. Arabinose-capped lipoarabinomannan, purified from rapidly growing mycobacteria, induces TNF-a production in macrophages in a TLR2-dependent manner (165,166). TLR4 agonists include gram-negative bacterial LPS, and unmethylated CpGcontaining mycobacterial DNA is a TLR9 agonist (165). Expression of TLR1–5 is present in almost all granulomas from TB patients. All TLR can utilize myD88 to propagate signals to target genes and generate rapid protective responses. Granulomas expressing IL-4 show low expression of TLR2 (126). In summary, the study of localized immunity has revealed prominent local TH1 responses that are characterized by enhanced DNA synthesis, activation of lung cells, large numbers of IFN-c–producing M. tuberculosis antigen–specific cells, and increased IL-12 and IL-18 production. This pattern of immunity that is considered to be protective is, however, observed consistently in affected TB lungs despite uncontrolled progression of M. tuberculosis infection. The final answers to this conundrum in M. tuberculosis immunity need to be found and may involve complex interactions between host cell responses and M. tuberculosis–induced immune evasion mechanisms. Probably, protective TH1 responses overlay synchronous deactivation events in the lungs or upregulated immune-mediated processes including apoptosis may facilitate extracellular bacterial replication. However, the evolving understanding of local and mucosal immunity and its initial interactions with inhaled M. tuberculosis suggest that research to maximize vaccine-based prevention of aerogenic M. tuberculosis infection needs to take into consideration the compartmentalization of immune responses and elicitation of local protective immunity. HIV-1 and Mycobacterium tuberculosis Infection in the Lung

HIV-1 replication is greatly enhanced at anatomical sites of active M. tuberculosis coinfection (167). The compartmentalization of antigenspecific cells at sites of infection in the local milieu of proinflammatory cytokines creates an environment that is conducive to HIV-1 replication with enhanced viral burden and conditions favoring dissemination of M. tuberculosis infection. The failure of effective immune response that permits development of opportunistic infections may in addition be due to continued exposure of immunoreactive cells to M. tuberculosis at sites of infection, with subsequent apoptosis of CD4 T-cells and non-CD4

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T-cells. This initiates a vicious cycle of simultaneous immune activation and loss of antigen-responsive T-cells, which permits persistence of M. tuberculosis infection (168). In BAC, cellular and immunocytological characteristics in HIV-1– coinfected TB patients compared with healthy controls portray an inflammatory cell profile with reduced CD4 T-cell (151) and increased CD8 T-cell numbers in affected lungs (151,169), increased AM and neutrophil numbers (169), and decreased constitutive IFN-c production (151). These findings suggest reduced enrichment and activation of immune cells in the lungs. In pleural TB, HIV-1 replication is enhanced both in the cellular (pleural compared with blood mononuclear cells) and acellular (pleural fluid compared with plasma) compartments of the pleural space (167,170). These observations are explained by augmented local TNF-a and HIV1–noninhibitory b-chemokine (MCP-1) concentrations, and low levels of HIV-1 inhibitory b-chemokines (MIP-1a), MIP-1b, and RANTES, with upregulation of the HIV-1 coreceptor, CCR5, by pleural fluid mononuclear cells (170). Source cells of HIV-1 in pleural fluid are, in part, HLA-DRþ cells, CD26þ lymphocytes, and CD14þ MØ (167). AM from HIV-infected subjects with CD4 T-cell counts lower than 200/mL and detectable HIV load produce HIV-1 (p24) upon stimulation with PPD and M. tuberculosis. This indicates that M. tuberculosis and its PPD can induce HIV replication in latently infected AM (171). AM in TB patients and upon in vitro M. tuberculosis infection express CXCR4, producing a permissive environment for replication of HIV-1 using CXCR4. Because progression to acquired immunodeficiency syndrome (AIDS) is associated with a shift in viral coreceptor use from CCR5 to CXCR4, these recent findings form a molecular basis for the observed acceleration of the course of HIV-1 infection to AIDS in TB (172). Intracellular M. tuberculosis growth is reduced in AM from HIV-1– infected subjects with CD4 T-cell counts greater than 200/mL compared with AM from healthy controls. As binding and internalization of M. tuberculosis are augmented in AM from HIV-1–infected subjects compared with healthy controls, this reduced intracellular M. tuberculosis growth is not due to impaired phagocytosis or a defect in innate immunity of AM (154). The Alveolar Epithelial Barrier

Epithelial cells and their products such as defensins and chemokines are important components of antibacterial mucosal innate immunity that are difficult to study in humans due to their inaccessibility. Because type II alveolar epithelial cells cover 5% to 8% of the alveolar surface, early interaction between M. tuberculosis and epithelial cells after entry of infectious microdroplets into the alveolar spaces is plausible. The mechanisms by which M. tuberculosis crosses the alveolar wall to establish infection in the human lung tissue or gain access to the lymphatic

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and circulatory system are not well defined. M. tuberculosis laboratory strains H37Ra (avirulent) and H37Rv (virulent) invade the human type II alveolar epithelial cell line (A549) in a microfilament- and microtubuledependent manner using antivitronectin receptor (CD51) and b1 integrin (CD29) as receptors (173) in vitro. Within A549 cells, H37Ra and H37Rv can replicate and survive (173–175). We have recently shown that infection of A549 cells with H37Ra induces production of human beta defensin 2 (176), a peptide with antimicrobial and chemokine activities. Earlier in vitro studies had provided evidence that M. tuberculosis (not BCG) can cross epithelial-endothelial barriers and that this passage triggers the release of IL-8 and MCP-1 (177) from both epithelial and endothelial cells. This data indicates that respiratory epithelium may create a gradient for infected mononuclear cells to migrate across the alveolar barrier following exposure to M. tuberculosis. Alveolar and other respiratory epithelial cells, thus, may be involved in initiating and linking innate and adaptive antimycobacterial immune responses. IV. Susceptibility to Mycobacterium tuberculosis Infection and Tuberculosis Development A. The Impact of HIV-1

Active immune surveillance is required to maintain the latency of quiescent M. tuberculosis foci. Concurrent HIV-1 infection profoundly alters the natural history of TB and increases the risk of active progressive primary TB and of reactivation TB (63,178). In nosocomial outbreaks, 30% to 40% of HIV-1–infected individuals develop TB within one to two months after diagnosis of the source TB index case and TB development is associated with skin test anergy and CD4 T-cell lymphopenia (63,179). The risk of developing reactivation TB among HIV-infected persons is 79-fold greater than in HIV-noninfected persons (178) and may be up to 170-fold higher in patients with AIDS (180). Risk of death from TB is increased in HIV-1–infected persons (181). In immunocompetent subjects, TB pathology is restricted to the lungs (85%) and rarely extrapulmonary or both pulmonary and extrapulmonary (15%) (182). With HIV-1 coinfection, TB is 38% pulmonary, 30% extrapulmonary, and a combination of both pulmonary and extrapulmonary disease in the remainder (183). Development of extrapulmonary TB is associated with compromised granulomatous tissue reactions (182–185) that result from HIV-1–induced alterations of cell-mediated immunity. With advanced immunosuppression, cavitary tissue damage and the number and size of cavitary lesions within the lung are reduced. M. tuberculosis granulomatous host responses are greatly impaired and correlate with the residual degree of immunocompetence and peripheral CD4 T-cell depletion. In early stages of HIV-1 infection, histological features of the TB granuloma are abundant epitheloid MØ, Langhans giant cells, and a peripheral rim of CD4 T-cells. M. tuberculosis numbers are low. With moderate immunodeficiency, Langhans giant cells

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are missing. Epitheloid differentiation and activation of MØ are absent. CD4 T-cells are depleted and M. tuberculosis numbers increased. Lastly, with advanced HIV-1–related immunosuppression and AIDS, granuloma formation is rare and there is little cellular recruitment and very few CD4 T-cells can be found. M. tuberculosis numbers are high (64). HIV-1 infection associated with immunosuppression leads to lowered resistance to exogenous reinfection (186). Perturbations in the cytokine expression, that is a reduced TH1 response, have been suggested as contributing to the susceptibility of HIVinfected patients to TB. Upon stimulation with M. tuberculosis in vitro, PBMC from HIV-infected TB patients show reduced proliferative and type 1 responses that are a direct result of CD4 T-cell depletion and related to IL10 production (187). Similarly, low CD4 cell counts and low IFN-c production are correlated with impaired ability to regulate growth of BCG in whole blood assays of HIV-1–infected children (32). TNF-a production is increased, suggesting that HIV-1–associated TB is accompanied by immune activation that triggers increased HIV-1 expression and accelerated progression to AIDS (188). In line with the observed clinical synergism between the two infections, blood MN from TB patients are highly permissive in vitro to productive infection with HIV-1 (189). M. tuberculosis and PPD increase in vitro HIV-1 replication in MN via transcriptional activation (190) and activation of NF-jB (191). Conversely, growth of M. tuberculosis is increased in HIV-1–infected human MN–derived MØ (192). In vivo viral load in HIV-1– and M. tuberculosis–coinfected persons is increased compared with single HIV-1–infected persons at CD4 T-cell counts greater than 500/mL but not at CD4 T-cell counts lower than 500/mL, suggesting that TB, as an early HIV-1 opportunistic infection, increases early viral replication and dissemination and progression of HIV-1 disease (193). IFN-c production is preserved in HIV-1–infected TB patients with CD4 T-cell counts of 200/mL to 500/mL and is low in patients with CD4 T-cell counts of 500/mL or more and in HIV-1–uninfected patients. TNFa levels are similar, regardless of the CD4 T-cell numbers (194). Interestingly, among TST-positive HIV-1–infected subjects, TB incidence is high and the development of TB is associated with an IL-10 response to PPD or with positive IL-5 responses when a BCG scar is present (195). Recent data in M. tuberculosis–stimulated PBMC from TST-nonreactive donors showed that IL-10 significantly decreases replication of T-cell–tropic HIV-1 isolates in M. tuberculosis recall antigen–stimulated cells (196). These effects likely result from the inhibition of TNF-a, which enhances HIV-1 replication. This and data showing increased numbers of IL-10– producing CD4 T-cells in TST-nonreactive TB patients (103) indicate that HIV-1 replication in M. tuberculosis–coinfected individuals is coregulated by Tregs. B. Immune Reconstitution Inflammatory Syndrome

Reappearance or paradoxical worsening of previous TB manifestations or appearance of new manifestations (fever, lymph node enlargement, cough,

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pulmonary infiltrates, etc.) despite administration of effective anti-TB therapy have been reported in HIV-1–infected patients after the initiation of antiretroviral therapy (ART) (78,79,197,198). Immune reconstitution inflammatory syndrome (IRIS) is a frequent and sometimes severe event that occurs in 30% to 45% of patients after initiation of ART (198). Exaggerated immune inflammatory responses have been observed upon reconstitution of immunity, specifically in individuals with strong increases in CD4 T-cell percentage and ratio of CD4 T-cells to CD8 T-cells, as well as TST conversion. Individuals starting treatment for disseminated TB and HIV-1 coinfection quickly increase frequencies of IFN-c–producing peripheral M. tuberculosis–specific blood CD4 T-cells (199). Further identification of immunological determinants of IRIS development could aid the diagnosis of IRIS and lead to preventive strategies. The development of IRIS in the context of ART may need to be considered as a relevant public health problem, because its incidence may sharply rise with wider availability of ART in TB-endemic countries with high rates of HIV-1 infection. C. Inhibitors of Tumor Necrosis Factor

TNF-a is essential for granuloma formation and maintenance. The importance and complexity of the role of TNF-a as a regulator of local antimycobacterial host defense has been clearly demonstrated in murine studies using anti–TNF-a antibodies and TNF-a receptor gene–disrupted or transgenic mice. These interventions result (i) in a decrease in number of granulomas and their delayed formation, (ii) decreased containment and elimination of infecting mycobacteria (BCG) (200), (iii) accelerated lethal course of M. tuberculosis infection, (iv) delay in iNOS production (201), and (v) widespread pulmonary inflammatory infiltrates, necrosis, and dysregulation of pulmonary cytokine and chemokine production (202). With the increased human use of TNF-a inhibitors to treat inflammatory conditions such as rheumatoid arthritis and Crohn’s disease (203), reports of simultaneous occurrence of granulomatous infectious diseases have increased in the past five years. Patients receiving TNF-a inhibitors have been shown to be at increased risk of TB reactivation disease (203–207). In a large retrospective study of the Food and Drug Administration adverse events reporting system, TB incidence rates were reported for between 35 and 144/100,000 treated patients (206). Currently under investigation are the relative risk of therapy with monoclonal anti–TNF-a antibodies and with TNF-a receptor antagonists and in vitro mechanisms of their interference with protective host immune mechanisms. D. Other Immunocompromising Conditions

Diabetes mellitus, chronic renal failure, carcinoma of head or neck, and iatrogenic immunosuppression, increase the relative risk for reactivation of latent M. tuberculosis infection and development of TB markedly by 2-, 3.6-, 10-, 15-, 16-, and 11.9-fold, respectively, relative to healthy individuals

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with no known risk factors (208). Persons with silicosis, end-stage renal disease, poorly controlled diabetes mellitus, chronic malnutrition, rapid weight loss, chronic treatment with corticosteroids and other immunosuppressive drugs, and tobacco smoking are also at increased risk of developing TB, although the relative risk is much less than that of HIV-infected persons. The duration and dose of corticosteroid use associated with an increased risk of TB are unknown; however, treatment for less than three to four weeks with doses of 15 mg of prednisone or less daily probably causes little increased risk.

E. T Helper 2 Cytokines and Helminth Infection

Whereas TH1 cytokines are considered protective in human M. tuberculosis infection, dominant TH2 cytokine immune profile and immune perturbation by chronic infections contribute to the development and alter the extent of human TB (209,210). Long-term control of M. tuberculosis infection is associated not just with elevated TH1 responses but also with inhibition of the TH2 response. Individuals progressing to TB tend to have decreased levels of TH1 cytokines and increased levels of IL-10 compared with healthy M. tuberculosis–infected and –uninfected community controls, whereas healthy M. tuberculosis–infected subjects have increased IL-4 antagonist and IL-4d2 message, compared with both TB patients or uninfected individuals (211,212). In a recent study of M. tuberculosis–exposed health-care workers, increased median percentages of IL-4–producing CD8 and cd T-cells were associated with progression to active TB. Individuals who remained healthy showed increased percentages of IFN-c–producing CD8 and cd cells and lower percentages of IL-4–producing CD8 and cd T-cells (197). PBMC from healthy donors respond to sonicated M. tuberculosis antigens with increased IL-4 gene activation, CD30 expression, and apoptosis, probably by sensitizing lymphocytes to TNF-a–mediated apoptosis. Interestingly, these changes are significantly greater than those observed when cells were stimulated with antigens from nonpathogenic Mycobacterium vaccae (210). IL-4 also modulates expression of TLR (126), thus interfering with the intracellular killing of M. tuberculosis and induction of TLR signaling–dependent immune mechanisms. TB without TST reactivity to PPD has been described in individuals with predominant TH2 type cytokine response patterns and occurs in geographic areas with high rates of Helminth infections. In individuals with Helminth infections, PPD-specific in vitro cellular proliferative responses are decreased and expression of costimulatory signaling molecules (CTLA-4) altered (213). Conversely, upon anthelmintic treatment, in vitro PPD-specific cell proliferation and IFN-c production, TST reactivity, and post-BCG vaccination PPD-specific immune responses are significantly increased (214). Lowered resistance to mycobacterial infections or failure of protection from anti-TB vaccines (214) may require special public health measures in Helminth-endemic areas.

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F. Mycobacterium tuberculosis Host Immune Evasion Mechanisms

The recent years have provided evidence that M. tuberculosis exploits and circumvents host immunoregulatory mechanisms to promote chronic infection, persistence, and the opportunity for transmission (215,216). For example, M. tuberculosis lipids arrest phagosome maturation and target host cell membrane–trafficking processes and organelle biogenesis (217), allowing escape from lysosomal bactericidal mechanisms and preventing efficient Ag presentation in phagocytic host cells. M. tuberculosis also interferes with the induction of IFN-c–regulated genes and the stimulation of MØ to kill M. tuberculosis (218). This has been shown in the human acute monocytic leukomia cell line named THP-1, in which induction of CD64 (FccR1) surface expression and transcription are impaired following M. tuberculosis infection despite normal activation of Signal Transducer and Activator of Transcription 1 (STAT1). An additional mechanism of M. tuberculosis interference with IFN-c–regulated genes has recently been described in human MN–derived MØ (219). IL-6 from M. tuberculosis–infected MØ was shown to decrease the transcription of class II transactivator and expression of IFN-c–induced MHC class II that affected directly the infected MØ and via a bystander effect also the uninfected MØ. The inflammatory cytokine microenvironment at the site of infection, where IL-6 is produced, may thus interfere with important protective IFN-c effects (219). In a murine model, M. tuberculosis 19-kDa lipoprotein and an M. tuberculosis cell wall peptidoglycan inhibit via a TLR2 and myD88–dependent mechanism macrophage responses to IFN-c at a transcriptional level and IFN-c activation of murine MØ to kill virulent M. tuberculosis (220). The 19-kDa lipoprotein also inhibits IFN-c–regulated expression of MØ HLA-DR protein and mRNA and of FccRI in a TLR2-dependent manner and thus Ag processing and presentation of soluble protein antigens to MHC-II–restricted CD4 T-cells (221). Another immunosuppressive mechanism of M. tuberculosis appears to be its inhibition of the phenotypic and functional maturation of human MN–derived DC (222). M. tuberculosis targets a DC-specific C-type lectin (DC-SIGN) (13,14) that is an important receptor of mycobacteria and of HIV-1 through the mycobacterial cell wall component manLAM, thus preventing mycobacteria- or LPS-induced DC maturation (14,223). This array of M. tuberculosis–induced alterations of host cell function and immune responses provides additional clues as to the lack of M. tuberculosis control and the unhindered M. tuberculosis infection at local sites of infection despite presence of protective immune mechanisms such as high IFN-c levels. G. The Impact of Mycobacterium tuberculosis Isolates on Human Immunity

There is increasing evidence that heterogeneity between M. tuberculosis isolates and variably expressed bacterial factors modify host CMI and epidemiological and clinical features. Strains of M. tuberculosis differ in their virulence and properties to induce host cytokines that modify the

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granulomatous tissue reaction as well as TST. For example, differences in M. tuberculosis phenotypes (H37Rv, CDC1551) result in differences in TST positivity in humans (224) and in TNF-a, IL-6, IL-10, and IL-12 production levels by human MN and of TNF-a in AM (225). Although not yet demonstrated in the human model, host immunomodulatory effects of an isolate of a subset of the W-Beijing family of M. tuberculosis (HN878) with hyperlethality in the murine model are correlated with a biologically active polyketide synthase–derived phenolic glycolipid (PGL) (226). Disruption of the synthesis of PGL in the HN878 strain was associated with an increase of TNF-a, IL-6, and IL-12 release from murine bone marrow MØ in vitro. Further, studies with H37Ra and H37Rv indicate that virulence of the infecting strain alters the release of chemokines such as RANTES, MCP-1, MIP-1a, and IL-8 (163), which affect recruitment of inflammatory cells capable of controlling infection and are involved directly in M. tuberculosis growth control. Taken together, these and other findings suggest that individual M. tuberculosis components confer immunomodulatory effects on host immune cells. M. tuberculosis manipulates its environment by interfering with the host immune response on multiple levels. This redundancy of interferences suggests their importance for the survival of M. tuberculosis during its coevolution with the human host. V. Resistance to Mycobacterium tuberculosis Infection A. Household Contact Studies

More than half of intensely exposed household contacts fail to manifest M. tuberculosis infection despite continued aerogenic M. tuberculosis exposure, presumably due to innate resistance. The initial interaction of M. tuberculosis with the alveolar environment controls growth of M. tuberculosis efficiently, because 50% to 75% of M. tuberculosis–exposed HHC of TB patients do not acquire M. tuberculosis infection as determined by TST (7,227). Because immunity in HHC reflects early immune responses that can be associated with protection and efficient M. tuberculosis growth control, study of HHC may permit identification of correlates of human protective immunity. Household contact studies offer the best possible approach to study human-to-human M. tuberculosis transmission and concurrent protective host immunity to M. tuberculosis under conditions of known exposure (228). Studies from our group showed increased immune responses against secreted M. tuberculosis Ag85 in PBMC from HHC (229) and increased frequencies of M. tuberculosis Ag85–specific IFN-c–producing BAC in HHC compared with healthy community controls (230). This presence of M. tuberculosis Ag85–reactive T-cells in BAC suggested induction of protective local memory immunity during concurrent M. tuberculosis exposure and probably containment of M. tuberculosis infection in the alveolar environment. This hypothesis was inferred from murine (231–233) and guinea

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pig (234) vaccine studies in which M. tuberculosis Ag85 conferred protection against M. tuberculosis. Recent data from our group show that autologous blood CD8 T-cells from concurrently aerogenically M. tuberculosis–exposed HHC, but not from unexposed healthy community controls, contribute to growth control of M. tuberculosis in AM (41). The findings also indicate that M. tuberculosis–specific effector CD8 T-cells expand in vivo in individuals who are exposed aerogenically to M. tuberculosis (41). Interestingly, there was a positive correlation between TNF-a—but not IFN-c or nitric oxide levels—and the growth-controlling activity of the AM/CD8 cocultures (41). Quantification of exposure to M. tuberculosis and respiratory uptake of M. tuberculosis in humans cannot be studied directly, making human resistance to M. tuberculosis difficult to study. Because the search for correlates of protective immunity is critical for the evaluation of rationally designed new antituberculous vaccines, new approaches to quantifying human M. tuberculosis exposure are under development (235). B. Host Immunogenetics

Genetic variation influences immune responses and may contribute to differential development of TB (236,237). There is evidence suggesting that innate resistance or susceptibility to TB disease or M. tuberculosis infection may be genetically determined. Understanding the essential host genes and alleles associated with susceptibility or resistance allows gaining insights into effector mechanisms of protection. Resistance to TB disease and M. tuberculosis infection is polygenic in nature. Associations with the development of mycobacterial infections and TB disease in population-based studies have been described for polymorphisms in multiple genes. A selection of these genes is listed subsequently: HLA (238–242), IFN-c gene (243,244), Natural Resistance Associated Macrophage Protein (NRAMP) (245–249), TGF-b and IL-10 (250,251), mannose-binding protein (252,253), IFN-c receptor (254), TLR2 (255,256), vitamin D receptor (257–259), and IL-1 (260,261). The identification of patients with mutations in single receptor genes that are involved in IL-12 and IFN-c binding and signaling provided evidence for the importance of TH1 cytokines in human resistance to mycobacteria. Defects in the IL-12R (262–264) and IL-12Rb1 (265,266) and complete or partial defects in the IFN-cR or IFN-cR1 genes (30,266–270) have been found worldwide in individuals with disseminated infections caused primarily by BCG (following vaccination) or nontuberculous poorly virulent mycobacteria. Studies with blood cells from such individuals often show an inability or reduced in vitro production of IFN-c (271) or TNF-a (269) upon stimulation. Interestingly, infections with M. tuberculosis or TB disease in association with the IL-12 or IFN-c receptor defects have rarely been reported (265,272,273). However, as the relative contribution of genes involved in resistance or susceptibilty to disease depends on the genetic background of the studied populations and the stage of infection, much remains to be understood.

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225. Engele M, Stossel E, Castiglione K, et al. Induction of TNF in human alveolar macrophages as a potential evasion mechanism of virulent Mycobacterium tuberculosis. J Immunol 2002; 168(3):1328–1337. 226. Reed MB, Domenech P, Manca C, et al. A glycolipid of hypervirulent tuberculosis strains that inhibits the innate immune response. Nature 2004; 431(7004):84–87. 227. Shaw JB, Wynn-Williams N. Infectivity of pulmonary tuberculosis in relation to sputum status. Am Rev Tuberc 1954; 69(5):724–732. 228. Guwatudde D, Nakakeeto M, Jones-Lopez EC, et al. Tuberculosis in household contacts of infectious cases in Kampala, Uganda. Am J Epidemiol 2003; 158(9): 887–898. 229. Torres M, Herrera T, Villareal H, et al. Cytokine profiles for peripheral blood lymphocytes from patients with active pulmonary tuberculosis and healthy household contacts in response to the 30-kilodalton antigen of Mycobacterium tuberculosis. Infect Immun 1998; 66(1):176–180. 230. Schwander SK, Torres M, Carranza CC, et al. Pulmonary mononuclear cell responses to antigens of Mycobacterium tuberculosis in healthy household contacts of patients with active tuberculosis and healthy controls from the community. J Immunol 2000; 165(3):1479–1485. 231. Lozes E, Huygen K, Content J, et al. Immunogenicity and efficacy of a tuberculosis DNA vaccine encoding the components of the secreted antigen 85 complex. Vaccine 1997; 15(8):830–833. 232. Huygen K, Content J, Denis O, et al. Immunogenicity and protective efficacy of a tuberculosis DNA vaccine. Nat Med 1996; 2(8):893–898. 233. Tascon RE, Colston MJ, Ragno S, et al. Vaccination against tuberculosis by DNA injection. Nat Med 1996; 2(8):888–892. 234. Horwitz MA, Lee BW, Dillon BJ, et al. Protective immunity against tuberculosis induced by vaccination with major extracellular proteins of Mycobacterium tuberculosis. Proc Natl Acad Sci USA 1995; 92(5):1530–1534. 235. Fennelly KP, Martyny JW, Fulton KE, et al. Cough-generated aerosols of Mycobacterium tuberculosis: a new method to study infectiousness. Am J Respir Crit Care Med 2004; 169(5):604–609. 236. Comstock GW. Tuberculosis in twins: a re-analysis of the Prophit survey. Am Rev Respir Dis 1978; 117(4):621–624. 237. Bellamy R, Beyers N, McAdam KP, et al. Genetic susceptibility to tuberculosis in Africans: a genome-wide scan. Proc Natl Acad Sci USA 2000; 97(14): 8005–8009. 238. Amirzargar AA, Yalda A, Hajabolbaghi M, et al. The association of HLA-DRB, DQA1, DQB1 alleles and haplotype frequency in Iranian patients with pulmonary tuberculosis. Int J Tuberc Lung Dis 2004; 8(8):1017–1021. 239. Ravikumar M, Dheenadhayalan V, Rajaram K, et al. Associations of HLA-DRB1, DQB1 and DPB1 alleles with pulmonary tuberculosis in south India. Tuberc Lung Dis 1999; 79(5):309–317. 240. Cox RA, Downs M, Neimes RE, et al. Immunogenetic analysis of human tuberculosis. J Infect Dis 1988; 158(6):1302–1308. 241. Goldfeld AE, Delgado JC, Thim S, et al. Association of an HLA-DQ allele with clinical tuberculosis. JAMA 1998; 279(3):226–228. 242. Singh SP, Mehra NK, Dingley HB, et al. Human leukocyte antigen (HLA)-linked control of susceptibility to pulmonary tuberculosis and association with HLA-DR types. J Infect Dis 1983; 148(4):676–681. 243. Lopez-Maderuelo D, Arnalich F, Serantes R, et al. Interferon-gamma and interleukin-10 gene polymorphisms in pulmonary tuberculosis. Am J Respir Crit Care Med 2003; 167(7):970–975.

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244. Lio D, Marino V, Serauto A, et al. Genotype frequencies of the þ874TregsA single nucleotide polymorphism in the first intron of the interferon-gamma gene in a sample of Sicilian patients affected by tuberculosis. Eur J Immunogenet 2002; 29(5):371–374. 245. Cervino AC, Lakiss S, Sow O, et al. Allelic association between the NRAMP1 gene and susceptibility to tuberculosis in Guinea-Conakry. Ann Hum Genet 2000; 64(Pt 6):507–512. 246. Skamene E, Schurr E, Gros P. Infection genomics: Nramp1 as a major determinant of natural resistance to intracellular infections. Annu Rev Med 1998; 49:275–287. 247. Bellamy R, Ruwende C, Corrah T, et al. Variations in the NRAMP1 gene and susceptibility to tuberculosis in West Africans. N Engl J Med 1998; 338(10):640–644. 248. Soborg C, Andersen AB, Madsen HO, et al. Natural resistance-associated macrophage protein 1 polymorphisms are associated with microscopy-positive tuberculosis. J Infect Dis 2002; 186(4):517–521. 249. Greenwood CM, Fujiwara TM, Boothroyd LJ, et al. Linkage of tuberculosis to chromosome 2q35 loci, including NRAMP1, in a large aboriginal Canadian family. Am J Hum Genet 2000; 67(2):405–416. 250. Stein CM, Guwatudde D, Nakakeeto M, et al. Heritability analysis of cytokines as intermediate phenotypes of tuberculosis. J Infect Dis 2003; 187(11):1679–1685. 251. Fenhalls G, Stevens L, Moses L, et al. In situ detection of Mycobacterium tuberculosis transcripts in human lung granulomas reveals differential gene expression in necrotic lesions. Infect Immun 2002; 70(11):6330–6338. 252. Selvaraj P, Narayanan PR, Reetha AM. Association of functional mutant homozygotes of the mannose binding protein gene with susceptibility to pulmonary tuberculosis in India. Tuberc Lung Dis 1999; 79(4):221–227. 253. El Sahly HM, Reich RA, Dou SJ, et al. The effect of mannose binding lectin gene polymorphisms on susceptibility to tuberculosis in different ethnic groups. Scand J Infect Dis 2004; 36(2):106–108. 254. Fraser DA, Bulat-Kardum L, Knezevic J, et al. Interferon-gamma receptor-1 gene polymorphism in tuberculosis patients from Croatia. Scand J Immunol 2003; 57(5):480–484. 255. Ogus AC, Yoldas B, Ozdemir T, et al. The Arg753GLn polymorphism of the human toll-like receptor 2 gene in tuberculosis disease. Eur Respir J 2004; 23(2):219–223. 256. Ben Ali M, Barbouche MR, Bousnina S, et al. Toll-like receptor 2 Arg677Trp polymorphism is associated with susceptibility to tuberculosis in Tunisian patients. Clin Diagn Lab Immunol 2004; 11(3):625–626. 257. Bornman L, Campbell SJ, Fielding K, et al. Vitamin D receptor polymorphisms and susceptibility to tuberculosis in West Africa: a case-control and family study. J Infect Dis 2004; 190(9):1631–1641. 258. Wilkinson RJ, Llewelyn M, Toossi Z, et al. Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis among Gujarati Asians in west London: a case-control study. Lancet 2000; 355(9204):618–621. 259. Bellamy R, Ruwende C, Corrah T, et al. Tuberculosis and chronic hepatitis B virus infection in Africans and variation in the vitamin D receptor gene. J Infect Dis 1999; 179(3):721–724. 260. Wilkinson RJ, Patel P, Llewelyn M, et al. Influence of polymorphism in the genes for the interleukin (IL)-1 receptor antagonist and IL-1beta on tuberculosis. J Exp Med 1999; 189(12):1863–1874. 261. Bellamy R, Ruwende C, Corrah T, et al. Assessment of the interleukin 1 gene cluster and other candidate gene polymorphisms in host susceptibility to tuberculosis. Tuberc Lung Dis 1998; 79(2):83–89.

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262. de Jong R, Altare F, Haagen IA, et al. Severe mycobacterial and Salmonella infections in interleukin-12 receptor-deficient patients. Science 1998; 280(5368): 1435–1438. 263. Altare F, Lammas D, Revy P, et al. Inherited interleukin 12 deficiency in a child with bacille Calmette-Guerin and Salmonella enteritidis disseminated infection. J Clin Invest 1998; 102(12):2035–2040. 264. Altare F, Durandy A, Lammas D, et al. Impairment of mycobacterial immunity in human interleukin-12 receptor deficiency. Science 1998; 280(5368):1432–1435. 265. Caragol I, Raspall M, Fieschi C, et al. Clinical tuberculosis in 2 of 3 siblings with interleukin-12 receptor beta1 deficiency. Clin Infect Dis 2003; 37(2):302–306. 266. Dorman SE, Holland SM. Interferon-gamma and interleukin-12 pathway defects and human disease. Cytokine Growth Factor Rev 2000; 11(4):321–333. 267. Jouanguy E, Altare F, Lamhamedi S, et al. Interferon-gamma-receptor deficiency in an infant with fatal bacille Calmette-Guerin infection. N Engl J Med 1996; 335(26):1956–1961. 268. Jouanguy E, Lamhamedi-Cherradi S, Lammas D, et al. A human IFNGR1 small deletion hotspot associated with dominant susceptibility to mycobacterial infection. Nat Genet 1999; 21(4):370–378. 269. Newport MJ, Huxley CM, Huston S, et al. A mutation in the interferon-gammareceptor gene and susceptibility to mycobacterial infection. N Engl J Med 1996; 335(26):1941–1949. 270. Altare F, Jouanguy E, Lamhamedi-Cherradi S, et al. A causative relationship between mutant IFNgR1 alleles and impaired cellular response to IFNgamma in a compound heterozygous child. Am J Hum Genet 1998; 62(3):723–726. 271. Holland SM, Dorman SE, Kwon A, et al. Abnormal regulation of interferon-gamma, interleukin-12, and tumor necrosis factor-alpha in human interferon-gamma receptor 1 deficiency. J Infect Dis 1998; 178(4):1095–1104. 272. Altare F, Ensser A, Breiman A, et al. Interleukin-12 receptor beta1 deficiency in a patient with abdominal tuberculosis. J Infect Dis 2001; 184(2):231–236. 273. Picard C, Fieschi C, Altare F, et al. Inherited interleukin-12 deficiency: IL12B genotype and clinical phenotype of 13 patients from six kindreds. Am J Hum Genet 2002; 70(2):336–348.

SECTION II: CLINICAL TUBERCULOSIS

7 Diagnosis of Pulmonary and Extrapulmonary Tuberculosis

PHUNG K. LAM and ANTONINO CATANZARO Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, San Diego, School of Medicine, UCSD Medical Center, San Diego, California, U.S.A.

PHILIP A. LOBUE Division of Tuberculosis Elimination, Field Services and Evaluation Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, U.S.A.

SHARON PERRY Division of Geographic Medicine and Infectious Diseases, Stanford University School of Medicine, Stanford, California, U.S.A.

I. Introduction The diagnosis of active tuberculosis is, and will always be, a clinical exercise. No single diagnostic test for tuberculosis exists that can be performed rapidly, simply, inexpensively, and accurately as a stand-alone test. In resource-limited countries, heavy dependence on the rapid but inaccurate acid-fast bacille (AFB) smear can lead to the consequence of underdiagnosis of tuberculosis. In affluent countries, the availability of a variety of conventional methods (e.g., chest radiographs, smear and culture examinations) may result overall in overdiagnosis of tuberculosis (1). Recently, approval of rapid and more accurate nucleic acid amplification (NAA) assays by the U.S. Food and Drug Administration (FDA) promises improvement in the rapid diagnosis of tuberculosis, but the cost of implementing this technology currently limits widespread use. Another technology, immune-based serologic assays, can be performed rapidly, simply, and inexpensively; however, low diagnostic accuracy 155

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has been a limitation. Because of the limitations of laboratory-based diagnostic methods, assessment of clinical suspicion of tuberculosis (CSTB) remains the cornerstone of tuberculosis diagnosis. Suspicion of tuberculosis drives the initiation and scope of diagnostic inquiries, and the suspicion of active tuberculosis drives the decision to treat. The influence of clinical suspicion varies in degree from great impact when reliability of a test is low to minimal impact when reliability is high, but it always plays some role in the diagnostic process. II. Medical History and Physical Examination The goal of the history taking and physical examination is to recognize individuals in whom the diagnosis of tuberculosis should be pursued further. Risk-factor assessment is a critical first step in the diagnostic process. Because tuberculosis is spread from person to person, any individual with close contact with a patient with pulmonary tuberculosis is potentially at risk. Socioeconomic factors associated with tuberculosis include racial/ ethnic minority status, immigration from a high-incidence country, low income, homelessness, residence in a congregate living facility (e.g., nursing home and correctional facility), and occupation (2–8). Predisposing medical conditions include HIV infection, diabetes mellitus, malignancy, organ transplantation, renal failure/dialysis, malnutrition, and silicosis (9–11). Tuberculosis is generally insidious at onset; symptoms may be minimal or absent until the disease advances. With pulmonary tuberculosis, the cardinal symptoms are cough, fever, sweats or chills, anorexia, weight loss, and malaise (12,13). Persistent cough, which may be dry or productive, is the most common symptom (14,15). Hemoptysis is usually seen with advanced illness (16). Dyspnea is more likely to occur with pleural involvement (effusion), but with extensive parenchymal or miliary disease, frank respiratory failure may ensue (17). Chest pain often results from involvement of the pleura or adjacent parenchyma (16). Individual symptoms and combinations of symptoms lack both sensitivity and specificity for diagnosis. Cough, the most sensitive symptomatic indicator of active disease, is described in 40% to 80% of patients with pulmonary tuberculosis, whereas fever and weight loss generally occur in less than half and hemoptysis is found in less than one-quarter (12,13,18). In one study, having three of the following four symptoms—cough for greater than 21 days, chest pain for greater than 15 days, absence of expectoration, and absence of dyspnea—was reported to have a sensitivity of 86%, but a specificity of only 49% (15). Similarly, physical examination findings are both insensitive and nonspecific for diagnosing pulmonary tuberculosis (14). Routine laboratory tests are typically normal except in patients with advanced disease (13). The most common hematologic abnormalities are mild anemia and leukocytosis (12,19). Hyponatremia and hypercalcemia have also been observed (20,21). III. The Tuberculin Skin Test Overall, 75% to 90% of patients with active tuberculosis react to tuberculin injection (22). Certain groups, such as those with suppressed cellular

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immunity including patients with HIV infection, may have rates of falsenegative Tuberculin Skin Test (TST) results exceeding 50% (22,23). False-positive results also occur. Causes include errors in administering and interpreting the TST, prior vaccination with bacille Calmette–Gue´rin (BCG), and prior infection with nontuberculous mycobacteria (NTM) (22). Nevertheless, tuberculin skin testing should be performed on all patients with suspected tuberculosis. A positive TST result provides epidemiologic data in support of the diagnosis of tuberculosis when other evidence is suggestive. IV. Interferon Release Assays Immune response to tuberculosis infection is known to be associated with a strong Th1 inflammatory response, a hallmark of which is release of the cytokine interferon-gamma (IFN-c) by CD4 cells. Two techniques have been developed to measure IFN-c in blood cells in response to Mycobacterium tuberculosis-specific antigens. QuantiFERON1 (Cellestis Ltd., Melbourne, Australia) uses enzyme-linked immunosorbent assays (ELISA) to measure the amount of IFN-c released in response to in vitro stimulation of whole blood with M. tuberculosis antigens. T-SPOT (Oxford Immunotec, Oxford, U.K.) uses enzyme-linked immunospot (ELISPOT) to count the number of IFN-c–producing cells on precoated plates. Both techniques are adaptable to use with a variety of M. tuberculosis antigens, including more highly specific recombinants such as CFP 10 and ESAT 6, which are encoded from the RD1 region of the M. tuberculosis genome. Because this genomic region is not present in any strains of BCG or the most common environmental mycobacteria such as Mycobacterium avium intracellulare, specificity is increased compared to the TST (24). QuantiFERON Gold is approved by the FDA as a test for M. tuberculosis infection (including disease) and can be used in conjunction with risk assessment, radiography, and other medical and diagnostic evaluations (25). In a recent study of QuantiFERON Gold in Japan, investigators reported a sensitivity of 89.0% in 118 culture-confirmed tuberculosis patients with less than one week of treatment and a specificity of 98.1% in 216 BCG-vaccinated subjects at low risk for tuberculosis (26). QuantiFERON Gold has not been evaluated in patients previously treated for tuberculosis infection or disease, in individuals with HIV infection, or in children. As with the TST, QuantiFERON Gold is helpful but insufficient for diagnosing M. tuberculosis complex infection in sick patients: a positive result can support the diagnosis of tuberculosis disease; however, infections by other mycobacteria (e.g., Mycobacterium kansasii) could also cause positive results (25). Other medical and diagnostic evaluations are necessary to confirm or exclude tuberculosis disease. T-SPOT-TB is undergoing clinical trials, but is not currently approved by the FDA. Practical advantages of both QuantiFERON Gold and T-SPOT-TB compared to the TST are that they require a single visit, eliminate observer variability, and do not influence results of future tests.

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The whole blood assay requires less blood and is technically much less demanding. However, the application of these tests in clinical practice is evolving as additional studies are in progress. Insights provided by these new tools are likely to further our understanding of the natural history of infection and improve tuberculosis control. V. Chest Radiography Primary tuberculosis refers to the initial pulmonary infection resulting from inhalation of M. tuberculosis-containing droplets. The chest radiograph in primary tuberculosis is usually normal. Alternatively, it may show a small area of nonspecific pneumonitis (usually indistinguishable from bacterial pneumonia), or hilar or paratracheal lymphadenopathy (14,27,28). Enlargement of hilar or mediastinal lymph nodes occurs in up to 43% of adults and 96% of children with primary tuberculosis (27,29). Healed parenchymal lesions appear on chest radiograph as calcified nodules (tuberculomas) and are often associated with calcified hilar lymph nodes. In a small percentage of individuals, the initial infection progresses and can manifest as (i) a pleural effusion (<10% of patients); (ii) extensive pneumonia; or (iii) enlargement of tuberculous lymph nodes causing bronchial obstruction (collapse-consolidation lesion, most common in children less than two years old) (27,28). Most of these findings resolve without treatment making the diagnosis elusive. Miliary or disseminated tuberculosis, which makes up 1% to 7% of all forms of tuberculosis, may also occur as a manifestation of primary tuberculosis (27,30). Reactivation pulmonary tuberculosis characteristically presents as an infiltrate in the apical or posterior segments of the upper lobes (27,28). Isolated infiltrates in the anterior segment of the upper lobe or basilar segments of the lower lobe are unusual and are more likely to be seen in combination with disease in the other commonly involved areas listed above (31). The infiltrate may appear as an ill-defined alveolar-filling process (exudative lesion) or may be fibronodular in appearance, although it usually (in about 80% of patients) presents as a combination of both (27). Cavity formation is seen in about 50% of patients, and fibrosis with volume loss occurs in about 30% (27,30). Bronchial stenosis and bronchiectasis are two other relatively common manifestations of reactivation tuberculosis. These findings are often easier to see on chest computed tomography (CT) scanning than plain films (27). Rapid progression of pulmonary disease with severe ventilation-perfusion disturbances presenting as the adult respiratory distress syndrome is also seen in rare instances (32). The radiographic appearance of pulmonary tuberculosis in HIVinfected patients is often ‘‘atypical.’’ It most commonly resembles that of primary disease, i.e., hilar and mediastinal adenopathy with or without noncavitating parenchymal infiltrates (33,34). Miliary disease has been reported to occur in up to 19% of HIV-infected patients, and pleural effusions are seen in approximately 10% (33,34). Chest radiographs may be normal in

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12% to 14% of HIV-infected patients with pulmonary tuberculosis confirmed by a positive sputum AFB smear or culture (33,34). Where there is significant clinical suspicion and plain film findings are ambiguous, CT may provide useful diagnostic information. CT has been shown to be more sensitive than plain films for detecting cavities, intrathoracic lymphadenopathy, miliary disease, bronchiectasis, bronchial stenosis, and pleural disease (27,35). At present, magnetic resonance imaging of the chest does not appear to have a role in the diagnosis of tuberculosis (35). VI. Respiratory Specimen Sampling: AFB Smear and Culture If pulmonary tuberculosis is suspected based on clinical or radiographic evaluation, the next step should be examination of the sputum for mycobacteria. For patients with a productive cough, collection of an early morning, freshly expectorated specimen is recommended (14,36). For patients unable to produce sputum, induction of sputum production via inhalation of nebulized hypertonic saline should be considered (37). Standard practice is to obtain at least three sputum specimens, collected 8 to 24 hours apart (38). If it is not possible to collect a sputum sample, even with induction, lavage of gastric secretions to collect aspirated tuberculosis organisms may be entertained, although this technique has been used primarily in children. Alternatively, bronchoscopy with lavage, brushings, transbronchial biopsy, or needle aspiration may be considered. Bronchoscopic sampling can enhance both the speed and the likelihood of making a diagnosis for an individual patient (39,40). However, recent systematic studies have not found bronchoscopy to provide an aggregate diagnostic yield superior to aerosol-induced sputum sampling (41). Direct microscopic examination of sputum for AFB is inexpensive, rapid, and easy to perform. Compared to mycobacterial culture, the sensitivity of a single sputum AFB smear is 30% to 40%, but increases to 65% to 80% with multiple specimens (42,43). The smear is more likely to be positive if disease is extensive (multilobar infiltrates or cavities) (44). Because direct microscopy cannot distinguish between M. tuberculosis and NTM, specificity is a concern. The prevalence of NTM in the environment and disease due to NTM varies widely according to geographic location and patient population. Due to the prevalence of tuberculosis in the population tested, many published studies have shown that the AFB smear continues to have a high specificity (>90%) and positive predictive value (70–90%), even in HIVinfected populations where the incidence of NTM may be high (18,45–47). Mycobacterial culture is more sensitive and specific for the diagnosis of tuberculosis than AFB smear. Using final clinical diagnosis of pulmonary tuberculosis as the standard, the sensitivity of sputum culture is greater than 80% (44,45). Mainly due to laboratory contamination of the specimen at the bedside or in the laboratory, false positives also occur with culture. Nevertheless, the specificity of culture has been reported to be as high as 98% (45).

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The major limitation of culture is the delay in obtaining results. Even while using newer liquid-based systems (BACTEC-460 or BACTEC MGIT960, Becton Dickinson, Sparks, MD), detection and identification of M. tuberculosis requires an average of two weeks (48). VII. Culture-Negative Pulmonary Tuberculosis A diagnosis of tuberculosis can be made in the absence of a positive culture. The combination of a reactive TST and a chest radiograph consistent with tuberculosis often leads a physician to begin antituberculous therapy even in the absence of a positive AFB smear. A subsequent clinical or radiographic response to multidrug therapy over an appropriate time course (one to three months) is considered sufficient to confirm the diagnosis of tuberculosis in culture-negative cases (16,49). VIII. Extrapulmonary Tuberculosis Extrapulmonary tuberculosis is seen in only about 15% of cases of immunocompetent individuals, but is found in up to 70% of patients with advanced HIV (10,50,51). The most common sites of extrapulmonary tuberculosis are peripheral lymph nodes, the pleura, the bones and joints, the genitourinary system, peritoneum, gastrointestinal tract, and the central nervous system (CNS) (50,51). In the presence of concurrent documented active pulmonary tuberculosis, a compatible clinical or radiographic presentation is usually sufficient to make the diagnosis of tuberculosis at an extrapulmonary site. Especially in immunocompromised individuals, however, disease at an extrapulmonary site may be the result of a second process (e.g., an HIV-infected patient with pulmonary tuberculosis and CNS toxoplasmosis). In these situations, if there is deterioration or failure to respond to tuberculosis therapy at the extrapulmonary site, additional diagnostic evaluation should be made. When disease is isolated to an extrapulmonary site, collection of excretions (urine or stool), aspiration of fluid (e.g., pleural fluid, ascites, cerebral spinal fluid), or tissue biopsy for AFB smear, culture, and histology may be necessary for diagnosis (50,52,53). In addition, for suspected pleural disease, high levels of adenosine deaminase and interferon-c in the pleural fluid have been associated with pleural tuberculosis in numerous studies (54,55). These tests should be considered if available; however, their sensitivity and specificity have not been fully evaluated in low-incidence populations. IX. Clinical Use of Diagnostic Tests: Comparing Sensitivity and Specificity to PPV and NPV Diagnostic accuracy is conveyed through four basic measures, as calculated in Table 1. The quality of a diagnostic test is evaluated by comparison to a gold standard, which is used to designate ‘‘true’’ tuberculosis status, preferably by both culture examination and response to antituberculosis therapy.

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Table 1 Calculations for Sensitivity, Specificity, and Positive and Negative Predictive Values Sensitivity Specificity PPV NPV

TP Tot TB TN Tot No TB TP Tot Testþ TN Tot Test


Note:

Test þ Test
Total

TB

No TB

Total

TP FN Tot TB

FP TN Tot no TB

Tot test þ Tot test
Grand tot

Abbreviations: PPV, positive predictive value; NPV, negative predictive value; TP, true positive; FN, false negative; FP, false positive; TN, true negative; Tot, total.

Sensitivity and specificity values describe the operating characteristics of a diagnostic test by measuring the ability of the test to correctly identify known tuberculosis and nontuberculosis cases, respectively. However for individual patients in the clinical setting, positive predictive value (PPV) and negative predictive value (NPV) are more useful. Given a positive test, the PPV indicates the likelihood that a patient actually has tuberculosis; given a negative test, the NPV indicates the likelihood that a patient actually does not have tuberculosis. PPV and NPV depend on disease prevalence in the patient population of interest. Figure 1 shows a hypothetical scenario where the same diagnostic test (i.e., with the same sensitivity and specificity) is used to diagnose tuberculosis in patient groups with low, intermediate, and high levels of clinical suspicion. In groups with higher clinical suspicion, higher prevalence of tuberculosis leads to higher PPVs but lower NPVs. Therefore, given a test result for an individual patient, clinicians must have a sense of the patient’s risk level based on characteristics of the patient pool and the individual before they can assess the likelihood that the patient has or does not have active tuberculosis. X. Using Newer Diagnostic Tests: Incorporating Clinical Suspicion of Tuberculosis A critical component of the diagnosis of tuberculosis is taking into account risks factors associated with individual patients and their settings. There are many presentations of tuberculosis; traditional and new diagnostic tests may perform better for some presentations than others. Clinical assessment

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100

Percent

80

PPV NPV

60 40 20 0 Low (prevalence = 5%)

Intermediate (prevalence = 30%)

High (prevalence = 90%)

Level of Clinical Suspicion of TB Figure 1 Positive and negative predictive values at varying tuberculosis prevalence, using a diagnostic test with sensitivity 70% and specificity 90%. Abbreviations: PPV, positive predictive value; NPV, negative predictive value.

can help to identify clusters, or subsets, of patients where a particular test can be most useful. Results from tests that are well suited for a given patient group or setting can be weighted more heavily in the diagnostic process, but clinical judgment founded on complete assessment of all aspects of a case is vital in the decision-making process. At the University of California in San Diego, we have developed the CSTB instrument to facilitate assessment of a patient’s likelihood of having active tuberculosis by helping clinicians to systematically document and follow the diagnostic process (18). Based on targeted testing recommendations of the Centers for Disease Control and Prevention (CDC), this tool extracts patient information pertinent for tuberculosis diagnosis from various epidemiologic, clinical, radiographic, and bacteriologic investigations, as discussed in the previous sections of this chapter and outlined in Table 2. Epidemiologic factors, including patient demographics and social history, are increasingly becoming an important part of shaping CSTB. Given the same symptom complex, patients identified by these factors to be at high risk of M. tuberculosis infection are more likely to have active tuberculosis than those who are identified as at low risk. The CSTB instrument assists clinicians in maintaining an active role in tuberculosis diagnosis by keeping patient information accessible and allowing them to quantify and track their suspicion of tuberculosis through the multiple stages of the diagnostic inquiry. Estimation of clinical suspicion is determined by answering the question ‘‘What do you think is the likelihood that, when all the information is available, this patient will have been proven to have active tuberculosis?’’ The CSTB scale ranges from 1 (lowest suspicion) to 99 (highest suspicion),

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Table 2 Key Factors Impacting Clinical Suspicion and Diagnosis of Active Pulmonary Tuberculosis Epidemiologic factors

Clinical findings

Demographics Country of birth Recent immigration from country with high TB incidence Ethnicity and race Social history Homelessness or homeless shelter Prison/jail in the past 2 yr Lifestyle factors Excessive alcohol use Tobacco use Poor nutrition Recreational drug use or participation in a drug rehabilitation program Men having sex with men Having multiple partners History of TB and other mycobacteria Exposure to TB in family, at work, or with acquaintances Previous treatment for active TB, with or without DOT History of TST and treatment for latent infection History of BCG vaccination History of nontuberculous mycobacterial infection

Symptoms for more than 3 wk Cough Hemoptysis Fever Night sweats Weight loss Enlarged lymph nodes Comorbidity HIV status, viral load, CD4 cell count Diabetes mellitus Organ transplant Silicosis Immunosuppressive disease (e.g., malignancy of any type and chronic renal failure) or medications (e.g., steroids, anti-TNF preparations, or other immunosuppressive agents) Abnormalities from physical examination Rales, wheezes, pleural changes Lymphadenopathy or splenomegaly Abnormal chest X ray Cavity Fibronodular changes Adenopathy Fibrosis Infiltration Bronchiectasis

Bacteriologic

Other findings

AFB smear results NAA test results Culture results

Diagnosis other than TB Pneumonia Bronchitis Cancer Histoplasmosis Coccidioidomycosis Response to treatment Symptoms cleared or improved Weight gain Chest X ray cleared or improved Microbiology conversion

Abbreviations: TNF, tumor necrosis factor; DOT, directly observed therapy; TST, tuberculin skin test; BCG, bacille Calmette–Gue´rin; AFB, acid-fast bacille; NAA, nucleic acid amplification.

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allowing latitude to change values when additional information becomes available. The CSTB value can help to classify patients into three general risk groups: low, intermediate, and high risk of active tuberculosis. Armed with a sense of a patient’s risk, the clinician can more easily interpret results of newer diagnostic tests such as the NAA assays (18) to make a presumptive diagnosis of tuberculosis prior to the completion of a case investigation. Our experience, supported by the results of a clinical trial, suggests this approach is very useful, although it has not been independently validated. XI. Newer Diagnostic Tests: NAA Assays With advances in molecular biology, polymerase chain reaction (PCR)based tests for diagnosis of tuberculosis first became available in the 1990s (56,57). These tests are based on amplification of target genomic sequence DNA or RNA that can then be detected with a nucleic acid probe. The method enables detection of as few as 1 to 10 bacilli in clinical specimens such as sputum and other fluids. Relative to smear examination, which requires a relatively large bacilli load (104/mL) and also identifies other acid-fast bacteria, the approach has promised to significantly enhance the sensitivity and specificity of laboratory diagnosis (58). In addition, the tests can be performed within 24 hours, making them attractive compared to culture for rapid diagnosis (59). Because PCR-based amplification detects dead as well as live organism sequences, the technology is theoretically most useful for initial diagnosis and not treatment follow-up (42). The basic technical requirements of these tests are now available to most clinical research laboratories in the industrialized world. In addition, a number of commercial kits have been developed, principal among them are the Gen-Probe Amplified M. tuberculosis Direct Test [AMTDII] (60– 68), the Roche Amplicor COBAS PCR test (69–73), the Abbott LCx ligase chain reaction assay (74–77), and more recently the Becton-Dickinson ProbeTec ET strand displacement system (78–80). The first two of these assays have been approved by the FDA for use in the diagnosis of pulmonary disease (81); the Gen-Probe format is currently the only one approved for use in diagnosis of AFB smear-negative as well as AFB smear-positive patients (58,81). Although none of these products are approved in the United States for use in other clinical specimens, including in the diagnosis of extrapulmonary disease, there is much interest in their potential for these applications, and the literature offers a number of studies about performance in these specimens (77,82–88). In laboratory trials, sensitivity in respiratory specimens has ranged from 50% to 95%, and specificity has ranged from 95% to 100% (42). Sensitivity is consistently highest in AFB smear-positive specimens, and lowest in specimens from smear-negative (89,90) and/or HIV-positive patients (10,91,92), whereas specificities are always very high. Similarly, sensitivity is lower in other specimens, such as gastric fluid (93,94), blood (95–100), CSF (101–104), urine (105,106), and most particularly pleural fluid

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(103,107–109), although specificity again remains high. However, compared to smear and culture, results in some studies have been encouraging for assistance with diagnosis in children (93,110), tuberculosis meningitis (101,103,111), or paucibacillary disease (112). Variability in the sensitivity of the NAAs has decreased in more recent trials. In addition to technical improvements, such as refinement of genomic targeting technology, use of inhibition assays and improvements in specimen preparation or volume requirements (113,114), refinements in calibration of output (60,64,115,116) have also improved discrimination. Perhaps the most important reason for reduced variability has been the recognition of study design requirements for technology assessment (18,117). This has resulted in better attention to patient selection for study, in particular the selection of patients on the basis of clinical judgment rather than laboratory specimen availability (118–121). Because laboratory studies do not provide the predictive values, including pretest probabilities, that tuberculosis clinicians work with in deciding diagnostic strategies (120,122), performance characteristics in AFB smear-positive and smearnegative groups can be insufficient, in as much as clinicians tend not to rely on any single criterion in their diagnostic assessments (112,123). In an important study (18), PPV of the NAA was 100% in patients classified by physicians as intermediate or high suspicion prior to any laboratory testing versus 30% (intermediate) and 94% (high) by AFB smear. Conversely, NPVs were 99% and 91% in patients considered by physicians to be of low or intermediate suspicion, versus 96% and 71% by smear examination. In this study, the intermediate suspicion group was highly heterogeneous, containing many HIV-positive and other atypical patients, thus emphasizing the importance of individualized clinical risk assessments in the evaluation of laboratory tests. Head-to-head comparisons of commercial products have not revealed great differences in accuracy or turnaround times (113,124–129), although laboratories may have workflow preferences. As with all PCR-based technologies, cross-contamination within the laboratory can result in amplification of contaminated product and false-positive results (130–132). However, the basic technology has improved considerably in the past decade, and most commercial applications are designed to detect and minimize these errors. The U.S. CDC is currently conducting an NAA evaluation program to monitor laboratory protocols for operating PCR-based amplification systems in diagnosis of tuberculosis (133). Compared to smear and culture, the commercial tests are relatively expensive. Laboratories operating in low-incidence areas may find the kits, which require an accumulation of test specimens, difficult to use cost-effectively (134–136). Conversely, in spite of greater usage potential, laboratories operating in low-income countries may find the costs of commercial products prohibitive (137,138). At the present time, the U.S. CDC and American Thoracic Society have adopted a cautiously optimistic attitude toward the NAAs, recommending their use as a confirmatory test when there is clinical suspicion

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of pulmonary disease based on other evaluations including physical, smear, radiographic, and epidemiologic assessments (42,81). Some questions remain regarding the cost-effectiveness of the tests, and their clinical utility, including their clinical utility for diagnosis in immunocompromised patients as well as in patients with extrapulmonary disease. However, the introduction of clinical suspicion standards has dramatically shifted the focus of NAA evaluation trials, with the promise of yielding more strategic information about clinical utility and cost-effectiveness in different settings and patient populations. XII. A Proposed Diagnostic Algorithm for the Diagnosis of TB Using Clinical Suspicion of TB with NAA Testing The first step is to collect the information discussed above and to determine the CSTB by answering the question: ‘‘What is the likelihood that at the conclusion of the evaluation, this patient will be determined to have active tuberculosis?’’ Expressed as a percentage, the risk can be identified approximately as being low (1–24%), intermediate (25–75%), or high (76–99%). This information will be used to help determine the number of specimens needed, and to help with interpretation of the NAA and AFB smear results for the rapid diagnosis of pulmonary tuberculosis. In all risk groups of tuberculosis suspects (high, low, and intermediate), the collection of two consecutive first-morning sputum examinations should be requested. If the patient cannot produce an adequate specimen, aerosol-induced sputum examinations are required. In each case, the first test on all specimens should be an NAA, such as the mycobacterium tuberculosis direct (MTD) assay, keeping in mind that the MTD is the only NAA test that is approved for both AFB smear-negative and smear-positive samples. An AFB smear should be done as a follow-up each time the MTD is positive to determine the degree of infectiousness. Due to the importance of mycobacterial tests in establishing the specific diagnosis of tuberculosis in cases with nonspecific symptoms, there is a tendency to believe that tuberculosis can be or should be diagnosed primarily or exclusively by examination of the microbiological data. The problem with this approach is that there is a small but definite incidence of falsepositive test results and a more substantial incidence of false-negative laboratory results, including those obtained through the use of NAA and culture. False-positive results occur randomly with regard to the clinical presentation. Because there are many more tuberculosis suspects who have low or intermediate CSTB, the false-positive results are more likely to be seen in these patients. The scheme described below requires that positives in this group be confirmed. Occasionally, false positives will occur in the high-CSTB cases as well. The harm done in this group by diagnosing a few extra cases of tuberculosis is minimal. These patients in general need treatment for latent tuberculosis infection (LTBI), and the treatment for active tuberculosis will be a step toward treatment of LTBI. Currently

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CDC guidelines recommend (and most laboratories agree) that NAA should be performed on all AFB smear-positive respiratory specimens; a positive NAA of an AFB smear-positive respiratory sample is diagnostic of tuberculosis. However, these guidelines are being revised and the final recommendations have not been determined. In the interim, one possible approach to testing respiratory samples for tuberculosis is discussed in the following sections. A. Testing on the First Specimen

The first specimen should be examined by MTD because only the MTD is FDA approved for AFB smear-positive and smear-negative sputum. If the MTD is positive, an AFB smear is performed. The CSTB determines the interpretation of the test results at this point. If the CSTB is intermediate or high, and the first specimen is both MTD positive and AFB smearpositive, the patient can be presumed to have tuberculosis and treated accordingly. A contact investigation should be conducted to identify contacts that have been infected and need to be treated. If the CSTB is intermediate or high, and the first specimen is MTD-positive and AFB smear-negative, the patient may be presumed to have active tuberculosis and treated accordingly; however, the contact investigation should be limited to close contacts. If the CSTB is low or if the first sputum MTD is negative, making a conclusion should be delayed until the results of further testing are available. B. Testing on the Second Specimen

The second specimen should also be examined by MTD because only the MTD is FDA approved for both AFB smear-positive and smear-negative sputum. If the MTD is positive, an AFB smear examination should be performed. Again, interpretation of test results depends on the CSTB. If the CSTB is intermediate or high and the second specimen is MTD positive (whether the first specimen was MTD positive or negative), the patient can be presumed to have tuberculosis and treated accordingly. If either specimen is AFB smear-positive, a contact investigation should be conducted to identify contacts that have been infected and need to be treated. If the CSTB is low and the second specimen is MTD positive but the first specimen was MTD negative, a third specimen should be examined. If the CSTB is low and the first and second specimens are MTD negative, tuberculosis can be considered excluded and the patient should have appropriate nontuberculosis diagnostic tests. C. Testing on the Third Specimen

A third sputum examination is really only needed when results are discordant between the CSTB and sputum results. In conclusion, one specimen may be sufficient to make a diagnosis if the CSTB is high or intermediate, and the MTD and AFB smears are positive. In most situations, two specimens are needed. Two positive MTDs make a diagnosis regardless of CSTB. Two negative MTDs are sufficient to rule out

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tuberculosis if the CSTB is low. AFB smears should only be performed on specimens that are MTD positive to determine the degree of infectiousness. Although this proposed algorithm has not been directly evaluated in clinical trials, it is based on review of our experience and examination of published clinical and laboratory studies. There are likely to be other algorithms that have potential merit. Whatever algorithm is eventually included in future CDC guidelines, it should be evaluated further with operational studies after implementation.

XIII. Creating New Diagnostic Tests Based on Older Technology: Serodiagnosis by Immunoassays Serodiagnostic tests using various antigens to measure antibodies to M. tuberculosis in serum offer several advantages. A variety of assay techniques (e.g., ELISA) exist, many of which are readily adaptable to regions with high prevalence of tuberculosis and limited resources. Serodiagnosis is potentially useful for early diagnosis of both pulmonary and extrapulmonary tuberculosis (139), even before clinical manifestation of the disease (140). It does not require collection of specimens from the site of disease and is, therefore, especially feasible for tuberculosis diagnosis in patients with extrapulmonary disease and in young children who are usually incapable of providing sputum for AFB smear and culture examination (141,142). There are also several substantial challenges to serodiagnosis of tuberculosis. The most favorable tests use purified proteins of limited species distribution, but host antibody response tends to be directed toward shared mycobacterial antigens (139). Variations in test accuracy appear to be population dependent, influenced by factors such as age, geographic origin, exposure to NTM, stage of disease, and past episodes of tuberculosis (142–145); in addition, immunosuppressed tuberculosis patients such as HIV-positive individuals may test negatively because of their inability to mount an appropriate immune response (143,146). Laboratory scientists have identified many M. tuberculosis-specific antigens with diagnostic potential, several of which have been studied frequently in the clinical context. The first antigen identified was MPT-64, although it remains controversial in tuberculosis diagnosis, particularly because it has been shown to be present in some BCG strains (141). The 38-kDa protein antigen was used in early commercial assays (147) and is considered the ‘‘diagnostic antigen of choice’’ (139). This antigen performed extremely well in Argentina and China, yielding 80% to 90% sensitivity, 84% to 100% specificity, and high predictive values (148,149); however, other studies found low sensitivity, especially in patients who were AFB smear negative or coinfected with HIV (147). In addition, patients with lepromatous leprosy also produce large amounts of antibodies to the 38-kDa antigen (150). Antigen 60 (A60), obtained from purified protein derivatives, is widely used but has produced discrepant results in various populations (143). A60 contains

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large amounts of lipoarabinomannan (LAM) polysaccharide antigen, and this constituent may be responsible for variability in A60 tests. In some populations, ELISA with LAM produced favorable results (151), but this has not been the general experience. Use of another antigen, tuberculosis glycolipid (TBGL), resulted in an increased sensitivity in Japan but different specificity values among patient groups (144). Another potentially useful antigen is 30 kDa, a major protein of mycobacteria. It is a fibronectinbinding protein that may be a major antigen for host recognition of tuberculosis. Although widely distributed among mycobacteria, it appears to have species-restricted epitopes and has performed well in serodiagnosis by ELISA (152,153). Recently, two closely related low-molecular mass proteins—early secreted antigenic target 6 (ESAT-6) and culture filtrate protein 10 (CFP-10)—were identified (141,154). They are readily recognized by host immune cells, and are absent from BCG strains as well as most environmental mycobacterial species (141). They can detect early active tuberculosis and subclinical infection (155,156). The performance of serodiagnostic tests varies among studies depending on (i) cutoff values selected to discriminate positive from negative test results, (ii) target population (e.g., infection with HIV or NTM, or BCG vaccination), and (iii) control groups (e.g., healthy controls or patients with other pulmonary disease). Some antigens are of greater value in AFB smear-positive disease (e.g., 38-kDa antigen), whereas others fare better in smear-negative and culture-positive disease (e.g., 19-kDa antigen) (157). Many studies have compared serodiagnostic tests in known cases of tuberculosis against healthy controls. Their use has been disappointing in clinical practice where true tuberculosis cases must be distinguished from patients suspected of having tuberculosis but who in fact have other conditions. Overall, all studies on serodiagnosis have revealed shortcomings in either sensitivity or specificity. With increasing numbers of tuberculosis antigens identified, combining multiple antigens in polyproteins and mixtures or integrating results from multiple tests has helped to increase diagnostic accuracy in studies of HIV-negative and HIV-positive patients and pulmonary and extrapulmonary tuberculosis. As shown in Table 3 for pulmonary tuberculosis, single-antigen tests with low sensitivity of 47% to 71% can be increased to 76% to 92% (144,147,153) by combining two to five antigens, and singleantigen tests with low specificity of 18% to 59% can be increased to 78% by combining four test results (158). In addition, combinations of ESAT-6 and CFP-10 yielded sensitivity of 73% to 93% (156,159), compared to 60% for each antigen individually (159), and specificity of 77% to 93% (not reported for antigens individually) (156,159). Furthermore, one study (not shown) found that a combination of ESAT-6 and CFP-10 is equally accurate in diagnosis of pulmonary and extrapulmonary tuberculosis in HIV-negative patients, with sensitivity of 77% and specificity of 94% (154). Several companies have developed serodiagnostic kits using multiple antigens (e.g., secreted and heat shock proteins, lipopolysaccharides, or

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Table 3 Studies on Single- and Multiple-Antigen Serodiagnostic Tests in Diagnosis of Pulmonary Tuberculosis

Okuda et al., 2004a Antigen 60 (A60) alone TBGL antigen alone LAM antigen alone A-60 and/or TBGL and/or LAM Houghton et al., 2002b 38 kDa protein alone 38 kDa in fused polyprotein (with four antigens) 38 kDa in fused polyprotein and/or AFB smear Uma Devi et al., 2003c 30 kDa antigen, isotype IgG alone 30 kDa antigen, isotype IgA alone Isotypes IgG and/or IgA Kanaujia et al., 2005d 38 kDa alone LAM alone MPT-64 antigen alone Glu-S alone 38 kDa and LAM and MPT-64 and Glu-S 38 kDa and LAM and MPT-64 and Glu-S with AFB smear van Pinxteren et al., 2000e ESAT-6 alone

a

Sensitivity

Specificity

PPV

NPV

71 70 68 92

91 89 97 84

89 87 96 86

75 74 74 90

47 76

96 97

91 96

68 83

93

Not reported

Not reported

Not reported

65

99

96

86

69

97

90

87

84

97

92

93

100 96 84 74 66

18 50 31 59 78

43 55 43 53 65

100 95 76 78 78

93

76

71

95

60

Not reported Not reported 93

Not reported Not reported 89

Not reported Not reported 81

CFP-10 alone

60

Combined ESAT-6 and CFP-10

73

Sample consisted of HIV-negative subjects only. Results shown for controls with other pulmonary disease (OPD). b Results are shown for HIV-negative subjects and healthy controls. c Results are shown for HIV-positive TB patients and healthy controls. d Sample includes subjects with HIV and nontuberculous mycobacteria infection. Controls had OPD. e Sample includes subjects with bacille Calmette–Gue´rin vaccination. Controls were healthy donors. Abbreviations: ESAT-6, early secreted antigenic target 6; TBGL, tuberculosis glycolipid; LAM, lipoarabinomannan; Glu-S, glutamine synthase; AFB, acid-fast bacille; IgG, immunoglobulin G; IgA, immunoglobulin A; PPV, positive predictive values; NPV, negative predictive values; CFP-10, culture filtrate protein.

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peptides) and methods (i.e., modifications of ELISA or immunochromatographic tests) (160). In a study of HIV-negative subjects, seven test kits individually yielded sensitivity values of 16% to 57% and specificity values of 80% to 97%; all tests performed equally in comparisons between pulmonary and extrapulmonary tuberculosis cases and between AFB smearpositive and smear-negative cases (160). In a study of HIV-positive subjects, eight test kits individually yielded sensitivity values of 0% to 63% and specificity values of 39% to 99% (146). Integrating results from serodiagnostic and other laboratory tests further increases diagnostic accuracy. As shown in Table 3, combining results of multiantigen tests and AFB smear significantly increased sensitivity from 66% to 76% to 93% (147,158), whereas the specificity did not change significantly (from 78–76%) (158). A study on a commercial multiantigen test kit also showed that the sensitivity (55%) can be increased to 72% by combining results from the test kit and AFB smear (161); specificity was not reported. In addition, one study found that combining results of the TBGL test and the Amplicor NAA test improved the sensitivity of the individual tests from 57% and 52%, respectively, to 78% (162); specificity values were not reported. Another study also found that combining results of a serodiagnostic kit and the Amplicor test improved the sensitivity of the individual tests from 38% and 57%, respectively, to 75%; specificity values of 87% and 100%, respectively, changed to 90% (112). Therefore, even with less than optimal diagnostic characteristics as stand-alone tests, serodiagnosis may contribute to rapid, low-cost diagnosis of tuberculosis, especially when combined with multiple antigens or used in conjunction with other laboratory tests. Strategies to help integrate serodiagnosis with CSTB are currently being developed. XIV. Conclusion Technological advancement has led to the development of several new approaches to tuberculosis diagnosis but has not helped to narrow the disparity in tuberculosis diagnostic capabilities between industrialized and developing countries. Use of the rapid and relatively accurate NAA assays has been limited to industrialized countries with well-equipped laboratories and well-trained technicians. Serodiagnosis has promised to be a rapid, simple, and inexpensive approach for developing countries, but well-designed clinical trials and further refinement of diagnostic strategies remain necessary. At the present time, these new tests have not replaced the conventional methods of tuberculosis diagnosis. Serodiagnostic tests may not be able to distinguish active tuberculosis from inactive tuberculosis infection or NTM infections. NAA assays may not be useful for monitoring treatment response. AFB smear remains the most useful method in determining a patient’s level of infectiousness and in evaluating treatment follow-up. In both industrialized and developing countries, the ability of clinicians to integrate laboratory findings and clinical suspicion remains

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88. Woods GL, Bergmann JS, Williams-Bouyer N. Clinical Evaluation of the GenProbe amplified mycobacterium tuberculosis direct test for rapid detection of Mycobacterium tuberculosis in select nonrespiratory specimens. J Clin Microbiol 2001; 39(2):747–749. 89. Lebrun L, Mathieu D, Saulnier C, Nordmann P. Limits of commercial molecular tests for diagnosis of pulmonary tuberculosis. Eur Respir J 1997; 10(8):1874–1876. 90. Sarmiento OL, Weigle KA, Alexander J, Weber DJ, Miller WC. Assessment by meta-analysis of PCR for diagnosis of smear-negative pulmonary tuberculosis. J Clin Microbiol 2003; 41(7):3233–3240. 91. Barnes PF, Lakey DL, Burman WJ. Tuberculosis in patients with HIV infection. Infect Dis Clin North Am 2002; 16(1):107–126. 92. Perry S, Catanzaro A. Use of clinical risk assessments in evaluation of nucleic acid amplification tests for HIV/tuberculosis. Int J Tuberc Lung Dis 2000; 4(2 suppl 1):S34–S40. 93. Delacourt C, Poveda JD, Chureau C, et al. Use of polymerase chain reaction for improved diagnosis of tuberculosis in children. J Pediatr 1995; 126(5 pt 1): 703–709. 94. Pierre C, Olivier C, Lecossier D, Boussougant Y, Yeni P, Hance AJ. Diagnosis of primary tuberculosis in children by amplification and detection of mycobacterial DNA. Am Rev Respir Dis 1993; 147(2):420–424. 95. Condos R, McClune A, Rom WN, Schluger NW. Peripheral-blood-based PCR assay to identify patients with active pulmonary tuberculosis. Lancet 1996; 347(9008):1082–1085. 96. Folgueira L, Delgado R, Palenque E, Aguado JM, Noriega AR. Rapid diagnosis of Mycobacterium tuberculosis bacteremia by PCR. J Clin Microbiol 1996; 34(3): 512–515. 97. Richter C, Kox LF, Van Leeuwen JV, Mtoni I, Kolk AH. PCR detection of mycobacteraemia in tanzanian patients with extrapulmonary tuberculosis. Eur J Clin Microbiol Infect Dis 1996; 15(10):813–817. 98. Ritis K, Tzoanopoulos D, Speletas M, et al. Amplification of IS6110 sequence for detection of Mycobacterium tuberculosis complex in HIV-negative patients with fever of unknown origin (FUO) and evidence of extrapulmonary disease. J Intern Med 2000; 248(5):415–424. 99. Rolfs A, Beige J, Finckh U, et al. Amplification of Mycobacterium tuberculosis from peripheral blood. J Clin Microbiol 1995; 33(12):3312–3314. 100. Schluger NW, Condos R, Lewis S, Rom WN. Amplification of DNA of Mycobacterium tuberculosis from peripheral blood of patients with pulmonary tuberculosis. Lancet 1994; 344(8917):232–233. 101. Hadgu A, Sternberg M. Nucleic acid amplification tests for diagnosis of tuberculous meningitis. Lancet Infect Dis 2004; 4(1):9–10. 102. Kox LF, Kuijper S, Kolk AH. Early diagnosis of tuberculous meningitis by polymerase chain reaction. Neurology 1995; 45(12):2228–2232. 103. Pai M, Flores LL, Pai N, Hubbard A, Riley LW, Colford JM Jr. Diagnostic accuracy of nucleic acid amplification tests for tuberculous meningitis: a systematic review and meta-analysis. Lancet Infect Dis 2003; 3(10):633–643. 104. Pfyffer GE, Kissling P, Jahn EM, Welscher HM, Salfinger M, Weber R. Diagnostic performance of amplified Mycobacterium tuberculosis direct test with cerebrospinal fluid, other nonrespiratory, and respiratory specimens. J Clin Microbiol 1996; 34(4):834–841. 105. Fontana D, Pozzi E, Porpiglia F, et al. Rapid identification of Mycobacterium tuberculosis complex on urine samples by Gen-Probe amplification test. Urol Res 1997; 25(6):391–394.

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8 Treatment of Tuberculosis

PHILIP C. HOPEWELL Division of Pulmonary and Critical Care Medicine, Medical Service, San Francisco General Hospital, Francis J. Curry National Tuberculosis Center, and Department of Medicine, University of California, San Francisco, California, U.S.A.

I. Tuberculosis Treatment as a Public Health Measure Effective chemotherapy for pulmonary tuberculosis is the most important means by which person-to-person transmission of Mycobacterium tuberculosis is prevented; thus, treatment of tuberculosis is not only a matter of individual health but also is an important public health intervention (1). Prompt, accurate diagnosis and effective treatment are the key elements in the public health response to tuberculosis and are the cornerstones of tuberculosis control. Effective treatment not only restores the health of the individual with the disease but also quickly renders the patient noninfectious and no longer a threat to the community. Thus, all providers who undertake treatment of patients with tuberculosis must recognize that not only are they treating an individual, but they are also assuming an important public health function, which entails a high level of responsibility to the community as well as to the individual patient. To discharge this responsibility, clinicians must have a sound understanding of the drugs and treatment regimens used and the ability to ensure that treatment is taken as prescribed.

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Hopewell II. History of Antituberculosis Chemotherapy

Although a number of remedies have been proposed, claimed to be effective, and used for treating tuberculosis for centuries, truly effective treatment for the disease is a relatively recent development (2). Streptomycin, the first effective antituberculosis drug, was introduced into experimental clinical use in 1945 (3). Soon thereafter, it was observed that although there was a striking initial improvement in patients who received streptomycin, they subsequently worsened, and the organisms isolated from these patients were resistant to streptomycin (4). The findings of clinical failure caused by drug-resistant organisms identified the major bacteriologic principle on which successful chemotherapy for tuberculosis depends: wild-strain populations of M. tuberculosis are not uniform in their susceptibility to antimycobacterial agents; thus, it is always necessary to treat with more than one drug to which the organisms are susceptible. The effectiveness of multiple-drug chemotherapy was first demonstrated in a British Medical Research Council study in which streptomycin was given in combination with para-aminosalicylic acid (2,5). Antituberculosis chemotherapy that was both effective and well tolerated became a reality in 1952 with the introduction of isoniazid, an effective, well-tolerated, and cheap drug (6). Again, however, it was found that single-drug treatment with isoniazid was inadequate and that resistance to the agent developed quickly. The combination of isoniazid and para-aminosalicylic acid with or without streptomycin therefore came to be the usual therapy for tuberculosis. Effective therapy using optimum combinations of isoniazid, streptomycin, and para-aminosalicylic acid produced a revolution in the care of patients with tuberculosis (7). Springett (8) reviewed death rates for cohorts of patients in Birmingham, England, for the years 1947, 1950, 1953, 1956, and 1959. There was a dramatic decrease in deaths during the 10 years after diagnosis, associated with the increasing use of chemotherapy. Nearly all of the reduction was accounted for by improvements in survival during the first year after diagnosis. In addition, not only were there many more survivors, but also among the survivors there were many fewer who continued to have persistently positive sputum and, thus, serve as ongoing sources of new infections. In 1967, the effectiveness of ethambutol as a substitute for p-aminosalicylic acid (PAS) was documented (9). Ethambutol was found to be much more tolerable and less toxic as a companion drug for isoniazid than PAS. Subsequently it was demonstrated that the combination of isoniazid and rifampicin, generally with ethambutol or streptomycin, could shorten the necessary duration of treatment from the standard 18 to 24 months to six to nine months (10). Investigators then began to focus on the differential effects of antituberculosis drugs and especially on the potential role of pyrazinamide (11,12). Dickinson et al. (13) demonstrated that streptomycin, rifampicin,

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and isoniazid are quickly bactericidal for rapidly growing M. tuberculosis in vitro. The in vitro conditions could be likened to the in vivo conditions under which the extracellular organisms in tuberculous lesions are living. Although both rifampicin and isoniazid are rapidly bactericidal, Mitchison and Dickinson (14) demonstrated that rifampicin is more effective in killing organisms that grow in spurts rather than continuously. Although both isoniazid and rifampicin are effective in killing intracellular organisms, pyrazinamide is especially effective in this regard, suggesting that the addition of pyrazinamide would strengthen the isoniazid–rifampicin combination. Two studies have substantiated that the addition of pyrazinamide for two months to a regimen of isoniazid and rifampicin does improve the effectiveness of a six-month regimen (15,16). Thus, a core regimen of isoniazid and rifampicin, supplemented by pyrazinamide and ethambutol for the initial two months, is now recommended as a standard treatment for both pulmonary and extrapulmonary tuberculosis (17,18). III. Antituberculosis Drugs As shown in Table 1 (19), 10 drugs are currently approved by the U.S. Food and Drug Administration for treating tuberculosis, plus six other drugs that are effective but not approved for this indication (17). An additional agent, thioacetazone, is available and used in some parts of the world, but is not approved for use in the United States. The table lists the drugs, available preparations, and the recommended doses. A. First-Line Drugs

For a succinct review of the mechanisms of action of current and potential antituberculosis drugs, see Ref. (20). Isoniazid

Isoniazid is a prodrug that requires conversion to its active form by the catalase–peroxidase enzyme system in M. tuberculosis (21,22). Once activated in susceptible organisms, the drug has profound early bactericidal activity, reducing bacillary populations by about two logs within 48 hours. Most strains of M. tuberculosis are inhibited by concentrations of isoniazid of 0.05 to 0.20 mg/mL. It is readily absorbed from the gastrointestinal tract; peak blood concentrations of approximately 5 mg/mL occur one to two hours after administration of a dose of 3 to 5 mg/kg body weight. The serum half-life varies, depending on whether a person is a rapid or slow acetylator; it is two to four hours in slow acetylators and 0.5 to 1.5 hours in rapid acetylators (23). The drug penetrates well into all body fluids and cavities, producing concentrations similar to those found in serum. Isoniazid exerts its effect mainly by inhibiting cell-wall mycolic acid synthesis (20). In any wild-strain population of M. tuberculosis, the frequency of isoniazid-resistant mutants is approximately one in 3.5
106 organisms (24). However, when isoniazid is used alone, a population of organisms resistant to the drug emerges rapidly. This was demonstrated in an early (Text continues on page 190.)

Pyrazinamide: tablet (500 mg, scored)

Rifapentine: tablet (150 mg, film coated)

First-line drugs Isoniazid: tablets (50, 100, 300 mg); elixir (50 mg/5 mL); aqueous solution (100 mg/ mL) for intravenous or intramuscular injection Rifampin: capsule (150, 300 mg); powder may be suspended for oral administration; aqueous solution for intravenous injection Rifabutin: capsule (150 mg)

Drug/preparation

10 mg/kg (600 mg) 10–20 mg/kg (600 mg)

5 mg/kg (300 mg) Appropriate dosing for children is unknown Approved for once/wk in continuation phase600 mg The drug is not approved for use in children 20–30 mg/kg (2.0 g) 15–30 mg/kg (2.0 g)

Adultsc (max.) Children (max.)

Adultsc (max.) Children

Adults (max.) Children (max.)

Children

Adults

5 mg/kg (300 mg) 10–15 mg/kg (300 mg)

Daily

Adults (max.) Children (max.)

Adults/childrena,b

Table 1 Antituberculosis Drugs, Preparations, and Doses

2/wk

40–50 mg/kg (4.0 g) 50 mg/kg (2.0 g)

5 mg/kg (300 mg) Appropriate dosing for children is unknown –

10 mg/kg (600 mg) 10–20 mg/kg (600 mg)

15 mg/kg (900 mg) 20–30 mg/kg (900 mg)

Doses

30–40 mg/kg (3.0 g) 40 mg/kg (2.0 g)

5 mg/kg (300 mg) Appropriate dosing for children is unknown –

10 mg/kg (600 mg) 10–20 mg/kg (600 mg)

10 mg/kg (600 mg) 15–20 mg/kg (600 mg)

3/wk

186 Hopewell

Streptomycin: aqueous solution (1 g vials) for intravenous or intramuscular administration Amikacin: aqueous solution (500 mg and kanamycin 1 g vials) for intravenous or intramuscular administration

Ethionamide: tablet (250 mg)

Adults (max.)

Second-line drugs Cycloserine: capsule (250 mg)

Adults (max.) Children (max.)

Adults (max.) Children (max.)

Children (max.)

Adults (max.)

Children (max.)

Adults (max.) Childrend (max.)

Ethambutol: tablets (100, 400 mg)

g

15–30 mg/kg (1 g)

g

15–30 mg/kg (1 g)

g

15–30 mg/kg/day (1 g) intravenous or intramuscular as a single daily dose

(Continued )

20 mg/kg (1 g)

20 mg/kg (1 g)

20–40 mg/kg/day (1 g)

g

There are no data to support intermittent administration

There are no data to support intermittent administration

–

There are no data to support intermittent administration

25–35 mg/kg (2.4g) 30 mg/kg (2.0 g)

g

There are no data to support intermittent administration

There are no data to support intermittent administration

–

There are no data to support intermittent administration

35–50 mg/kg (4.0 g) 50 mg/kg (2.5 g)

g

10–15 mg/kg/daye (1.0 g in two doses), usually 500–750 mg/day in two doses 10–15 mg/kg/day (1.0 g/day) 15–20 mg/kg/day (1.0 g/day), usually 500–750 mg/day in a single daily dose or two divided dosesf 15–20 mg/kg/day (1.0 g/day)

15–20 mg/kg (1.6 g) 15–20 mg/kg (1.0 g)

Treatment of Tuberculosis 187

Adults (max.) Children (max.)

Capreomycin: aqueous solution (1 g vials) for intravenous or intramuscular administration PAS: granules (4 g packets) can be mixed with food; tablets (500 mg) are still available in some countries, but not in the United States; a solution for intravenous administration is available in Europe Levofloxacin: tablets (250, 500, 750 mg); aqueous solution (500 mg vials) for intravenous injection Children

Adults

Children

Adults

Adults/childrena,b

Drug/preparation

h

500–1000 mg daily

There are no data to support intermittent administration –

There are no data to support intermittent administration –

There are no data to support intermittent administration There are no data to support intermittent administration There are no data to support intermittent administration There are no data to support intermittent administration

8–12 g/day in two or three to four divided doses (10 g)

15–30 mg/kg (1 g)

15–30 mg/kg (1 g)

g

3/wk

15–30 mg/kg/day (1 g) as a single daily dose

2/wk g

Doses

g

Daily

Table 1 Antituberculosis Drugs, Preparations, and Doses (Continued )

188 Hopewell

Children

Children Adults

Adults

h

400 mg daily

h

400 mg daily

There are no data to support intermittent administration – There are no data to support intermittent administration –

There are no data to support intermittent administration – There are no data to support intermittent administration –

b

Dose per weight is based on an ideal body weight. Children weighing more than 40 kg should be dosed as adults. For purposes of this document, adult dosing begins at age 15 years. c Dose may need to be adjusted when there is concomitant use of protease inhibitors or non-nucleoside reverse transcriptase inhibitors. d The drug can likely be safely used in older children but should be used with caution in children <5 years in whom visual acuity cannot be monitored. In younger children, EMB at the dose of 15 mg/kg/day can be used if there is suspected or proven resistance to INH or RIF. e It should be noted that, although this is the dose recommended generally, most clinicians with experience using cycloserine indicate that it is unusual for patients to be able to tolerate this amount. Serum concentration measurements are often useful in determining the optimum dose for a given patient. f The single daily dose can be given at bedtime or with the main meal. g 15 mg/kg/day (1 g), and 10 mg/kg in persons more than 59 years of age (750 mg). Usual dose 750 to 1000 mg intramuscular or intravenous typically given as a single dose five to seven days a week and reduced to two to three times a week after first 2–4 months or after culture conversion, depending on the efficacy of the other drugs in the regimen. h The long-term (more than several weeks) use of fluoroquinolones in children and adolescents has not been approved because of concerns about effects on bone and cartilage growth. However, most experts agree that the drug should be considered for children with tuberculosis caused by organisms resistant to both INH and RIF. The optimal dose is not known. Abbreviations: INH, isoniazid; RIF, rifampian; EMB, ethambutol; PAS, p-aminosalicylic acid. Source: From Ref. 19.

a

Moxifloxacin: tablets (400 mg); aqueous solution (400 mg/ 250 mL) for intravenous injection Gatifloxacin: tablets (400 mg); aqueous solution (200 mg/ 20 mL; 400 mg/40 mL) for intravenous injection

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clinical trial in which 11%, 52%, and 71% of patients to whom isoniazid alone was given developed resistant strains after one, two, and three months of treatment, respectively (25). Hepatitis is the major toxic effect of isoniazid. Asymptomatic aminotransferase elevations up to five times the upper limit of normal occur in 10% to 20% of persons receiving INH alone for treatment of latent tuberculosis infection (26). Recent data indicate that the incidence of clinical hepatitis is lower than was assumed previously. In 11,141 patients managed in an urban tuberculosis control program who were receiving INH alone as treatment for latent tuberculosis infection, hepatitis occurred in only 0.1% to 0.15% (27). A meta-analysis of six studies estimated the rate of clinical hepatitis in patients given INH only to be 0.6% (28). When isoniazid was given in combination with rifampicin, the rate of clinical hepatitis averaged 2.7% in 19 reports. For INH alone, the risk of hepatotoxicity increases with increasing age; it is uncommon among persons under 20 years of age but is nearly 2% in persons aged 50 to 64 years (29). The risk also may be increased in persons with underlying liver disease, in those with a history of heavy alcohol consumption, and, data suggest, in the postpartum period, particularly among Hispanic women (29,30). A large survey estimated the rate of fatal hepatitis to be 0.023%, but more recent studies suggest the rate is substantially lower (27,31,32). The risk may be increased in women. Death has been associated with continued administration of INH despite onset of symptoms of hepatitis (32). Peripheral neuropathy, the second most frequent serious adverse reaction associated with isoniazid, occurs especially with other disorders that may cause neuropathy (HIV infection, diabetes mellitus, uremia, and alcoholism). The neuropathy can nearly always be prevented or reversed by administration of pyridoxine 25 to 50 mg/day. Rifamycins

Of the rifamycins (rifampicin, rifabutin, and rifapentene), rifampicin is by far the most widely used. Like isoniazid, rifampicin is also rapidly bactericidal for M. tuberculosis. It is quickly absorbed from the gastrointestinal tract; serum concentrations of 6 to 7 mg/mL occur 1.5 to 2 hours after ingestion. The halftime in blood is 3 to 3.5 hours, although this may be decreased in persons who have been taking the drug for several weeks (33). The halftime increases with increasing doses of the drug. For sensitive strains of M. tuberculosis, the minimum inhibitory concentration is approximately 0.5 mg/mL, although there is a variation among strains (34). Approximately 75% of the drug is protein-bound, but it penetrates well into tissues and cells. Penetration through noninflamed meninges is poor; however, therapeutic concentrations are achieved in cerebrospinal fluid when the meninges are inflamed (35). Among wild strains of M. tuberculosis, the rate of rifampicin resistance-conferring mutations is approximately 10
1010 per bacterium per generation (24). Rifampicin exerts its effect by binding to the b subunit of

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RNA polymerase (20,36). For this reason, it has activity against many bacteria other than M. tuberculosis. Approximately 96% of rifampicin-resistant strains have mutations in the rpoB gene, the product of which is the b subunit of RNA polymerase (20,36). The mechanism for resistance in the remaining 4% is not known. Resistance to rifampicin, unaccompanied by resistance to other antituberculosis drugs, has been reported to occur almost exclusively among patients with HIV infection, particularly among patients being treated with highly (once or twice weekly) intermittent regimens (37–39). Adverse reactions to rifampicin when it is given daily include rashes, hepatitis, gastrointestinal upset, and, rarely, thrombocytopenia. The rate of these reactions has been variable, but in general is quite low (17). Hepatitis occurred in 3.1% of the patients in the US Public Health Service study of six-month isoniazid–rifampicin treatment (40). Twice weekly administration of higher doses of rifampicin is associated with several immunologically mediated reactions, including thrombocytopenia, an influenza-like syndrome, hemolytic anemia, and acute renal failure (41). Drug–drug interactions due to induction of hepatic microsomal enzymes by rifampicin are relatively common and are of particular concern in patients with HIV infection. The rifamycins interact with the protease inhibitor and non-nucleoside reverse transcriptase inhibitor classes of antiretroviral agents (17). The interaction of these classes of drugs is bidirectional: protease inhibitors decrease clearance of rifamycins, and rifamycins, by inducing hepatic P-450 cytochrome oxidases, accelerate clearance of protease inhibitors (42). Of the rifamycin derivatives, rifabutin has the least effect on the concentration of antiretroviral agents. The practical implications of these interactions on treatment regimens are discussed subsequently. Rifampicin induces the metabolism of a number of other drugs, including methadone, warfarin, oral contraceptives, digoxin, macrolide antibiotics, and ketoconazole (17). [A complete list of interactions with the rifamycins is found in Ref. (17).] Doses of these drugs need to be adjusted when rifampicin is given. Ketoconazole and, to a lesser extent, fluconazole interfere with absorption of rifampicin, thereby decreasing its serum concentration. Rifabutin, although not approved by the US Food and Drug Administration for tuberculosis, may be used as a substitute for rifampicin in treating tuberculosis (17). Because of its lesser propensity to induce cytochrome P450 enzymes, rifabutin is generally reserved for patients who are taking any medication for which there are unacceptable interactions with rifampicin. It may also be used for patients who are intolerant of rifampicin. There is nearly complete cross-resistance among the rifamycins. The toxicity profile of rifabutin is similar to that of rifampicin except that in some studies with HIV-infected patients, neutropenia has been reported and uveitis has been described when the drug is given with a macrolide antibiotic (clarithromycin and azithromycin) that reduces rifabutin clearance (17). Rifapentine, which has the longest serum half-life of the rifamycins, has been shown in controlled clinical trials to be effective in combination

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with isoniazid given once weekly in the continuation phase of treatment for pulmonary tuberculosis (43). It should be emphasized, however, that there are important limitations on the use of this regimen. It is not to be used for patients with HIV infection, for patients who have cavitary lesions on chest film, or for patients who have positive sputum smears at the end of the initial phase of treatment; thus, a once-weekly rifapentine regimen should not be used when radiographic examination and HIV testing are not available (or not performed routinely). The toxicity profile of rifapentine is similar to that of rifampicin. Ethambutol

Ethambutol in usual doses of 15 mg/kg body weight has a static effect on M. tuberculosis. It is used mainly to reduce the risk of rifampicin resistance in patients with tuberculosis caused by strains that have primary resistance to isoniazid. Peak plasma concentrations occur two to four hours after ingestion. With doses of 15 mg/kg, the peak concentration is approximately 4 mg/mL (44). The concentration increases proportionally with increasing doses. In persons with normal renal function, the halftime in blood is approximately four hours. Minimum inhibitory concentrations of the drug for M. tuberculosis range from 1 to 5 mg/mL. Protein binding is minimal, but penetration into cells is thought to be poor. Cerebrospinal fluid concentrations of ethambutol, even in the presence of meningeal inflammation, are low (45). Like isoniazid, ethambutol appears to exert its effect by interfering with cell-wall biosynthesis. Specifically, the target for ethambutol is thought to be an arabinosyl transferase (20). Mutations in the embB gene that, together with embA and embC, code for arabinosyl transferases are found in approximately 70% of ethambutol-resistant strains (36). The rate of resistance-conferring mutations is 0.5
104 for ethambutol (24). Retrobulbar neuritis is the main adverse effect of ethambutol. Symptoms include blurred vision, central scotomata, and red–green color blindness. This complication is dose related, occurring in 15% of patients given 50 mg/kg, 1% to 5% with 25 mg/kg, and less than 1% with 15 mg/kg (17). The frequency of ocular effects is increased in patients with renal failure, presumably in relation to increased serum concentrations of the drug. Streptomycin

Streptomycin is rapidly bactericidal, although its effectiveness is inhibited by an acid pH (17). The drug is not absorbed when given orally and must be given parenterally. Peak serum concentrations occur approximately one hour after an intramuscular dose. With a dose of 15 mg/kg, the peak concentration is in the range of 40 mg/mL. The halftime in blood is approximately five hours. Sensitive strains of M. tuberculosis are inhibited by streptomycin in a concentration of 8 mg/mL. The drug has good tissue penetration; however, it enters the cerebrospinal fluid only in the presence of meningeal inflammation. Streptomycin and ethambutol have been found to be of approximately equal effectiveness in combination regimens;

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however, because of a relatively high prevalence of resistance to streptomycin, particularly in developing countries and because it requires injection, its usefulness is limited. Streptomycin exerts its effect by interfering with ribosomal protein synthesis. This effect is mediated by binding of the drug to 16S rRNA inhibiting initiation of translation (20). Mutations in the genes that code for 16S rRNA (rrs and rpsL) have been found in 65% to 77% of resistant strains. Mutations in rpsL have been associated with high-level streptomycin resistance, whereas low-level resistance has been associated with rrs mutations (36). The rate of resistance-conferring mutations is one in 3.8
106 generations (24). Ototoxicity is the most common serious adverse effect of streptomycin (17). This usually results in vertigo, but hearing loss may also occur. The risk of ototoxicity is related both to cumulative dosage and to peak serum concentrations. In general, peak concentrations of greater than 40 to 50 mg/mL should be avoided, and the total dose should not exceed 100 to 120 g (17). Streptomycin is contraindicated in pregnancy because of its effect on fetal auditory system development. Streptomycin should be used with caution in patients with renal insufficiency because of increased risk of nephrotoxicity and ototoxicity. The dosing frequency should be reduced to two to three times a week (17). Pyrazinamide

Pyrazinamide is active against M. tuberculosis at an acid pH, which suggests that the drug is activated under those conditions (20,46). The drug is particularly active against dormant or semidormant M. tuberculosis in macrophages or in the acidic environment within areas of caseation, and is rapidly bacteriostatic but only slowly bactericidal. Absorption from the gastrointestinal tract is nearly complete; peak serum concentrations occur approximately two hours after ingestion. Concentrations generally range from 30 to 50 mg/mL with doses of 20 to 25 mg/kg. The serum half-life is 9 to 10 hours. At a pH of 5.5, the minimal inhibitory concentration of pyrazinamide for M. tuberculosis is 20 mg/mL. Penetration of the drug into cells and tissues seems to be fairly good, although data with regard to tissue concentrations are limited. The mechanism of action of pyrazinamide is thought to be disruption of membrane energy metabolism (20). The genetic mechanism of mycobacterial resistance to pyrazinamide appears to be any of a large number of mutations in the pncA gene, which encodes the enzyme pyrazinamidase (20,36). This enzyme appears to be necessary for the intracellular conversion of pyrazinamide to its active form, pyrazinoic acid. Mutations in the pncA gene are found in approximately 70% of pyrazinamide-resistant strains (20,36). The most important adverse reaction to pyrazinamide is liver injury. This appears to be a dose-related occurrence. In a large U.S. Public Health Service study in which pyrazinamide was given in a dose of 25 mg/kg daily for six months, hepatotoxicity occurred in 2% to 3% of patients (47). At a

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dose of 40 mg/kg per day, also given for six months, 6% of patients developed hepatitis. All patients were receiving isoniazid and para-aminosalicylic acid in addition to pyrazinamide. An increased frequency of hepatotoxicity has been reported in studies of pyrazinamide combined with rifampicin in a two-month treatment regimen for latent tuberculosis infection in persons without HIV infection (48). Hyperuricemia occurs in nearly all patients taking pyrazinamide. Although gout is not common, diffuse arthralgias, apparently unrelated to the hyperuricemia, occur frequently. The drug may also cause nausea, vomiting, and skin rashes, including photosensitive dermatitis. B. Second-Line Drugs

Four additional agents are approved by the U.S. Food and Drug Administration for treating tuberculosis: PAS, ethionamide, cycloserine, and capreomycin. In addition, the fluoroquinolones, amikacin and kanamycin, have antituberculosis effects and are used in treating patients with tuberculosis caused by drug-resistant organisms or who are intolerant of first-line drugs (17). Of the second line drugs, the fluoroquinolones are perhaps most useful and, therefore, the most widely used (49,50). The fluoroquinolones should not be considered as first-line agents but should be reserved for patients with drug-resistant organisms or who cannot tolerate first-line drugs (17). The target of the fluoroquinolones is DNA gyrase, an enzyme that operates to increase coiling of DNA. Inhibition of gyrase in turn inhibits DNA synthesis. Resistance to these agents is mediated by mutations in gyrA and gyrB genes, which encode for DNA gyrase (36). Not many strains have been sequenced, but gyrA or gyrB mutations have been found in 42% to 85% of resistant isolates. The quinolones are generally well tolerated. The most frequent adverse effects include nausea, vomiting, dizziness, anxiety, and other central nervous system (CNS) effects. Because of the broad spectrum of antimicrobial action, diarrhea may be associated with the quinolones. Photosensitivity and arthropathy may also occur (51). There are few clinical studies of the usefulness of quinolones in multiple-drug regimens. Optimal dosages and durations of quinolone administration are not known. Both animal and limited human data suggest that moxifloxacin is the most potent of the existing quinolones and is the most promising of this class of drugs (52–54). All of the other oral second-line agents are difficult to administer because of adverse effects. It is recommended that consultation with an expert be obtained before these drugs are undertaken (17). Administration of PAS is associated with a high frequency of gastrointestinal upset. Hypersensitivity reactions occur in 5% to 10% of patients taking the drug. In addition, the usual dose of 10 to 12 g/day requires ingestion of 20 to 24 tablets. Administration has been made somewhat easier by use of a granular formulation of the drug. Ethionamide likewise causes a high frequency of gastrointestinal side effects, often necessitating discontinuation of the drug.

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Cycloserine causes behavioral disturbances in a large number of patients. These disturbances range from irritability and depression to psychosis. In addition, seizures and peripheral neuropathy occur, especially with high doses and when cycloserine and isoniazid are given together. In addition to the adverse effects of PAS, ethionamide, and cycloserine, none of these drugs is particularly potent against M. tuberculosis. Kanamycin, amikacin, and capreomycin are not absorbed from the gastrointestinal tract and thus require parenteral administration. All three drugs may cause hearing loss related both to peak concentrations and to cumulative doses and, in addition, may impair renal function. IV. Promoting Adherence to Treatment For antituberculosis chemotherapy to be effective in both its individual and public health roles, it must be conducted properly. Successful treatment of tuberculosis requires use of appropriate drugs in appropriate doses for appropriate durations, and assurance that the patient is adhering to the regimen. Accomplishing the goals of therapy requires individualization of the means of supervision, often with creative innovations, to enable assessment of adherence and to address poor adherence when it is identified. It must be emphasized that, because of the public health considerations related to tuberculosis, successful therapy is the responsibility of those supervising the care of the patient. Health-care providers undertaking treatment of patients with tuberculosis must provide a means for ensuring that therapy is completed successfully, within the limits of the regimens themselves. Although it is well known that patients with tuberculosis can be extremely difficult to manage, this difficulty does not absolve treating clinicians of their responsibility to render the patient noninfectious and permanently cured. The reasons for poor adherence to treatment for tuberculosis are complex and numerous, and prediction of who will be adherent and who will not is unreliable (55). It is clear that there is no single approach to management that is effective for all patients, conditions, and settings. Consequently, interventions that target adherence must be tailored or customized to the particular situation of a given patient (17). Concordance, defined in this context as an agreement between a patient with tuberculosis and the health-care provider, reinforces their mutual contribution and responsibility to achieve successful treatment (56). Components of this approach include setting clinic hours to suit the patient’s schedule; providing treatment support in the clinic, the patient’s home, or other locations; and offering incentives and enablers such as transportation reimbursements. Such an approach must be developed in close collaboration with the patient to achieve optimum adherence. This patient-centered, individualized approach to treatment support is a core element of all tuberculosis care and control efforts. A central element in ensuring completion of therapy is giving the drugs under direct observation [directly observed therapy (DOT)] (17).

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Ancillary measures, such as pill counting or testing for drug metabolites in urine, may also be useful for the assessment of adherence. Use of DOT has been shown to be associated with improved outcomes of therapy in several cohort analyses (57–59). Patient-centered approaches using the full range of accepted measures to ensure medication ingestion are central to the World Health Organization’s (WHO) global tuberculosis control strategy, known as DOTS, which comprises four elements in addition to DOT (see Chapter 27) (60). The success of the strategy has been demonstrated most clearly in Peru and China (61,62). However, concerns have been raised that the direct observation of medication ingestion, not the full DOTS strategy, does not lead to better outcomes compared with self-supervised treatment (63). V. Current Treatment Regimens There are a number of different sets of recommended treatment regimens published by different organizations and agencies. In spite of apparent differences, however, all are based on the same principles, all use the same drugs, and all agree that six months is the minimum duration of treatment for bacteriologically confirmed tuberculosis. The main differences among recommendations lie in the rhythm of administration and are based mainly on the availability of resources for supervision. The treatment regimens that are recommended currently by the American Thoracic Society, Centers for Disease Control and Prevention, and the Infectious Diseases Society of America (ATS/CDC/IDSA) (17) are shown in Table 2 (19). These recommendations are intended to guide treatment in areas where mycobacterial culture, drug-susceptibility testing, chest radiography, and second-line drugs are available routinely. The treatment recommendations of the WHO (Table 3) (18) are directed toward low- and middle-income countries where the above facilities are not available routinely. The basic treatment regimen recommended by both ATS/CDC/IDSA and WHO for previously untreated patients with either pulmonary or extrapulmonary tuberculosis consists of an initial phase of isoniazid, rifampicin, pyrazinamide, and ethambutol for two months, followed by four months of isoniazid and rifampicin (17,18). As shown in Table 2, there are several variations in the pattern of administration of the basic regimen. In large part, these variations are designed to enable closer supervision of medication ingestion. WHO recommendations also include a continuation phase of isoniazid and ethambutol given daily when circumstances do not allow for effective supervision beyond the initial phase. This is intended to minimize the likelihood of rifampicin resistance developing. However, in a comparative clinical trial, the isoniazid, ethambutol continuation phase regimen was significantly less effective than the isoniazid, rifampicin continuation phase regimen (64). Moreover, it has been shown that in patients with HIV infection, the outcome is significantly better when the regimen contains rifampicin throughout (65).

Drugs

INH RIF PZA EMB

INH RIF PZA EMB

INH RIF PZA EMB

Regimen

1

2

3

Initial phase

Thrice weekly for 24 doses (8 wk)

7 days per week for 14 doses (2 wk), then twice-weekly for 12 doses (6 wk) or 5 days per week for 10 doses (2 wk)e, then twice weekly for 12 doses (6 wk)

7 days per week for 56 doses (8 wk) or 5 days per week for 40 doses (8 wk)e

Interval and doses (minimum duration)

c

3a

INH/RIF

INH/RPT

2bg

INH/RPT

1cg INH/RIF

INH/RIF

1b

2a

INH/RIF

Drugs

1a

Regimen

c,d

Once weekly for 18 doses (18 wk) Thrice-weekly for 54 doses (18 wk)

7 days per week for 126 doses (18 wk) or 5 days per week for 90 doses (18 wk)e Twice-weekly for 36f doses (18 wk) Once weekly for 18 doses (18 wk) Twice-weekly for 36f doses (18 wk)

Interval and doses (minimum duration)

Continuation phase

44 or 40 (26 wk) 78 (26 wk)

92–76 (26 wk) 74 or 58 (26 wk) 62–58 (26 wk)

182–130 (26 wk)

Range of total doses (minimum duration)

Table 2 Drug Regimens for Culture-Positive Pulmonary Tuberculosis Caused by Drug-Susceptible Organisms

B (I)

B (I)

A (II)

B (I)

A (I)

A (I)

HIV

a

b

(Continued )

B (II)

E (I)

B (II)

E (I)

A (II)

A (II)

HIVþ

Rating (evidence)

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INH RIF EMB

4

7 days per week for 56 doses (8 wk) or 5 days per week for 40 doses (8 wk)

Interval and doses (minimum duration)

c

Drugs INH/RIF

INH/RIF

Regimen 4a

4b

c,d

Range of total doses (minimum duration)

Twice-weekly for 62 doses (31 wk)

118–102 (39 wk)

7 days per week for 217 273–195 doses (31 wk) or 5 (39 wk) days per weeks for 155 doses (28 wk)e

Interval and doses (minimum duration)

Continuation phase

C (I)

C (I)

HIV

a

b

C (II)

C (II)

HIVþ

Rating (evidence)

b

Definitions of evidence ratings: A, preferred; B, acceptable alternative; C, offer when A and B cannot be given; E, should never be given. Definitions of evidence ratings: I, randomized clinical trial; II, data from clinical trials that were not randomized or were conducted in other populations; III, expert opinion. c When DOT is used, drugs may be given five days a week and the necessary number of doses adjusted accordingly. Although there are no studies that compare five with seven daily doses, extensive experience indicates this would be an effective practice. d Patients with cavitation on initial chest radiograph and positive cultures at completion of two months of therapy should receive a seven-month [28 week; either 196 doses (daily) or 56 doses (twice-weekly)] continuation phase. e Five-day-a-week administration is always given by DOT. Rating for five-day-a-week regimens is AIII. f Not recommended for HIV-infected patients with CD4 cell counts less than 100 cells/mL. g Options 1c and 2b should only be used in HIV-negative patients who have negative sputum smears at the time of completion of two months of therapy and who do not have cavitation initial on the chest radiograph (see text). For patients started on this regimen and found to have a positive culture at two months, treatment should be extended an extra three months. Abbreviations: INH, isoniazid; RIF, rifampian; RPT, rifapentine; PZA, pyrazinamide; EMB, ethambutol; DOT, directly observed therapy. Source: From Ref. 19.

a

Drugs

Regimen

Initial phase

Table 2 Drug Regimens for Culture-Positive Pulmonary Tuberculosis Caused by Drug-Susceptible Organisms (Continued )

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Table 3 Recommended Treatment for Persons Not Treated Previously Ranking Preferred

Optional

Initial phase INH, RIF, PZA, EMBa,b daily, 2 mo INH, RIF, PZA, EMBa,b 3x/wk, 2 mo INH, RIF, PZA, EMBb daily, 2 mo

Continuation phase INH, RIF daily, 4 mo INH, RIF 3x/wk, 4 mo INH, EMB daily, 6 moc

a

Streptomycin may be substituted for EMB. EMB may be omitted in uncomplicated childhood tuberculosis. c Associated with higher rate of treatment failure and relapse; should not be used in patients with HIV infection. Abbreviations: INH, isoniazid; RIF, rifampicin; PZA, pyrazinamide; EMB, ethambutol. Source: From Ref. 18. b

Especially in areas of high prevalence of drug resistance or among persons in whom epidemiological circumstances indicate a risk of drug resistance, where quality-assured laboratory facilities are available, initial isolates should have drug-susceptibility tests performed. If resistance is identified, regimens can be tailored to suit the specific pattern. Drugsusceptibility tests should be repeated if M. tuberculosis is isolated after three or more months of treatment. The recommendation of a four-drug initial phase is based in part on findings of the British Medical Research Council (66), which strongly suggest that where the prevalence of initial resistance to isoniazid is likely to be high, treatment regimens should include an initial two-month, four-drug phase, after which rifampicin plus isoniazid should be given for a fourmonth continuation phase. The results of this regimen are almost as good in the presence of resistance to isoniazid as for fully susceptible organisms. Prolonging treatment beyond six months does not appear to increase the rate of success. The risk of not taking this approach is the development of rifampicin resistance. Several factors have been found to be predictive of a poor therapeutic outcome (17,43,67). In the U.S. Public Health Service Study 22, the presence of cavitation on the initial chest film and sputum culture positivity at the time of completion of the initial phase of treatment were highly predictive of an adverse outcome—either treatment failure or relapse (43). For this reason, for patients with cavitation on the initial chest film and who have positive sputum cultures at the end of the initial phase of treatment, prolongation of the continuation phase to seven months, making a total of nine months of treatment is recommended by the ATS, CDC, and IDSA treatment guidelines (17). These recommendations differ from those of WHO. In many parts of the world where radiographic examination and culture technology are not available, following these guidelines is not possible.

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Additional factors that have been associated with poor clinic attendance and, therefore, with a lower chance of favorable responses include use of alcohol, younger age (but above 18 years), and unmarried status (17). After two to three months of chemotherapy, 75% to 90% of patients taking regimens containing isoniazid and rifampicin should have negative sputum cultures. Failure of the sputum to become negative may indicate that either the patient is not taking the drugs or, much less commonly, the organisms are resistant to the drugs being used. Patients who continue to have M. tuberculosis in their sputum after two to three months of treatment should be started on directly observed therapy, if not already being supervised in this manner, and should have drug-susceptibility tests performed, if facilities are available. If resistance is found, the regimen should be modified based on the results. If sputum samples are still positive after four to five months of therapy, the regimen should be considered to have failed and a new regimen begun, ideally, based on recent drug-susceptibility test results. Patients in whom organisms at the outset of treatment are sensitive to the first-line antituberculosis drugs and who experience relapse after completion of a regimen that contained isoniazid and rifampicin commonly retain full drug susceptibility. In general, management of these patients consists of reinstituting the regimen previously used. However, if the patient is severely ill, at least three new agents should be added to the regimen for the possibility of drug resistance. Drug-susceptibility testing should be performed and the regimen modified if resistance is detected. In addition, treatment should be given under direct observation. Patients who experience relapse after completing a regimen that did not contain rifampicin should be considered to harbor organisms that are resistant to the drugs used, at least until susceptibility is proven. The likelihood of resistance is directly related to the duration of previous treatment (68). Resistance to isoniazid increases approximately 4% per month of treatment for durations of less than one year. Resistance to streptomycin increases at approximately 2.5% per month of prior treatment. The basic principle of treatment for patients whose organisms are resistant to one or more of the first-line drugs is the administration of at least two (but generally three to four) agents to which there is demonstrated sensitivity (17). Unfortunately, there are no data to provide evidence-based guidelines as to the relative effectiveness of various regimens and the necessary duration of treatment. Clearly, if the organism is susceptible to isoniazid and rifampicin, a usual regimen can be expected to be successful. In the presence of resistance to isoniazid, treatment with rifampicin and ethambutol, supplemented by pyrazinamide, also is likely to be successful. There are data suggesting that 12 months of treatment with rifampicin and ethambutol is sufficient (17); however, in patients with organisms resistant to isoniazid, such decisions should be made on a case-by-case basis. Tuberculosis caused by organisms resistant to multiple antituberculosis drugs, including at least isoniazid and rifampicin multidurg resistance (MDR),

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presents particularly difficult management problems. The Global Drug Surveillance Project conducted by the WHO and the International Union Against Tuberculosis and Lung Disease in 35 countries has shown that drug resistance in general is ubiquitous and that there are areas in the world in which rates of multidrug resistance are truly alarming (69–71). These include Latvia, the Delhi region in India, Estonia, the Dominican Republic, and Argentina. Fortunately, rates of MDR tuberculosis do not seem to be increasing (71). The outcome of treatment in persons with tuberculosis caused by MDR organisms is generally less favorable than that of treatment of disease caused by susceptible organisms, although data are sparse. At least in part, the outcome depends on the number of agents to which the organisms are susceptible, the promptness and appropriateness of therapy, the number of previous courses of therapy, and the HIV status of the patient. For example, in a group of patients with MDR tuberculosis who had undergone multiple previous courses of chemotherapy, the rate of successful outcome was only slightly better than 50% (72). However, in both New York and San Francisco, non–HIV-infected patients with MDR tuberculosis who had not been extensively treated previously had a much better rate of success (92% and 97%, respectively), albeit with a much shorter follow-up time (73,74). In the report from San Francisco, the prognosis for patients with HIV infection and MDR tuberculosis was very poor, and all 11 patients died during the period of the study. This group of patients was treated prior to the availability of highly active antiretroviral therapy (HAART) (74), so it is not known whether HAART would improve the outcome. Consultation with an expert is advised when treating patients with MDR tuberculosis. Often, the regimen chosen represents the last chance for cure, and treatment must be performed correctly. The regimen should be based on the results of drug-susceptibility tests when available. In most instances, however, the results are not known until several weeks after the therapy is started. In such instances, treatment should be determined on the basis of the patient’s history of prior therapy, avoiding reliance on agents taken previously and on the prevailing resistance patterns in the community or subpopulation of which the patient is a member. VI. Treatment in Special Situations A. Infection with Human Immunodeficiency Virus

The recommended treatment regimen for HIV-infected patients with tuberculosis consists of the same six-month regimen as described for non–HIVinfected patients (17,18). However, there are several important areas in which therapy for persons with both tuberculosis and HIV infection differs. The eight-month regimen included in the WHO treatment recommendations, in which there is a six-month continuation phase of isoniazid and ethambutol, is not recommended for treating patients who are coinfected with HIV (18,65). Also, there is an association between HIV infection

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and acquired rifampicin resistance (36,37,75). The cause of rifampicin monoresistance is not clear but both resistance and an increased rate of adverse outcomes have been associated with the use of highly intermittent (twice or once weekly) drug administration in the continuation phase. Rifamycin monoresistance has also been associated with prior use of rifabutin as prophylaxis for Mycobacterium avium complex infections (76). Because of the increased risk adverse outcomes and of rifamycin resistance, the rifapentine once-weekly regimen is contraindicated for any patient with HIV infection and a twice-weekly regimen is not recommended for HIV-infected patients with CD4 cell counts of less than 100/mL (17). An important consideration in treating tuberculosis in patients with HIV infection is the potential for interactions of antituberculosis agents, especially the rifamycins, with other drugs, especially the protease inhibitor class of antiretroviral agents [reviewed in detail in Ref. (17)]. The most practical means of minimizing the effects of the interactions is to use an antiretroviral regimen that excludes protease inhibitors. This regimen should consist of two nucleoside reverse transcriptase inhibitors plus efavirenz. Because animal studies suggest a possibility of congenital abnormalities with efavirenz, this drug should not be used in women of childbearing age; they should be treated with nevirapine, and rifabutin in place of rifampicin. Monitoring of serum drug concentrations may be useful in avoiding the adverse consequences of the interactions (77). However, in many parts of the world neither rifabutin nor measurements of therapeutic drug concentration are available, thus treatment for both diseases must be given under careful clinical monitoring. The optimum time to initiate an antiretroviral regimen in patients being treated for tuberculosis has not been determined. The general recommendation is that for patients with tuberculosis and HIV infection having less than 200 CD4 cells/mL, an antiretroviral regimen should be started (78). With CD4 cell counts of 200 to 350/mL, the possible benefits are less clear, but treatment should be considered. Because of the potential for frequent changes in recommendations for treating tuberculosis in patients with HIV infection, there is regular updating of the information in the CDC website (79) and the NIH website (80). These sites should be consulted for the most up-to-date recommendations. Another feature of tuberculosis treatment in persons with HIV infection is the paradoxical worsening (immune reconstitution syndrome) that may occur in persons in whom antiretroviral therapy is initiated (81–83). Paradoxical reactions also occur in patients who do not have HIV infection, but the frequency is less. Presumably these reactions are the result of reconstitution of the immune response to mycobacteria. Typical features include a new onset of fever, lymphadenopathy, and worsening appearance of lesions on chest radiographs (81–83). When these features occur, it is important to rule out treatment failure as well as other opportunistic diseases. Treatment is usually symptomatic with nonsteroidal anti-inflammatory agents. In some

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instances, the reactions are severe enough to warrant the use of corticosteroids, although this approach is not of proven benefit. Finally, in large part because of high death rates early in the course of treatment of HIV-infected persons with tuberculosis, rates of treatment success are less than in cohorts of non–HIV-infected patients. Apart from these deaths, which are often due to advanced HIV infection, the rate of treatment success is nearly equal to that of persons without HIV infection. However, as indicated by the increased rates of treatment failure and relapse with highly intermittent therapy, there is less margin of safety for drug administration in persons with HIV infection. Thus, direct observation of therapy is extremely important to be certain of a high level of adherence. If there are problems with treatment, such as breaks in therapy, delayed conversion, or persistence of symptoms, prolonging therapy beyond six months should be seriously considered (17). B. Pregnancy and Breast Feeding

Active untreated tuberculosis is more of a hazard to a pregnant woman and her fetus than is treatment for the disease. In a pregnant woman or a mother of a young infant, it is important to provide the most effective therapy for tuberculosis. Treatment should be initiated with isoniazid, rifampicin, and ethambutol. Pyrazinamide is included in WHO’s recommendations for treating tuberculosis in pregnant women, but it has not been included in the ATS/CDC/IDSA recommendations because of insufficient information about possible harmful effects (17,18). Without pyrazinamide in the drug regimen, treatment must be given for a total of nine months. Streptomycin, which interferes with the development of the fetal ear and may cause congenital deafness, is the only antituberculosis drug for which there is documented evidence of harmful effects on the fetus. This potential is presumably shared by amikacin, kanamycin, and capreomycin; however, there is little or no information about the effects of these drugs, or of cycloserine and ethionamide, on the fetus. Although several antituberculosis drugs are present in breast milk, their concentrations and the total amounts that could possibly be ingested by a nursing infant are so small that adverse effects would be unlikely. No modifications of treatment regimens are necessary for nursing mothers. C. Other Associated Conditions

Tuberculosis occurs in association with many other conditions either because an underlying disorder alters immune responsiveness, thereby predisposing to tuberculosis, or because tuberculosis and the accompanying condition may occur frequently in the same social and cultural setting. Examples of the former class of disorders include hematologic or reticuloendothelial malignancies, immunosuppressive therapy, HIV infection, chronic renal failure, diabetes mellitus, and malnutrition. Alcoholism and its accompanying disorders and other forms of substance abuse are

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also very common in patients with tuberculosis. All of these conditions may influence therapy. The response of the impaired host to treatment may not be as satisfactory as that of a person with normal host responsiveness. For this reason, therapeutic decisions must be made on a much more individualized basis and, when possible, steps are taken to correct the immunosuppression. In patients with impaired renal function, streptomycin, kanamycin, amikacin, and capreomycin should be avoided if at all possible or given two to three times a week in the usual dose. If there is severe impairment of renal function, it may be necessary to reduce the frequency of administration of ethambutol and pyrazinamide to two to three times per week (17). The drugs should be administered after hemodialysis. Liver disease, particularly alcoholic hepatitis and cirrhosis, is commonly associated with tuberculosis. In general, the complications of potentially hepatotoxic antituberculosis drugs have not been greater in patients with liver disease (84). However, detecting any such adverse effects may be difficult because of the preexisting disorder of hepatic function. Moreover, treatment of a person with normal liver function may cause minor hepatotoxicity, whereas the same treatment could have major consequences in a patient with severe liver disease. Options in treating patients with severe liver disease include treatment without isoniazid, using rifampicin, ethambutol, and pyrazinamide for six months; treatment without pyrazinamide for a total duration of nine months; treatment with only one potentially hepatotoxic drug, usually retaining rifampicin and adding ethambutol and a fluoroquinolone for a total of 12 to18 months; and treatment with a regimen that contains no hepatotoxic drugs—streptomycin, ethambutol, a fluoroquinolone, and perhaps another second-line drug for 18 to 24 months (17). In patients with severe liver disease, routine testing of liver function should be performed at baseline and during treatment. Finally, in patients with psychiatric disorders, close supervision of treatment with direct observation of drug ingestion is essential. VII. Adjunctive Treatments for Pulmonary Tuberculosis A. Corticosteroids

The use of corticosteroids in pulmonary tuberculosis has been and remains controversial. However, corticosteroids may, under certain conditions, be of at least short-term benefit in patients with pulmonary tuberculosis. These conditions were defined by a controlled trial reported by Johnson and colleagues (85) in which all patients were treated with effective antituberculosis chemotherapy and were assigned at random to receive either methylprednisolone or placebo. This study demonstrated that corticosteroid treatment benefited the seriously ill patient (defined by low serum albumin concentration, low body weight, and weight loss) who had extensive tuberculosis. This benefit was evidenced mainly by an increase in the rate of radiographic clearing; there was no adverse effect on the bacteriologic

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response. In less severely ill patients, methylprednisolone was either of no benefit or actually decreased the speed of sputum conversion. Long-term effects were not examined. These data suggest a role for corticosteroid treatment in patients with severe tuberculosis and severe systemic effects. Although not considered in the study by Johnson et al., steroids may also be of benefit in patients with marked abnormalities of gas exchange and respiratory failure. It should be emphasized, however, that adequate antituberculosis chemotherapy must be given before using corticosteroid treatment in patients with severe pulmonary tuberculosis. B. Surgical Interventions

Surgical resection may be indicated in several situations (see also Chapter 15). In patients with tuberculosis caused by MDR organisms, which is anatomically limited within the lung, resection may be an effective therapeutic option (86). Before an operation in such patients, it is important to reduce the bacillary population as much as possible with drugs to which the organism is susceptible. Determining the optimum time to perform surgery, however, can be difficult, because the effectiveness of a limited second-line drug regimen cannot always be predicted. Resection may also be necessary because of massive hemoptysis associated with current or old tuberculosis or a mycetoma in a residual cavity, because of residual lung damage with recurrent bacterial infections, or because of a bronchopleural fistula with (usually) a tuberculous empyema. In addition to these therapeutic indications for surgery, it is fairly common for tuberculosis to be diagnosed by examination of a resected pulmonary mass or nodule, which was thought to be malignant. In any situation involving possible lung surgery in patients with or suspected of having tuberculosis, including the resection of a solitary nodule in a patient with a positive tuberculin reaction, the patient should have been receiving adequate antituberculosis chemotherapy before the operation. This minimizes the possibility of spread of tuberculosis within the lung and of bronchial stump infection and empyema. The optimum duration of treatment before the operation is not clear. In emergencies such as massive hemoptysis, at least single doses of the drugs should be given, whereas with elective procedures, it is best to wait at least until the sputum smear is negative. If the sputum smear is negative to begin with, two weeks of treatment is reasonable. VIII. Extrapulmonary Tuberculosis A. Disseminated Tuberculosis

Standard antituberculosis chemotherapeutic regimens should be employed for disseminated tuberculosis unless meningitis is present, in which case the recommended duration is 9 to 12 months (17). Corticosteroids may be useful, as mentioned previously, for severe pulmonary disease with respiratory failure.

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A six-month regimen is recommended for treatment of tuberculous lymphadenitis (87–89). However, even with effective regimens, the rate of response is much slower than with pulmonary tuberculosis. Lymph nodes may enlarge, new nodes may appear, and fistulas may develop during treatment that ultimately proves effective, but true bacteriologic relapse after completion of therapy is unusual. This transient worsening may be a manifestation of the immune reconstitution syndrome. Corticosteroid treatment has been used to shrink intrathoracic nodes and relieve bronchial obstruction, primarily in children. In a controlled study, Nemir et al. (90) demonstrated that corticosteroids increase the rate of resolution of radiographic changes thought to be due to bronchial narrowing by lymph nodes or endobronchial lesions in children with primary tuberculosis. Apart from this indication, there is no clear role for corticosteroids in lymphatic tuberculosis. Surgical intervention may be necessary to make a diagnosis of tuberculous lymphadenitis, and on occasion surgical incision and drainage are needed to prevent spontaneous drainage and fistula formation. Surgical excision of involved nodes, strictly as an adjunct to chemotherapy, is associated with perhaps a slightly worse outcome than medical treatment with aspiration of the node or medical treatment alone (88). C. Pleural Tuberculosis

Treatment of the hypersensitivity variety of tuberculous pleural effusion consists of standard antituberculosis drug regimens (17). Drainage via tube thoracostomy is rarely necessary, although repeat thoracenteses may be required to relieve symptoms. Occasionally, early in the course of eventually successful therapy, the amount of fluid in the thorax increases before decreasing. In general, the amount of residual pleural scarring is small. The use of corticosteroids may increase the rate of resolution and decrease the residual fluid, but such treatment is rarely indicated. The second variety of tuberculous involvement of the pleura is a true empyema. This is much less common than tuberculous pleurisy with effusion and results from a large number of organisms spilling into the pleural space, usually from rupture of a cavity or an adjacent parenchymal focus via a bronchopleural fistula. Although standard chemotherapy should be instituted for tuberculous empyema, it is unlikely to clear the pleural space infection, probably because penetration of the antituberculosis agents into the pleural cavity is limited. For this reason, surgical drainage is often necessary and may be required for a prolonged period of time both as treatment for the infection and because of the frequent association with a bronchopleural fistula. Drainage may be accomplished with a standard thoracostomy tube. In selected patients, creation of an Eloesser flap, in which a small portion of rib overlying the empyema space is resected and the skin is sutured to the pleura, is the procedure of choice. Corticosteroids have no role in treating this form of pleural tuberculosis.

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D. Genitourinary Tuberculosis

There are several treatment considerations for genitourinary tuberculosis apart from standard chemotherapy (91). Nephrectomy, formerly a mainstay of therapy for renal tuberculosis, is now seldom indicated; however, in patients who have tuberculosis caused by MDR organisms and who can tolerate removal of a kidney, nephrectomy may be indicated. Nephrectomy may also be indicated for patients who have recurrent pyogenic bacterial infections in a kidney destroyed by tuberculosis, for persistent pain and massive hematuria. Surgical or endoscopic procedures may also be necessary to correct ureteral strictures and to augment the capacity of a contracted bladder. E. Bone and Joint Tuberculosis

Standard chemotherapy of six to nine months duration is highly successful in skeletal tuberculosis, but surgery is occasionally a necessary adjunct. The longer duration of treatment has been suggested because of the difficulties in assessing response. Several controlled studies have documented that chemotherapy conducted largely on an ambulatory basis is effective in curing spinal tuberculosis without the need for immobilization (92,93). The role of emergency spinal-cord decompression in patients with Pott’s disease and early neurologic findings is not clear, and if paraplegia is already present, the benefit of surgical intervention is even less clear. Moreover, there is no well-defined surgical procedure of choice. Surgery may be indicated in other forms of articular tuberculosis when there is an extensive destruction of the joint or surrounding soft tissues, in which case synovectomy and joint fusions may be necessary. F. Central Nervous System Tuberculosis

Isoniazid penetrates the blood–brain barrier quite readily, and, in the presence of meningeal inflammation, rifampicin enters the cerebrospinal fluid in concentrations sufficient to inhibit growth of the organism. Although data are limited, pyrazinamide seems to penetrate the barrier easily, at least in the presence of inflammation, and streptomycin achieves inhibitory concentrations when there is meningitis. Ethambutol penetrates poorly, and doses of 25 mg/kg body weight produce subinhibitory concentrations. In view of the potential catastrophic consequences of poorly treated tuberculous meningitis, the possibility that no organisms can be isolated, and the length of time required for drug-susceptibility studies to be done, the potential for resistant organisms should be taken into account when treatment is initiated. If there are no epidemiological indicators of possible resistance, a regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol should be effective. The recommended length of the continuation phase is seven months for total treatment duration of 9 to 12 months, although there are no clinical trials that serve to define the optimum duration of treatment (17). Corticosteroid treatment has a beneficial effect in patients with tuberculous meningitis and cerebral edema (94). In addition, in the presence of

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high cerebrospinal fluid protein concentration, corticosteroids reduce the frequency of adhesive arachnoiditis and spinal fluid block. In children in less severe stages of disease, corticosteroid therapy has been shown to decrease the frequency of sequelae (95,96). Dexamethasone is recommended for all patients, especially those with alterations in their level of consciousness, given the severity of the process, reasonably good data supporting corticosteroid use in more severe forms of the disease, and a paucity of information in patients with less severe tuberculosis meningitis. The recommended dose of dexamethasone is 12 mg/day for three weeks, then decreased gradually during the next three weeks. The other major CNS form of tuberculosis, the tuberculoma, presents a more subtle clinical picture than does tuberculous meningitis. The response to antituberculosis chemotherapy is good, and corticosteroids are indicated only if there is an increase in intracranial pressure. Tuberculomas seem relatively more common in persons with HIV infection and may worsen with life-threatening consequences with the immune reconstitution syndrome. G. Abdominal Tuberculosis

Standard chemotherapy is quite effective in abdominal tuberculosis. Corticosteroids have been advocated in tuberculous peritonitis to reduce the risk of adhesions causing intestinal obstructions, but this recommendation is controversial because the frequency of obstruction is generally low. Surgery is often necessary to establish a diagnosis and, in addition, may be necessary to relieve intestinal obstruction. H. Pericardial Tuberculosis

Because of the potentially life-threatening nature of pericardial tuberculosis, treatment with antituberculosis agents should be instituted promptly, once the diagnosis is made or strongly suggested. The likelihood of pericardial constriction appears to be greater in patients who have had symptoms for longer period and early therapy may reduce the incidence of this complication. Several studies have suggested that corticosteroids have a beneficial effect in treating both tuberculous pericarditis with effusion and constrictive pericarditis (97,98). However, a meta-analysis of studies examining the effects of corticosteroids in tuberculous pericarditis concluded that, although steroids could have an important effect, the studies were too small to be conclusive (98). Nevertheless, patients with proven tuberculous pericarditis who are receiving adequate antituberculosis therapy and who have no major contraindications to the use of corticosteroids should receive them. The optimum regimen is not known, but prednisone, 60 mg/day for four weeks, followed by 30 mg/day for four weeks, 15 mg/day for two weeks, and 5 mg/day for one week is the recommended regimen (17). Corticosteroid therapy should not be used if there is a strong suspicion that the infection is caused by a drug-resistant organism unless adequate antituberculosis chemotherapy can be ensured.

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In general, if hemodynamic compromise occurs, pericardiectomy is necessary. Although pericardiocentesis generally improves the circulatory status, the improvement is usually temporary. Pericardial windows with drainage into the left pleural space also generally provide only temporary relief. The criteria for selecting patients for pericardiectomy are not clear, apart from those patients who have severe hemodynamic compromise. IX. New Drugs for Tuberculosis The goals of new antituberculosis drug development are: first, to develop a drug that will enable shortening of the minimum duration of treatment for bacteriologically proven tuberculosis from the current six months to one to two months; second, to provide new drugs for treating MDR tuberculosis; and third, to develop more effective treatments for latent tuberculosis infection (99). The past 10 to 15 years have seen an explosion of knowledge concerning the biochemistry, genomics, and proteomics of M. tuberculosis, all of which can potentially contribute to identification of new drug targets (20). As of this writing, six drugs with antituberculosis activity are undergoing clinical testing in humans and another three are in preclinical testing (Stop TB Partnership. Global Plan to Stop TB, 2006–2015). At least 17 additional compounds or categories of compounds are at various stages in the discovery phase of testing. Of the drugs in human trials, two are existing quinolones, moxifloxacin and gatifloxacin; one is a nitroimidazole, PA824; one is a diarylquinoline, R207910; one is a pyrrole, LL-3858; and one is a proprietary compound. The quinolones have been discussed previously and have been used fairly extensively, albeit without a clear definition of the role and maximal benefit for these agents. However, there is preliminary evidence that inclusion of a quinolone, probably moxifloxacin because of its greater potency, may enable the duration of treatment to be shortened (53,54). PA-824 is a prodrug that is thought to act on cell-wall lipid biosynthesis (100). It is active against MDR organisms, suggesting that the target enzyme is new, and is as active as isoniazid against susceptible organisms, having an MIC of 0.015 to 0.25 mg/mL. It appears safe in mice, but human data are not yet available. The diarylquinolines are thought to act by inhibiting the proton pump of ATP synthase, and the lead compound, R207910, has an MIC of 0.030 to 0.120 mg/mL both for fully susceptible and for resistant strains of M. tuberculosis (101,102). The drug appears to be specific for mycobacteria and is active against wide range pathogenic and saprophytic members of the family. The frequency of resistance mutations ranges from 5
107 to 5
108 depending on the drug concentration, a frequency comparable to that of rifampicin. R207910 has early bactericidal effect comparable to or greater than that of isoniazid and a delayed effect that exceeds that of rifampicin. It also has a long plasma and tissue half-life in mice facilitating its time-dependant killing properties. Early human safety and tolerability

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studies suggest that, at least for short exposure periods, it is well tolerated, even with plasma concentrations that are well above the effective concentration in mice. Although the drug has undergone only limited human testing, its properties suggest that it may prove to be an exceptionally effective agent in treating tuberculosis. However, as was pointed out by Dye (103), without effective systems for their delivery, the potential benefit of even the most promising antituberculosis drugs will not be realized. References 1. Hopewell PC, Pai M. Tuberculosis, vulnerability, and access to quality care. JAMA 2005; 293:2790–2793. 2. Mitchison DA. The diagnosis and therapy of tuberculosis during the past 100 years. Am J Respir Crit Care Med 2005; 171:699–706. 3. Hinshaw HC, Feldman WH. Streptomycin in the treatment of clinical tuberculosis: a preliminary report. Proc Staff Meet Mayo Clin 1945; 20:313–318. 4. McDermott W, Muschenheim C, Hadley SJ, et al. Streptomycin in the treatment of tuberculosis in humans: I. Meningitis and generalized hematogenous tuberculosis. Ann Intern Med 1947; 27:769–822. 5. Medical Research Council. Treatment of pulmonary tuberculosis with streptomycin and para-aminosalicylic acid. BMJ 1950; 2:1073–1085. 6. Robitzek EH, Selikoff IJ. Hydrazine derivative of isonicotinic acid (Rimifon, Marsalid) in the treatment of acute progressive caseous-pneumonic tuberculosis. A preliminary report. Am Rev Tuberc 1952; 65:402–428. 7. Medical Research Council. Long-term chemotherapy in the treatment of chronic pulmonary tuberculosis with cavitation. Tubercle 1962; 43:201–211. 8. Springett VH. Ten-year results during the introduction of chemotherapy for tuberculosis. Tubercle 1971; 52:73–87. 9. Bobrowitz ID, Robins DE. Ethambutol-isoniazid versus PAS-isoniazid in original treatment of pulmonary tuberculosis. Am Rev Respir Dis 1967; 96:428–438. 10. Fox W, Mitchison DA. Short-course chemotherapy for tuberculosis. Am Rev Respir Dis 1975; 111:325–353. 11. Mackaness GB. The intracellular activation of pyrazinamide and nicotinamide. Am Rev Tuberc 1956; 74:718–728. 12. Fox W, Ellard GA, Mitchison DA. Studies on the treatment of tuberculosis undertaken by the British Medical Research Council tuberculosis units, 1946–1986, with relevant subsequent publications. Int J Tuberc Lung Dis 1999; 3(10 suppl 2):S231–S279. 13. Dickinson JM, Aber VR, Mitchison DA. Bactericidal activity of streptomycin, isoniazid, rifampin, ethambutol and pyrazinamide alone and in combination against Mycobacterium tuberculosis. Am Rev Respir Dis 1977; 116:627–635. 14. Mitchison DA, Dickinson JM. Bactericidal mechanisms in short-term chemotherapy. Bull Int Union Tuberc 1978; 53:270–275. 15. Snider DE Jr., Graczyk J, Bek E, et al. Supervised six-month treatment of newly diagnosed pulmonary tuberculosis using isoniazid, rifampin and pyrazinamide with and without streptomycin. Am Rev Respir Dis 1984; 130:1091–1094. 16. Coombs DL, O’Brien RJ, Geiter LJ. USPHS tuberculosis short-course therapy trial 21: effectiveness toxicity and acceptability. The report of the final result. Ann Intern Med 1990; 112:407–415. 17. American Thoracic Society; Centers for Disease Control and Prevention; Infectious Diseases Society of America. Treatment of tuberculosis. Am J Respir Crit Care Med 2003; 167:604–661.

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41. Girling DJ, Hitze KL. Adverse reactions to rifampicin. Bull WHO 1979; 57:45–49. 42. Burman WJ, Jones BE. Treatment of HIV-related tuberculosis in the era of effective antiretroviral therapy. Am J Respir Crit Care Med 2001; 164:7–12. 43. Benator D, Bhattacharya M, Bozeman L, et al. Rifapentine and isoniazid once a week versus rifampicin and isoniazid twice a week for treatment of drug-susceptible pulmonary tuberculosis in HIV-negative patients: a randomized clinical trial. Lancet 2002; 360:528–534. 44. Lee CS, Gambertoglio JG, Brater DC, et al. Kinetics of ethambutol in the normal subject. Clin Pharmacol Ther 1977; 22:615–621. 45. Bobrowitz ID. Ethambutol in tuberculous meningitis. Chest 1972; 61:629–632. 46. McDermott W, Tompsett R. Activation of pyrazinamide and nicotinamide in acidic environments. Am Rev Tuberc 1954; 70:748–753. 47. United States Public Health Service Tuberculosis Therapy Trial: Hepatic toxicity of pyrazinamide used with isoniazid in tuberculous patients. Am Rev Respir Dis 1959; 80:371–387. 48. United States Public Health Service. Update: Adverse event data and revised American thoracic Society/CDC recommendations against the use of rifampin and pyrazinamide for treatment of latent tuberculosis infection—United States, 2003. MMWR 2003; 52:735. 49. Kennedy N, Berger L, Curram J, Fox R, et al. Randomized controlled trial of a drug regimen that includes ciprofloxacin for the treatment of pulmonary tuberculosis. Clin Infect Dis 1996; 22:827–833. 50. Gillespie SH, Kennedy N. Fluoroquinolones: a new treatment for tuberculosis? Int J Tuberc Lung Dis 1998; 2:265–271. 51. Lipsky BA, Baker CA. Fluoroquinolone toxicity profiles: a review focusing on newer agents. Clin Infect Dis 1999; 28:352–364. 52. Sato A, Tomioka K, Sano H, et al. Comparative antimicrobial activities of gatifloxacin, sitafloxacin and levofloxacin against Mycobacterium tuberculosis replicating within Mono Mac 6 human macrophage and A-549 type II alveolar cell lines. J Antimicrob Chemother 2003; 52:199–203. 53. Nuernberger EL, Yoshimatsu T, Tyagi S, et al. Moxifloxacin-containing regimens of reduced duration produce a stable cure in murine tuberculosis. Am Rev Respir Dis 2004; 170:1131–1134. 54. Sulochana S, Rahman F, Paramasivan CN. In vitro activity of fluoroquinolones against Mycobacterium tuberculosis. J Chemother 2005; 17:169–173. 55. World Health Organization. Adherence to long-term therapies. Evidence for action. WHO 2003. 56. Maher D, Uplekar M, Blanc L, Raviglione M. Concordance and tuberculosis treatment (editorial). Brit Med J 2003; 327:822–823. 57. Chaulk CP, Moore-Rice K, Rizzo R, et al. Eleven years of community-based directly observed therapy for tuberculosis. JAMA 1995; 274:945–951. 58. Weiss SE, Slocum PC, Blin FX, et al. The effect of directly-observed therapy on the rates of drug resistance and relapse in tuberculosis. N Engl J Med 1994; 330:1179–1184. 59. China Tuberculosis Control Collaboration: Results of directly-observed shortcourse chemotherapy in 112,842 Chinese patients with smear-positive tuberculosis. Lancet 1996; 347:807–809. 60. World Health Organization: WHO Tuberculosis Programme. Framework for Effective Tuberculosis Control. WHO Report WHO/TB/94.179. Geneva: World Health Organization, 1994. 61. Suarez PG, Watt CJ, Alarcon E, et al. The dynamics of tuberculosis in response to 10 years of intensive control effort in Peru. J Infect Dis 2001; 184:473–478.

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62. Chen F, Zhao H, Duanmu H, et al. The DOTS strategy in China; results and lessons after 10 years. Bull World Health Organ 2002; 80:430–436. 63. Volmink J, Matchaba P, Garner P. Directly observed therapy and treatment adherence. Lancet 2000; 355:1345–1350. 64. Jindani A, Nunn AJ, Enarson DA. Two 8-month regimens of chemotherapy for treatment of newly diagnosed pulmonary tuberculosis: international multicentre randomised trial. Lancet 2004; 364:1244–1251. 65. Korenromp EL, Scano F, Williams BG, et al. Effects of human immunodeficiency virus infection on recurrence of tuberculosis after rifampin-based treatment: an analytical review. Clin Infect Dis 2003; 37:101–112. 66. Mitchison DA, Nunn AJ. Influence of initial drug resistance on the response to short-course chemotherapy of pulmonary tuberculosis. Am Rev Respir Dis 1986; 133:423–430. 67. Darbyshire JH, Aber VR, Nunn AJ. Predicting a successful outcome in shortcourse chemotherapy. Bull Int Union Tuberc 1984; 59:22–23. 68. Costello HD, Caras GJ, Snider DE Jr. Drug resistance among previously treated tuberculosis patients: A brief report. Am Rev Respir Dis 1980; 121:313–316. 69. Pablos-Mendez A, Raviglione MC, Laszlo A, et al. Global surveillance for antituberculosis drug resistance, 1994–1997. N Engl J Med 1998; 338:1641–1649. 70. Espinal MA, Laszlo A, Simonsen L, et al. Global trends in resistance to antituberculosis drugs. N Engl J Med 2001; 344:1294–1303. 71. World Health Organization. Anti-Tuberculosis Drug Resistance in the World. Third Global Report. WHO/HTM/TB/2004.343. 72. Goble M, Iseman MDR, Madsen LA, et al. Treatment of pulmonary tuberculosis resistant to isoniazid and rifampin: Results in 171 cases. N Engl J Med 1993; 32:527–532. 73. Telzak EE, Sepkowitz K, Alpert P, et al. Multidrug resistant tuberculosis in patients without HIV infection. N Engl J Med 1995; 333:907–911. 74. Burgos M, Gonzalez LC, Paz EA, et al. Treatment of multidrug resistant tuberculosis in San Francisco: an outpatient–based approach. Clin Infect Dis 2005; 40:968–975. 75. Centers for Disease Control and Prevention. Notice to Readers: Acquired rifamycin resistance in persons with advanced HIV disease being treated for active tuberculosis with intermittent rifamycin-based regimens. MMWR 2002; 51:214–215. 76. Bishai WR, Graham NMN, Harrington S, et al. Brief report: Rifampicin resistant tuberculosis in a patient receiving rifabutin prophylaxis. N Engl J Med 1996; 334:1573–1575. 77. Burman W, Gallicano K, Peloquin C. Therapeutic implications of drug interactions in the treatment of HIV-related tuberculosis. Clin Infect Dis 1999; 28:419–430. 78. World Health Organization. Scaling Up Antiretroviral Therapy in Resource-limited Settings. World Health Organization. Geneva, 2002. 79. http://www.cdc.gov/nchstp/tb/TB HIV Drugs/TOC.htm. 80. http://www.aidsinfo.nih.gov/guidelines. 81. Narita M, Ashkin D, Hollander ES, et al. Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS. Am J Respir Crit Care Med 1998; 158:157–161. 82. Wendel KA, Alwood KS, Gachuhi R, et al. Paradoxical worsening of tuberculosis in HIV-infected persons. Chest 2001; 120:193–197. 83. Ramos A, Asensio A, Perales I, et al. Prolonged paradoxical reaction of tuberculosis in an HIV infected patient after initiation of highly active antirtetroviral therapy. Eur J Clin Microbiol Infect Dis 2003; 22:374–376.

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84. Girling DJ. Adverse effects of antituberculosis drugs. Drugs 1982; 23:56–74. 85. Johnson JR, Turk TL, MacDonald FM. Corticosteroids in pulmonary tuberculosis: III. Indications. Am Rev Respir Dis 1966; 94:62–73. 86. Chan ED, Laurel V, Strand MJ, et al. Treatment and outcome analysis of 205 patients with multidrug-resistant tuberculosis. Am J Respir Crit Care Med 2004; 169:1103–1109. 87. Campbell IA. The treatment of superficial tuberculous lymphadenitis. Tubercle 1990; 71:1–3. 88. Campbell IA, Dyson AJ. Lymph node tuberculosis: A comparison of various methods of treatment. Tubercle 1977; 58:171–179. 89. British Thoracic Society Research Committee: Short course therapy for tuberculosis of lymph nodes: A controlled trial. BMJ 1985; 290:1106–1108. 90. Nemir RL, Cardona J, Vagiri F, et al. Prednisone as an adjunct in the chemotherapy of lymph node-bronchial tuberculosis in childhood, a double blind study: II. Further term observations. Am Rev Respir Dis 1967; 95:402–410. 91. Gow JG. Genitourinary tuberculosis: a study of short course regimens. J Urol 1976; 115:707–711. 92. Medical Research Council Working Party on Tuberculosis of the Spine: a five-year assessment of controlled trials of in-patient and out-patient treatment and of plaster-of-Paris jackets for tuberculosis of the spine in children on standard chemotherapy. J Bone Joint Surg 1976; 58:399–411. 93. Medical Research Council Working Party on Tuberculosis of the Spine: five-year assessments of controlled trials of ambulatory treatment, debridement and anterior spinal fusion in the management of tuberculosis of the spine. J Bone Joint Surg 1978; 60:163–177. 94. O’Toole RD, Thornton GF, Mukherjee MK, et al. Dexamethasone in tuberculous meningitis. Ann Intern Med 1969; 70:39–48. 95. Giris NI, Forid Z, Kilpatrick ME, et al. Dexamethasone as an adjunct to treatment of tuberculous meningitis. Pediatr Infect Dis 1991; 10:179–185. 96. Wang JT, Hung CC, Sheng WH, et al. Prognosis of tuberculous meningitis in adults in the era of modern antituberculous chemotherapy. J Microbiol Immunol Infect 2002; 35:215–222. 97. Strang JIG, Kakaza HHS, Gibson DG, et al. Controlled trial of prednisolone as an adjunct in treatment of tuberculous constrictive pericarditis in Transkei. Lancet 1987; 2:1418–1422. 98. Mayosi BM, Ntsekhe M, Volmink JA, et al. Interventions for treating tuberculous pericarditis. Cochrane Database of Systematic Reviews (4) CD000526, 2002. 99. O’Brien RJ, Nunn PP. The need for new drugs against tuberculosis. Am J Respir Crit Care Med 2001; 163:1055–1058. 100. Stover CK, Warrener P, Vandevantner DR, et al. A small molecule nitroimidazpyran drug candidate for the treatment of tuberculosis. Nature 2000; 405:962–966. 101. Andries K, Verhasselt P, Guillemont J, et al. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science 2005; 307:223–227. 102. Cole ST, Alzari PM. Enhanced: TB—a new target, a new drug. Science 2005; 307:214–215. 103. Dye C. The science of social diseases. Science 2005; 307:181.

9 Diagnosis of Latent Tuberculosis Infection

DICK MENZIES

T. MARK DOHERTY

Epidemiology, Biostatistics, and Occupational Health, Montreal Chest Institute, McGill University, Montreal, Quebec, Canada

Department of Infectious Disease Immunology, Statens Serum Institute, Copenhagen, Denmark

I. Tuberculin Skin Testing A. Introduction

Among tests presently used in clinical medicine, the tuberculin skin test (TST) is one of the few that were introduced into clinical use 100 years ago. Given such a long history of use, it may seem surprising that the interpretation of the TST remains controversial today. However, this reflects the changing epidemiology, clinical features, investigation, and management of tuberculosis (TB). In industrialized countries, new problems have arisen in the interpretation of the TST in certain high-risk populations because of aging, HIV infection, intravenous drug use, and other phenomena that may adversely affect immune responsiveness. The first tuberculin test material was prepared by Koch, who filtered heat-sterilized cultures of Mycobacterium tuberculosis grown on veal broth and then evaporated the filtrate to 10% of the original volume (1). This became known as old tuberculin (OT). Koch tried OT unsuccessfully as a therapeutic agent. In 1907, von Pirquet recognized its potential value for detection of persons infected with TB (2). In 1910, Mantoux introduced the intradermal technique, which still bears his name (3). 215

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OT proved unreliable and nonspecific because the filtrate was very heterogeneous. In 1934, Dr. Florence Seibert working at the Phipps Institute in Philadelphia developed a technique of extraction of protein from autoclaved TB bacteria grown on artificial media. Results with this purified protein derivative (PPD) proved much more reproducible and specific (4). After considerable work to standardize this material, a large quantity was carefully prepared by Dr. Seibert in 1939, termed PPD-Standard, or PPD-S (5). By international agreement, since that time all tuberculin skin testing material produced must be bioequivalent to this standard lot. North American manufactured tuberculin test material, which is bioequivalent to PPD-S, will be referred to as PPD-T in this review. Other tuberculin testing materials have been produced from M. tuberculosis and from other mycobacteria. These are summarized in the glossary of terms. The final refinement of the tuberculin test was the addition of Tween, a detergent that minimized the adsorption of tuberculin protein to glass or plastic. This allowed prolonged storage and further improved the reproducibility of results using the test (6–9). Injection of tuberculin material intradermally into a person previously infected with M. tuberculosis will result in infiltration of previously sensitized lymphocytes circulating in peripheral blood. At the site of injection, CD4 and CD8 T lymphocytes will accumulate, as well as monocytes and macrophages. These release inflammatory mediators, which produce edema and erythema. Although there is increased blood flow, the locally increased metabolic activity of these inflammatory cells results in relative hypoxia and acidosis, which may be severe enough to result in ulceration and necrosis (10). Tuberculin reactions have often been equated with immunity against M. tuberculosis. This is erroneous, even though both result from exposure and acquisition of infection. It has been well established that TST reactions and immunity are, in fact, independent phenomena (11–13). New molecular biology techniques (14) could prove useful to better understand these two phenomena. It would be of enormous benefit if we could distinguish tuberculin reactions that indicate immunity (decreased risk of developing TB) from those that indicate increased future risk of TB. B. Technical Aspects of Tuberculin Skin Testing Administration of the Test

Tuberculin material, manufacturer, and technique of administration may affect TST results. At the present time, the only accepted material for use in tuberculin testing is PPD. Manufacturers must ensure that each batch of tuberculin material is standardized against the original batch lot of PPD-S—in testing of experimental animals infected with the H37Rv strain of M. tuberculosis. There are two North American manufacturers: Connaught Laboratories (now, Aventis-Pasteur, manufacturing Tubersol1) and Parkdale Pharmaceuticals (manufacturing Aplisol1). Earlier studies demonstrated that Tubersol had higher sensitivity when compared to

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Aplisol (8,15), and there have been a number of reports of false-positive results using Aplisol (16–18). In a more recent study, results with the two products were closely comparable (19). In Europe, the Serum Statens Institute of Copenhagen, Denmark, developed a tuberculin test material termed RT-23. After considerable standardization work (20), this product was accepted as a standard tuberculin by the World Health Organization (WHO) (20,21) and is widely used outside North America. In one comparative study, two tuberculin units (2TU) of RT-23 had nearly identical sensitivity to 5TU of PPD-S, although specificity was slightly lower (22). The results of these two test materials are similar enough that results from studies using 2TU of RT-23 can be considered comparable to results of studies using 5TU of PPD-T. Tuberculin test materials are commercially available in strengths ranging from 1 to 250TU per test dose. Administration of 1TU PPD-S is not recommended because this preparation has a sensitivity of only 50% in children (23) and 80% in adults (24) with confirmed active TB. Also, the theoretical advantage of reduced occurrence of adverse events with the lower dose has not been demonstrated (25). Higher strength formulations such as 100TU PPD-S or 250TU are not recommended because virtually all subjects with sensitivity to nontuberculous mycobacteria (NTM) will be positive (26), and these reactions are more likely to revert later (27). As well, there is no relationship between reactions to these higher dose tests and the likelihood of true TB infection (28). Despite clear recommendations by WHO (29) and other organizations (30,31), published studies continue to use nonstandard doses such as 1TU PPD-S (32,33), 3TU PPD-S (34), or 1TU RT23 (35). Use of these lower doses may reduce sensitivity. In other studies, excessive doses such as 10TU PPD-S have been used (31)—this will worsen specificity. The TST can be administered using the Mantoux method of intradermal injection, or using multipuncture techniques such as the Heaf or Tine tests (the Heaf test is no longer distributed in the United Kingdom). Results of studies comparing the Mantoux with multipuncture techniques are summarized in Table 1. Multipuncture techniques have lower sensitivity with false-negative rates of 15% reported (43). Sensitivity can be improved by lowering the cut-point, but this will reduce specificity (36). Results of the multipuncture tests are much less reproducible than when the Mantoux technique is used (37,44). Problems of the multipuncture devices include uneven coating of the tuberculin material on the tines (45) and difficulty of standardizing the technique of administration (43). Jet injectors have been used, particularly in surveys of young children, but the depth and amount injected is much less reliable so results are even more variable (46). Based on this evidence, it can be strongly recommended that for all tuberculin testing a dose bioequivalent to 5TU of PPD-S be administered using the Mantoux technique of intradermal injection. Use of a 26-gauge needle is recommended. Smaller needles will result in less pain, bruising, and bleeding (47), but the dose administered appears to be less reliable (47).

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Table 1 Comparison of Multipuncture Techniques with Mantoux

Author (Ref.)

Tine Mantoux 5TU % 10þ mm Criteria for Sensitivity Specificity (positive) positive (%) (%) N tested

Badger et al. (36)

1001

43

Furcolow et al. (37) Fine et al. (38)

770

46

589

64

Donaldson and Elliota (39)

135

Hansen et al. (40) 829

2 mm 6 mm 2 mm

97 78 97

66 86 90

100

2 mm 5 mm 2 mm

98 90 84

66 86 –

5

2 mma 2 mm

90 69

– 98

Mantoux 5TU Katz et al. (41)

852

43%b

Carruthers (42)

7805

6.60

Heaf Grades 2–4 Grades 3–4 Grade 4 Grades 2–4 Grades 3–4 Grade 4

75 66 15 71 34 7

84 87 98 98 99 99

Note: Mantoux with five tuberculin units purified protein derivative-standard (PPD-S) considered gold standard in all studies. a In this study, second set of results using Tine with PPD. All other results of Tine using old tuberculin. b In this study, tuberculin skin test of 5þ mm considered positive. Abbreviation: TU, tuberculin units.

Failure to inject the correct dose (e.g., due to leakage) will result in smaller reactions (29) and so may lead to false-negative results. The size of the wheal produced following intradermal injection is affected by age and gender, so this is not a reliable way to verify the amount injected (21,48). If injections are given subcutaneously, larger, more diffuse reactions will result (49), which are more difficult to read (29). The site of injection is not important (29), although the inner or volar aspect of the forearm is generally used for convenience. The site of testing should be varied, especially with the two-step protocol, because repeated tests at exactly the same site may result in false positive reactions (50). Reading the Test

Timing and method of reading as well as experience of readers may affect results. Reading after six hours was suggested as indicative of active disease

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because 72% of 109 patients with smear-positive active TB had reactions of 5þ mm after six hours compared to only 3.5% of 143 healthy volunteers (51). However, in a subsequent study, reactions after six hours were equally common in patients with inactive TB or other respiratory diseases, and in health-care workers with heavy exposure (52), i.e., this was a nonspecific phenomenon. Readings at 24 hours were compared to readings at 48 hours in another study. Using the 48-hour readings as the gold standard, readings at 24 hours had only 71% sensitivity and a 9% false-positive rate (53). Readings were made every day for seven days following tuberculin testing of 308 adults with active TB (mean age 51). In total, 296 (97%) had positive reactions 48 to 72 hours following testing. Reading at 96 hours was almost as sensitive, but by day 7, 21% had reverted to negative (24). Among 380 elderly nursing home residents (mean age 75), 23 (19%) of those with positive reactions (10þ mm) at 48 hours had reverted to negative after seven days (54). On the other hand, 20 other residents with negative reactions at 48 hours had positive reactions after seven days (54). When two-step testing is performed, reading the first tuberculin test after seven days has been suggested because the second test can be administered immediately for those with negative reactions. This approach is more practical but is not recommended, because about 20% of persons with an initial positive TST would be missed. These persons would lose the potential benefits of detecting Latent TB infection (LTBI). As well, a substantial number may be found with positive TST at one week, who would have been TST negative at 48 to 72 hours. Their risk of TB (and hence their appropriate management) is unknown. All information regarding risk of TB (reviewed below) is based on TST measured 48 to 72 hours after testing. Therefore, readings should be made 48 to 72 hours following administration, given the reduced sensitivity and uncertain interpretation of readings made later (21). Induration can be defined by palpation, or the ballpoint method, introduced by Sokal (55). Correlation between these two reading techniques is very high (R ¼ 0.94) (56) and differences between readings are small (56–59), regardless of reader experience (57,59). Overall, the ballpoint technique appears to be slightly faster (58), more sensitive (58), and less variable (59). Self-reading by patients has resulted in clinically significant misclassification in 8.5% of Heaf tests (60) and 11% misclassification following Mantoux testing (53). In the latter study, of 525 patients with negative tuberculin tests, only five patients believed there was significant induration (specificity 99%). On the other hand, of 212 patients with reactions of 10þ mm measured by a trained observer, only 79 patients believed they had any reaction (sensitivity ¼ 37%) (53). Under-reading by patients was also reported in New York, where only 1 of 18 patients with a positive tuberculin reaction correctly interpreted their reaction as positive (61). Table 2 summarizes the variability of results with the Mantoux and multipuncture techniques. Biological variation estimated from two simultaneous tuberculin tests is remarkably small given the inherent variability resulting from administration and reading. Standard deviation of readings and

Subjects (N)

Griffith (69)

Pouchot et al. (68) Variability of Heaf test readings Carruthers (67) 3

69

2 1

2

3 2.7–3.5

2.5

1.3–1.9 –

4 2 7 4 4 6 2 3

–

–

1

96

46

Chaparas et al. (62) 1036 Variability of Mantoux readings: within readers Bearman et al. (63) 36 Furcolow et al. (37) 670 Variability of Mantoux readings: between readers Loudon et al. (64) 53 Fine et al. (38) 189 Erdtman et al. (65) 121 Perez-Stable and Slutkin (66) 537 Howard and Solomon (53) 806 Carruthers (67) 46

1

Readers (N)

Variability of Mantoux reactions: two tests in same subjects Furcolow et al. (37) 212

Author (Ref.)

Standard deviation (mm)

Table 2 Variability of Tuberculin Test Results with Mantoux and Heaf Tests

21 7

25–35

12–23

10

4 11 20

9 12

1.2

5

7 1

Misclassified positive/negative (%)

Difference of 1 grade Interobserver Intraobserver

Difference of 3þ mm Difference of 4þ mm

Difference 5–9 mm Difference 10þ mm

Comments

220 Menzies and Doherty

Diagnosis of Latent Tuberculosis Infection

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misclassification errors are considerably less within than between readers, although differences between readers should average less than 2 mm (21). In two studies (63,65), systematic differences between one reader and the others contributed the majority of variance and misclassification errors—a potentially correctable problem through further training and/or elimination of such readers. Another potential cause of reader error is terminal digit preference or rounding. This problem can result in substantial misclassification, particularly if there is conscious or unconscious bias on the part of the reader. This can be reduced by use of simple measuring calipers, such as those used by mechanics or tailors, available in most hardware stores for less than US $10. Adverse Reactions

Adverse reactions to TST are rare. Vasovagal reactions can occur as with any injection. Immediate wheal and flare with a local rash was seen in 2.3% of allergy clinic patients (70). These reactions were associated with a history of atopy but not with positive tuberculin reactions at 48 to 72 hours. Lymphangitis has been reported following testing using Mantoux or Heaf techniques (71), and is associated with severe blistering and/or ulceration at the site of injection. Severe anaphylaxis has been reported on one occasion following Mantoux testing. A patient with active tuberculous lymphadenitis developed shock with renal and hepatic dysfunction within hours of receiving an 1TU dose of PPD-T (25). There have been two cases of anaphylaxis, one of them fatal (72,73), associated with Tine testing. In the nonfatal case, serum immunoglobulin E to PPD was undetectable and the authors believed that the gum used as an adherent to coat the tuberculin material on the tines was responsible (72). Allergic reactions are not more likely in persons with positive tuberculin reactions. In approximately 1% to 2% of patients with positive reactions, there may be severe blistering and even ulceration. Hydrocortisone cream is often given but was of no benefit in the only randomized controlled trial to assess its use (74). An undocumented history of a prior positive tuberculin test is not a contraindication to tuberculin testing because patient recall is often inaccurate, and severe reactions are not more frequent (75). There is no evidence whatsoever that tuberculin testing poses any risk in pregnancy (76) nor that tuberculin reactions are influenced by pregnancy (77), although the manufacturers’ product monograph mentioned this as a potential precaution in past years (78). Similarly, tuberculin testing is not contraindicated in nursing mothers. C. Interpreting the Tuberculin Skin Test: False-Negative and False-Positive Reactions

Interpretation of any test in clinical medicine requires understanding of the causes and likelihood of false-negative and false-positive results in the population being tested.

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Table 3 Causes of False-Negative Tuberculin Tests Technical (can be corrected) Material Poor quality production or contamination. Inadequate concentration (e.g., 1TU) Improper storage (exposure to light or heat), non-stabilized (no Tween), or use after expiry date Administration Material not injected properly, e.g., too deep (can also cause larger reactions) Interval between drawing up in syringe and administration too long (> 20 min) Reading Inexperienced or biased reading, rounding error Reading too soon (< 40 hr) or too late (> 80 hr) Error in recording result Biological (cannot be corrected) Viral infections HIV infection (most important) Measles Mumps Varicella (chickenpox) Live virus vaccination (measles, mumps, varicella, rubella, yellow fever) Tuberculosis Active TB disease—particularly if more advanced pulmonary or miliary Other illnesses Malignancies, especially lymphomas Renal failure Malnutrition Major surgery Therapy Immune suppression Corticosteroid (
15 mg prednisone daily for 2–4 wk) Cancer therapy Transplant therapy Infliximab Age Very young (infants) Elderly Abbreviation: TU, tuberculin unit.

False-Negative Tests

As summarized in Table 3, the TST may be false negative because of technical problems in the preparation or storage of material, or in the administration or reading of the test. Most of these problems can be avoided by meticulous technique in test administration and reading. Proper storage is important because test material will deteriorate if exposed to light or heat or if frozen. However, some misclassification is inevitable because of the variability related to differences in administration, biological response, and reading. Biological causes of false-negative results are more difficult to avoid. False-negative tests may occur in patients with active TB disease: estimates

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range from 5% to 8% in cross-sectional studies of patients already on treatment (79) to 17% (7) at the time of diagnosis, 30% among elderly patients (80), and 50% in patients with advanced disease in Nigeria (81). False-negative tests in TB patients are associated with more advanced forms of TB (82), malnutrition (83), and elevated serum creatinine levels (84). Malnutrition and associated immunological changes have also been implicated in the temporary anergy seen in refugees from Southeast Asia (85). An important cause of false-negative reactions is HIV infection. The proportion of false-negative reactions in dually infected (HIV and TB patients ranges from 15 to 28% in those with CD4 counts greater than 400 to 500 up to 100% in patients with CD4 counts less than 200 (86–89). As shown in Figure 1 it is interesting to note that even though the proportion of HIV seropositive patients with false-negative TST increases as the CD4 count falls, the pattern of reactions in the populations does not change (88,90–92). It appears that rather than progressive diminution in size, there is simply a greater proportion of individuals with negative tests as the CD4 count falls. This suggests that the TST response is an all-or-nothing phenomenon; once immunity falls below a certain threshold the tuberculin response is lost. Another important cause of false-negative tests is older age (93). In North American populations, the proportion with a positive tuberculin reaction increases up to the age of 65, after which it declines. As seen in Figure 2, although the number with reactions diminishes with older age, the size of reactions does not change—findings confirmed elsewhere (95). These cross-sectional findings have been confirmed in longitudinal studies, which have demonstrated reversion of positive tuberculin reactions in elderly nursing home residents (54,96,97). As with HIV-infected patients, it seems that tuberculin reactions in the elderly do not diminish gradually but ‘‘turn off,’’ suggesting that there is some threshold reached during aging. The trigger or threshold for reversion (and presumably conversion) is unknown.

Figure 1 Effect of CD4 counts (as a marker of immune status) on tuberculin reactions in HIV infected. HIV negative ¼ black fill; HIV þ > 600 ¼ white fill; HIV þ 400 to 599 ¼ white fill with vertical strips; HIV þ 200 to 399 ¼ white fill with black dots; HIV þ < 200 ¼ white fill with vertical and horizontal lines. Source: From Ref. 88.

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Figure 2 Effect of age on initial tuberculin reactions in Arkansas nursing home residents. Group 50 to 64 ¼ solid line with black diamond; group 65 to 79 ¼ solid line with white square; group 80þ ¼ solid line with white diamond. Source: Redrawn from Ref. 94; data courtesy of Dr. W. Stead.

Anergy testing, reviewed extensively elsewhere (98), has been suggested for the assessment of individuals with negative tests (99). Reactions to antigens such as mumps, Candida, diphtheria, or tetanus are seen in almost all healthy adults (100). Therefore, an individual who does not react to any of these antigens may have a false-negative tuberculin test. On the other hand, a tuberculin test result can be considered true negative if an individual reacts to one or more of these common antigens. As shown in Figure 3, among HIV-infected patients with negative tuberculin tests, the incidence of TB was significantly higher in those who were anergic compared to those who were not (101–103). In another study, negative tuberculin tests were strongly associated with anergy (86). However, in individual patients, results of anergy testing can be very misleading, because anergy status may change over time independent of changes in tuberculin status (89,104,105). Because of this, anergy testing is not recommended for management of individual patients (106), although this may be useful for epidemiological studies in HIV-infected populations (107).

Figure 3 Incidence of active tuberculosis in the HIV-infected, by tuberculin and anergy test results. Intravenous drug users (IVDU)-Spain ¼ black fill; IVDUSpain ¼ white fill; IVDU-Italy ¼ white fill with black dots. Source: From Refs. 101–103.

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False-Positive Tests: Bacille Calmette–Gue´rin Vaccination

Of the 1.2 million infants born each year worldwide, approximately 88% receive bacille Calmette–Gue´rin (BCG) vaccination (see Chapter 19). BCG vaccination of tuberculin-negative individuals will almost invariably result in tuberculin conversion within four to eight weeks (108,109). The size of TST reactions two to three months after BCG vaccination is affected somewhat by the vaccine manufacturer (109), dose (110), and method of administration (110,111). On occasion, individual strains produced by different manufacturers have been associated with significantly fewer tuberculin conversions (11,109). Generally, such strains are discarded because regulatory agencies require that BCG strains induce tuberculin conversion in over 90% of recipients. This is based on observations in the preantibiotic era that TB incidence and related mortality in students who were TST negative when they entered nursing school was considerably higher than in TST-positive entrants (112–114). However, this was actually because of the protective effect of prior TB infection, because none of these students had received BCG (115). As well, there is convincing evidence from several studies that postvaccinal TST reactions have no relationship to protective efficacy (11,116–118). The continuing insistence by regulatory agencies that 90% of BCG vaccinees manifest a positive TST within two to three months is primarily because actual immunity is very hard to measure. From a TB control program point of view, it would be much more practical if BCG vaccination conferred immunity. yet had no effect on tuberculin reactions. Although virtually all recipients will have positive tuberculin reactions within two months of BCG vaccination, these reactions will wane over time. Waning is faster in those vaccinated in infancy (108,119). As summarized in Table 4, among all subjects who received BCG vaccination in infancy, only 3% to 5% will manifest a positive TST as a result of this vaccination (119–121,131). This may reflect the relative immaturity of the immune systems in infancy (132), although protective efficacy is, if anything, higher (133,134). Of those vaccinated at an older age, tuberculin reactions are larger and wane more slowly. However, even after an interval of more than 10 to 15 years, on average 30% to 35% will still have BCG-related positive TST reactions (108,109,120,121,124,133). The pattern of TST reactions is similar to that in TB-infected persons (135,136). In the great majority of countries with intermediate or high incidence of TB, BCG vaccination is given routinely at birth. In some countries, particularly those in Europe, vaccination is given at a later age and may be repeated. As shown in Figure 4A, among foreign-born schoolchildren and young adults in Montreal, history of BCG vaccination appeared to be an important cause of reaction in subjects from low-incidence countries but was less important in subjects from countries with higher incidence of TB (137). False-Positive Tests: Nontuberculous Mycobacteria

NTM exist in soil and water in the environment, particularly where the climate is warm and moist (138–141). The mechanism of acquisition of

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Table 4 Importance of Bacille Calmette–Gue´rin and Nontuberculous Mycobacteria as Causes of False-Positive Tuberculin Skin Test Reactions Number Cause BCG in infancy (age 0–1) (tested after 5þ yr) BCG at older age (2 and older) (tested after 5þ yr) Nontuberculous mycobacteria

False positive attributablea

Studies

Subjects

Mean (%)

Range (%)

7

2,155

6

0–12

35,119–123

6

1,614

39

8–80

109,120,121, 123–125

5

13,635

2

1–11

126–130

References

a

For every 100 persons with the cause in question (e.g., sensitivity to NTM antigen) the percent that will have false positive TST reactions of 10 mm or greater. Abbreviations: BCG, bacille Calmette–Gue´rin; TST, tuberculin skin test.

infection or sensitization to NTM antigens is unclear. However, as summarized in Table 5, in many parts of the world, a high proportion of individuals will have sensitivity to at least one NTM antigen by the age of 20 years. Although much less pathogenic than M. tuberculosis (147), these NTM may result in disease in humans, particularly lymphadenitis in young children, pulmonary disease in adults, and disseminated disease in patients with immune suppression (148,149). Antigens purified from the NTM (NTM antigens) have been given to patients with disease due to NTM. Sensitivity and specificity varied considerably in these studies. Testing with NTM antigens cannot be recommended for clinical use to diagnose nontuberculous mycobacterial disease (150–153). The NTM are also important because many of the antigens from NTM and M. tuberculosis are similar. This results in cross-reactivity when tuberculin testing. In experimental studies, animals infected with different mycobacteria developed the largest reactions to antigens prepared from the corresponding specific mycobacteria, and smaller reactions to antigens from other mycobacteria (154,155). In experimental studies, the pattern of reactions to PPD-S in different human populations (79) could be reproduced by testing guinea pigs infected with M. tuberculosis, NTM, or neither (155). The importance of NTM as a cause of false-positive TST depends upon the relative prevalence of infection with M. tuberculosis, and NTM. The latter is determined primarily by climate and geography, so is likely to remain stable. As the prevalence of true TB infection declines, the relative importance of NTM will increase. Because cross-reactions to PPD-S, due to infection with NTM, are smaller than reactions due to infection with

Diagnosis of Latent Tuberculosis Infection

227

Figure 4 Effect of BCG vaccination on TST. (A) Initial tuberculin reactions. (B) Two-step reactions (booster). Never had BCG-V ¼ white fill with black vertical lines; had BCG-V ¼ black fill. Source: From Refs. 121 (A), 120 (B).

M. tuberculosis, increasing the cut-point for a positive test will improve the specificity. This is the rationale for the recommendation of a 15-mm cutpoint in the United States (156) where the expected prevalence of true TB infection is low, but NTM sensitivity is high (at least in the southern United States). However the 15-mm cut-point for a positive TST is close

17–22 11–17 7–19 15–65

1958–1965 1975 1989 2002

Abbreviation: NTM, nontuberculous mycobacteria.

United States–Kansas Tropical/subtropical United States–Florida Kenya Vietnam The Gambia

14–19 7–11 7–11 17–22

1967

Temperate climates Canada–B.C.

17–22 11–17 8–9

15–17

Age

1965–1970 1980–1985 1958–1965

1958–1965 1987 1986

United States–New York Canada–Montreal Sweden

Netherlands

1967

Year

Cold climates Canada

Place

3076 344 153 499 746

3917 2894 13,546 10,312 4180

5552 24,763 25,138 3710 1368 1451

Subjects (N)

Antigens from NTM

M. M. M. M. M.

M. M. M. M. M. avium avium avium avium scrofulaceum

avium scrofulaceum scrofulaceum scrofulaceum avium

Mycobacterium avium Mycobacterium scrofulaceum M. avium M. avium M. avium M. scrofulaceum

Table 5 Prevalence of Sensitivity to Nontuberculous Mycobacteria

68 62 37 68 49

11 19 5 21 39

15 7 21 3 32 38

Prevalence 5þ mm reactions (%)

(143) (130) (145) (146)

(143)

(144)

(26)

(143) (126) (128)

(142)

Reference

228 Menzies and Doherty

Diagnosis of Latent Tuberculosis Infection

229

to the mode of tuberculin reactions in those with true TB infection (79). Therefore, adoption of a higher cut-point to improve specificity will reduce the sensitivity of the tuberculin test by approximately 40%. In experimental animals infected with NTM, the proportion demonstrating cross-reactivity to tuberculin antigens was reasonably constant (155). This appears to be true in human populations, although the populations studied and the nontuberculous mycobacterial antigens used varied considerably (157). D. Interpreting the Tuberculin Skin Test—Thinking in Three Dimensions The First Dimension: Size

This dimension is the easiest to understand (but the least important). Size criteria commonly used in different countries are summarized in Table 6. A criterion of 5 mm for a diagnosis of latent TB has sensitivity of more than 98%, but lower specificity. This criterion is used when maximum sensitivity is desirable because the risk of development of active disease is high. A criterion of 10 mm has sensitivity of 90%, and specificity of more than 95% in countries with low prevalence of NTM and/or high prevalence of true TB infection. This is used in clinical situations where risk is somewhat increased. A criterion of 15 mm or more has sensitivity of only 60 to 70%, but has high specificity ( > 95%) in most parts of the world. This criterion is not appropriate for use in countries with low NTM, nor in countries with high prevalence of true infection. In these settings, specificity is not much improved with this higher cut-point, yet the sensitivity is reduced considerably. The Second Dimension: Predictive Value of a Positive Initial Tuberculin Test What Is the Expected Prevalence of True Positive Tests (i.e., Tuberculosis Infection)?

As shown in Table 7, the prevalence of positive TST varies widely. Prevalence is very low in schoolchildren and young adults, although it is substantially higher in certain ethnic minorities (158,161,162). Particularly high rates of infection are found among the urban poor such as intravenous drug users, persons receiving social assistance (163,166), and homeless persons (168,169). The elderly also have high rates of positive tests attributable to the much higher risk of tuberculous infection during their youth. Among the foreign-born, prevalence of infection is correlated with incidence of TB in their country of origin and age of immigration. Contacts of active cases also have high prevalence of TB infection as shown in Table 8. Risk of infection is higher if the index case is smear positive or if the contact is close. However, absolute levels of risk have been estimated in relatively few studies that measured the prevalence of infection in noncontacts from the general population.

230

Menzies and Doherty

Table 6 The First Dimension of Interpretation of Tuberculin Test—Size Tuberculin reaction size (mm induration) 0–4

5þ

10þ 15þ

Setting in which reaction considered positive HIV infection with immune suppression and expected risk of tuberculosis infection is high (e.g., patient is from a population with high prevalence of TB infection, is a close contact of an active contagious case, or has an abnormal X-ray). This reaction size is not normally considered positive but in the presence of immune suppression may be important HIV infection Close contact of active contagious case Abnormal chest X-ray with fibronodular disease Other immune suppression (TNF-alpha inhibitors, chemotherapy, etc.) All other persons—in most countries No clinical risk factors and healthy. From population with low prevalence of TB infection and high prevalence of NTM sensitivity

Abbreviations: NTM, nontuberculous mycobacteria; TNF, tumor necrosis factor.

What Is the Likelihood of a False-Positive Test?

As shown in Table 9, BCG vaccination and NTM have important effects on the predictive value when the expected prevalence of true infection is low, such as in North America and Western Europe. On the other hand, when the expected prevalence of tuberculous infection is high, such as in close contacts of smear-positive cases or persons from high TB incidence countries, then the predictive value of a positive tuberculin test is high. In these situations, the effects of BCG vaccination and sensitivity to NTM can be ignored. The Third Dimension: Risk of Tuberculosis for a Given Tuberculin Skin Test

The third dimension to consider is the risk of development of disease. As shown in Table 10, the likelihood of developing TB disease varies by several orders of magnitude in different populations with positive TST. Interestingly, the incidence of TB was lower among TST reactors in a large Danish cohort (186,193) than in some tuberculin-negative cohorts (158,190,191). Use of this Danish data in cost-benefit or risk-benefit analyses may represent an underestimate of the likelihood of disease in most tuberculin reactors. When the three dimensions are considered together, then it can be seen that annual risk of developing active disease varies considerably depending upon whether BCG vaccination has been received and the presence or absence of risk factors in individuals with the same size of tuberculin reaction (such as 10þ mm). Individuals with a reaction of 5 to 9 mm (Text continues on page 237.)

Country (city)

Population

Ethnic group

United States

Trump et al. (162)

Military recruits

Schoolchildren

Menzies et al. (120) Canada (Montreal) University students Prevalence in special populations within low-incidence countries Reichman et al. (163) United States Methadone clinic (New York) Several (54,164,165) United States Nursing home Canada residents Holland Friedman et al. (166) United States ETOH/drug users, (New York) welfare

United States (Boston)

Barry et al. (161)

50–74 75–84
85 36 (9) 36 (9) 36 (9)

All

White Black Hispanic

N/A

17–22 17–22 20–68 20–68 20–68 17–22 11 (1) 16 (2) 16 (2) 17 (2) 17 (2) 17–24 17–24 17–24 21 (2)

Age: mean (SD) or range

All

White Black Hispanic White Black Hispanic > 95% white

Native-born, non–BCG-vaccinated general populations in low incidence countries Comstock et al. (158) United States Military recruits White Black Reichman and O’Day United States Workers, Board of White (159) (New York) Education Black Hispanic Cross and Hyams (160) Unites States Military recruits All Menzies (126) Canada (Montreal) Schoolchildren > 95% white

Author (reference)

Table 7 Prevalence of Positive Tuberculin Reactions

340 559 643 97 477 311

3788

1,125,193 70,550 37,224 10,364 2744 618,074 1351 628 661 1235 457 1588 386 167 837

No. tested (N)

(Continued )

46 28 17 18 33 31

23

3.8 12.4 8.3 23 26 1.5 1.3 2.9 1.4 4.9 6.4 0.8 5.2 5.4 1.8

TST positive (10þ mm) (%)

Diagnosis of Latent Tuberculosis Infection 231

Country (city)

Population

United States Canada

Blum et al. (176)

Yuan (177)

All countries

> 90% from Mexico

Afghanistan All countries TB endemic

13 (5)

720

4840

All ages

9328 954 221 7 231 1358 865 780

All ages 21 18 11–19 0–14

Refugees Refugees Refugees Refugees New immigrants Male refugees Refugees Schoolchildren, workers Immigrant applicants Schoolchildren

843

170 254 104

No. tested (N)

8 (1) 21 21 (3)

36

All

All

15–34 35–54 35 (9)

Age: mean (SD) or range

White males

Ethnic group

Note: Results of Mantoux testing with purified protein derivative-5 tuberculin units (TU) or RT23-2TU. Abbreviations: BCG, bacille Calmette–Gue´rin; ETOH, alcohol; TST, tuberculin skin test.

Pakistan Canada Canada

Spinaci et al. (174) Godue et al. (175) Menzies et al. (137)

Canada Urban poor (Vancouver) Paul et al. (168) United States Homeless (New York) Zolopa et al. (169) Unites States Homeless (San Francisco) Foreign-born populations within low incidence countries Nolan and Elarth (170) United States Southeast Asia Morse et al. (171) United States Southeast Asia Veen (85) Netherlands Southeast Asia Fitzpatrick et al. (172) United States Southeast Asia Ormerod (173) Britain India/Pakistan

Grzybowski et al. (167)

Author (reference)

Table 7 Prevalence of Positive Tuberculin Reactions (Continued )

23

42

14 38 37

35 44 39 52 13

32

16 44 69

TST positive (10þ mm) (%)

232 Menzies and Doherty

0–14 All ages 0–19 0–19 0–14 0–16 0–19 0–19 0–14 0–16

0–14 All ages 0–19 0–19 0–14 0–16 0–19 0–19 0–14 0–16

Canada (white) (Aboriginal) Holland (general) New Zealand (general)

England (general) New York City (general) Canada (white) (Aboriginal) Holland (general) New Zealand (general) Canada (white) (Aboriginal) Holland (general) New Zealand (general)

Age range

England (general) New York City (general) Canada (white) (Aboriginal) Holland (general) New Zealand (general)

Country (population)

a General population estimate for this study from Ref. 159. Abbreviation: TST, tuberculin skin test.

Van Geuns et al. (181) Karalus (182)

Van Geuns et al. (181) Karalus (182) Casual contacts Grzybowski et al. (180)

Van Geuns et al. (181) Karalus (182) Smear-negative, culture-positive cases Close/household contacts Zwanenberg (178) Zaki (179) Grzybowski et al. (180)

Van Geuns et al. (181) Karalus (182) Casual contacts Grzybowski et al. (180)

Smear-positive cases Close/household contacts Zwanenberg (178) Zaki et al. (179) Grzybowski et al. (180)

Author (reference)

2270 413 602 307

96 1096 1340 527 128 146

5364 654 1733 898

225 3330 2501 854 115 155

Tested (N)

Contacts

20 39 23

46 40 30 45 35 1.4

30 50 30 1.1

73 52 48 55 70 24

TST positive (%)

21 41 1 <1

38 13a 21 41 1 <1

21 41 1 <1

38 13a 21 41 1 <1

General population TSTþ (%)

Table 8 Prevalence of Positive Tuberculin Reactions in Contacts of Active Cases (All Index Cases Had Culture-Confirmed Active Pulmonary Tuberculosis)

Diagnosis of Latent Tuberculosis Infection 233

None

None

Age of 6

Age of 6

Birthplace of subject

Northern United States or Canada

Southern United States

Western Europe

Southeast Asia

Screening Close contact Casual contact Screening Close contact Casual contact Screening Close contact Casual contact Screening Close contact Casual contact

Clinical situationa 1 40 10 1 40 10 1 40 10 50 70 55 (40 þ 50) (10 þ 50)

þ1 þ1

þ1 þ1

þ1 þ1

True positive 1 1 1 3 3 3 2 2 2 3 3 3

NTM

– – 15 15 15 15 15 15

– – –

BCG

False positive

50 95 86 25 88 67 10 68 39 83 92 85

Predictive value of a positive test (%)

b

Clinical situation: screening means test done in absence of exposure/risk factor; contacts are of smear-positive, culture-positive case of TB. Expected prevalence ¼ (prevalence of TB infection in 20-year-olds from general population)þ (additional prevalence of TB infection depending on clinical situation) (see Table 7 for prevalence in populations and Table 8 for prevalence according to the clinical situation). Abbreviation: BCG, bacille Calmette–Gue´rin; NTM, nontuberculous mycobacteria.

a

History of BCG vaccination

Expected prevalence of reactions (%)b

Table 9 Predictive Value of a Positive Initial Tuberculin Skin Test (10þ mm) for Latent Tuberculosis Infection in a 20-Year-Old Adult

234 Menzies and Doherty

Denmark

Netherlands

Britain

Contacts of active cases Veening (187)

Recent conversion Sutherland (188)

Italy

Antonucci et al. (102)

Horwitz et al. (186)

Spain

Guelar et al. (101)

United States Eastern Europe

Spain

Moreno et al. (103)

Hong Kong

United States

HIV-infected Selwyn et al. (183)

Abnormal chest X-ray Hong Kong Chest Service (184) Nolan and Elarth (170) IUAT (185)

Country

Author (reference)

Adolescence

Contacts of Sþ cases

Elderly men with silicosis Vietnam refugees Inactive TB—all Lesions < 2 cm Lesions > 2 cm Young adults all Suspicious CXR Calcified

IVDU

IVDU

IVDU

IVDU

Group

Population

2

Year 1 Years 2–4

12

5 5

2–5

2

1.3 (1)

2–6

2–5

Follow-up period (yr)

2170

128

185 6990 4701 2094 286,000

116

49 168 108 268 87 733 197 2498

Number

Table 10 Risk of Tuberculosis According to Size of Tuberculin Skin Test Reactions and Other Factors

426 710 48


6

5þ 20þ

(Continued )

2600 4250

7031 2521

650 286 232


10
6


5

5400

7900 300 10,400 8290 11,100 2350 5420 2130

Annual incidence of TB (per 100,000)


10c


5 <5
5 < 5a
5b < 5a
5 < 5a

TST (criterion in mm)

Diagnosis of Latent Tuberculosis Infection 235

United States

United States

Puerto Rico Denmark

Comstock et al. (158)

Ferebee (191)

Comstock et al. (192) Horwitz et al. (186)

Children Young adults

Military recruits White Black Asian Mental institution patients

18–20 12

10

4

4

5

5.8

Follow-up period (yr)

b

Anergic and nonanergic combined. Excludes those still on INH therapy. c 94% had reactions of 10þ mm to 1 tuberculin unit of RT23. d Tested with 1 or 10TU RT-20/2 22. e Tested with 10TU. Abbreviations: CXR, chest X-ray; TST, tuberculin skin test; INH, Isoniazid; TU, tuberculin unit.

a

United States

Edwards et al. (190)

Military recruits

Vietnam refugees

United States

Nolan and Elarth (170)

Group

Inuit

Country

Normal chest X-ray, no other risk factor Comstock et al. (189) Alaska

Author (reference)

Population

82,269 286,000

1,082,3366 62,027 8238

570 275 3115 6028

Number


10
10
10 T1
10 T1 ¼ 5–9 T2
10 T2 < 5
6d
6e


5 <5
10 < 10
12 1–11 0

TST (criterion in mm)

Table 10 Risk of Tuberculosis According to Size of Tuberculin Skin Test Reactions and Other Factors (Continued )

79 93 196 122 82 66 19 90 23

972 378 133 10 377 110 36

Annual incidence of TB (per 100,000)

236 Menzies and Doherty

Diagnosis of Latent Tuberculosis Infection

237

Table 11 Interpretation of the Tuberculin Skin Test in Three Dimensionsa

Conditions Low risk reactors Fibronodular disease CXR Fibronodular disease CXR Recent TST conversion

BCG vaccination Positive Relative predictive Annual risk of (given after risk of TST size value (%) active TB (%) 2 yr of age) disease (in mm) 1.0 1.0 6.0 6.0 6.0 6.0 15.0 15.0

5–9 mm 10þ mm 5–9 mm 10þ mm 5–9 mm 10þ mm 10þ mm 10þ mm

No No No No Yes Yes No Yes

100 100 100 100 25 25 100 25

0.04 0.1 0.24 0.6 0.06 0.15 1.5 0.38

a

Four clinical examples given. Risk of disease in low risk reactors taken from Ref. 158. Abbreviations: TST, tuberculin skin test; BCG, bacille Calmette–Gue´rin; CXR, chest x-ray.

may have much greater risk of developing disease if they have fibronodular disease on their chest X-ray than low risk reactors with a 10 mm or more tuberculin reactions. Some examples are shown in Table 11. E. Serial Tuberculin Testing: Boosting, Conversion, and Reversion

Repeated tuberculin testing can result in larger reaction sizes because of nonspecific variation or as a result of boosting or true conversion. Nonspecific increases occur because of differences in administration, reading, and minor variation in response. The combined effect of these factors results in standard deviation of results of 2 to 3 mm (see again Table 2). Therefore, random variation should result in increased reactions of less than 6 mm (two standard deviations) in 95% of all those tested (194). Increases of 6 mm or more, therefore, should represent a true biological phenomenon. This could be conversion or boosting. Both terms refer to a newly positive tuberculin test after an initially negative test. Boosting is defined as recall of immunity in the absence of new infection. Conversion is defined as development of new hypersensitivity to mycobacteria following new TB or nontuberculous mycobacterial infection, including BCG vaccination. This distinction is not merely academic—boosting is associated with a substantially lower risk of TB—as little as 0.05% annually. Conversion has been associated with 4% to 6% annual incidence of TB in adolescents (188) or contacts of smear-positive active TB (187). The boosting phenomenon, first noted among BCG vaccine recipients in 1955 (195), is seen when there has been mycobacterial sensitization many years earlier. It is believed to occur when there are too few sensitized lymphocytes in circulation to produce a significant local response following the initial intradermal injection of tuberculin material. However, this injection

238

Menzies and Doherty

results in a rapid increase in the population of sensitized lymphocytes in circulation, so that a second test as little as a week later will produce a much larger reaction. Boosting is maximal if the interval between the first and second test is between one and five weeks (191,196,197) and is significantly less frequent if the interval is only 48 hours (198) or more than 60 days (197), although it can be seen up to two years after a first tuberculin test (195,198,199). As shown in Table 12, the boosting phenomenon has been demonstrated in almost all populations. The prevalence is usually less but is roughly proportional to the prevalence of initial tuberculin reactions in the same populations. In elderly patients, boosting may occur after a third (96) or even a fourth (164) sequential test. This has also been described in a group of malnourished Southeast Asian refugees (85). It can be seen in Table 13 that boosting is strongly associated with BCG vaccination at all ages. As shown in Figure 4B, among foreign-born subjects, history of BCG vaccination was a more important cause of boosting than country of origin (137). In a study of persons sensitized to NTM antigens, only 1.4% had significant reactions to a first test with 5TU of PPD-T, compared to 12% to 13% who demonstrated boosting after a second test with the same antigen (Table 13) (120,202). Based on this, it could be predicted that of young adults in the southern United States, 70% of whom will be sensitive to NTM antigens (143), only 1% to 3% will have positive initial reactions to PPD-T but 7% to 9% will demonstrate boosting—remarkably close to observed results in health-care workers in Alabama (199). There has been considerable debate regarding the definition of boosting. This debate seems pointless as there is no evidence that the size of the boosting reaction determines prognosis (except if one is using size to distinguish boosting from conversion—see below). A simple and practical definition is that the second test is positive if induration is 10 mm or greater. Subjects with such a result should be referred for medical evaluation including a chest X-ray and not undergo further tuberculin testing. If the chest X-ray is normal and there are no associated factors that increase the risk of TB reactivation, then preventive therapy is probably not warranted. This is because a positive second TST is much less likely to represent true infection (120,197) and because in two longitudinal surveys, the risk of TB was lower in subjects with a positive second TST compared to subjects with a positive initial TST from the same population (191,213). It must also be remembered that in several large scale longitudinal surveys, the risk of TB was very low among those whose initial TST was less than 10 mm (158,170). Boosting is best distinguished from conversion on clinical grounds. One can confidently attribute an increase in reaction size to boosting when the increase in reaction is seen after an interval of one to five weeks, and there has been little or no possibility of exposure, such as a health-care worker undergoing pre-employment testing. On the other hand, conversion can be confidently stated to have occurred following BCG vaccination in a

Morse et al. (209) Cauthen et al. (197) Menzies et al. (137) Morse et al. (171) Veen (85)

New York State United States Montreal New York State Netherlands

Boston Boston United States Uganda United States

United States Alabama Rochester, New York Montreal Maryland Chicago San Francisco San Francisco Washington W. Virginia Tennessee Holland

Setting

323 162 709 345c HIV-900 HIVþ95 211 2469 323 524 221

510 223

750 N/A 416 951 2558 267 411 1726

26 12 N/A 71 13 13 44 36 32 46 39

30 29

N/A 8.2 3.1 2.2 3.8 2.6 35 27

Initial testa

61 61 2.72 292 83 122 311 31 161 43 183

19 141

5.91 8.31 01 2.51 0.33 6.61 61 141

Second testb

Percent with positive

b

Initial test—% based on number undergoing T1, considered positive if
10 mm. Second test—% based on number undergoing T2, considered positive if 1; increase of 6 mm or more and TST2
10; TST1 < 5 mm and TST2
5 mm; TST1 < 10 mm and TST2
10 mm. c Number extrapolated from figures given in paper.

a

Foreign-born

IVDU

Hospital patients HIV-infected

Alvarez et al. (203) Van den Brande and Demedts (164) Barry et al. (204) Burstin et al. (205) Webster et al. (206) Hecker et al. (207) Lifson et al. (208)

Thompson et al. (198) Bass and Serio (199) Valenti et al. (200) Menzies et al. (120) Gross et al. (201) Richards et al. (202) Slutkin et al. (54) Gordin et al. (96)

Health-care workers

Nursing home residents

Author (reference)

Population

No. subjects undergoing T1

Table 12 Prevalence of Positive Initial and Second Tuberculin Skin Test from Two-Step Testing

Diagnosis of Latent Tuberculosis Infection 239

240

Menzies and Doherty

Table 13 Effect of Bacille Calmette–Gue´rin Vaccination and Nontuberculous Mycobacteria on Results of Two-Step Tuberculin Testing Population

No. subjects

Initial (PPD1) 10þ mm

BCG vaccination Never vaccinateda 3699 BCG in infancy 1469 BCG after age 5 3159 Nontuberculous mycobacterial sensitivity Not sensitive to NTM 362 Reacts to NTM antigens 128

Two-step (PPD2) 10þ mm

Reference

5.9% 6.3% 43%

4.0% 9.9% 18%

120,210 211,212 123

1.6% 2.2%

1.4% 12.7%

120,202

a

Data for never vaccinated from two studies in Canadian-born populations in Montreal, Canada: (i) schoolchildren and young adults; and, (ii) health-care workers. Abbreviations: NTM, nontuberculous mycobacteria; BCG, bacille Calmette–Gue´rin; PPD, purified protein derivative.

previously tuberculin-negative individual or in a situation of high risk of exposure, such as in an outbreak investigation, or a close contact of a highly contagious index case. One can also be more confident that an increased reaction is due to true conversion if several prior tuberculin tests were negative, particularly if two-step tuberculin testing was performed (199). But in many situations, it is difficult to distinguish conversion from boosting on clinical grounds alone. In these situations, the size of the second reaction and/or the increase in size can be used, although many conflicting size criteria have been recommended, i.e., increases of 10 mm (214,215), 12 mm (216), 15 mm (156), and 18 mm (199). The last three criteria are based on cross-sectional studies in elderly subjects (216), populations with high prevalence of BCG vaccination and/or NTM (217,218). These studies did not fully account for the possibility of boosting, which may have influenced the findings. At the present time, it is difficult to recommend any one cut-point to define conversion. The criterion should be lowered for young children or adolescents, close contacts, and immunocompromised hosts, because they have increased risk of disease. The cut-point should also be lowered if there were two or more negative tuberculin tests in the past—particularly if prior two-step testing has been negative. As with initial tuberculin testing, tuberculin conversions should be interpreted in light of the likelihood of true conversion as opposed to boosting and the likelihood of disease, if truly infected, as well as risks associated with preventive therapy in a particular patient. Another important issue is the interval between acquisition of infection and tuberculin conversion. This determines the interval between the first and second test in contact investigations—the so-called window period. Traditionally, this has been considered to be 12 weeks (149), but all

Diagnosis of Latent Tuberculosis Infection

241

available evidence from BCG vaccination and natural infection points to a shorter interval. Following BCG vaccination, all but one of 120 recipients had TST reactions of more than 11 mm within six weeks (219). In a separate group of 163 BCG recipients, all had TST >5 mm in less than four weeks (219). In animals experimentally infected with M. tuberculosis, all developed a positive TST within two to three weeks if the bacillary load was small (220), as it usually is in natural infection. Following inadvertent vaccination with M. tuberculosis (the Lu¨beck disaster), tuberculin reactions were positive in all children within three to seven weeks (221). As shown in Figure 5, the interval from exposure to development of clinical illness accompanied by a positive tuberculin test averaged 37 days and ranged from 19 to 57 days in 127 well documented cases (222–224). If the interval from infection to conversion is never more than eight weeks, then the window period for contact investigation could be shortened to eight weeks. This would mean that new conversions among high-risk contacts would be detected one month sooner. A more important advantage is that this could simplify the contact investigation of low-risk casual contacts and substantially reduce the occurrence of false-positive conversions. When two sequential tuberculin tests are done, boosting is much more likely to account for apparent conversion in casual contacts in populations where BCG or NTM sensitivity are common (225). This results in unnecessary medical and radiological evaluation as well as potentially unnecessary therapy for these individuals. Also, the resultant overestimate of conversion may result in further extension of contact investigation. In most situations, four to six weeks are needed to confirm M. tuberculosis in the index case and evaluate the close or high-risk contacts. Following the concentric circle approach, investigation of casual contacts will not be indicated in many instances. However, if the risk of transmission appears elevated based on the evaluation of the first circle of close contacts, then the lower-risk casual

Figure 5 Interval from infection to tuberculin conversion in 127 cases with documented time of exposure. Number with conversion ¼ black fill. Source: From Refs. 222–224.

242

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contacts should be identified and tuberculin tested. As a result, casual contacts are often first tested only five to seven weeks after the contact is broken. Following current recommendations, tuberculin testing would be repeated 8 to 12 weeks after the contact was broken. If all tuberculin conversions have occurred by eight weeks, then a single tuberculin test at that time would be sufficient to detect all low-risk casual contacts with infection. Performing only one test at eight weeks would avoid the difficulties of distinguishing boosting from conversion in this group. Waiting for eight weeks to perform a single test would not be appropriate for young children and/or immunocompromised contacts, such as HIV-infected populations. In these groups, false-positive results from boosting are of less concern because risk of active disease following new TB infection is much greater. Serial tuberculin testing has also revealed that tuberculin reversion may occur (27). Among 179 sailors treated with Isoniazid (INH) following tuberculin conversion, the majority later demonstrated reversion (226), although some of the initial tuberculin conversions may have actually resulted from the booster phenomenon in this study. Among South African schoolchildren with reactions of 14þ mm who were retested three times over the next two years, average reaction size was slightly smaller (perhaps because of regression to the mean) but more than 95% of reactions remained more than 10 mm on all occasions (227). Of 346 children with TST
10 mm who were treated for primary TB in Houston between 1953 and 1960 and were retested 3 to 10 years later, only 29 (8.4%) reverted (228). Reversion is most common for those who react only to 250TU dose (27), have initial reactions in the 5- to 9-mm range (228) or in the 10- to 14-mm range (27,226,229), or demonstrate the booster phenomenon (97,229). Reversion is also more likely if only a third sequential tuberculin test is positive (229). The phenomenon of reversion emphasizes that once a tuberculin reaction reaches 10 mm or greater, results of further testing become uninterpretable. If the tuberculin reaction reverts to negative and then becomes positive again, no clinical or epidemiological information is available to allow interpretation of such a phenomenon. II. Chest X-ray (for Diagnosis of Tuberculosis Infection) The chest X-ray examination is not usually considered a tool to diagnose TB infection. However, it is quite common that a chest X ray is done for some other reason and radiographic abnormalities consistent with previous TB infection are detected. As well, many high-income countries, such as Canada and the United States, screen incoming permanent residents, some of whom will have radiographic abnormalities. Individuals are considered to have ‘‘inactive TB’’ when the chest X ray shows certain abnormalities consistent with TB infection and a tuberculin test reaction of at least 5 mm. These individuals have increased risk of reactivation and may be considered for treatment of LTBI (see Table 1 and Chapter 7).

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The following radiographic findings are commonly believed to represent inactive TB, and although some are associated with increased risk of reactivation of active TB disease in future, others are not: 1.

2.

3.

4.

5.

Granulomas, which may be calcified or not, give the subject approximately double the risk of reactivation of active disease (186,230,231). Calcified hilar lymph nodes—if there are no parenchymal lesions, this group does not appear to have increased risk relative to tuberculin reactors with normal radiographs. Costophrenic angle blunting—this is due to past pleural effusion or pleurisy—which can have many causes. The most common cause in individuals from TB endemic areas is previous primary TB—such individuals have increased risk of reactivation of TB disease. Apical pleural capping—this is not felt to be related to TB infection and is a nonspecific finding that is more common in older individuals (232). Apical fibronodular disease—this is associated with increased risk ranging from 6 (170) to 19 times (230,231) that of tuberculin reactors with normal X rays. Individuals with more extensive abnormalities have greater risk of disease (185).

III. Interferon-c Release Assays Recently, in vitro T-cell–based assays that measure interferon-c (IFN-c) release have been developed. These assays operate on the basis that T-cells previously sensitized to TB antigens produce high levels of IFN-c when reexposed to the same mycobacterial antigens (233). At the present time, two different types of IFN-c release assays (IGRA) are commercially available and possible alternatives to tuberculin skin testing. These are the Quantiferon-TB GOLD or QFT (Cellestis Limited, Carnegie, Victoria, Australia) and the T SPOT-TB (Oxford Immunotec, Oxford, U.K.) assays. For the QFT, patients’ whole blood is incubated with M. tuberculosis antigens, and the resulting production of IFN-c is measured using an enzyme-linked immunosorbent assay. The T SPOT-TB assay incubates peripheral blood mononuclear cells with M. tuberculosis antigens, and measures the number of T-cells producing IFN-c using an enzyme-linked immunospot (ELISPOT) assay [interested readers are directed to two excellent reviews (233,234)]. Although early generation IFN-c assays used PPD as the stimulating antigen, newer assays use M. tuberculosis specific proteins—the early secretory antigenic target 6 (ESAT-6) and culture filtrate protein 10 (CFP-10), encoded by genes located within the RD-1 segment of the M. tuberculosis genome. These antigens are not found in BCG and many NTM species (233). At the present time, the QFT assay has been approved by the U.S.

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Food and Drug Administration (FDA), whereas the T-SPOT TB assay has been approved for use in many European countries and Canada. A. Sensitivity, Specificity, and Reproducibility

As shown in Table 14A–C, IGRA have had variable sensitivity when assessed in patients with newly diagnosed active TB. Sensitivity was lower with the earlier version of the QFT using PPD (235–240,242,243). Sensitivity averaged 85% to 90% with the Quantiferon tests using a combination of ESAT-6 and CFP-10 (34,240,243,244), or ELISPOT using ESAT-6 (32,33,185,245–247). Interestingly, sensitivity was even lower in patients who had completed treatment of active TB (235,239,248). Tuberculin skin testing has been performed in the same patients in only five studies (236,239,242,248). In newly diagnosed TB patients, TST sensitivity has ranged from 86% to 93% (236,239,242)—similar to other studies reviewed earlier. On the other hand, in previously treated patients, sensitivity of the TST is much higher than IGRA—and the 95% average sensitivity (239,248) was similar to that reported in earlier studies in previously treated patients. The major advantages of the new IGRA are their potential for improved specificity in BCG-vaccinated populations and their ability to be automated for settings where large numbers of individuals need to be screened. In populations who have received BCG vaccination in infancy, there is little discernable effect on TST reactions, as has been reported elsewhere, nor on Quantiferon assays using PPD. But, as shown in Table 15A–C, specificity is superior with IFN-c assays using RD-1 antigens in populations who have received BCG vaccination at an older age such as Table 14A Sensitivity of Interferon-c Assays in Patients with Active Tuberculosis (Summary)

Test

Studies (N)

Quantiferon-PPD

7

Quantiferon-ESAT-6 Quantiferon-ESAT-6 þ CFP-10 ELISPOT–ESAT-6  CFP-10

3 4 6

QFT-PPD in cured active TB

3

a

References 235–238 239–241 237,242,243 34,240,243,244 32,33,245,246 185,247 235,239,248

Subjects (N)

IFN-c TST sensi- sensitivity tivity

278

76%

86%a

97 205 223

57% 86% 88%

93%b – –

149

64%

95%c

Only two studies (236,239) performed tuberculin skin test with adequate technique. Only one study (242) performed TST with adequate technique. c Only two studies (239,248) performed TST with adequate technique. Abbreviations: TST, tuberculin skin test; PPD, purified protein derivative; IFN-c, interferon-c; CFP-10, culture filtrate protein 10; ESAT, early secretory antigenic target; ELISPOT, enzyme linked immunospot; QFT, Quantiferon-TB GOLD. b

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Table 14B Sensitivity of Quantiferon-TB GOLD Using Early Secretory Antigenic Target-6–Culture Filtrate Protein-10 Antigens QFT sensitivity Reference

Location

Number of patients

HIV infection

237a 242 243

Australia Gambia Denmark

19 30 48

Negative NS NS

240 34 244

Denmark Japan Denmark

18 118 21

NS Negative NS

N

(%)

11/19 13/30 31/48 40/48 14/18 105/118 18/21

58b 43b 65b 83 78 89c 86

a

In this study 0 of 19 were QFT positive using the MPT64 antigen. These three sets of results are for testing with ESAT-6 only. All other results for combination of ESAT-6 and CFP-10. c In this study reactions to: ESAT-6 þ CFP-10 > ESAT-6 > CFP-10. Abbreviations: QFT, Quantiferon-TB GOLD; CFP, culture filtrate protein; ESAT, early secretory antigenic target. b

Table 14C Sensitivity of Enzyme Linked Immunospot Using Early Secretory Antigenic Target-6 Sensitivity of ELISPOT Reference

Number of patients

Place

32

India

50

245

United Kingdom

33

United Kingdom

25 PTB 11 LNTB 17 EPTB 47

246

Zambia

50 Sþ

185

Germany

247

United Kingdom

13 adults 14 children 13

Total

223

HIV infection All 6 HIV(þ) 44 HIV() NS

Clinically not HIV 39 HIV(þ) 11 HIV() NS NS

N

%

40/50 6/6 34/44 23/25 10/11 NS 45/47

80 100 77 92 91

34/39 11/11 11/13 9/14 13/13

87a 100

196/223

96

100 88

a In the same study the sensitivity of culture filtrate protein-10 and ESAT-6 was 90%. Abbreviations: ELISPOT, enzyme linked immunospot; PTB, pulmonary tuberculosis; LNTB, lymph node tuberculosis; EPTB, extra pulmonary tuberculosis.

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Table 15A Specificity of Interferon-c Release Assays in Populations at Low Risk for Tuberculosis Infection (Summary) Test Quantiferon-PPD

Quantiferon– ESAT-6þ CFP-10 ELISPOT–ESAT-6

Studies (N) 8

References 235,237,239, 249 240,241,248, 250

Subjects (N)

IGRA TST specificity specificity

1079 No BCG

96%

99%a

73 BCG

73%

87%

105 No BCG 353 BCG

98% 98%

97% 46%b

97%

–c

5

34,237,240 243,244

4

32,33,245,246 145 BCGc

a

Tuberculin skin test (TST) performed with adequate technique in all but one study (240). TST performed with adequate technique in three studies (237,240,251). c In the four studies with enzyme linked immunospot 123/145 ¼ 85% had received bacille Calmette–Gue´rin. Results not presented separately. No TST done. Abbreviations: IGRA, IFN-c release assays; TST, tuberculin skin test; BCG, bacille Calmette– Gue´rin; PPD, purified protein derivative; ESAT-6, early secretory antigenic target 6; CFP-10, culture filtrate protein 10; ELISPOT, enzyme linked immunospot. b

in the United Kingdom and many European countries. In these populations, the specificity of ELISPOT or Quantiferon with RD-1 antigens has been excellent at 97% to 98% (32–34,237,240,243–246). Specificity of the TST or Quantiferon or ELISPOT using PPD antigens has been much lower. When TST and IFN-c assays have been performed in the same subjects whose probability of TB infection has been defined clinically, it has been possible to estimate concordance of the TST with the newer assays. As seen in Table 16, there is very substantial discordance in both high-risk (235,236,239,241,248) and low-risk (239,249) populations. Some of the discordant TST positive and IGRA negative reactions have been attributed to sensitivity to NTM or BCG vaccination (239). However, the frequent occurrence of IGRA-positive and TST-negative discordant reactions has not been explained in any of these studies (35,239). Of particular concern is that the number of positive discordant reactions far exceeds the concordant positive reactions in low-risk populations (239,249). This raises concerns that the IGRA may result in significant numbers of false-positive tests in screening low-prevalence populations, including populations that have not received BCG vaccination. The reproducibility of results from IGRA has been examined in several studies. In two studies performed by the manufacturer, reproducibility of test results over time was high (254). In a multicenter study in the United States, the degree of discordance between TST and Quantiferon results varied significantly between centers. The authors attributed this to differences

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Table 15B Specificity of Quantiferon ‘‘Gold’’ with Early Secretory Antigenic Target 6/Culture Filtrate Protein 10 Antigens No BCG vaccination

BCG vaccination

TST specificity (%)

Reference

Location

N

Quantiferon specificity (%)

237a 240 34 243 244

Australia Denmark Japan Denmark Denmark

50 15

100 100

100 100

40

95

90

N

Quantiferon specificity (%)

TST specificity (%)

50 19 213 39 32

100 89 98 100 94

87 53 35 ND ND

a Used higher cut-point for positive QFT test (30 ratio) instead of 15 ratio used in all other studies. Abbreviations: TST, tuberculin skin test; BCG, bacille Calmette–Gue´rin.

in TST reading (239), although this was later disputed (248). In the most comprehensive study, a large group of health-care workers with positive TST had serial Quantiferon assays every two months for one year. In this study, 37% of positive tests were followed by a negative test, and 16% of Table 15C Specificity of Enzyme Linked Immunospot with Early Secretory Antigenic Target 6 (Tuberculin Skin Test Was Not Done in Any Study) Reference 32

245 33

246a Total a

Country

Type of exposure

United Unexposed healthy Kingdom adults All U.K. born, no travel United Unexposed Kingdom ‘‘control’’ United Medical patients Kingdom without past TB history (most immigrants) Unexposed healthy (all U.K. born) United Unexposed healthy Kingdom (all U.K. born)

Number of subjects 40

BCG (%)

Antigen

33/40 PPD

Specificity (%) 17

ESAT-6

100

32

28/32 ESAT-6

100

47

36/4

PPD ESAT-6

45 92

26

26/26 PPD ESAT-6 33/40 PPD ESAT-6

21 100 17 100

40 145

123

PPD ESAT-6

30 97

It appears these were the same subjects and results in this study as in the study reported in (32), so excluded from totals. Abbreviations: BCG, bacille Calmette–Gue´rin; PPD, purified protein derivative; ESAT-6, early secretory antigenic target 6.

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Table 16 Agreement Between New Interferon-c Release Assays and Tuberculin Testing



Agreement

Concordanta as % of all positive

212 1042 63 414 108 815

79%

55%

83%

64%

79%

51%

97%

6%

TST þ

Tests (Refs.)

Populations at increased risk for TB infection QFT-PPD (235,236,239,241,248) þ 501  204 QFT-ESAT-6 þ CFP-10 (35,252) þ 251  76 ELISPOT-ESAT-6 or CFP-10 þ 306 (122,246,251,253)  184 Populations at very low risk for TB infection QFT-PPD (239,249) þ 3  16

31 1511

a

Concordant—the percentage of subjects with any test positive who had both tests positive. Abbreviations: PPD, purified protein derivative; ESAT-6, early secretory antigenic target 6; CFP10, culture filtrate protein 10; ELISPOT, enzyme linked immunospot; QFT, QuantiferonTB GOLD.

negative tests were followed by a positive result, for an overall weighted kappa of 0.51 (238). This raises concerns that utilizing these new tests for detection of new infection through serial testing in exposed groups may be unreliable due to random (and still unexplained) variability in the results. IV. Conclusions The following can be concluded about diagnosis of latent TB infection: 1. 2.

3.

The TST is a test—not a condition. As with all tests in clinical medicine, the tuberculin test is most useful when it is clearly indicated. Tuberculin testing and IFN-c assays are tests for diagnosis of latent TB infection. Neither type of test is recommended for the diagnosis of active disease—sensitivity is only 70% to 85%, and the tests cannot distinguish active disease from latent infection. Individuals with tuberculin reactions that are
10 mm (5 mm in certain situations, and 15 mm in others) should be referred for medical and radiological evaluation. Chest radiography is useful to evaluate tuberculin reactions to exclude the possibility of active TB. Chest radiography also helps to identify those with latent infection at increased risk of disease. This is not recommended as a primary tool to diagnose latent TB infection, because only 10% to 15% of infected individuals have abnormal chest radiographs.

Diagnosis of Latent Tuberculosis Infection 4.

5.

6.

7.

8.

9.

10. 11.

249

There is no association between tuberculin reactions and immunity subsequent to BCG vaccination. Therefore, the ideal TB vaccine would stimulate immunity, but have no effect on tuberculin reactions. When interpreting the TST, greater emphasis should be placed on thinking in three dimensions. This means considering the positive predictive value, and risk of development of active TB, in addition to simply the size of the reaction. The boosting phenomenon is common, particularly in populations with high prevalence of sensitivity to NTM antigens and/or BCG vaccination. Because boosting is strongly affected by prior exposure to NTM or BCG, the specificity is less, meaning the risk of developing TB is lower than for positive initial TST in the same population. TST conversion occurs within eight weeks of mycobacterial infection. The best definition of tuberculin conversion is unclear. An increase of 6 mm or more with final TST size of 10 mm or more will be the most sensitive criteria. Data from cross-sectional studies in different populations suggest that an increase of 10 mm will be most useful. Larger increases will be more specific but will reduce sensitivity. The dictum, ‘‘once TST positive, always positive’’ may not be true. However, the corollary, ‘‘once the TST is documented positive, further tuberculin testing is of no utility’’ is correct. Persons with a positive TST should never have further tuberculin testing, although proper documentation should remain available. Among casual contacts, even of smear-positive cases, undergoing a second tuberculin test at the end of the ‘‘window period,’’ the majority of new reactions detected will result from the boosting phenomenon rather than new infection. Therefore, investigations of casual low-risk contacts should be restricted to a single tuberculin test performed eight weeks after the end of exposure, when such testing is indicated. Anergy testing, while useful in population studies, is of limited clinical value in the management of individual patients. In the diagnosis of TB infection, IGRA have a number of potential advantages over the TST. Current commercially available assays that utilize M. tuberculosis specific antigens such as ESAT-6 and CFP-10 minimize false-positive test results due to vaccination with BCG, and infections with certain NTM. Other benefits of these tests are that they require only a single visit by the patient, pose no risk of serious adverse reactions, and do not influence future test results (i.e., no ‘‘boosting’’).

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13.

14.

15.

16.

A major advantage of the TST is that results have been validated through follow-up of large cohorts to determine subsequent incidence of active TB. Based on this epidemiologic information, risk of disease in an individual with certain risk factors and a given TST reaction can be predicted with some accuracy. At the present time, none of the IFN-c assays have been validated prospectively in this way. The unit costs to perform the TST are less than for the IFN-c assays. However, this may be offset in high-income countries by the need for two visits by the patient to see a health professional. To date, no rigorous cost-benefit analyses have been published comparing the TST with either of the two commercially available IFN-c assays. This information is needed to define the public health and economic implications of utilizing these tests. The occurrence of many discordant TST-IFN-c reactions is of concern because this phenomenon is common and unexplained. Prospective studies with simultaneous performance of TST and IFN-c assays would be of great interest. IGRA have been approved for use in many countries, and recommended by authoritative agencies in some. However, their higher unit costs, uncertainty regarding future risk of active TB disease, and concerns about reproducibility make it difficult to recommend their use for the diagnosis of latent TB infection at the present time. Ongoing studies will help clarify many of the unresolved issues and better define indications for these tests over the next five years. Identification of persons with latent TB infection who will develop active disease remains an imperfect art. The new IFN-c assays hold the promise, together with other molecular biology advances, to improve our understanding of latent TB infection and our ability to predict development of active TB.

Glossary Heaf

Mantoux

OT

PPD

Multipuncture method of tuberculin testing introduced by Heaf in 1951. The prongs are dipped in tuberculin solution and then pressed into the skin. Intradermal method of tuberculin skin testing, first described by Mantoux in 1910. Tuberculin material is injected intradermally, and the resultant induration is measured 48 to 72 hours later. Old tuberculin. Material for tuberculin testing, first prepared by Robert Koch. Not purified, nor standardized. Had poor specificity. Purified protein derivative. Material for tuberculin testing, prepared from culture of mycobacterial species, filtered, and (Continued)

Diagnosis of Latent Tuberculosis Infection

PPD-B

PPD-G

PPD-S

PPD-T

RT-23

Tine

251

purified by precipitation with ammonium sulfate or trichloroacetic acid. PPD-Battey. Material first produced at the Battey Institute from Mycobacterium intracellulare (part of the M. avium intracellulare complex). This antigen is of no clinical use, and is used primarily for epidemiologic surveys to determine prevalence of NTM, as cause of false-positive tuberculin tests. PPD Gause. Material produced from M. scrofulaceum. This antigen is of no clinical utility, and is used for epidemiologic surveys, although less commonly than PPD-B. Standard lot of PPD produced from M. tuberculosis by Dr. Florence Seibert in 1941. Stored by FDA (in United States) and used as worldwide standard lot. One tuberculin unit is defined as 0.02 mg of PPD-S (so 5TU ¼ 0.1 mg). All commercial lots of PPD must be tested for bioequivalence against PPD-S. Commercial PPD produced from M. tuberculosis, and used mainly in North America. There are two major manufacturers: AventisPasteur (Tubersol), and Parke-Davis (Aplisol). Commercial PPD produced from M. tuberculosis, validated against PPD-S, and standardized by WHO. This tuberculin material is the most commonly used outside North America. Manufactured by Statens Serum Institute (Copenhagen). Multipuncture method of tuberculin testing. Four prongs (tines) coated with dried tuberculin material are pressed into the skin for about two seconds.

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235. Streeton JA, Desem N, Jones SL. Sensitivity and specificity of a gamma interferon blood test for tuberculosis infection. Int J Tuberc Lung Dis 1998; 2(6):443–450. 236. Pottumarthy S, Morris AJ, Harrison AC, Wells VC. Evaluation of the tuberculin gamma interferon assay: potential to replace the Mantoux skin test. J Clin Microbiol 1999; 37(10):3229–3232. 237. Johnson PDR, Stuart RL, Grayson ML, et al. 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 1999; 6(6):934–937. 238. Stuart RL, Olden D, Johnson PD, et al. Effect of anti-tuberculosis treatment on the tuberculin interferon-gamma response in tuberculin skin test (TST) positive health care workers and patients with tuberculosis. Int J Tuberc Lung Dis 2000; 4(6): 555–561. 239. Mazurek GH, LoBue PA, Daley CL, et al. Comparison of a whole-blood interferon gamma assay with tuberculin skin testing for detecting latent Mycobacterium tuberculosis infection. JAMA 2001; 286(14):1740–1747. 240. Brock I, Munk ME, Kok-Jensen A, Anderson P. Performance of whole blood IFN-c test for tuberculosis diagnosis based on PPD or the specific antigens ESAT-6 and CFP-10. Int J Tuberc Lung Dis 2001; 5(5):462–467. 241. Fietta A, Meloni F, Cascina A, et al. Comparison of a whole-blood interferongamma assay and tuberculin skin testing in patients with active tuberculosis and individuals at high or low risk of Mycobacterium tuberculosis infection. Am J Infect Control 2003; 31(6):347–353. 242. Vekemans J, Lienhardt C, Sillah JS, et al. Tuberculosis contacts but not patients have higher gamma interferon responses to ESAT-6 than do community controls in the Gambia. Infect Immun 2001; 69(10):6554–6557. 243. Ravn P, Munk ME, Andersen AB, et al. Reactivation of tuberculosis during immunosuppressive treatment in a patient with a positive QuantiFERON-RD1 test. Scand J Infect Dis 2004; 36(6–7):499–501. 244. Brock I, Weldingh K, Leyten EM, Arend SM, Ravn P, Andersen P. Specific T-cell epitopes for immunoassay-based diagnosis of Mycobacterium tuberculosis infection. J Clin Microbiol 2004; 42(6):2379–2387. 245. Pathan AA, Wilkinson KA, Klenerman P, et al. Direct ex vivo analysis of antigenspecific IFN-c-secreting CD4 T cells in Mycobacterium tuberculosis-infected individuals: associations with clinical disease state and effect of treatment. J Immunol 2001; 167:5217–5225. 246. Chapman AL, Munkanta M, Wilkinson KA, et al. Rapid detection of active and latent tuberculosis infection in HIV-positive individuals by enumeration of Mycobacterium tuberculosis-specific T cells. AIDS 2002; 16(17):2285–2293. 247. Scholvinck E, Wilkinson KA, Whelan AO, Martineau AR, Levin M, Wilkinson RJ. Gamma interferon-based immunodiagnosis of tuberculosis: comparison between whole-blood and enzyme-linked immunospot methods. J Clin Microbiol 2004; 42(2):829–831. 248. Bellete B, Coberly J, Barnes GL, et al. Evaluation of a whole-blood interferongamma release assay for the detection of Mycobacterium tuberculosis infection in 2 study populations. Clin Infect Dis 2002; 34(11):1449–1456. 249. US Food and Drug Administration. WRAIR study. A comparison of QuantiFERON-TB interferon-gamma test with the TST for detection of M. tuberculosis infection in military recruits. QuantiFERONTB-P010033. Summary of safety and effectiveness, January 5, 2005. Found in FDA document on safety and effectiveness of QuantiFERON. http://www.fda.gov/cdrh/pdf/p010033b.doc.

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250. Katial RK, Hershey J, Purohit-Seth T, et al. Cell-mediated immune response to tuberculosis antigens: comparison of skin testing and measurement of in vitro gamma interferon production in whole-blood culture. Clin Diagn Lab Immunol 2001; 8(2):339–345. 251. Piersimoni C, Callegaro A, Nista D, et al. Comparative evaluation of two commercial amplification assays for direct detection of Mycobacterium tuberculosis complex in respiratory specimens. J Clin Microbiol 1997; 35(1):193–196. 252. Brock I, Weldingh K, Lillebaek T, Follmann F, Andersen P. Comparison of tuberculin skin test and new specific blood test in tuberculosis contacts. Am J Respir Crit Care Med 2004; 170(1):65–69. 253. Ewer K, Deeks J, Alvarez L, et al. Comparison of T-cell-based assay with tuberculin skin test for diagnosis of Mycobacterium tuberculosis infection in a school tuberculosis outbreak. Lancet 2003; 361(9364):1168–1173. 254. US Food and Drug Administration. QuantiFERONTB-P010033. Summary of safety and effectiveness, January 5, 2005. http://www.fda.gov/cdrh/pdf/p010033b.doc.

10 Treatment of Latent Tuberculosis Infection

DAVID L. COHN

WAFAA M. EL-SADR

Denver Public Health and the Division of Infectious Diseases, Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado, U.S.A.

Division of Infectious Diseases, Harlem Hospital Center and International Center for AIDS Care and Treatment Programs (ICAP), Columbia University, College of Physicians and Surgeons, and Mailman School of Public Health, New York, New York, U.S.A.

I. Introduction Preventive therapy refers to the treatment of patients who are known, or are likely, to be infected with tubercle bacilli, but without active disease with a simple regimen (usually isoniazid), with the intention of preventing tuberculosis (TB) in the future. In TB control, the term ‘‘preventive therapy’’ may be misleading in that it implies primary prevention of infection rather than its actual use for ‘‘early treatment’’ or ‘‘secondary prevention’’ in patients who have an established infection of Mycobacterium tuberculosis. Hence, the terminology ‘‘treatment of latent tuberculosis infection’’ (LTBI) has been adopted rather than ‘‘preventive therapy’’ to more accurately describe this strategy (1). Both terms will be used in the text that follows. In resource-limited countries, treatment of LTBI is a relatively uncommon TB control strategy. In these settings, the highest priority of control programs is case detection and treatment of active cases, both to decrease morbidity and mortality and to prevent secondary transmission to others (2). However, in industrialized countries, especially in the United States and Canada, preventive therapy is an important and effective component of TB control programs. 265

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The human immunodeficiency virus (HIV) epidemic and its effect on the incidence of TB in most countries of the world have rekindled interest in the treatment of LTBI as a potential TB control strategy on a global basis (2–4). Several recently completed clinical trials have demonstrated the efficacy of different regimens in preventing TB, and other ongoing studies are evaluating feasibility and cost-effectiveness of such strategies. In addition, the Institute of Medicine, in making recommendations on the elimination of TB in the United States, emphasized the importance of diagnosis and treatment of LTBI as an essential TB control strategy (5). This chapter builds on Chapter 8, which describes the diagnosis of LTBI, risk factors for LTBI, and groups and individuals who are candidates for the treatment of LTBI. In this chapter, we review older studies of treatment of LTBI, which were largely conducted in immunocompetent populations, as well as more recent studies in HIV-infected persons and other populations. A description of efficacy and tolerability of various regimens is included, with emphasis on toxicity related to the use of rifampicin and pyrazinamide. Current and updated recommendations for the treatment of LTBI are discussed, including those relevant to special populations and resource-limited settings. This chapter also includes a discussion of practical issues related to TB programs and their implementation of treatment of LTBI. We conclude with a discussion of future directions and research for the treatment of LTBI. II. Efficacy of Treatment of LTBI A. Studies in Immunocompetent Hosts

From 1951 through 1970, several randomized, controlled clinical trials of isoniazid for the treatment of LTBI were conducted (6). These trials were carried out in several countries and involved more than 100,000 participants at risk for TB, including contacts of patients with active TB, persons with positive tuberculin skin reactions, institutionalized patients with mental disease, persons with inactive TB, and children with primary TB (Table 1) (6–23). Most studies compared 12 months of isoniazid to that of placebo. The effectiveness of treatment, as measured by differences in rates of TB between all persons randomized to placebo and isoniazid, varied from 25% to 92%. However, when analysis was restricted to persons who were adherent with the medication, the protective efficacy was approximately 90%. Substantial protection was conferred even if pill taking was irregular but sustained, suggesting the likelihood that intermittent treatment would be efficacious. The largest study of the treatment of LTBI ever conducted was sponsored by the International Union Against Tuberculosis (IUAT), which evaluated the efficacy of isoniazid therapy among individuals who were tuberculin skin test–positive and had inactive fibrotic lung lesions; 27,830 participants were enrolled from seven European countries (19). This placebo-controlled trial had several unique characteristics including the

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evaluation of different durations of preventive therapy, i.e., 12, 24, and 52 weeks of daily isoniazid, and stratification based on chest X-ray findings. The IUAT study demonstrated that isoniazid given for 52 weeks resulted in a 75% reduction of confirmed TB, a 65% reduction with 24 weeks, but only a 21% reduction with 12 weeks of isoniazid preventive therapy (IPT), compared to placebo. In patients who were designated as ‘‘completer-compliers’’ (at least 80% compliance during each month of the regimen), reduction of TB was 93% in those who received isoniazid for 52 weeks, 69% for 24 weeks, and 31% for 12 weeks, compared to placebo. In the subgroup of patients with fibrotic lesions greater than 2 cm, 52 weeks of therapy (88% reduction) was superior to 26 weeks (67% reduction). However, in patients with small lesions on chest X-ray, the results of therapy for 52 weeks (64% reduction) and for 26 weeks (66% reduction) were similar. Effectiveness data from the IUAT study, published data on isoniazidassociated hepatitis, and cost information obtained from a survey of U.S. TB programs were used to assess the cost-effectiveness of various durations of isoniazid (24). The cost per case of TB prevented with the six-month regimen was determined to be half of the cost of either the 3- or 12-month regimens. This analysis was largely responsible for the widespread adoption, in 1986, of the six-month regimen of isoniazid for the treatment of LTBI in HIV-negative persons with normal chest radiographs in the United States (25). However, based on a reanalysis of data from community studies in Alaska, the protection conferred by taking at least nine months of isoniazid was considered greater than taking six months, but not likely that further protection was conferred by extending the duration of treatment from 9 to 12 months (26). From studies in animal models, there was reason to believe that regimens using rifampicin or rifampicin and pyrazinamide for short courses of therapy could be as effective as those using isoniazid (27,28). In tuberculinpositive patients with silicosis in Hong Kong, rifampicin for three months, isoniazid and rifampicin for three months, and isoniazid for six months resulted in 63%, 41%, and 48% protection, respectively, compared to placebo (29). These data led to a series of comparative trials using short-course rifampicin-containing regimens in HIV-infected patients, as discussed below. B. Studies in HIV-Infected Persons

The high incidence of TB in HIV-infected patients, especially in developing countries, the considerable morbidity and mortality of HIV-associated TB, and secondary transmission to others provided the rationale for several new studies of preventive therapy in the past decade. The high rates of TB in cohort studies of HIV-infected persons (Table 2) (30–37) permitted clinical trials with smaller sample sizes and of shorter duration than in the aforementioned studies in immunocompetent populations. Summary results of prospective, randomized clinical trials in HIVinfected persons are shown in Table 3 (38–48). In a study conducted in (Text continues on page 273.)

Contacts of cases (2238) Contacts of cases (775)

Egsmose et al. (9); Kenya; 1959–1963/1965

Contacts of new cases (25,033)

Study subjects (n)

Bush et al. (8); Japan; 1957/1968

Close contacts of TB cases Ferebee and Mount (7); United States, Puerto Rico, Mexico; 1957–1959/1962

Author (Ref.); location; years of study/publication

End point: pulmonary lesions or excretion of bacilli

Individual

Family

Unit of randomization/ end points

Placebo INH for 1 yr

Placebo INH for 1 yr

Placebo INH for 1 yr

4.8% 2.1% Pulmonary lesions 9.1 0

Reactors

10.8% 5.0%

Nonreactors

1.0% 0.7%

100

56

54

30

60

Reactors 26.9 11.1

Placebo INH for 1 yr Placebo INH for 1 yr

60

Reduction (%)

6.2

15.4

10-yr rate/1000

TB rates

INH for 1 yr

Placebo

Drug regimen(s)

Outcomes

Table 1 Prospective, Randomized Clinical Trials of Treatment of Latent TB Infection in Largely Immunocompetent Populations

Comments

268 Cohn and El-Sadr

Contacts of cases (261) Railway workers (548)

Veening (11); Netherlands; 1960–1964/1968

Chiba et al. (12); Japan; 1951–1962/1963

Adults without TB (8081)

Entire suburb, persons without TB (15,910)

Groth-Peterson et al. (15); Greenland; 1956/1960 Horowitz et al. (16); 1966

Nyboe et al. (17); Tunisia; 1958/1963

Community trials or institutions Comstock et al. (13,14); 30 communities Alaska; (6275) 1957–1963/1967,1979

Household contacts (327)

Del Castillo et al. (10); Phillipines; 1961–1965

Housing blocks

Village

Household

Individual

Individual

End points: chest X-ray abnormality

Placebo INH for 1 yr

Placebo INH for 26 weeks: twice-weekly 13 wks alternating with 13 wks no Rx

Placebo INH for 1 yr

Placebo INH for 1 yr

Placebo INH for 1 yr

Placebo INH for 1 yr

3.1 2.3

Rate/1000

6-yr rate per 1000 82.7 57

6-yr rate per 1000 46.1 19.0

1.03% 0.39%

7-yr follow-up 9.4% 0.8%

2-yr follow-up 13.9% 8.2%

26

31

59

62

92

41

(Continued )

Random urine checks, poor compliance

Treatment of Latent TB Infection 269

Ferebee et al. (18); United States; 1957–1960/1963

Author (Ref.); location; years of study/publication

Mental institutions, reactors and nonreactors (27,924)

Study subjects (n)

Ward or building

Unit of randomization/ end points

Placebo INH for 1 yr

Placebo INH for 1 yr

6.9 2.1

Abnormal chest X-ray 36.0 18.4 Normal chest X-ray

70

49

47

5–9 mm 8.2 4.7

Placebo IHN for 1 yr

Placebo

68

62

Reduction (%)

INH for 1 yr

9.6 3.6

10-yr rate/1000 overall

TB rates


10 mm 12.2 3.9

Placebo INH for 1 yr

Drug regimen(s)

Outcomes

Table 1 Prospective, Randomized Clinical Trials of Treatment of Latent TB Infection in Largely Immunocompetent Populations (Continued )

Comments

270 Cohn and El-Sadr

Ferebee (6); United States; 1960–1964/1970

Inactive lesions 2/3 prior active TB 1/3 inactive (4575)

Patients with inactive lesions on chest X-ray Tuberculin skin IUAT (19); Czechoslovakia, Finland, test positive German Democratic and fibrotic Republic, Hungary, Poland, lung disease, Romania, Yugoslavia; consistent with TB and 1969–1977/1982 stable for prior year (27,830)

Individual

Individual

Placebo INH for 1 yr

Placebo INH for 12 wks INH for 24 wks INH for 52 wks

Placebo INH for 12 wks INH for 24 wks INH for 52 wks

Placebo INH for 12 wks INH for 24 wks INH for 52 wks

Placebo INH for 12 wks INH for 24 wks INH for 52 wks

19.0 7.0

2-yr rate/1000

21.3 16.2 7.0 2.4

Large lesions > 2 cm2

‘‘Completers-compliers’’ 15.0 10.4 4.7 1.1 Small lesions < 2 cm2 11.6 9.2 4.0 4.2

14.3 11.3 5.0 3.6

5-yr rate/1000 All assigned participants

63

— 24 67 89

— 20 66 64

— 31 69 93

— 21 65 75

(Continued )

Urine test for INH q3 mos

Pill calendars given; symptoms of hepatitis monitored

Treatment of Latent TB Infection 271

Ward

Individual Asymptomatic children with primary TB (2750) < 3 y.o., PPD > 5 mm > 3 y.o., PPD > 5 mm and primary TB on chest X-ray

Mental patients with inactive TB (513) 225 pts no prior TB in hospital 288 prior TB in hospital

Study subjects (n)

Unit of randomization/ end points

Placebo INH for 1 yr

Placebo INH for 2 yrs

Placebo INH for 2 yrs

Drug regimen(s)

30.2 3.6

10-yr rate/1000

6-yr rate/1000 93.0 76.0 Rates among pts with prior TB 245.0 132.0

TB rates

Outcomes

Abbreviations: INH, isoniazed; IUAT, International Union Against Tuberculosis; PPD, purified protein derivative.

Children with primary TB Ferebee, Mount (6,22,23); United States, Canada, Mexico, Puerto Rico; 1955–1960/1961, 1970

Katz et al. (20,21); United States; 1958–1964/1965

Author (Ref.); location; years of study/publication

Table 1 Prospective, Randomized Clinical Trials of Treatment of Latent TB Infection in Largely Immunocompetent Populations (Continued )

88

46

18

Reduction (%)

Greater benefit in children with abnormal chest X-rays

Comments

272 Cohn and El-Sadr

Treatment of Latent TB Infection

273

Table 2 Annual Risk of Developing Tuberculosis in HIV-Infected Persons Author (Ref.); location; years of study

Risk/100 patient-years (no. of patients studied) PPDþa

PPDb

7.9 (49)e Selwyn et al. (30); — U.S./IDUe; 1985–1987 9.7 (25) 6.6 (68) Selwyn et al. (31); U.S./IDUf; 1988–1990 Markowitz et al. (32); 3.5 (66) 0.7 (603) U.S./23% IDUg; 1988–1994 Moreno et al. (33); 10.4 (84) 12.4 (112) Spain/80% IDUf; 1985–1990 16.2 (26) 2.6 (235) Guelar et al. (34); Spain/60% IDUf; 1988–1992 Antonucci et al. (35); 5.4 (197) 3.0 (1649) Italy/72% IDU; 1990–1993 Braun et al. (36); — — Zaire/women; 1987–1989 5.5 (73) — Allen et al. (37); Rwanda/women; 1988–1992

PPDc

PPDd

Total

0.3 (166)

—

2.1 (215)

—

—

7.7 (93)

—

0.2 (429)

0.7 (1107)

—

5.4 (151)

9.1 (374)

—

0 (87)

—

—

0.45 (849)

2.2 (2695)

—

—

3.1 (249)

2.1 (221)

—

2.4 (401)

a

PPDþ ¼
5 mm. PPD ¼ < 5 mm (anergic). c PPD ¼ < 5 mm (not tested for anergy). d PPD ¼ < 5 mm (not anergic). e Seventy-three percent did not receive isoniazid preventive therapy (IPT). f Did not receive or complete IPT. g Fifty-five percent did not receive IPT. —, Not reported. Abbreviations: PPD, purified protein derivative; IDU, injection drug user. Source: Adapted from Ref. 3. b

Haiti, HIV-infected patients were randomized to vitamin B6 alone or isoniazid plus B6; 42% of the B6 recipients and 66% of the isoniazid recipients were tuberculin positive, respectively (38). The incidence of TB was significantly higher in the B6 recipients than in those who received isoniazid (7.5 per 100 person-years vs. 2.2 per 100 person-years); this difference was greater in those who were tuberculin positive (10.0 per 100 person-years (Text continues on page 277.)

Whalen et al. (41); Uganda; 1993–1997

Halsey et al. (40); Haiti; 1990–1994

Wadhawan et al. (39); Zambia; 1988–1992

PPDþ (25)

Pape et al. (38); Haiti; 1986–1992

PPDþ (462)

PPDþ (556)

—

22.2%

PPDþ (380)

PPDþ (464) PPDþ (536)

22.5%

—

—

CD4 cell counts or percent

PPDþ (370)

NT (298)

NT (246)

PPD (35) PPD (20)

PPDþ (38)

Study subjects PPD status (n)

Author (Ref.); location; years of study

INH 300 mg qD (6) INH, 600–800 mg b.i.w. (6) RIF 450– 600 mg/PZA 1500–2500 mg b.i.w. (2) Placebo, qD (6) INH 300 mg, qD (6) INH 300 mg/ RIF 600 mg qD (3) INH 300 mg/ RIF 600 mg/ PZA 2000 mg, qD (3)

Placebo, qD (6)

Placebo, qD (12) INH 300 mg, qD (12) Placebo, qD (12) INH 300 mg, qD (12)

Drug regimen (mo)

10 (2)

7 (1) 9 (2)

21 (5)

19 (5)

14 (4)

7 (2)

23 (9)

5 (14) 2 (10)

2 (5)

6 (24)

1.73

1.32

3.41 1.08

1.8

1.7

2.6

11.3

5.7 3.2

1.7

10.0

0.43 (0.20–0.92)

1 0.32 (0.14–0.76) 0.41 (0.19–0.89)

1.1

0.4 (0.20–0.82) 1

1

0.17 (0.03–0.83) 1 0.56 (0.11–2.5)

1

TB rate/100 Relative risk No. TB personof TB (95% cases (%) years CI)

58 (13)

58 (11) 57 (10)

64 (14)

71

72

—

6 (17) 2 (10)

3 (8)

7 (28)

No. deaths (%)

9.8

8.9 8.3

10.2

0.64 (0.39–1.03) 9.1

1

—

Death rate/ 100 personyears

Table 3 Prospective, Randomized Clinical Trials of Treatment of Latent TB Infection in HIV-Infected Patients

0.9 (0.7–1.4)

1 0.9 (0.6–1.2) 0.8 (0.5–1.2)

—

—

3.6 (1.0–12.4) 1

Relative risk of death (95% CI)

274 Cohn and El-Sadr

PPDþ/ (342) PPDþ/(342)

Hawken et al. (43); Kenya; 1992–1996

INH 300 mg, qD (12) RIF 600 mg/ PZA 20 mg/ kg, qD (2) Placebo, qD (12) INH 300 mg, qD (12)

—

PPDþ (791)

PPD (111) PPD (126)

454/mm3

PPDþ (792)

Gordin et al. (45); U.S., Mexico, Haiti, Brazil; 1991–1997

Fitzgerald et al. (46); Haiti; 1998–1999

427/mm3

Anergic (257) Anergic (260)

247/mm3 233/mm3

INH 300 mg, qD (6) Placebo, qD (6) INH 300 mg, qD (6) Placebo, qD (6) INH 300 mg, qD (6) Placebo, qD (6) INH 300 mg, qD (6)

Placebo, qD (6) INH 300 mg, qD (6) Placebo (INH), b.i.w. (6) INH 900 mg, b.i.w. (6) RIF 600 mg/ PZA 3500 mg b.i.w. (3) Placebo, qD (6)

321/mm3

346/mm3

—

Gordin et al. (44); U.S.; 1991–1996

PPD (235) PPD (224)

PPDþ (67) PPDþ (69)

PPDþ/ (350)a PPDþ/ (352)a PPDþ/ (351)a

Mwinga et al. (42); Zambia; 1992–1996

Anergic (323) Anergic (395)

4.65

25 (7)

4 (4) 6 (5)

28 (4)

29 (4)

6 (2) 3 (1)

25 (7)

1.5 1.9

1.2

1.2

0.9 0.4

2.73 3.28

8.03 5.59

4.29

3.86

4.94

27 (8)

23 (7)

8.06

3.06 2.53

44 (13)

10 (3) 9 (2)

1 1.26 (0.36–4.37)

0.95 (0.56–1.61)

1

0.92 (0.49–1.71) 1 0.60 (0.23–1.60) 1 1.23 (0.55–2.76) 1 0.48 (0.12–1.91)

1

0.62 (0.38–0.99) 0.58 (0.35–0.95)

1 0.75 (0.30–1.89) 1

15 (14) 19 (15)

139 (18)

159 (20)

126 (49) 129 (50)

62 (18)

57 (17)

68 (19)

59 (17)

58 (17)

76 (23) 86 (22)

5.7 6.0

5.7

6.5

17.8 17.7

10.64

9.58

11.76

10.02

9.62

22.3 23.5

(Continued )

1 1.05 (0.55–2.03)

0.87 (0.69–1.11)

1

1.11 (0.77–1.58) 1 0.33 (0.09–1.23) 1 1.39 (0.90–2.12) 1 0.96 (0.75–1.23)

1

1.05 (0.731.50) 1.24 (0.87–1.76)

1 1.05 (0.77–1.42) 1

Treatment of Latent TB Infection 275

271/mm3

232/mm3

Anergic (82)

Anergic (77)

No treatment INH 300 mg, qD (6) INH 300 mg/ RIF 600 mg, qD (3) RIF 600 mg/ PZA 1500– 2500 mg, qD (2)

Drug regimen (mo)

1 (1)

3 (4)

4 (5) 3 (3)

1.2

3.1

3.1 3.4

0.39 (0.04–3.98)

1 1.07 (0.24–4.80) 0.98 (0.22–4.40)

TB rate/100 Relative risk No. TB personof TB (95% cases (%) years CI)

5 (6)

4 (5)

11 (14) 9 (11)

No. deaths (%)

—

Death rate/ 100 personyears

—

Relative risk of death (95% CI)

Note: PPDþ¼
5mm; PPD¼ < 5mm. a Percent tuberculin-positive: 27% in placebo, 23% in INH, 22% in RIF/PZA. Abbreviations: PPD, purified protein derivative; NT, not tested; INH, isoniazid; RIF, rifampicin; PZA, pyrazinamicle; qD, daily; b.i.w., twice weekly. Source: Adapted from Ref. 48.

215/mm3 193/mm3

Anergic (77) Anergic (83)

Rivero et al. (47); Spain; 1994–1998

CD4 cell counts or percent

Study subjects PPD status (n)

Author (Ref.); location; years of study

Table 3 Prospective, Randomized Clinical Trials of Treatment of Latent TB Infection in HIV-Infected Patients (Continued )

276 Cohn and El-Sadr

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vs. 1.7 per 100 person-years). Also, isoniazid appeared to confer a protective effect on progression to symptomatic HIV disease, AIDS, and death in the tuberculin-positive cohort, suggesting a possible role for M. tuberculosis as a cofactor in HIV disease progression. Two studies conducted in Africa compared daily isoniazid with placebo for six months duration. In a prospective single-blinded study in Zambia, 9% of vitamin B6 recipients (11.3 per 100 person-years) developed TB compared with 2% of isoniazid recipients (2.6 per 100 person-years) (39). In a double-blind study in Kenya, there was no overall benefit to isoniazid (4.29 per 100 person-years) compared to placebo (3.86 per 100 person-years), unlike in prior studies (43). However, only 23% of persons were tuberculin positive; in that group there appeared to be some evidence of protection by isoniazid (although this was not statistically significant), whereas none was noted in tuberculin-negative patients. Other studies have evaluated regimens other than isoniazid and have used twice-weekly dosing with partial supervision. In a study conducted in Haiti, isoniazid twice weekly for six months was compared to rifampicin and pyrazinamide twice weekly for two months in tuberculin-positive subjects (40). After the first 10 months, there was a greater incidence of TB in the group randomized to rifampicinand pyrazinamide (3.7%) compared to isoniazid (1.0%), but after 36 months of study, there were no significant differences (5.4% and 5.0%, respectively). The early protection conferred by isoniazid was thought to be due to the longer duration of therapy compared to rifampicin and pyrazinamide. Unlike the prior study in Haiti, there were no differences in survival in the two groups. Adherence rates were better in the individuals on rifampicin and pyrazinamide than on isoniazid for all comparable cutoff points (i.e., 50%, 80%, and 100% of study regimens taken). A large placebo-controlled trial in Zambia compared isoniazid twice weekly for six months and rifampicin and pyrazinamide twice weekly for three months (42). Both tuberculin-positive and tuberculin-negative patients were enrolled and, similar to the study in Kenya, 24% of patients were tuberculin positive. Both isoniazid (4.94 per 100 person-years) and rifampicin and pyrazinamide (4.5 per 100 person-years) were more effective than placebo (8.06 per 100 person-years), each showing about 40% protection. There were no differences in survival among the three regimens. The effect of preventive therapy was greater in those with positive tuberculin tests, hemoglobin
10 g/dL, and absolute lymphocyte counts
2  109/L. A long-term follow-up of participants showed that the benefits of either regimen waned over time, but after 2.5 years, the cumulative risk of TB was still lower when comparing the treatment groups to placebo (49). No long-term effects on mortality or HIV progression were demonstrated. The largest clinical trial of preventive therapy in HIV-infected persons was conducted in Uganda (41). In tuberculin-positive patients, isoniazid daily for six months (1.08 per 100 person-years), isoniazid and rifampicin daily for three months (1.32 per 100 person-years), and isoniazid, rifampicin, and pyrazinamide daily for three months (1.73 per 100 person-years) were all

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more effective than placebo (3.41 per 100 person-years). Isoniazid alone showed a 70% reduction compared to placebo, and appeared to be more effective than the three-drug regimen; this may have been due to treatment discontinuation or noncompliance related to toxicity in the three-drug arm. There were no differences in survival in the four groups. Long-term follow-up of the participants in this trial showed that those randomized to isoniazid had a waning clinical benefit, whereas patients who received the rifampicin-containing regimens had more durable protection (50). In a large international study performed in the United States, Mexico, Haiti, and Brazil on tuberculin-positive patients, rifampicin and pyrazinamide given daily for two months (1.2 per 100 person-years) were found to be as effective as 12 months of isoniazid (1.2 per 100 personyears), the standard regimen then used in the United States (45). Once again, no differences in survival were noted. As in the Haiti study of twice-weekly regimens of two months versus six months, adherence to the two-month regimen (defined as taking drugs for 60 days) was greater, 80%, than with the 12-month regimen (i.e., continuous treatment for six months or more), 68%. Efficacy of preventive therapy in anergic or tuberculin-negative patients has been evaluated in four studies. In the study from Uganda, patients were randomized to receive six months of daily isoniazid or placebo; there were no apparent differences in efficacy or survival, although confidence intervals were wide (41). Not surprisingly, the death rate was higher in the anergic cohort (22%) than in the tuberculin-positive groups (8–10%). Longer followup suggested that a modest degree of protection occurred with the use of isoniazid (50). In a study in the United States in anergic patients at high risk of TB, isoniazid for six months showed a slight protective effect against TB compared to placebo, but this difference was not statistically significant, and there was no impact on survival (44). In an additional study conducted in Haiti, tuberculin-negative (91% with positive skin test reactions to candida or mumps antigens) patients were randomized to vitamin B6 versus isoniazid plus B6 for 12 months (46). There were no differences in rates of TB, progression to AIDS, or deaths. In a study of anergic patients in Spain, rates of TB and death were similar in patients who received no treatment, isoniazid for six months, isoniazid and rifampicin for three months, or rifampicin and pyrazinamide for two months (47). Hence, the study results in anergic patients were similar in high-incidence countries (Uganda, TB rate 2.5–3.1%; Haiti, TB rate 1.5– 1.9%; Spain, TB rate 1.2–3.4% per year; respectively) and in a low-incidence country (United States, TB rate 0.4–0.9% per year). Three meta-analyses of randomized trials of preventive therapy in HIV-infected patients showed a relative risk for TB of 0.57, 0.58, and 0.64 in patients who received anti-TB drugs compared to those who received placebo, respectively (51–53). Among tuberculin-positive participants, these rates were 0.32, 0.40, and 0.38, and among tuberculin-negative or anergic participants, 0.82, 0.84, and 0.83, respectively.

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In summary, a great deal of information was learned from the controlled trials in HIV-infected patients. In tuberculin-positive, HIV-infected patients, isoniazid given for 6 to 12 months was effective in preventing TB in about 60% to 70% of patients. Rifampicin and pyrazinamide given for two or three months and isoniazid and rifampicin for three months appear to be as effective as isoniazid, possibly with a longer duration of effect, and regimens may be given daily or twice weekly. In contrast, in tuberculin-negative or anergic HIV-infected patients, isoniazid for six months did not appear to be very effective. Medications were generally well tolerated, and adherence was better with regimens of two to three months than 6 to 12 months. The promising results of these studies in large part led to new American Thoracic Society (ATS) and U.S. Centers for Diseases Control and Prevention (CDC) recommendations for the treatment of LTBI in 2000 (1). III. Safety and Tolerability of Treatment of LTBI A. Studies in Immunocompetent Hosts

The relative risks and benefits of isoniazid in the treatment of LTBI have been debated for over three decades. Although isoniazid is generally considered to be a well-tolerated medicine, concern has been expressed regarding the development of isoniazid-associated hepatitis. The issue received attention when 19 of 2321 participants in a study of preventive therapy developed liver disease and two died (54). This report and others resulted in the design of a large United States Public Health Service (USPHS) study to better assess the risk of isoniazid-associated hepatitis (55). Of 13,838 participants from 21 cities, the rate of isoniazid-associated hepatitis was 10.2 per 1000 person-years; increased risk of hepatitis was associated with age, alcohol consumption, and in Asian men. Eight deaths were reported (0.8%), with seven in one city. The CDC subsequently recommended that patients should be evaluated on a monthly basis during preventive therapy and to restrict prophylaxis to those at high risk of TB, if older than 35 years (56). It was also recognized that asymptomatic elevations in transaminase levels occurred in 10% to 20% of patients initiating isoniazid and that this was not associated with increased risk of clinical hepatitis (57). From 1975 to 1991, six studies of the risks and benefits of isoniazid when used for the treatment of LTBI, most of which used decision analyses, showed different results and conclusions (58–63). Some studies raised concerns about the use of isoniazid owing to hepatotoxicity and associated fatalities; others suggested age cutoffs for treatment, providing potential for greater safety; and one stratified risk by gender and ethnicity. These studies used different assumptions of the risks of TB, hepatitis, and mortality in association with isoniazid, as well as different estimates of the magnitude of benefit to be expected. In 1983, the preventive therapy guidelines were further modified when ATS recommended regular monitoring of liver function tests among those older than 35 years of age and discontinuation of therapy if there was a three- to five-fold rise in transaminase levels (64).

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To further evaluate the problem, the CDC evaluated all known cases of death associated with the use of isoniazid in the United States (65). Of 177 cases, an increased risk of death was noted among older persons, women, and those in the postpartum period. Another retrospective study of the risk of death following the institution of the aforementioned monitoring guidelines identified two deaths among over 200,000 persons who initiated isoniazid (0.001%) with no deaths noted among postpartum women, suggesting that risk was much lower with proper monitoring (66). In a prospective study of over 11,000 consecutive patients in Seattle who received isoniazid preventive therapy from 1989 through 1995, there were only 11 cases (0.1%) of hepatotoxicity (using routine clinical monitoring and laboratory tests when indicated), all of which were reversible, and there were no deaths (67). Taken together, these studies supported modification of prior recommendations, and in 2000, ATS/CDC recommended that targeted skin testing be offered only to groups at risk of LTBI, and that treatment be offered to all persons found to be tuberculin positive, irrespective of age (1). In patients with silicosis, the use of rifampicin alone resulted in fewer alanine aminotransferase (ALT) abnormalities at three months (4%) than with isoniazid alone (28%) or the combination (31%), compared to placebo (5%) (29). There were no differences, however, in serious adverse events. In a study conducted in Montreal, Canada of 116 tuberculin-positive patients randomized to receive rifampicin for four months or isoniazid for nine months, 86% and 62% of patients took more than 90% of their prescribed regimens, respectively (68). Adverse events requiring discontinuation occurred in 3% of the rifampicin group and 14% of the isoniazid group, including hepatitis in 0 and 5%, respectively. Similarly, in a study conducted in New Jersey of patients treated with rifampicin for four months, 85% completed the regimen, compared to 66% treated with isoniazid for nine months (69). Prior to the studies of rifampicin and pyrazinamide in HIV-infected patients, pilot studies to assess the safety and tolerability of this regimen were conducted in 402 HIV-negative patients, who were randomized to rifampicin and pyrazinamide for two months, rifampicin for four months, or isoniazid for six months (70,71). The rifampicin and pyrazinamide regimen was associated with a higher number of aspartate aminotransferase (AST) elevations of more than 100 U/L (17 compared with one with rifampicin and five with isoniazid), and more frequent adverse reactions resulting in drug discontinuation (15 compared with zero with rifampicin and two with isoniazid). The rates of adverse reactions and elevated AST were higher than those reported in studies involving HIV-infected patients and those described in a clinical trial of isoniazid, rifampicin, and pyrazinamide for the treatment of active TB in HIV-negative persons (72). Additional information on the tolerability of rifampicin and pyrazinamide regimen is provided below. B. Studies in HIV-Infected Persons

Studies of preventive therapy in HIV-infected patients showed that several regimens were generally well tolerated (38,40–42,45,47). All studies used

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clinical monitoring at patient visits and some biochemical monitoring when indicated; one routinely checked liver function tests at baseline and at two months (45). In a four-arm study in Uganda, the two arms of isoniazid alone and isoniazid and rifampicin had relatively few adverse experiences, with slightly higher rates of arthralgias (3%) and rashes (2%) than in the placebo group (1%). The three-drug regimen of isoniazid, rifampicin, and pyrazinamide was poorly tolerated, resulting in treatment discontinuation in 6% of patients, arthralgias in 11%, rashes/pruritus in 6%, paresthesias in 6%, and gastrointestinal complaints in 4% (41). Measurements of adherence, based on isoniazid metabolite testing in urine, were 95% for patients on isoniazid, 90% on isoniazid and rifampicin, and 83% on three drugs (73). In the two-arm international study that compared isoniazid to rifampicin and pyrazinamide, there was a higher rate of treatment discontinuation with rifampicin and pyrazinamide (9%) than with isoniazid (6%) (45). Nausea and vomiting were more common with rifampicin and pyrazinamide (2%) than with isoniazid (0.1%), whereas elevated liver function tests were more common with isoniazid (3%) than with rifampicin and pyrazinamide (1%). Owing to later reports of hepatotoxicity associated with the use of rifampicin and pyrazinamide (see below), the study data were reanalyzed (74). Of patients who received rifampicin plus pyrazinamide and isoniazid, respectively, 0.6% and 1.8% had serum bilirubin 2.5 mg/dL or more, and 2.1% and 1.6% have AST elevations more than 250 U/L. Older age was the only identified risk factor for increases in AST in both arms. In a study conducted in Florida, 135 patients received twice weekly directly observed therapy (DOT) with a rifamycin and pyrazinamide (94 rifabutin and 41 rifampicin), of whom 3.7% discontinued due to side effects (75). Pruritus or rash occurred in 10 patients and elevated ALT in one patient, compared to no discontinuations due to side effects or to hepatitis in 93 historical controls treated with self-administered isoniazid for 12 months. Completion rates were 93% in those who received a rifamycin and pyrazinamide and 61% in those treated with isoniazid. C. Toxicity Associated with the Use of Rifampicin and Pyrazinamide

Owing to the relative paucity of data in HIV-negative persons, the ATS/ CDC guidelines called for additional research to ascertain the acceptability, tolerability, and effectiveness of rifampicin and pyrazinamide in this population. After widespread implementation of the new recommendations starting in October 2000, CDC received reports of severe hepatic injury associated with the use of the two-month regimen resulting in hospitalization, and, in some instances, death (76,77). Through March 2004, there had been 50 cases of hepatotoxicity requiring hospitalization and 12 fatalities (of whom two were HIV positive) (78). Investigations showed that in some situations, patients had underlying liver disease (known and unknown) and/or positive serologies for viral hepatitis (18%); 71% had history of

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alcohol use, 66% were taking other hepatotoxic medications, and six patients had prior isoniazid-related hepatotoxicity. Patients who died were more likely to be older and on more medications than those who survived. However, no single or consistent risk factors were identified to predict who would tolerate the rifampicin and pyrazinamide regimen. Initially, the incidence of these serious events could not be determined as the total number of persons treated with this regimen during this time period was unknown (79). In order to estimate the incidence of and risk factors for severe liver injury associated with the use of rifampicin and pyrazinamide, the CDC conducted a survey of city health departments (80). Of the 50 cases reported, 30 were included in the survey and 7 had died. Of 8387 patients who were reported to have started rifampicin and pyrazinamide, approximately 81% received daily therapy and 19% twice-weekly therapy. Of these, 207 patients discontinued because of AST elevations greater than five times the upper limit of normal (rate: 25.6 per 1000 treatment initiations); an additional 151 patients discontinued because of symptoms of hepatitis (rate: 18.7 per 1000 treatment initiations). Of the 30 patients with severe hepatic injury, the estimated rates of hospitalization (in those who recovered) and death were 2.8 [95% confidence interval (CI) ¼ 1.9–4.5] and 0.9 (95% CI ¼ 0.2–2.0) per 1000 treatment initiations, respectively. A review of early studies of isoniazid when used for the treatment of LTBI showed hospitalization rates as high as 5.0 per 1000 treatment initiations and mortality as high as 1.0 per 1000. However, for studies of isoniazid after 1999, hospitalization rates were 0.1 to 0.2 (median 0.10) and mortality rates of 0 to 0.3 (median 0.04) per 1000 initiations (80). Several additional studies were completed by health departments or correctional facilities after the publication of the guidelines, and provided more information about the safety and acceptability of rifampicin and pyrazinamide in largely HIV-negative patients (Table 4) (81–91). In a randomized prospective trial, the SCRIPT study, the safety and tolerance of rifampicin and pyrazinamide for two months were compared to isoniazid for six months in HIV-negative persons with LTBI in San Francisco, Boston, and Atlanta (83). Of patients who received rifampicin and pyrazinamide, 7.7% had grade 3 or 4 hepatotoxicity (ALT >5 times and >10 times the upper limit of normal, respectively), compared to 1% of the patients assigned to isoniazid; the rate of drug discontinuation was also higher in the rifampicin and pyrazinamide group (5.9% vs. 3%). In the Fulton County Jail in Georgia, of inmates with LTBI who started daily rifampicin and pyrazinamide, 48% completed 60 doses and 44% were unexpectedly released prior to completion; this completion rate was significantly greater than for the 4% of inmates who completed at least six months of isoniazid during the same and a previous time period (81). Treatment was discontinued in one inmate due to ALT elevation greater than 10 times the upper limit of normal and in 12 (7%) for minor complaints. Similarly, in the Maryland Department of Public Safety and

0 0

307 282

Prospective, randomized

Prospective, randomized

Retrospective cohort

Leung (87); Hong Kong; 2000–2002

Priest (88); Tennessee, U.S.; 2000–2001

McNeill (86); Prospective, not North Carolina; U.S.; randomized 1999–2001

8 (7)

36

2 (2) 1 (1) 0

0 0

110 114 40d

36d 423

78

9 (6)

148

28 (5)

589

Prospective cohort

0

HIVpositivea no. (%)

168

Study subjects (n)

Prospective cohort

Study design

Lee (84); Retrospective Illinois, U.S.; chart review 1999–2001 Stout (85); Prospective North Carolina, U.S.; cohort 1999–2002

Bock (81); Georgia, U.S.; 1998–1999 Chaisson (82); Maryland, U.S.; 1999–2001 Jasmer (83); three cities, U.S.; 1999–2001

Author (Ref.); location; years of study

RIF 450–600 mg/PZA, 1000–1500 mg qD (2) INH 300 mg qD (6) RIF 600 mg/PZA, 50 mg/kg b.i.w. (2)

RIF 600 mg/PZA, 20 mg/kg qD (2) RIF 600 mg/PZA, 50 mg/kg b.i.w. (2) RIF 600 mg/PZA 15 mg/kg qD (2) INH 300 mg qD (6)

RIF 600 mg/PZA 15–20 mg/kg qD (2) RIF 450–600 mg/PZA 1500–2500 mg b.i.w. (2) RIF 600 mg/PZA 20 mg/kg qD (2) INH 300 mg qD (6) RIF 600/PZA 15–20 mg/kg qD (2)

Drug regimen (mo)

1 (3) 13 (3)

6 (15)

—

—

6 (5)

3 (2)

—

0

—

No. with hepatitisb (%)

1 (3) 24 (6)c

14 (35)

5 (4)

8 (7)c

2 (6) 25 (6)

14 (35)

—

—

8 (7)

26 (18)

14 (9)c

4 (4)

8 (3)

28 (9)

—

13 (8)

Discontinuations 2 adverse events (%)

2 (1)

16 (8)

1 (0.2)

2 (1)

No. with AST or ALT
5 ULNa(%)

Table 4 Studies of RIF and PZA in Treatment of Latent Tuberculosis Infection in Largely HIV-Negative Patients

(Continued )

23 (64) 352 (83)

22 (55)

67 (59)

78 (71)

77 (68)

85 (57)

160 (57)

187 (61)

538 (91)

81 (48)

Completion no. (%)

Treatment of Latent TB Infection 283

0

153

199

Prospective, randomized

17 (1)

INH 300 mg qD INH 300 mg qD, RIF 600 mg, PZA 20–30 mg/kge RIF 600 mg/PZA 15– 20 mg/kg qD (2) RIF 600 mg/PZA 20–25 mg/kg b.i.w. (2) INH 300 mg qD (6)

RIF 600 mg/PZA 20– 30 mg/kg qD

Drug regimen (mo)

—

—

26 (2)

— —

—

No. with hepatitisb (%)

5 (3)

8 (5)

19 (14)

66 (5)

43 (4)c

15 (10)

17 (3) 16 (4)

14 (8)

Discontinuations 2 adverse events (%)

18 (3) 14 (3)

14 (8)

No. with AST or ALT
5 ULNa(%)

145 (73)

106 (70)

561 (46)

— —

—

Completion no. (%)

b

HIV positive, of persons tested. Hepatitis refers to patients with symptoms; patients with AST or ALT elevations include both symptomatic and asymptomatic patients. c Two patients each in three studies (84,86,88) were hospitalized due to hepatotoxicity; all recovered. One patient in one study died from hepatotoxicity (90). d All patients had silicosis. e Patients with active tuberculosis, treated for initial two months with INH, RIF, and PZA. —, Not reported. Abbreviations: RIF, rifampicin; PZA, pyrazinamide; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit normal; INH, isoniazid; qD, daily; b.i.w., twice weekly.

a

0

1211

Prospective cohort

0 15 (4)

528 410

Lobato (90); eight cities, U.S.; 2000–2001 Tortajada (91); Spain; 2001–2003

1 (1)

166

Prospective/ retrospective cohort

van Hest (89); Netherlands; 2000–2001

HIVpositivea no. (%)

Study design

Study subjects (n)

Author (Ref.); location; years of study

Table 4 Studies of RIF and PZA in Treatment of Latent Tuberculosis Infection in Largely HIV-Negative Patients (Continued )

284 Cohn and El-Sadr

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285

Corrections, of inmates started on twice-weekly rifampicin and pyrazinamide, 91% completed the two-month regimen, and only 10 (1.7%) had hepatotoxicity (nine with aminotransferase levels three to five times normal) (82). In North Carolina, patients in a health department were offered either dailyrifampicinor pyrazinamidefortwomonthsorisoniazidforsixmonths(86). Treatment was completed by 71% of patients in the rifampicin and pyrazinamide group compared to 59% in the isoniazid group. Hepatotoxicity (ALT >160 U/L) occurred in 13% of patients receiving rifampicin and pyrazinamide (7% with ALT greater than five times the upper limit of normal), compared to 4% of isoniazid recipients. Severe hepatotoxicity (ALT > 1600 U/L) occurred in 2 of 53 persons (5%) receiving rifampicin and pyrazinamide, but after more intensive biochemical monitoring was implemented, there were no additional serious events in 67 patients. In another study in North Carolina, patients received rifampicin and pyrazinamide, of whom 61% were homeless and 17% used alcohol to excess; 68% completed a two-month course (85). About one-third received daily self-administered therapy and two-thirds received twice-weekly DOT. Four of the patients (3.5%) developed confirmed hepatitis (AST or ALT greater than five times normal with symptoms or >10 times normal without symptoms), and two others had suspected hepatitis (symptoms but no laboratory confirmation). Seventeen patients (15%) discontinued the medications transiently because of gastrointestinal side effects or rash, but nine were able to restart and complete the regimen. At three health departments and five jails in the United States, homeless and incarcerated persons with LTBI were treated with two months of daily rifampicin and pyrazinamide, either directly observed or given as seven-day supplies (90). Of 1211 persons treated, 46% completed therapy and 5.5% discontinued due to adverse events; 11% had AST levels >2.5 times upper limit of normal, of whom 49% completed the regimen. Fifteen patients had severe hepatotoxicity (AST >500 U/L) of whom nine were symptomatic; one patient died. Infection with hepatitis C or in combination with hepatitis B was a risk factor for hepatotoxicity. Other studies conducted in Tennessee, the Netherlands, Illinois, and Spain showed rates of hepatotoxicity with rifampicin and pyrazinamide of 6%, 8%, 9%, and 10%, respectively (Table 4) (84,88,89,91). In a randomized trial of patients with silicosis in Hong Kong, 35% of patients who received rifampicin and pyrazinamide had AST levels greater than five times upper limit of normal, compared to 3% of patients who received isoniazid (87). In the 11 studies shown in Table 4, of 3673 patients who received rifampicin and pyrazinamide, seven were hospitalized (0.2%) and one (0.03%) died. In summary, these studies showed that similar to the results in trials in HIV-infected subjects, completion rates with the two-month regimen of rifampicin and pyrazinamide were often higher than with isoniazid therapy, and ranged from 46% to 91%. Significant hepatotoxicity (aminotransferases greater than five times the upper limit of normal) occurred in

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0.2% to 10% (35% in silicosis) of patients, and tended to decrease when patients were monitored more carefully, but not invariably. In some studies, the twice-weekly regimen appeared to be associated with less hepatotoxicity than the daily regimen, either due to less cumulative drug exposure or to closer monitoring. Taken together, the risk of hepatotoxicity and serious liver injury in these studies is considerably greater with rifampicin and pyrazinamide than in most studies of isoniazid-associated hepatotoxicity (1,65,67,80,92). The reason for the apparent disparity of rates of hepatotoxicity with the use of rifampicin and pyrazinamide in HIV-infected and HIV-negative patients is unclear (74). This may be due to immunologically mediated injury in HIV-negative patients, sample sizes that were too small to detect rare events in clinical trials of HIV-infected patients, differences in the selection of populations, or differences in monitoring and detection of adverse events in different studies (79,93).

IV. Treatment of LTBI in Special Populations A. Pregnant and Breast-Feeding Women

Pregnancy has minimal influence on the pathogenesis of TB or the likelihood of progression of LTBI to disease (94,95). Among most pregnant women eligible for the treatment of LTBI, many experts would postpone treatment until after delivery. Additionally, some experts prefer delay in initiation of treatment for LTBI until two to three months after delivery. This is based on the results of two studies in which the risk of hepatotoxicity appeared to be increased among women receiving isoniazid during the immediate postpartum period (65,96). However, for subgroups of pregnant women with LTBI who are at substantial risk of developing TB or where hematogenous dissemination of organisms to the placenta is possible (97), initiation of LTBI treatment has been recommended during pregnancy. These include tuberculin-positive pregnant women who are HIVinfected, those with recent skin test conversion, and women with a recent history of a close contact with a case of TB (1,98). Although isoniazid crosses the placenta, extensive use during pregnancy has shown that it is not teratogenic (99). For rifampicin, a thorough review showed that 3% of fetuses exposed in utero had abnormalities compared to 2% for ethambutol and 1% for isoniazid (100). However, rifampicin has been extensively used for the treatment of TB during pregnancy and is generally considered to be safe. There are limited data on the safety of breast-feeding for infants of mothers receiving isoniazid for the treatment of LTBI. Although measurable amounts of isoniazid have been detected in breast milk, only a small proportion of the adult dose is secreted in breast milk (<2%); it is unlikely to be detectable in the serum of infants (101). Based on these data, most experts support breast-feeding by women receiving isoniazid after appropriate counseling regarding risks and benefits.

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B. Children

Children and infants who are recently infected are at significant risk for development of TB as described in Chapter 10. Identification of children eligible for LTBI in the United States has been recently reviewed in a consensus statement of the Pediatric Tuberculosis Collaborative Group (102). Importantly, when TB occurs in infants and young children, disseminated disease and TB meningitis are more common than in older children and adults, providing a strong imperative to provide treatment of LTBI for at-risk children. Several studies have demonstrated the efficacy of isoniazid for treatment of LTBI in children with primary infection or who are contacts of cases (7,22,23). Hepatotoxicity from isoniazid in infants and children is rare and in general children tolerate the drug better than adults (103,104). There are no controlled trials on the use of rifampicin or rifampicin plus pyrazinamide for the treatment of LTBI in children. However, rifampicin appeared to be safe when used in children exposed to a patient with isoniazid-resistant TB (105). A regimen of rifampicin and isoniazid for three months has been used successfully in England in tuberculin-positive children who were household contacts or immigrants from high-prevalence countries (106). A study of a small number of children with LTBI treated with rifampicin and pyrazinamide suggested that it was well tolerated (107). C. Contacts of Isoniazid-Resistant TB

There are few data on the efficacy of treatment of LTBI in persons exposed to cases of isoniazid-resistant TB. In an outbreak of TB resistant to isoniazid and streptomycin in homeless persons, of exposed tuberculin skin test converters who received no preventive therapy, 6 of 71 (9%) developed TB, compared to 3 of 38 (8%) who received isoniazid, and 0 of 98 who received rifampicin or isoniazid and rifampicin (108). Similarly, of 157 high school students who took rifampicin after being exposed to an infectious case of isoniazid-resistant TB, none developed TB after two years (105). However, one episode of rifampicin prophylaxis failure was reported among contacts of an isoniazid-resistant case of TB in a community outbreak (109). There is no clear consensus on the choice of regimen for a contact with history of exposure to a patient with probable or confirmed isoniazidresistant TB. A decision analysis and Delphi methodology were used to recommend either rifampicin alone or in combination with isoniazid or ethambutol in this setting (110). These results were supported by ATS recommendations in 1983 (64) and by an expert panel of the American College of Chest Physicians in 1985 (111). D. Contacts of Multidrug-Resistant Tuberculosis

The occurrence of outbreaks of multidrug resistant tuberculosis (MDR-TB) and the rise in resistance rates worldwide have focused attention on options for preventive therapy for individuals exposed to such cases (112). This is particularly important when there is exposure to a case of TB with organisms resistant to both isoniazid and rifampicin. Regimens for use in the

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latter situation have not been evaluated in prospective studies. In contacts of cases of MDR-TB who received ofloxacin and pyrazinamide, gastrointestinal side effects, asymptomatic elevations of serum aminotransferases, and hepatitis have been reported (113,114). A Delphi technique among 31 experts failed to achieve consensus on a defined course of action for persons exposed to MDR-TB (115). V. Recommendations for the Treatment of LTBI A. General

Recommended regimens for the treatment of LTBI are shown in Table 5 (1,77,92). These recommendations utilize the USPHS rating system that provides the strength of the recommendation and the quality of the supporting evidence. They represent the deliberations of an expert committee convened by ATS and CDC in 1998 and were published in 2000 after extensive review (1). The recommendations were updated in 2001 following the reports of serious hepatotoxicity with rifampicin and pyrazinamide (77), and then updated again in 2003 after completion and review of the aforementioned CDC health department survey and other studies (92). In most settings in industrialized countries, isoniazid is the preferred treatment, given 300 mg daily for nine months. Where directly observed preventive therapy (DOPT) is indicated and available, 900 mg twice weekly for nine months is administered. Pyridoxine (vitamin B6, 10–25 mg) is often included with isoniazid and might prevent peripheral neuropathy and central nervous system effects. In selected situations, depending on priorities and available resources, programs may choose to administer therapy for six months, which has also been shown to be effective. In HIV-infected patients, both 6 and 12 months of therapy have been shown to be effective in randomized trials, but have not been compared to each other. Previously, 12 months of therapy was recommended, owing to the high risk of TB with HIV infection (i.e., greater than with fibrotic lung lesions) and because some studies showed that the protective effect on isoniazid appeared to wane over time (40,49,50). In order to achieve consistency and simplicity in recommendations, a nine-month regimen is now recommended for all eligible patients in industrialized countries (1,98). The optimal length of isoniazid in HIV-infected patients is still unknown. Baseline laboratory testing is not routinely indicated for all patients who initiate treatment with isoniazid (1). However, in industrialized countries, patients with known or suspected liver disease, those who use alcohol, and persons with other chronic medical conditions should have baseline measurements of AST or ALT and serum bilirubin. During treatment, clinical monitoring is indicated in all patients, including education of patients about symptoms and signs of adverse effects. Laboratory monitoring should be performed if baseline liver function tests are abnormal, there is a history of liver disease, or patients have symptoms or signs of hepatotoxicity.

Rifampicin

Isoniazid

Isoniazid

Drug

Daily for 4 mo

Twice weekly for 6 mod

Daily for 6 mod

Twice weekly for 9 moc,d

Daily for 9 moc,d

Interval and duration In HIV-infected patients, isoniazid may be administered concurrently with nucleoside reverse transcriptase inhibitors, protease inhibitors, or NNRTIs DOT must be used with twice-weekly dosing Not indicated for HIV-infected persons, those with fibrotic lesions on chest radiographs, or children DOT must be used with twice-weekly dosing For persons who are contacts of patients with isoniazid-resistant, rifampicin-susceptible TB In HIV-infected patients, most protease inhibitors or delavirdine should generally not be administered concurrently with rifampicin. Rifabutin can be used with protease inhibitors and NNRTIs (except delavirdine)e

Comments

Table 5 Recommended Drug Regimens for Treatment of Latent Tuberculosis Infection in Adults

B (III)

B (II)

(Continued )

C (I)

C (I)

B (II)

A (II)

HIVþ

B (II)

B (I)

B (II)

A (II)

HIV

Ratinga (evidence)b

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Twice weekly for 2–3 mo

Daily for 2 mo

Interval and duration Rifampicin and pyrazinamide generally should not be offered for the treatment of LTBI for HIV-infected or HIV-negative persons DOT must be used with twice-weekly dosing

Comments

D (III)

D (II)

D (II)

D (III)

HIVþ

HIV

b

Strength of recommendation: A ¼ should always be offered, B ¼ should generally be offered, C ¼ optional, D ¼ should generally not be offered. Quality of evidence: I ¼ randomized clinical trial data, II ¼ data from clinical trials that are not randomized or were conducted in other populations, III ¼ expert opinion. c Recommended regimen for children <18 years of age. d Recommended regimens for pregnant women. e Rifabutin should not be used with delavirdine, and saquinavir should be augmented with ritonavir. When used with other protease inhibitors or nonnucleoside reverse transcriptase inhibitors, dose adjustment of rifabutin may be required. f Rifampicin and pyrazinamide should not be used in patients who: are taking other medications associated with liver injury, drink excessive amounts of alcohol, have underlying liver disease, or have had isoniazid-associated liver injury. Patients should have clinical and biochemical monitoring (serum ALT or AST and bilirubin) at baseline, 2, 4, 6, and 8 weeks of treatment. Abbreviations: NNRTI, non-nucleoside reverse transcriptase inhibitor; DOT, directly observed therapy. Source: Adapted from Refs. 1, 77, 92.

a

Rifampicin and pyrazinamidef

Drug

Ratinga (evidence)b

Table 5 Recommended Drug Regimens for Treatment of Latent Tuberculosis Infection in Adults (Continued )

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The ATS and CDC now recommend that rifampicin and pyrazinamide for two months generally not be offered to persons with LTBI (Table 5) (92). The regimen should not be given to patients who are taking other medications associated with liver injury, drink excessive amounts of alcohol, have underlying liver disease, or have a history of isoniazid-associated liver injury. When the potential benefits outweigh the risks (e.g., in a patient at high risk for TB, who is not likely to complete six to nine months of isoniazid or four months of rifampicin), the use of rifampicin and pyrazinamide for two months may be considered, as long as oversight is provided by a clinician with expertise in the treatment of LTBI. Patients prescribed rifampicin and pyrazinamide should have no more than a two-week supply dispensed at a time. They should have clinical and laboratory monitoring (AST or ALT and bilirubin) at each visit, i.e., baseline, two, four, and six weeks, and at eight weeks to ensure completion of therapy (77). In HIV-infected persons receiving protease inhibitors or non-nucleoside reverse transcriptase inhibitors (with the exception of efavirenz), rifampicin is contraindicated owing to drug interactions. Either rifabutin may be substituted for rifampicin, or isoniazid should be used. B. Pregnant Women

For pregnant women who are tuberculin positive, isoniazid daily or twice weekly for nine months is recommended. Some experts delay the treatment of LTBI until the postpartum period, unless the patient is HIV infected, has evidence of other immunosuppressive condition, has had a recent tuberculin skin test conversion, or has a recent close contact to a person with infectious TB. Women who are treated for LTBI during pregnancy or in the immediate postpartum period should have careful clinical and laboratory monitoring. Both mother and infant should receive supplemental vitamin B6. There is no consensus on treatment of LTBI in pregnant women in resource-limited countries. C. Children

Children and adolescents should be treated with isoniazid given daily or twice weekly for nine months (1,102). Monitoring of liver function tests at baseline or during treatment is not recommended in children unless they have existing medical conditions that increase the risk of hepatotoxicity. The optimal length of therapy with rifampicin is unknown; the American Academy of Pediatrics recommends six months of treatment (116). A regimen of rifampicin and pyrazinamide is not recommended due to hepatotoxicity observed in adults and lack of data in children (102). D. Persons Intolerant to Isoniazid or Contacts of Isoniazid-Resistant TB

For persons intolerant to isoniazid or who are likely to be infected with isoniazid-resistant organisms rifampicin for four months or rifampicin and pyrazinamide for two months (with the caveats described above) may be used. If intolerant to pyrazinamide, rifampicin for four months should

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be used. If a patient has had documented hepatotoxicity when treated with isoniazid, rechallenge with rifampicin and pyrazinamide for the treatment of LTBI is not recommended; rifampicin may be considered. E. Contacts of MDR-TB

For persons who are contacts of cases of MDR-TB, pyrazinamide and ethambutol or pyrazinamide and a quinolone (e.g., ofloxacin) for 6 to 12 months are recommended, provided the organisms from the index patient are known to be susceptible to these agents (1,117). Immunocompetent contacts may be observed or treated for six months, and immunocompromised contacts (e.g., HIV-infected persons) may be treated for 12 months. Persons suspected of having infection with MDR-TB should be followed for at least two years, irrespective of treatment regimen. For children exposed to patients with MDR-TB, ethambutol and pyrazinamide are generally recommended; long-term use of quinolones is discouraged in children (1). F. Resource-Limited Countries

Although treatment of LTBI is not routinely recommended in countries with limited resources, in 1993, the World Health Organization (WHO) and International Union Against Tuberculosis and Lung Disease recommended treatment in tuberculin-positive (
5 mm) individuals with HIV infection, in recognition of the risk of TB in HIV-infected persons and the demonstrated efficacy of preventive therapy (2). In 1998, WHO and the United Nations AIDS Program broadened this recommendation, so that preventive therapy should be offered as part of a package for persons living with HIV, including access through voluntary counseling and testing sites (4). The recommendation, however, states that the treatment of LTBI should only be used in settings where it is possible to exclude active TB and in which monitoring can be ensured. Isoniazid daily for six months (selfadministered) is the recommended regimen for resource-limited settings. The WHO TB-HIV Working Group has highlighted the importance of integration of the management of both conditions (118). As more people seek counseling and testing services and access to antiretroviral therapy increases, the addition of preventive therapy to the package of care is essential. VI. Programmatic and Other Issues Related to the Treatment of LTBI A. Adherence

Adherence to treatment of active TB has received considerable attention. Treatment defaulting or missing of doses is associated with treatment failure and relapse as well as with development of drug-resistant TB (119). These adverse outcomes led to the development and support for DOT programs around the world (120). On the other hand, until recently little attention has been paid to adherence in the context of treatment of LTBI. Available evidence indicates that completion of the treatment course for LTBI and

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adherence with required doses has been associated with decreased risk of development of TB disease (6,19). In addition, adherence with clinic visits allows for proper monitoring of patients in order to identify adverse events and to reinforce the importance of adherence. Thus, recent guidelines for the treatment of LTBI highlight the importance of ensuring adherence during patient visits, monitoring the number of doses taken by patients, incorporating regimens into patients’ daily routines, and considering DOPT (1). Due to economic constraints in resource-limited settings, greater emphasis on patient education and encouragement from staff is more feasible than DOPT. Interest in this issue has generated important research endeavors to identify effective strategies to optimize adherence. Studies have sought to determine knowledge and attitudes regarding LTBI and its treatment among both providers and patients, because these factors are of particular importance in achieving LTBI treatment goals (121). Information from such research is critical for TB control programs in order to assist them in shaping their provider and patient-targeted interventions. Importantly, partnerships have been forged between TB control programs and community groups that can enable them to achieve treatment goals for LTBI (122). Various strategies and interventions for enhancement of adherence to treatment for LTBI have been evaluated (123). The impact of the use of peers to improve adherence for the treatment of LTBI gave conflicting results. In studies of treatment of LTBI in adolescents, peer counseling and coaching were effective in enhancing adherence (124,125). In contrast, among injection drug users, the use of incentives was more effective than the use of peers (126). It is possible that the effectiveness of peer workers is determined by defining the characteristics of the peer, the selection process, their supervision, and other program characteristics. In a randomized trial of different interventions in jail inmates who were then released, completion of isoniazid for six months was better in those who received educational sessions than incentives (127). Another strategy that has been adapted from treatment of active TB disease is DOT. This has been facilitated by the availability of LTBI regimens that can be taken on an intermittent basis, and DOPT is recommended when intermittent LTBI regimens are prescribed (1,128). Studies and clinical practice have shown higher completion rates with twice weekly or daily DOPT than daily self-administered therapy (129–132), and in one study, lower completion rates with DOPT (133). In summary, TB programs and providers should pay particular attention to enhance adherence of treatment of LTBI with educational materials and appropriate service components tailored to specific patient populations (1,123).

B. Feasibility

Although efficacy in HIV-infected patients has been firmly established in clinical trials, the true effectiveness in other settings may be different. This is of special concern in developing countries, where resources are limited

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and the relative impact of treatment of LTBI has been debated. Successful program implementation is dependent on the availability of the following: tuberculin skin testing (if used), ability to exclude active TB, isoniazid for treatment, laboratory and clinical resources for patient monitoring, and resources to facilitate and enhance adherence with treatment. In a study from Uganda, HIV-infected patients were recruited from an HIV counseling and testing site for isoniazid treatment of LTBI, including tuberculin skin testing, and significant attrition at each step of the process was noted (134). Of the 23% of clients who tested HIV positive, 24% returned for HIV test results and had tuberculin skin testing, and of those, 39% initiated treatment with isoniazid; 62% completed at least 80% of a six-month regimen. Overall, of 5594 HIV-infected patients who returned for HIV test results, 322 (6%) completed their course of isoniazid treatment. In a more recent study in Uganda, of patients already receiving HIV care and who were prescribed isoniazid for treatment of LTBI (without prior tuberculin skin testing), a similar percentage initiated isoniazid and 73% completed a six-month course (135). These completion rates were similar in an urban setting (Kampala) and a rural setting (Mbarara). Of note, many patients in the rural setting were excluded because they lived more than 15 km from the clinic. This finding is similar to a feasibility study conducted in Zambia, where distance from a counseling and testing center and problems with transportation were barriers to enrollment (136). In a WHO initiative (ProTest) using voluntary HIV counseling and testing sites as entry points for a package of care for TB and HIV services in Malawi, South Africa, and Zambia, completion rates for a six-month regimen ranged from 24% to 59% (137). Despite these variable completion rates, the program provided increased access to counseling and testing services, intensified case finding for TB, the integration of both isoniazid and cotrimoxazole preventive therapy, HIV prevention activities, and the demonstrated collaboration needed to be able to implement antiretroviral therapy. In contrast to the studies from Africa, in a hospital-based study in Thailand of 412 HIV-infected patients, 89% initiated isoniazid treatment and 69% completed a nine-month course (138). In two HIV/AIDS clinics in Thailand, 82% of patients completed a six-month regimen of isoniazid, and completion rates were similar in those who did or did not have tuberculin skin test testing (139). In infectious disease hospital units in Italy, after high attrition during the initial steps of tuberculin screening and eligibility assessment, 71% completed 6 to 12 months of isoniazid (140). It is likely that initiation of isoniazid and treatment completion rates are dependent on efforts and resources devoted to the program, as well as access to and location of clinics, with differences in standards of care in different regions. C. Cost-Effectiveness and Cost-Benefit

There have been few studies investigating the cost-effectiveness and costbenefit of treatment of LTBI in HIV-infected patients. In a feasibility study in Uganda, the incremental cost of a preventive therapy program was about

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$18.00 per patient, assuming counseling and testing services were already in place. However, a formal cost-effectiveness analysis was not performed (134). A modeling of cost-effectiveness of preventive therapy in Zambia showed that if treatment prevented only two additional cases of TB, costs would exceed benefits (benefit/cost ratio ¼ 0.86), whereas if five new cases were prevented, benefits would exceed the costs (benefit/cost ratio ¼ 1.71) (141). Other scenarios suggested cost-effectiveness if targeted programs could access significant populations of risk, such as in selected occupational settings. Data from feasibility studies suggest that about 19 to 70 clients need to be screened to prevent one case of TB; whether this is cost-effective is contingent on marginal costs incurred to establish and run the preventive therapy program within the infrastructure present in a region or country (4). Using decision analysis, the cost-effectiveness of short-course regimens of preventive therapy in HIV-infected patients was evaluated and compared to isoniazid for 12 months (142). Isoniazid for six months, isoniazid plus rifampicin for three months, and rifampicin plus pyrazinamide for two months all had clinical and economic benefits similar to isoniazid for 12 months. Studies and decision analysis models in other populations also suggest the cost-effectiveness of treatment of LTBI. In two studies of injection drug users followed in methadone maintenance clinics, the use of DOPT with isoniazid for 6 to 12 months was determined to be cost-effective (143,144). In people immigrating to the United States from high-prevalence countries, detection and treatment of LTBI with isoniazid, rifampicin, or rifampicin plus pyrazinamide would lead to substantial health and economic benefits (145). In particular, immigrants from Vietnam, Haiti, and the Philippines were more likely to benefit from rifampicin-containing regimens, due to higher rates of isoniazid resistance in those countries. In HIVnegative patients in the SCRIPT Study, treatment with isoniazid for six months was slightly more cost-effective than rifampicin and pyrazinamide for two months, owing to higher frequency of adverse events and lower completion rates in those who received rifampicin and pyrazinamide (146). D. Impact on Epidemiology of TB

With the decrease in the incidence of TB in the United States over the past decade, LTBI and its treatment have gained more significance; the Institute of Medicine highlighted the importance of treatment of LTBI as a component of the national strategy for TB elimination in the United States (5). Focus on specific populations with LTBI who are at greatest risk for the development of TB (i.e., HIV-infected patients, persons with old healed TB, contacts of TB cases, recent tuberculin skin test converters, and young children) should be targeted by control programs (1,147). Outreach to foreign-born populations with substantial rates of LTBI has also been advocated in order to reach another group who are at significant risk of development of TB (148). These efforts, if associated with high completion rates in treatment of LTBI, are likely to advance the efforts toward TB elimination in the United States and other industrialized countries.

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From a global perspective, TB has dramatic impact on the health of populations in resource-limited countries (149). With the spread of the HIV epidemic in many of the same countries, explosive rates of TB have been reported from these countries, because HIV infection is the most potent risk factor for progression of TB (36,37). Some have recognized the importance of the HIV epidemic on TB control efforts and called for a concerted and coordinated effort for better management of HIV-infected patients with regard to TB (150). In addition, a targeted strategy for treatment of LTBI, which focuses on patients at highest risk, could have an impact on transmission of TB (151). Whether treatment of LTBI could have an impact on rates of TB is controversial (152). In modeling studies, use of treatment of LTBI among HIV-infected patients or mass LTBI treatment would have significant impact on TB case rates and TB mortality (153,154). In another study using a Markov model, use of LTBI treatment in HIV-infected patients in sub-Saharan Africa would result in longer survival, decreased TB incidence, and savings in medical and social costs (155). However, a more recent analysis challenges this concept and suggests that the public health impact of preventive therapy on a population in sub-Saharan Africa would be small (156). The recent expansion of HIV care and treatment programs, including the use of antiretroviral therapy, offers an opportunity to develop programs that aim at providing eligible HIV-infected patients with treatment for LTBI (118,150). Several challenges confront the implementation of such programs. Pilot programs have been established through the WHO (137); however, more extensive programs are needed to evaluate this strategy. VII. Future Directions Continued research in the treatment of LTBI should be pursued in several directions (1,157). Demonstration projects and additional studies of feasibility, adherence, and cost-effectiveness are necessary, especially in developing countries and in HIV-infected populations. Further studies of intermittent DOPT regimens should be done to obtain additional information on effectiveness, tolerability, safety, and ease of implementation. In HIV-infected patients, longer duration of therapy, i.e., 12-month regimens or lifelong therapy should be evaluated, especially in areas where antiretroviral therapy may not be readily available. In areas where antiretroviral therapy is used or will be implemented, the added benefit of preventive therapy should be determined. Studies in infants and children with both current and new medications need to be conducted. New regimens with novel agents, such as rifapentine or other drugs developed in the future, should be evaluated in an attempt to continue improving the effectiveness and safety of the treatment of LTBI and to decrease duration of therapy. Finally, in areas where resistance to isoniazid is high or is increasing, additional studies of rifampicin-containing regimens or new drugs are necessary.

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VIII. Conclusions Over the past five decades, numerous clinical trials have clearly demonstrated that treatment with several different regimens is effective in preventing TB in persons with LTBI. In industrialized countries, treatment of LTBI is an important component of control programs, in which targeted tuberculin testing of high-risk persons will identify candidates for the treatment of LTBI, and resources can be devoted to completion of therapy. In low- or middle-income countries with much higher burdens of TB, case detection and treatment of active cases remain the highest priority. In those areas where programs have achieved some success in achieving WHO-recommended targets for TB control (i.e., case detection rate of 70% and a cure rate of 85% of smear-positive cases), preventive therapy for selected individuals or targeted populations should be seriously considered, such as in household contacts of active cases, persons with HIV infection, persons in correctional facilities, and workers in selected occupations. Greater implementation of this strategy may have considerable impact on global TB control. Acknowledgments We thank Ms. Michelle Puplava for assistance in preparation of the manuscript. References 1. American Thoracic Society, Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med 2000; 161(4 Pt 2):S221–S247. 2. World Health Organization, International Union Against Tuberculosis and Lung Disease. Tuberculosis preventive therapy in HIV-infected individuals. A joint statement of the International Union Against Tuberculosis and Lung Disease (IUATLD) and the Global Programme on AIDS and the Tuberculosis Programme of the World Health Organization (WHO). Tuber Lung Dis 1994; 75(2):96–98. 3. O’Brien RJ, Perriens JH. Preventive therapy for tuberculosis in HIV infection: the promise and the reality. AIDS 1995; 9(7):665–673. 4. World Health Organization. Preventive therapy against tuberculosis in people living with HIV. Wkly Epidemiol Rec 1999; 74(46):385–398. 5. Institute of Medicine. Ending Neglect: The Elimination of Tuberculosis in the United States. Washington, D.C.: National Academy Press, 2000. 6. Ferebee SH. Controlled chemoprophylaxis trials in tuberculosis. A general review. Adv Tuberc Res 1970; 26:28–106. 7. Ferebee SH, Mount FW. Tuberculosis morbidity in a controlled trial of the prophylactic use of isoniazid among household contacts. Am Rev Respir Dis 1962; 85: 490–510. 8. Bush OB Jr, Sugimoto M, Fujii Y, et al. Isoniazid prophylaxis in contacts of persons with known tuberculosis. Second report. Am Rev Respir Dis 1965; 92(5):732–740. 9. Egsmose T, Ang’awa JO, Poti SJ. The use of isoniazid among household contacts of open cases of pulmonary tuberculosis. Bull World Health Organ 1965; 33(3): 419–433.

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Cohn and El-Sadr endemic tuberculosis: results of a randomized trial. J Acquir Immune Defic Syndr 2001; 28(3):305–307. Rivero A, Lopez-Cortes L, Castillo R, et al. Randomized trial of three regimens to prevent tuberculosis in HIV-infected patients with anergy. Enferm Infecc Microbiol Clin 2003; 21(6):287–292. Cohn DL, El-Sadr WM. Treatment of latent tuberculosis infection. In: Reichman L, Hershfield E, eds. Tuberculosis: A Comprehensive International Approach. 2nd ed. New York: Marcel Dekker, 2000:471–502. Quigley MA, Mwinga A, Hosp M, et al. Long-term effect of preventive therapy for tuberculosis in a cohort of HIV-infected Zambian adults. AIDS 2001; 15(2):215–222. Johnson JL, Okwera A, Hom DL, et al. Duration of efficacy of treatment of latent tuberculosis infection in HIV-infected adults. AIDS 2001; 15(16): 2137–2147. Wilkinson D, Squire SB, Garner P. Effect of preventive treatment for tuberculosis in adults infected with HIV: systematic review of randomised placebo controlled trials. BMJ 1998; 317(7159):625–629. Bucher HC, Griffith LE, Guyatt GH, et al. Isoniazid prophylaxis for tuberculosis in HIV infection: a meta-analysis of randomized controlled trials. AIDS 1999; 13(4):501–507. Woldehanna S, Volmink J. Treatment of latent tuberculosis infection in HIV infected persons. Cochrane Database Syst Rev 2004(1):1–86. Garibaldi RA, Drusin RE, Ferebee SH, et al. Isoniazid-associated hepatitis. Report of an outbreak. Am Rev Respir Dis 1972; 106(3):357–365. Kopanoff DE, Snider DE Jr, Caras GJ. Isoniazid-related hepatitis: a U.S. Public Health Service cooperative surveillance study. Am Rev Respir Dis 1978; 117(6): 991–1001. Centers for Disease Control. Report of the ad hoc committee on isoniazid on liver disease. Am Rev Respir Dis 1971; 104:454–459. Scharer L, Smith JP. Serum transaminase elevations and other hepatic abnormalities in patients receiving isoniazid. Ann Intern Med 1969; 71(6):1113–1120. Israel HL. Isoniazid-associated hepatitis. Reconsideration of the indications for administration of isoniazid. Gastroenterology 1975; 69(2):539–542. Comstock GW, Edwards PQ. The competing risks of tuberculosis and hepatitis for adult tuberculin reactors. Am Rev Respir Dis 1975; 111(5):573–577. Taylor WC, Aronson MD, Delbanco TL. Should young adults with a positive tuberculin test take isoniazid? Ann Intern Med 1981; 94(6):808–813. Rose DN, Schechter CB, Silver AL. The age threshold for isoniazid chemoprophylaxis. A decision analysis for low-risk tuberculin reactors. JAMA 1986; 256(19): 2709–2713. Tsevat J, Taylor WC, Wong JB, et al. Isoniazid for the tuberculin reactor: take it or leave it. Am Rev Respir Dis 1988; 137(1):215–220. Jordan TJ, Lewit EM, Reichman LB. Isoniazid preventive therapy for tuberculosis. Decision analysis considering ethnicity and gender. Am Rev Respir Dis 1991; 144(6):1357–1360. American Thoracic Society. Treatment of tuberculosis and other mycobacterial diseases. Am Rev Respir Dis 1983; 127(6):790–796. Snider DE Jr, Caras GJ. Isoniazid-associated hepatitis deaths: a review of available information. Am Rev Respir Dis 1992; 145(2 Pt 1):494–497. Salpeter SR. Fatal isoniazid-inducted hepatitis: its risk during chemoprophylaxis. West J Med 1993; 159(5):560–564.

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67. Nolan CM, Goldberg SV, Buskin SE. Hepatotoxicity associated with isoniazid preventive therapy: a 7-year survey from a public health tuberculosis clinic. JAMA 1999; 281(11):1014–1018. 68. Menzies D, Dion MJ, Rabinovitch B, et al. Treatment completion and costs of a randomized trial of rifampin for 4 months versus isoniazid for 9 months. Am J Respir Crit Care Med 2004; 170(4):445–449. 69. Reichman LB, Lardizabal A, Hayden CH. Considering the role of four months of rifampin in the treatment of latent tuberculosis infection. Am J Respir Crit Care Med 2004; 170(8):832–835. 70. Geiter LJ, O’Brien RJ, Kopanoff DE. Short course preventive therapy for tuberculosis. Am Rev Respir Dis 1990; 141:A437. 71. Geiter LJ. Results of a Randomized, Controlled Trial to Assess the Toxicity and Patient Adherence with Two Short-course Regimens for the Prevention of Tuberculosis, a Two-Month Regimen of Rifampin and Pyrazinamide or a Four-Month Regimen of Rifampin Only, in Comparison with Control Regimen of Six MonthsIsoniazid. Baltimore, MD: Johns Hopkins University, 1997. 72. Combs DL, O’Brien RJ, Geiter LJ. USPHS Tuberculosis Short-Course Chemotherapy Trial 21: effectiveness, toxicity, and acceptability. The report of final results. Ann Intern Med 1990; 112(6):397–406. 73. Pekovic V, Mayanja H, Vjecha M, et al. Comparison of three composite compliance indices in a trial of self-administered preventive therapy for tuberculosis in HIVinfected Ugandan adults. Uganda-Case Western Reserve University Research Collaboration. J Clin Epidemiol 1998; 51(7):597–607. 74. Gordin FM, Cohn DL, Matts JP, et al. Hepatotoxicity of rifampin and pyrazinamide in the treatment of latent tuberculosis infection in HIV-infected persons: is it different than in HIV-uninfected persons? Clin Infect Dis 2004; 39(4):561–565. 75. Narita M, Kellman M, Franchini DL, et al. Short-course rifamycin and pyrazinamide treatment for latent tuberculosis infection in patients with HIV infection: the 2-year experience of a comprehensive community-based program in Broward County, Florida. Chest 2002; 122(4):1292–1298. 76. Centers for Disease Control and Prevention. Fatal and severe hepatitis associated with rifampin and pyrazinamide for the treatment of latent tuberculosis infection—New York and Georgia, 2000. MMWR 2001; 50(15):289–291. 77. Centers for Disease Control and Prevention. Update: fatal and severe liver injuries associated with rifampin and pyrazinamide for latent tuberculosis infection, and revisions in American Thoracic Society/CDC recommendations—United States, 2001. MMWR 2001; 50(34):733–735. 78. Ijaz K, Jereb JA, Lambert LA, et al. Severe or fatal liver injury in fifty U.S. patients taking rifampin and pyrazinamide for latent tuberculosis infection. Clin Infect Dis. 2006; 42(3):346–355. 79. Burman WJ, Reves RR. Hepatotoxicity from rifampin plus pyrazinamide: lessons for policymakers and messages for care providers. Am J Respir Crit Care Med 2001; 164(7):1112–1113. 80. McElroy PD, Ijaz K, Lambert LA, et al. National survey to measure rates of liver injury, hospitalization, and death associated with rifampin and pyrazinamide for latent tuberculosis infection. Clin Infect Dis 2005; 41(8):1125–1133. 81. Bock NN, Rogers T, Tapia JR, et al. Acceptability of short-course rifampin and pyrazinamide treatment of latent tuberculosis infection among jail inmates. Chest 2001; 119(3):833–837. 82. Chaisson RE, Armstrong J, Stafford J, et al. Safety and tolerability of intermittent rifampin/pyrazinamide for the treatment of latent tuberculosis infection in prisoners. JAMA 2002; 288(2):165–166.

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83. Jasmer RM, Saukkonen JJ, Blumberg HM, et al. Short-course rifampin and pyrazinamide compared with isoniazid for latent tuberculosis infection: a multicenter clinical trial. Ann Intern Med 2002; 137(8):640–647. 84. Lee AM, Mennone JZ, Jones RC, et al. Risk factors for hepatotoxicity associated with rifampin and pyrazinamide for the treatment of latent tuberculosis infection: experience from three public health tuberculosis clinics. Int J Tuberc Lung Dis 2002; 6(11):995–1000. 85. Stout JE, Engemann JJ, Cheng AC, et al. Safety of 2 months of rifampin and pyrazinamide for treatment of latent tuberculosis. Am J Respir Crit Care Med 2003; 167(6):824–827. 86. McNeill L, Allen M, Estrada C, et al. Pyrazinamide and rifampin vs. isoniazid for the treatment of latent tuberculosis: improved completion rates but more hepatotoxicity. Chest 2003; 123(1):102–106. 87. Leung CC, Law WS, Chang KC, et al. Initial experience on rifampin and pyrazinamide vs. isoniazid in the treatment of latent tuberculosis infection among patients with silicosis in Hong Kong. Chest 2003; 124(6):2112–2118. 88. Priest DH, Vossel LF Jr., Sherfy EA, et al. Use of intermittent rifampin and pyrazinamide therapy for latent tuberculosis infection in a targeted tuberculin testing program. Clin Infect Dis 2004; 39(12):1764–1771. 89. van Hest R, Baars H, Kik S, et al. Hepatotoxicity of rifampin-pyrazinamide and isoniazid preventive therapy and tuberculosis treatment. Clin Infect Dis 2004; 39(4):488–496. 90. Lobato MN, Reves RR, Jasmer RM, et al. Adverse events and treatment completion for latent tuberculosis in jail inmates and homeless persons. Chest 2005; 127(4):1296–1303. 91. Tortajada C, Martinez-Lacasa J, Sanchez F, et al. Is the combination of pyrazinamide plus rifampicin safe for treating latent tuberculosis infection in persons not infected by the human immunodeficiency virus? Int J Tuberc Lung Dis 2005; 9(3):276–281. 92. Centers for Disease Control and Prevention. Adverse event data and revised American Thoracic Society/CDC recommendations against the use of rifampin and pyrazinamide for treatment of latent tuberculosis infection—United States, 2003. MMWR 2003; 52(31):735–739. 93. Saukkonen J. Rifampin and pyrazinamide for latent tuberculosis infection: clinical trials and general practice. Clin Infect Dis 2004; 39(4):566–568. 94. Good JT Jr., Iseman MD, Davidson PT, et al. Tuberculosis in association with pregnancy. Am J Obstet Gynecol 1981; 140(5):492–498. 95. Carter EJ, Mates S. Tuberculosis during pregnancy: the Rhode Island experience, 1987 to 1991. Chest 1994; 106(5):1466–1470. 96. Franks AL, Binkin NJ, Snider DE Jr., et al. Isoniazid hepatitis among pregnant and postpartum Hispanic patients. Public Health Rep 1989; 104(2):151–155. 97. Cantwell MF, Shehab ZM, Costello AM, et al. Brief report: congenital tuberculosis. N Engl J Med 1994; 330(15):1051–1054. 98. Centers for Disease Control. Prevention and treatment of tuberculosis among patients infected with human immunodeficiency virus: principles of therapy and revised recommendations. MMWR 1998; 47(RR-20):1–53. 99. Scheinhorn DJ, Angelillo VA. Antituberculous therapy in pregnancy: risks to the fetus. West J Med 1977; 127(3):195–198. 100. Snider DE Jr., Layde PM, Johnson MW, et al. Treatment of tuberculosis during pregnancy. Am Rev Respir Dis 1980; 122(1):65–79. 101. Snider DE Jr., Powell KE. Should women taking antituberculosis drugs breast-feed? Arch Intern Med 1984; 144(3):589–590.

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102. Pediatric Tuberculosis Collaborative Group. Targeted tuberculin skin testing and treatment of latent tuberculosis infection in children and adolescents. Pediatrics 2004; 114(4 suppl):1175–1201. 103. Stein MT, Liang D. Clinical hepatotoxicity of isoniazid in children. Pediatrics 1979; 64(4):499–505. 104. O’Brien RJ, Long MW, Cross FS, et al. Hepatotoxicity from isoniazid and rifampin among children treated for tuberculosis. Pediatrics 1983; 72(4):491–499. 105. Villarino ME, Ridzon R, Weismuller PC, et al. Rifampin preventive therapy for tuberculosis infection: experience with 157 adolescents. Am J Respir Crit Care Med 1997; 155(5):1735–1738. 106. Ormerod LP. Rifampicin and isoniazid prophylactic chemotherapy for tuberculosis. Arch Dis Child 1998; 78(2):169–171. 107. Magdorf K, Arizzi-Rusche AF, Geiter LJ, et al. Compliance and tolerance of new antitubercular short-term chemopreventive regimens in childhood—a pilot project. Pneumologie 1994; 48(10):761–764. 108. Polesky A, Farber HW, Gottlieb DJ, et al. Rifampin preventive therapy for tuberculosis in Boston’s homeless. Am J Respir Crit Care Med 1996; 154(5):1473–1477. 109. Livengood JR, Sigler TG, Foster LR, et al. Isoniazid-resistant tuberculosis. A community outbreak and report of a rifampin prophylaxis failure. JAMA 1985; 253(19):2847–2849. 110. Koplan JP, Farer LS. Choice of preventive treatment for isoniazid-resistant tuberculous infection. Use of decision analysis and the Delphi technique. JAMA 1980; 244(24):2736–2740. 111. Bailey WC, Byrd RB, Glassroth JC, et al. Preventive treatment of tuberculosis. Chest 1985; 87(suppl):S128–S132. 112. Pablos-Mendez A, Raviglione MC, Laszlo A, et al. Global surveillance for antituberculosis-drug resistance, 1994–1997. World Health Organization-International Union against Tuberculosis and Lung Disease Working Group on Anti-Tuberculosis Drug Resistance Surveillance. N Engl J Med 1998; 338(23):1641–1649. 113. Horn DL, Hewlett D Jr., Alfalla C, et al. Limited tolerance of ofloxacin and pyrazinamide prophylaxis against tuberculosis. N Engl J Med 1994; 330(17):1241. 114. Ridzon R, Meador J, Maxwell R, et al. Asymptomatic hepatitis in persons who received alternative preventive therapy with pyrazinamide and ofloxacin. Clin Infect Dis 1997; 24(6):1264–1265. 115. Passannante MR, Gallagher CT, Reichman LB. Preventive therapy for contacts of multidrug-resistant tuberculosis. A Delphi survey. Chest 1994; 106(2):431–434. 116. American Academy of Pediatrics. Tuberculosis: Report of the Committee on Infectious Diseases. 25th ed. Elk Grove Village, IL: American Academy of Pediatrics, 2003. 117. Centers for Disease Control. Management of persons exposed to multidrugresistant tuberculosis. MMWR 1992; 41(RR-11):61–71. 118. World Health Organization, Stop TB Department, Department of HIV/AIDS. Interim policy on collaborative TB/HIV activities. WHO/HTM/TB/2004.330; WHO/HTM/HIV/2004.1. Geneva, Switzerland, 2004. 119. Weis SE, Slocum PC, Blais FX, et al. The effect of directly observed therapy on the rates of drug resistance and relapse in tuberculosis. N Engl J Med 1994; 330(17):1179–1184. 120. World Health Organization. Treatment of tuberculosis: guidelines for national programmes. Geneva: World Health Organization, 2003 (WHO/CDS/TB 2003.131). 121. Carey JW, Oxtoby MJ, Nguyen LP, et al. Tuberculosis beliefs among recent Vietnamese refugees in New York State. Public Health Rep 1997; 112(1):66–72.

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122. Nolan CM. Community-wide implementation of targeted testing for and treatment of latent tuberculosis infection. Clin Infect Dis 1999; 29(4):880–887. 123. Franks J, Hirsch-Moverman Y, Colson P, Charles P. Felton National Tuberculosis Center at Harlem Hospital. Adherence to treatment for latent tuberculosis infection: a manual for health care providers. New York, 2005; 1–54. 124. Morisky DE, Malotte CK, Ebin V, et al. Behavioral interventions for the control of tuberculosis among adolescents. Public Health Rep 2001; 116(6):568–574. 125. Hovell MF, Sipan CL, Blumberg EJ, et al. Increasing Latino adolescents’ adherence to treatment for latent tuberculosis infection: a controlled trial. Am J Public Health 2003; 93(11):1871–1877. 126. Malotte CK, Hollingshead JR, Larro M. Incentives vs. outreach workers for latent tuberculosis treatment in drug users. Am J Prev Med 2001; 20(2):103–107. 127. White MC, Tulsky JP, Goldenson J, et al. Randomized controlled trial of interventions to improve follow-up for latent tuberculosis infection after release from jail. Arch Intern Med 2002; 162(9):1044–1050. 128. Blumberg HM. Treatment of latent tuberculosis infection: back to the beginning. Clin Infect Dis 2004; 39(12):1772–1775. 129. Nolan CM, Roll L, Goldberg SV, et al. Directly observed isoniazid preventive therapy for released jail inmates. Am J Respir Crit Care Med 1997; 155(2):583–586. 130. Heal G, Elwood RK, FitzGerald JM. Acceptance and safety of directly observed versus self-administered isoniazid preventive therapy in aboriginal peoples in British Columbia. Int J Tuberc Lung Dis 1998; 2(12):979–983. 131. Chaisson RE, Barnes GL, Hackman J, et al. A randomized, controlled trial of interventions to improve adherence to isoniazid therapy to prevent tuberculosis in injection drug users. Am J Med 2001; 110(8):610–615. 132. Batki SL, Gruber VA, Bradley JM, et al. A controlled trial of methadone treatment combined with directly observed isoniazid for tuberculosis prevention in injection drug users. Drug Alcohol Depend 2002; 66(3):283–293. 133. Matteelli A, Casalini C, Raviglione MC, et al. Supervised preventive therapy for latent tuberculosis infection in illegal immigrants in Italy. Am J Respir Crit Care Med 2000; 162(5):1653–1655. 134. Aisu T, Raviglione MC, van Praag E, et al. Preventive chemotherapy for HIVassociated tuberculosis in Uganda: an operational assessment at a voluntary counselling and testing centre. AIDS 1995; 9(3):267–273. 135. Aisu T, Cohn DL, Mubiru F, et al. Feasibility of isoniazid preventive therapy of tuberculosis in HIV-infected persons in Uganda (abstract 453). 1st IAS Conference on HIV Pathogenesis and Treatment, Buenos Aires, Argentina, 2001:212. 136. Godfrey-Faussett P, Baggaley R, Mwinga A, et al. Recruitment to a trial of tuberculosis preventive therapy from a voluntary HIV testing centre in Lusaka: relevance to implementation. Trans R Soc Trop Med Hyg 1995; 89(4):354–358. 137. World Health Organization. Report of a ‘‘lessons learnt’’ workshop on the six ProTEST pilot projects in Malawi, South Africa and Zambia. WHO/HTM/TB/ 2004.336, Durban, South Africa, February 3–6, 2004. 138. Ngamvithayapong J, Uthaivoravit W, Yanai H, et al. Adherence to tuberculosis preventive therapy among HIV-infected persons in Chiang Rai, Thailand. AIDS 1997; 11(1):107–112. 139. Hiransuthikul N, Nelson KE, Hiransuthikul P, et al. INH preventive therapy among adult HIV-infected patients in Thailand. Int J Tuberc Lung Dis 2005; 9(3): 270–275. 140. Antonucci G, Girardi E, Raviglione M, et al. Guidelines of tuberculosis preventive therapy for HIV-infected persons: a prospective, multicentre study. GISTA (Gruppo Italiano di Studio Tubercolosi e AIDS). Eur Respir J 2001; 18(2):369–375.

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11 Childhood Tuberculosis

FLOR M. MUNOZ

JEFFREY R. STARKE

Pediatrics Section of Infectious Diseases and Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, U.S.A.

Pediatrics Section of Infectious Diseases, Baylor College of Medicine and Ben Taub General Hospital, Houston, Texas, U.S.A.

I. Introduction A. General Information

Tuberculosis continues to be a significant cause of morbidity and mortality for children throughout the world. Because most children with tuberculosis infection and disease acquire the organism from adults in their environment, the epidemiology of childhood tuberculosis reflects that in adults. The World Health Organization (WHO) has estimated that, at the beginning of the 21st century, there are on average 8.8 million new cases and 2 million deaths due to tuberculosis worldwide. Children account for at least 1.5 million new cases every year. More than 90% of the new cases are reported in the developing world. Two billion people, one-third of the world population, are infected with Mycobacterium tuberculosis (1,2). Although tuberculosis can have profound consequences for the affected children and their family, childhood tuberculosis has a limited influence on the immediate epidemiology of the disease within a community because children are rarely the source of infection to contacts. However, the occurrence of tuberculosis in children is a marker for recent and ongoing transmission of infection among all the groups in a society. Infected 307

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children also represent a large proportion of the pool from which future tuberculosis cases will arise. Programs that target children for treatment of tuberculosis infection and disease might have little short-term results on disease rates, but will be critical to achieve long-term control of the disease, particularly in countries with low incidence of tuberculosis. B. General Characteristics of Childhood Tuberculosis

The pathophysiology and the clinical presentation of tuberculosis disease differ between infants, children, and adults. Childhood tuberculosis usually occurs as a direct consequence of the initial infection with M. tuberculosis, which can rapidly progress to disease in the youngest (less than two years of age) children, and which tends to involve extrapulmonary sites more commonly than in adults. Although not always easily distinguished, three different stages of childhood tuberculosis are recognized: exposure, infection, and disease. Exposure means that a child has had significant contact with an adult with infectious pulmonary tuberculosis, but the tuberculin skin test is negative, the chest radiograph is normal, and the child has not developed signs or symptoms of disease. A limitation in the ability to diagnose childhood tuberculosis exists in this stage, given the possibility of early infection and rapid development of severe disease, before the skin test becomes reactive. For this reason, WHO recommends that children under five years of age who have household exposure to a case of pulmonary tuberculosis receive treatment [usually isoniazid (INH)] (3). Tuberculosis infection is diagnosed by a reactive skin test in children with no signs or symptoms of disease, and with a normal chest radiograph. Children in this stage should receive treatment to prevent the development of disease. Tuberculosis disease occurs when the child with tuberculosis infection becomes symptomatic or radiographic manifestations of tuberculosis become apparent. The risk of a child acquiring tuberculosis infection is directly related to the degree of exposure to infectious adults or adolescents in his/her environment. In the prechemotherapy era, 60% to 80% of children exposed to a household source case with an acid-fast bacille (AFB)-positive sputum smear became infected, whereas only 30% to 40% became infected if the source case’s AFB sputum smear was negative (4). The progression to disease is determined primarily by the child’s age and immune status. Immunocompetent infants with untreated tuberculosis infection have a 40% risk of developing disease within one year, and compared to adults they more often develop serious disease—meningitis, disseminated disease, and severe pulmonary tuberculosis. The diagnosis of tuberculosis is difficult to establish in children, even in countries with modern clinical and laboratory facilities. The clinical presentation is variable and nonspecific, often mimicking other common pediatric diseases. Confirmation by culture is possible in less than 40% of cases at best, due to the pathophysiology of the disease and absence of productive cough (5). Treatment of pediatric tuberculosis is also challenging because

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of the paucity of data on the pharmacokinetics and toxicity of tuberculosis drugs in children and the lack of pediatric formulations for most of these drugs. The particularities of childhood tuberculosis also pose a challenge to research. Definitions of treatment failure and relapse of tuberculosis in a child usually must be based on clinical grounds because they are rarely associated with a positive culture. The low rate of culture confirmation makes investigations of new diagnostic techniques in children difficult to design and interpret. Because slow steady improvement of childhood pulmonary tuberculosis is possible even without drug therapy, studies that measure the effectiveness of interventions must include long-term evaluations. Well-controlled studies of childhood tuberculosis are rare, owing to the fairly small numbers of patients seen at most centers able to perform the studies. II. Epidemiology A. Worldwide Disease

It is difficult to assess the worldwide extent of childhood morbidity due to tuberculosis because of scarce and incomplete data, and because of the difficulty of diagnosing childhood tuberculosis with certainty in many countries. Reported disease rates are grossly underestimated and the prevalence of latent infection without disease is completely unknown in most areas of the world. In 1989, the WHO estimated that, in the developing world, there were 1.3 million cases and 450,000 deaths annually from tuberculosis in children under 15 years of age (6). Although more recent global estimates are not available, data from a few individual countries indicate that the proportion of cases of tuberculosis in children in developing countries is high, representing 15% to 40% of all cases, and causing more than 10% of pediatric hospital admissions and deaths, particularly in countries with high human immunodeficiency virus (HIV) burden (7–9). In contrast, in developed countries childhood tuberculosis represents 5% or less of all cases (10). There is no indication that tuberculosis rates among children in developing nations are declining. Actually, there is evidence that the burden of childhood tuberculosis in HIV-endemic regions has increased in recent years (11). Opportunities for exposure from parents increase because the prevalence of tuberculosis in adults peaks at the younger age of 25 to 35 years. Childhood tuberculosis is a common cause of pneumonia and death in some African countries, where cases of extrapulmonary tuberculosis in children are more frequently observed (12,13). Trends of childhood tuberculosis in industrialized nations are well illustrated by recent data from Canada (14). The number of reported cases of tuberculosis in children younger than 15 years of age declined from 430 in 1970 to 109 in 2001, an average annual decline of 4%. The incidence of childhood tuberculosis declined from 6.6/100,000 in 1970 to 1.9/100,000 in 2001. During this period, 45% of the cases occurred in children younger than five years of age. Incidence rates below 1 per 100,000 are reported

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in several European countries. In most industrialized countries, the mortality rates for children from newborn to four years of age have been and are still about twice that for children aged 5 to 15 years, mostly because of the higher incidence of tuberculous meningitis and disseminated disease in the younger population. B. Disease in the United States

The most complete recent epidemiological data for childhood tuberculosis comes from the United States. Reported tuberculosis cases in children younger than 15 years of age declined from 6036 in 1962 to 1261 in 1985, an average annual decline of about 6% (15). Case rates declined in a similar fashion from 10 per 100,000 children in 1962 to 2.4 per 100,000 in 1985. However, beginning in 1988, the number of cases increased, reaching a peak in 1992 when the number of childhood tuberculosis cases had risen by 40% (16). During the last decade, the total number of cases decreased 5% to 7% annually. The largest decline in the incidence of tuberculosis and tuberculosis case rates in the United States occurred in children under 15 years of age, from 3.0 per 100,000 in 1993 to 1.5 per 100,000 in 2003, a 50% decline (17). Children under 15 years of age represent approximately 6% of all tuberculosis cases in the United States. New cases in children will serve as reservoir of the disease in the future, unless they are appropriately treated. The most important factors that influence the persistence of tuberculosis in the United States include (i) increasing rates of tuberculosis in foreign-born individuals immigrating to the United States who are previously infected or develop disease after their arrival, (ii) the worldwide epidemic of HIV infection and its effect on multidrug-resistant tuberculosis, and (iii) transmission of tuberculosis among undiagnosed individuals with limited access to medical care and inadequate housing and nutrition (17). There is no evidence that the likelihood of infection with M. tuberculosis in children is influenced by either age or gender; however, both influence the risk of an infected child developing active disease. From 1992 to 2002, 59% of pediatric tuberculosis cases in children in the United States occurred in children younger than five years of age, the group at highest risk for the disease (18). The interval between ages 5 and 14 years is often called ‘‘the favored age,’’ because children in this group consistently have a lower rate of tuberculosis disease than any other segment of the population. Age also affects the anatomical site of involvement with tuberculosis. Younger children are more likely to develop meningeal, miliary, or lymphatic tuberculosis, whereas adolescents more frequently present with pleural, peritoneal, or genitourinary disease (Table 1). Although tuberculosis in adults occurs mostly among men, and the rate of infection in adolescent males is higher than that of adolescent females (19), it appears that during the latter part of childhood and during adolescence, girls have a higher incidence and mortality from tuberculosis than do boys. Among infants and young children, there is no difference in incidence between the sexes.

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Table 1 Median Age of Tuberculosis by Predominant Site in Persons Younger than 20 Years of Age: United States, 1988 Site

Percentage of cases

Median age (yr)

77.5 13.3 3.1 1.9 1.2 1 0.9 0.8 0.3 0.1

6 5 16 2 8 12 1 16 13 –

Pulmonary Lymphatic Pleural Meningeal Bone/joint Other Miliary Genitourinary Peritoneal Not stated Source: Adapted from Ref. 4.

In the United States, in every age group including childhood, tuberculosis case rates are strikingly higher in ethnic and racial minority groups than in whites. The difference is most likely a result of environmental factors, such as socioeconomic status, housing conditions, and exposure to high-risk adults. Approximately 80% to 87% of childhood tuberculosis cases in the United States occur among African-Americans, Hispanics, Asians, and Native Americans, with a relatively higher number of cases in the Hispanic population in more recent years (17). One of every four children with tuberculosis is foreign born. In California, a high-incidence state, tuberculosis case rates in foreign-born children (12.1 per 100,000) are much higher than in U.S.-born children (1.1 per 100,000) (18). Childhood tuberculosis in the United States is mainly concentrated in cities with populations greater than 250,000 residents. C. Transmission

Transmission of tuberculosis is from person to person, usually by droplets of mucus that become airborne when the individual coughs or sneezes. Children with primary tuberculosis rarely, if ever, infect other children or adults because tubercle bacille are sparse in their respiratory secretions, and cough is often lacking in the clinical presentation of typical forms of childhood tuberculosis such as hilar adenopathy or pulmonary and miliary disease (20). When young children do cough, they lack the tussive force of adults and they rarely produce sputum. Infants, children with advanced pulmonary disease requiring intubation, and older children and adolescents with reactivation forms of tuberculosis, such as cavities or extensive infiltrates, may be infectious to others and their secretions must be properly handled. Occasionally, transmission of M. tuberculosis from a child may occur by direct contact with infected fluids or discharges such as urine or purulent sinus tract drainage. Fomites, such as syringes, gastric lavage

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tubes, or bronchoscopes, are rare sources of infection. In the hospital setting, infection of healthcare workers from pediatric patients with primary tuberculosis is very rare, and adult family members and visitors with previously undetected tuberculosis are more likely to be the source of infection (21). Children are usually infected with M. tuberculosis by an adult in the same household. Children cared for or exposed to adults with unrecognized tuberculosis, inadequately treated tuberculosis, or multidrug-resistant M. tuberculosis disease are most likely to become infected. Casual extrafamilial contact is less frequently the source of infection, but school janitors and teachers, bus drivers, nurses, day care workers, and candy-store keepers have been implicated as the source of infection in individual cases and epidemics (22–24). In the northern hemisphere, childhood tuberculosis appears to be more common from January to June, perhaps because of increased close indoor contact during winter months and more frequent coughing in adults produced by winter and spring respiratory infections. D. HIV-Related Tuberculosis in Children

The ongoing epidemic of infection with the HIV has had a profound effect on the epidemiology of tuberculosis. Beside population migration, infection with HIV is the most important factor contributing to the persistence of tuberculosis. At the beginning of the 21st century, 9% of all new cases of tuberculosis in adults worldwide are attributed to HIV infection (25), with a significantly higher proportion in the WHO African region (31%) and in some industrialized countries, including the United States (26%). Up to 12% of deaths from tuberculosis can be attributable to HIV. Adults with HIV infection are more likely to develop tuberculosis from latent infections, and those who develop tuberculosis have a more rapid progression to disease (26,27). The HIV epidemic can increase the incidence of tuberculosis in children by two major mechanisms: (i) HIV-infected adults with tuberculosis may horizontally transmit M. tuberculosis to children, a portion of whom will develop tuberculosis disease; (ii) children with HIV infection may be at increased risk of progressing from tuberculosis infection to disease. Children generally acquire M. tuberculosis from adults with active, usually smear positive, pulmonary disease. Pulmonary involvement is common among HIV seropositive adults with tuberculosis, especially when the tuberculosis precedes other opportunistic infections (28). The impact of the HIV epidemic on pediatric tuberculosis has been reported in several studies. A retrospective population study in Florida, United States implied that an observed increase in childhood tuberculosis cases was linked with an increase in tuberculosis cases among HIV-infected adults (29). In several African countries and in India, where tuberculosis infection rates in children are generally higher then in the United States, HIV-infected pediatric cohorts have a higher risk of developing tuberculosis (30). In the United States, the incidence of tuberculosis in HIV-exposed or -infected children was reported in one study to be up to 100-fold higher than in noninfected

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children of comparable age (31). In New York City, 3% of 1400 HIVinfected children were diagnosed with tuberculosis disease during 1989 to 1995 (32). The difficulty encountered in many reports, however, is that the diagnosis of tuberculosis in children is mostly based on clinical criteria, especially in the youngest, in whom the highest rates of HIV infection are found, and the presentation of tuberculosis can be similar to that of other opportunistic infections. Furthermore, HIV testing in children with tuberculosis is limited and performed much less frequently than in adults (18). For these reasons, tuberculosis in HIV-infected children is probably underdiagnosed and under-reported in both developed and developing countries. When HIV-infected children develop tuberculosis, the clinical features are similar to those of immunocompetent children, but a greater degree of severity, a more rapid progression of the disease, and a higher mortality rate have been reported (33–36). There may be an increased tendency for extrapulmonary or disseminated disease. Common sites of extrapulmonary tuberculosis in HIV-infected children include lymph nodes, pericardium, peritoneum, pleura, and hematogenous spread (33,34,36,37). Unusual presentations such as chronic fever, tachypnea, or lobar infiltrates may be found in HIV-infected children, making the diagnosis of tuberculosis more difficult (33,38). Children who acquire HIV infection by vertical transmission may have a rapid progression of tuberculosis from infection to disease (31). Congenital tuberculosis has also been reported in infants born to HIVpositive mothers with tuberculosis. Early manifestations of congenital tuberculosis include failure to gain weight, progressive hepatomegaly with fever, upper respiratory symptoms, progressive pneumonia, and meningitis. An acute syndrome of progressive jaundice and abdominal distension has also been described in HIV-infected children (39). Treatment failure for tuberculosis is more likely to occur in children infected with HIV. E. Tuberculosis Infection

Although there are estimates that about one-third of the world’s population is infected with M. tuberculosis, it is impossible to determine how many children actually have asymptomatic tuberculosis infection. Because all but two countries in the world have used bacille Calmette–Gue´rin (BCG) vaccine extensively, population surveys for tuberculosis infection using the tuberculin skin test are rarely performed, although the positivity associated with BCG is relatively short lived (40,41). Even in the United States, the incidence of childhood tuberculosis infection is unknown, because a positive skin test is a reported condition in only a few states, and national surveys were discontinued in 1971. At that time, the incidence of tuberculosis infection among five- and six-year olds was about 0.2%. The most efficient method of finding children infected with M. tuberculosis is through contact investigations of adults with infectious pulmonary tuberculosis. On average, 30% to 50% of household contacts have a reactive tuberculin skin test. Even in countries where BCG is used extensively, a positive tuberculin skin in a child who has had close contact with an adult

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with infectious tuberculosis probably represents infection with M. tuberculosis, and chemotherapy to halt the progression of infection to disease should be given, especially if the child is under five years of age. In the United States, children in the general population currently have a low risk for infection with tuberculosis. However, several studies show that in some large cities, the risk of infection is high. In Boston public schools, 5.1% of 7th graders and 8.9% of 10th graders are tuberculin skin test positive (42). In Los Angeles and Houston, 2% to 5% of elementary school children are infected (5,43). For some populations, screening targeted to highrisk groups and preventive chemotherapy programs are recommended to diminish the pool of infected children and eliminate future cases of disease. III. Pathogenesis A. Primary Tuberculosis in Children

The primary complex of tuberculosis consists of local disease at the portal of entry and the regional lymph nodes that drain the areas of the primary focus. The primary complex may occur anywhere in the body, but it is found in the lung in over 95% of cases, because M. tuberculosis is usually inhaled. While the primary complex is developing, tubercle bacille usually spread through the bloodstream and lymphatics to many parts of the body. In 1% to 3% of infections, the dissemination is massive, leading to miliary or meningeal tuberculosis. More commonly, small numbers of bacille leave tuberculous foci scattered in various tissues, which may or may not develop into significant extrapulmonary tuberculosis later in life. After four to eight weeks, cell-mediated immunity and delayed hypersensitivity (marked by a positive skin test) usually develop. At this time, the primary complex often heals and further dissemination is arrested. The onset of delayed hypersensitivity may be accompanied by a febrile reaction that lasts one to three weeks; at this time, the tissue reaction intensifies, often causing the primary complex to become visible on chest radiographs. B. Timetable of Childhood Tuberculosis

A fairly predictable sequence of events related to the primary tuberculosis infection and its complications was described by Wallgren (44). This timetable is very useful for the clinician because it provides guidance to formulate a realistic prognosis, understanding of what complications to look for and when, and a productive approach to finding the source case for infection. Symptomatic lymphohematogenous spread, miliary or tuberculous meningitis occur usually in the first two to six months after the initial infection. Endobronchial tuberculosis, often accompanied by segmental pulmonary changes, usually develops between four and nine months after infection. Clinically significant lesions of bones or joints do not appear until at least one year after infection, whereas renal lesions develop 5 to 25 years later. Progression of the primary infection in infants and young children can

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occur very fast, with complications noted usually in the first year after infection, or within the first five years in older children. Complications later in life are often secondary to reactivation of previously dormant bacille, acquired and controlled but not eliminated during childhood. The interval between the initial infection and reactivation of pulmonary tuberculosis is extremely variable, depending on the age of the child during initial infection; in adolescents, the interval is often months to several years, whereas in infants it is much longer. C. Pregnancy and the Newborn

True congenital tuberculosis is very rare, with less than 400 cases reported in the medical literature. It is unclear whether the rate of congenital tuberculosis infection is higher in infants born to mothers infected with HIV with active tuberculosis, but cases of true congenital infection have been reported recently in this setting (45). Two major routes for true congenital infection have been described. The first is transplacental, hematogenous passage of M. tuberculosis via the umbilical vein, from a mother with active lymphohematogenous spread, commonly associated with tuberculous pleural effusion, meningitis, or miliary disease during pregnancy or soon after (46–49). Hematogenous dissemination may also lead to infection of the placenta, with transmission to the fetus (50), although even massive involvement of the placenta does not always give rise to congenital tuberculosis. In either event, bacille would first reach the liver of the fetus, where a primary focus involving the periportal lymph nodes would develop, and produce hepatomegaly or even widespread miliary disease. The organisms can also pass through the liver into the main circulation, leading to a primary focus in the fetal lung. The tubercle bacille in the lung may remain dormant until after birth, and become active when oxygenation and circulation increase significantly (51). A second mechanism for congenital tuberculosis infection is through aspiration or ingestion of infected amniotic fluid in utero. Amniotic fluid can be infected from tuberculous endometritis or the presence of ruptured caseous lesions in the placenta. Inhalation of amniotic fluid is the most likely cause of congenital tuberculosis, if multiple primary foci are present in the lung or gut and middle ear (52). A third route of infection, postnatal acquisition of M. tuberculosis by inhalation of tubercle bacille from the mother, is the most common source of infection for the neonate (53). Other less common sources include ingestion of infected amniotic fluid or secretions during delivery, contamination of traumatized skin or mucous membranes, and rarely by ingestion of infected breast milk. Breastfeeding is not contraindicated when mothers are receiving appropriate chemotherapy. It is often impossible to differentiate postnatal infection from true congenital tuberculosis on clinical grounds. The distinction is not of major importance for the baby, because the treatment regimens are the same. However, determining the true source of infection is vital for proper evaluation and treatment of the mother and other adults in the baby’s environment.

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Munoz and Starke IV. Clinical Forms of Pediatric Tuberculosis A. Endothoracic Asymptomatic Infection

Asymptomatic tuberculosis is an infection with M. tuberculosis associated with tuberculin skin test reactivity, but no clinical or radiographic findings. This presentation is more common in school-aged children than in younger infants; 80% to 95% of infected children, but only 40% to 50% of infants, have asymptomatic infection. Although computed tomography of the chest may reveal enlarged lymph nodes when the chest radiograph is normal (54), it is not routinely recommended for the diagnosis of tuberculosis infection or disease. Cultures from these children are rarely positive. Children in this category are ideal candidates for single-drug chemotherapy, to kill the small number of bacille before symptomatic disease occurs. Pulmonary

A primary pulmonary complex includes the parenchymal focus and regional lymphadenitis. Almost 70% of primary foci are subpleural, and localized pleurisy is a common part of the primary complex. This begins with the deposition of one or more infected droplets into lung alveoli. All lobar segments are at equal risk of being seeded and, in 25% of cases, there are multiple primary lung foci. The initial parenchymal inflammation usually is not visible on chest radiograph, but a localized, nonspecific infiltrate may be seen. The infection spreads within days to regional lymph nodes. When tuberculin hypersensitivity develops, within 3 to 10 weeks after infection, the inflammatory reaction in the lung parenchyma and lymph nodes intensifies. The hallmark of pediatric primary tuberculosis in the lung is the relatively large size and importance of the hilar, mediastinal, or subcarinal adenitis compared with the relatively small size of the initial parenchymal focus. Because of the patterns of lymphatic drainage, a left-sided parenchymal lesion often leads to bilateral adenopathy, whereas a right-sided focus is associated with right-sided adenopathy only. In most children, the parenchymal infiltrate and adenitis resolve early. In some children, especially infants, the lymph nodes continue to enlarge (Figs. 1 and 2). Bronchial obstruction begins as the nodes impinge on the neighboring regional bronchus, compressing it and causing diffuse inflammation of its wall (55). The inflammation may intensify, and the lymph nodes erode through the bronchial wall, leading to perforation and formation of thick caseum in the lumen, with partial or complete obstruction of the bronchus (56–58). The common radiographic sequence is hilar adenopathy, followed by localized hyperaeration and eventually atelectasis (59,60). The resulting radiographic shadows have been called ‘‘epituberculosis,’’ ‘‘collapse consolidation,’’ or ‘‘segmental lesions.’’ These findings are similar to those caused by aspiration of a foreign body; in tuberculosis, the lymph node acts as the foreign body. Obstructive hyperaeration of a lobar segment may accompany bronchial obstruction (61). This unusual complication occurs most often in children younger than two years of age, and may be accompanied by

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Figure 1 A segmental pulmonary lesion in a child with primary tuberculosis. The complex includes hilar adenopathy, atelectasis, and localized pleural reaction.

wheezing. The obstruction will usually resolve spontaneously, but this may take months to occur. Surgical removal of the lymph nodes may hasten clinical improvement, but is rarely necessary. The most common complication of the bronchial obstruction is the fan-shaped lesion (Fig. 1), which results from a combination of the primary pulmonary focus, the caseous material from an eroded bronchus, the host inflammatory response, and the subsequent atelectasis. Up to 40% of children younger than one year of age who are infected with M. tuberculosis will develop a segmental lesion, compared with 25% of children ages 1 to 10 years, and 16% of children ages 11 to 15 years. Segmental lesions and obstructive hyperaeration can occur together. Physical signs and symptoms caused by hilar adenopathy and segmental lesions are surprisingly uncommon, but are more frequently seen in infants. Occasionally, the initiation of the primary infection is marked by fever and cough. As the primary complex progresses, nonspecific symptoms such as fever, cough, night sweats, and failure to thrive may occur. Pulmonary signs are usually absent. Some children have localized wheezing or diminished breath sounds, which are rarely accompanied by tachypnea or respiratory distress. Nonspecific symptoms and pulmonary signs are sometimes

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Figure 2 Chest radiographs of a child with primary complex tuberculosis, showing the importance of obtaining a lateral view. Although the postero-anterior view (A) appears normal, the lateral view (B) shows hilar adenopathy.

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alleviated by antibiotics, suggesting that bacterial superinfection distal to the bronchial obstruction may be present. Involvement of other groups of intrathoracic lymph nodes can cause various clinical manifestations. Enlarged subcarinal nodes, which can cause splaying of the large bronchi, may impinge on the esophagus and cause difficulty in swallowing or cause a bronchoesophageal fistula. Infected nodes may compress the subclavian vein, producing edema of the hand or arm. Nodes may rupture into the mediastinum and point in the right or left supraclavicular fossa. Most cases of tuberculous bronchial obstruction in children resolve fully, radiographically, with or without antituberculosis chemotherapy. However, up to 60% of untreated children will have residual anatomical sequelae not always apparent in radiographs. Chemotherapy is given to halt local progression of disease, prevent dissemination of disease, and prevent future chronic pulmonary tuberculosis. Without therapy, calcification of the caseous lesions is common. Healing of the pulmonary segment is occasionally complicated by scarring or contraction that may be associated with cylindrical bronchiectasis and bronchial stenosis (Fig. 3). These complications are usually clinically silent when they occur in the upper lobes, and they are quite rare in children who have successfully completed chemotherapy. Progressive Pulmonary Disease

A rare but serious complication of primary tuberculosis occurs when the primary focus enlarges steadily and develops a large caseous center. The radiograph shows bronchopneumonia or lobar pneumonia. Liquefaction may result in the formation of a thin-walled primary cavity associated with large numbers of tubercle bacille. A tension cavity develops rarely as a result of a valve-like mechanism, allowing air to enter into an adjacent bronchus, leading to further intrapulmonary dissemination. Rupture into the pleural space can lead to bronchopleural fistula or pyopneumothorax. Unlike with segmental lesions, significant symptoms and signs usually accompany locally progressive disease. High fever, night sweats, weight loss, and severe cough with sputum production are common. Physical signs include diminished breath sounds, rales, dullness, and egophony over the cavity. The clinical picture is similar to that of pyogenic pneumonia caused by Staphylococcus aureus or Klebsiella pneumoniae. Before the introduction of antituberculosis chemotherapy, prognosis was poor, with a fatality rate of 30% to 50%. However, with current therapy, the prognosis for complete recovery is excellent. Chronic Pulmonary Disease

Chronic pulmonary tuberculosis (‘‘adult’’ or ‘‘reactivation’’ type) represents endogenous reactivation of a site of tuberculosis infection established previously. In high-burden countries, this presentation could also be due to recent infection or reinfection. Even before the discovery of antituberculosis drugs, chronic pulmonary tuberculosis occurred in only 6% to 7% of pediatric patients (62). Children with a healed primary tuberculosis infection

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Figure 3 A chronic pulmonary tuberculosis lesion in the left upper lobe of a child who had respiratory symptoms for eight months before diagnosis.

acquired before age two years rarely develop chronic pulmonary disease; it is more common among those who acquire the initial infection after age seven years, particularly if they become infected close to the onset of puberty. The most common pulmonary sites are the original parenchymal focus, the regional lymph nodes, or the apical seedings (Simon foci). This form of disease is identical to pulmonary disease in adults and usually remains localized to the lungs because the presensitization of the tissues to mycobacterial antigens evokes an immune response that prevents further lymphohematogenous spread. Pleural Effusion

Tuberculous pleural effusions originate in the discharge of bacille onto the pleural space from a subpleural primary pulmonary focus or from subpleural caseous lymph nodes (63). The discharge may be small and the

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pleuritis localized and asymptomatic, or a larger discharge may cause a generalized effusion, usually three to six months after infection. The effusion is usually unilateral, but it can be bilateral (64). Clinically significant pleurisy with effusion occurs in 5% to 30% of tuberculosis cases in young adults, but is infrequent in children younger than six years of age and almost nonexistent in those younger than two years. It is virtually never associated with a segmental pulmonary lesion and occurs rarely with miliary tuberculosis. The onset of symptoms and signs is usually abrupt, with fever, chest pain, shortness of breath, dullness to percussion, and diminished breath sounds. Fever can be high and may last for several weeks, even when antituberculosis chemotherapy is given. Diagnosis can be difficult, because the acid-fast stain of the pleural fluid is usually negative, and the culture is positive in only 30% to 50% of cases. A pleural punch biopsy and culture is more likely to establish the diagnosis by finding typical tubercles on histopathology and/or recovering the organism. The prognosis of pleural effusion in children is excellent. Pericarditis

The most common form of cardiac tuberculosis is pericarditis. It is relatively rare, occurring in between 0.4% and 4% of tuberculosis cases in children. Tuberculous pericarditis usually arises from direct invasion of lymphatic drainage from subcarinal lymph nodes. Early in the course, the pericardial fluid is serofibrinous or occasionally hemorrhagic. Continued fibrosis may lead to obliteration of the pericardial sac, with the development of constrictive pericarditis over months to years. The presenting symptoms are nonspecific, including low-grade fever, malaise, fatigue, and weight loss. Chest pain is unusual in children with tuberculous pericarditis. As the infection progresses, a pericardial friction rub or distant heart sounds with pulsus paradoxus may be present. Congestive heart failure is rare. An acidfast smear of the pericardial fluid rarely reveals the organism, but cultures are positive in 30% to 70% of cases. Pericardial biopsy may be necessary to confirm the diagnosis. Partial or complete pericardectomy may be required when constrictive pericarditis is present. B. Lymphohematogenous

It is suspected that tubercle bacille are disseminated to distant sites from the primary complex in all cases of tuberculosis infection. The clinical picture produced by the lymphohematogenous dissemination depends on the quantity of organisms released and the host immune response. The occult dissemination usually produces no symptoms, but it is the event that leads to development of extrapulmonary foci that can become the site of disease months to years after the initial infection. Children rarely experience a protracted hematogenous infection caused by the intermittent release of tubercle bacille when a caseous focus erodes through the wall of a blood vessel. The clinical onset may be acute with high spiking fevers, but more often, the course is indolent and prolonged. Multiple organ involvement is frequent; the most common findings are hepatosplenomegaly, deep and

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superficial adenitis, and crops of papulonecrotic tuberculids. Pulmonary findings are common early on, but meningitis is a late complication. Paradoxically, culture confirmation may be difficult and often requires a biopsy of deep tissue such as that of bone marrow or liver. Miliary tuberculosis arises when massive numbers of tubercle bacille are released into the blood stream, resulting in simultaneous disease in two or more organs. This usually is an early complication of the primary infection, occurring within two to six months after formation of the primary complex. The disease is most common in infants and young children. The clinical manifestations of miliary tuberculosis are protean and depend on the numbers of disseminated organisms and the involved organs (65). The onset is occasionally explosive, with the child becoming gravely ill in a matter of days. More often, the onset is insidious with weight loss, anorexia, malaise, and low-grade fever developing over weeks. Within several weeks, hepatosplenomegaly and generalized lymphadenopathy develop in 50% to 70% of children. The chest radiograph may be normal initially or show evidence of only the primary complex. Within three to four weeks, the lung fields become filled with tubercles in 90% of cases. The child may develop respiratory distress and diffuse rales or wheezing. Meningitis occurs in only 20% to 30% of cases, but in the era before antituberculosis chemotherapy, most cases of miliary tuberculosis terminated as meningitis (66). Cutaneous lesions are often absent, but the appearance of crops of papulonecrotic tuberculids or nodules may be an important diagnostic clue. Choroid tubercles appear several weeks after onset with variable frequency. The diagnosis can be difficult, requiring a high index of suspicion by the clinician. Up to 30% of children have a negative tuberculin skin test, especially late in the course. A biopsy of liver or bone marrow may facilitate a more rapid diagnosis. The diagnosis can be confirmed by culture in about 33% of cases. With proper chemotherapy, the prognosis of miliary tuberculosis in children is excellent. However, resolution may be slow, with fever declining in two to three weeks and chest radiograph abnormalities persisting for months. C. Central Nervous System

Involvement of the central nervous system is the most serious complication of tuberculosis in children. Before the development of chemotherapy, tuberculous meningitis was uniformly fatal. The pathogenesis of central nervous system tuberculosis results from formation of a metastatic caseous lesion in the cerebral cortex or meninges during the occult lymphohematogenous dissemination of the primary infection. This lesion, the so-called Rich focus, may increase in size and discharge tubercle bacille into the subarachnoid space. A thick, gelatinous exudate infiltrates the cortical or meningeal blood vessels, producing inflammation, obstruction, or infarction. The brain stem usually is the site of greatest involvement, which accounts for the frequent dysfunction of cranial nerves III, VI, and VII. Eventually, the basilar cisterns become obstructed, leading to a communicating hydrocephalus.

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Tuberculous meningitis complicates about 1 of every 300 untreated primary infections (67). This disease is rare in children younger than four months of age, because it takes that long for the causative pathological sequence to develop. It is most common in children younger than four years of age and usually occurs within two to six months of the primary infection. The clinical onset of tuberculous meningitis in children is usually gradual, but may be abrupt (68). The more rapid progression of disease tends to occur in young infants, who may experience symptoms for only several days before the onset of acute hydrocephalus, brain infarct, or seizures (69,70). The usual course can be divided into three stages. The first stage, which often lasts one to two weeks, is characterized by nonspecific symptoms such as fever, irritability, headache, sleepiness, and malaise. There are no focal neurological signs, but infants and young children may experience a loss or stagnation of developmental milestones. Usually, this stage can be recognized only in retrospect. The second stage often begins abruptly, with lethargy, convulsions, nuchal rigidity, hyper-reflexia, hypertonia, vomiting, and cranial nerve palsies. The onset of this stage usually correlates with the development of hydrocephalus, increased intracranial pressure, and meningeal irritation. Some children lack signs of meningeal irritation, but show signs of encephalitis, such as disorientation, abnormal movements, and speech abnormalities (71). The third stage is marked by coma, irregular pulse or respiration, hemiplegia, or paraplegia, and, eventually, death. Prognosis is directly related to the clinical stage during diagnosis (72). The occurrence of the syndrome of inappropriate antidiuretic hormone secretion is common and is also linked to a poor prognosis (73). The most important clue to the diagnosis of tuberculous meningitis in a child is the history of a recent contact with an adult with pulmonary tuberculosis (74,75). The tuberculin skin test result is negative in up to 40% of cases, and the chest radiograph is normal in up to 50% of cases (76). The cerebrospinal fluid (CSF) leukocyte cell count ranges from 10 to 500 per mm3; polymorphonuclear cells may be predominant early, but a lymphocyte preponderance is more typical. The CSF glucose level is typically between 20 and 40 mg/dL, whereas the CSF protein concentration is elevated and may be markedly high (>400 mg/dL). The success of microscopic examination of stained CSF and mycobacterial culture is related to the amount of CSF sampled. Computed tomography may help establish the diagnosis of tuberculous meningitis and can aid in evaluating the success of therapy. Tuberculoma is manifested clinically as a brain tumor. As many as 30% of brain tumors in a population of children may be tuberculomas, depending on the incidence of tuberculosis in the population. Tuberculomas are most common in children younger than 10 years of age. Whereas most tuberculomas in adults are supratentorial, many in children are infratentorial, most often located at the base of the brain near the cerebellum. Headache, convulsions, fever, and other signs and symptoms of an intracranial space–occupying lesion are common.

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In general, extrapulmonary tuberculosis is more common in children than adults (77). Up to 30% of children with tuberculosis have extrapulmonary manifestations (5). A complete review of various types is beyond the scope of this chapter, but a few salient points can be emphasized. The most common form of extrathoracic tuberculosis in children is infection of the superficial lymph nodes, sometimes called scrofula (78,79). The nodes most commonly involved are in the tonsillar and submandibular regions. Early, the nodes are firm, nontender, and discrete, most often unilateral, but can be bilateral. Systemic signs and symptoms other than low-grade fever are usually absent. Although the nodes generally enlarge slowly, there may be rapid enlargement associated with high fever, tenderness, and fluctuance. If untreated, necrosis of the node usually occurs, accompanied by thinning and erythema of the skin and, eventually, rupture through the skin with formation of a sinus tract. Skeletal tuberculosis in children is rare in technically advanced countries, but is still common in developing nations. It most commonly affects the vertebrae, resulting in a paravertebral abscess and spondylitis (Pott’s disease), but also can affect, in order of incidence, the knee, hip, elbow, and smaller joints (80). Abdominal tuberculosis and tuberculous peritonitis occur most often in adolescents and are similar clinically to disease in adults (81,82). Tuberculosis affecting the structures of the eye, middle ear, sinuses, kidneys, and skin may occur, but is fairly rare in children (83–85). E. Adolescents

Tuberculosis in adolescents falls into two major categories: tuberculosis acquired as an initial infection during adolescence and tuberculosis acquired in early childhood that manifests during adolescence. Most commonly, recently infected adolescents develop a classic primary complex, with relatively few signs or symptoms (86). Occasionally, the primary complex may progress rapidly to chronic pulmonary tuberculosis while the hilar lymph node involvement characteristic of primary tuberculosis is still present. A primary tuberculosis infection in infancy rarely leads to chronic tuberculosis in adolescence. A primary infection acquired between ages 7 and 10 years is more likely to result in reactivation during adolescence. When primary tuberculosis is acquired during adolescence, chronic pulmonary tuberculosis often develops within one to three years, a phenomenon that is two to six times more common in girls than in boys (87). In both sexes, the adolescent growth spurt is the time of greatest risk. Because of this propensity to progress fairly rapidly to contagious pulmonary tuberculosis, high-risk adolescents are an important target group for tuberculin skin testing and case finding. F. Neonates

The clinical manifestations of congenital infection with tuberculosis in the fetus and newborn vary according to the site and size of the caseous lesions. Clinical symptoms usually become apparent in the second or third week of

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life, in the form of failure to gain weight, respiratory distress, fever, hepatic or splenic enlargement, poor feeding, lethargy or irritability, lymphadenopathy, abdominal distention, ear discharge, or skin lesions (47,49,88). The clinical presentation can be similar to that caused by bacterial sepsis and other congenital infections, such as syphilis and cytomegalovirus. Diagnosis is often difficult, with 50% of cases discovered at autopsy. The tuberculin skin test is almost always negative. The chest radiograph may be normal initially and become abnormal as the disease progresses, but most neonates have an abnormal chest radiograph, 50% with a miliary pattern. Up to 50% of infected newborns develop meningitis, but the rate of isolation of mycobacteria from the spinal fluid is low. The diagnosis is usually established by finding acid-fast bacille in gastric aspirates, urine, middle ear fluid, bone marrow aspirate, or liver biopsy. The major clue to diagnosis, however, is finding tuberculosis in the mother. Infants born to a mother with tuberculosis can be protected from postnatal infection by (i) giving INH to the newborn (89–92) or (ii) isolating the infant from the infectious adult while initiating treatment on the adult and administering BCG to the newborn (93). Breastfeeding is safe while the mother is on antituberculosis therapy because only small amounts of the drugs are present in the milk and acid-fast bacille rarely appear in breast milk (94). V. Diagnosis of Tuberculosis in Children A. General Principles

Throughout the world, the most highly predictive method for diagnosing tuberculosis in children consists of finding the triad of a positive tuberculin skin test, an abnormal chest radiograph, and history of recent (less than one year) exposure to an adult with probable or definitive tuberculosis. In many parts of the world, the latter may be the only clue, which, when associated with compatible clinical symptoms, should prompt initiation of specific therapy. In children, particularly those under 10 years of age, a definitive diagnosis by acid-fast smear of sputum or gastric secretions or isolation of M. tuberculosis is difficult and uncommon. Although several scoring systems have been described to aid in the diagnosis of tuberculosis based on clinical signs and symptoms, history of exposure, and available tests, none has been formally validated, and the sensitivity, specificity, and results of their use in one geographic region or a particular patient population might not be applicable to others (95). B. Tuberculin Skin Test

A positive tuberculin skin test is the hallmark of the primary infection with M. tuberculosis. The reference test used, i.e., the Mantoux test, employs a dose of five tuberculin units [five units of purified protein derivative (PPD)-5 equivalent or two units of RT-23], with a sensitivity and specificity of approximately 95% (96). This implies that approximately 5% of children

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with tuberculosis infection will not react to tuberculin. The positive predictive value of the Mantoux test depends primarily on the prevalence of tuberculosis infection in the population; this test provides a positive predictive value of 99% when the prevalence is 90% or more, but the same test applied to a population with only 1% prevalence of infection, the positive predictive value is only 8%. In these circumstances, 85% of the positive results are false positives, probably due to biologic variability, nonspecific reactions, or exposure to environmental nontuberculosis mycobacteria, which produce lower degrees of sensitivity that diminishes within months. Therefore, in the United States, it is currently recommended by the American Academy of Pediatrics and the Centers for Disease Control (CDC) and Prevention to avoid routine skin testing of low-risk children, and to target children with specific or high risk factors for single or periodic tuberculin skin testing. The interpretation of a positive skin test varies according to these risk factors (Table 2) (97–100). The effect of previous vaccination with BCG on the interpretation of the tuberculin skin test is often debated. However, the effects of BCG on the tuberculin test are less pronounced in children than commonly recognized. A transient reactivity is usually present in young, recently vaccinated children (101), but less than 50% of infants given BCG vaccine have a reactive tuberculin skin test at 9 to 12 months, and most (80–90%) have no reaction to tuberculin by three to five years after vaccination (102). In general, in the United States, prior receipt of a BCG vaccine should not influence the interpretation of the initial tuberculin skin test of a child (103). In the rest of the world, receipt of BCG is taken into consideration when interpreting the results of the tuberculin skin test (TST). The WHO guidelines indicate that the area of induration should be more than 15 mm to be considered positive in a recent BCG recipient, and more than

Table 2 Interpretation of a Positive Mantoux Tuberculin Reaction According to Risk Factors More than 5 mm Persons who had contacts with infectious persons Persons with an abnormal chest radiograph HIV-infected and other immunosuppressed patients

Less than 10 mm

More than 15 mm

Infants Children in contact with adults at high risk Foreign-born persons from high prevalence countries; residents from prisons, nursing homes, and institutions; persons who inject drugs; persons with other medical risk factors; health care workers

No risk factors

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10 mm if there is no history of BCG vaccination. However, more important than the results of the TST is assuring that a contact investigation takes place whenever a child is found to have a positive TST, irrespective of a history of previous BCG vaccination, given that the likelihood of a recent infection is higher in endemic areas and the need to initiate appropriate therapy. In children, the tuberculin reaction appears in three weeks to three months after the initial infection and persists for many years, even after successful completion of therapy (104). However, young infants generally produce less induration in response to tuberculin than older children or adults. A lower or absent tuberculin reactivity (anergy) can be seen in the presence of malnutrition, debilitating or immunosuppressive illnesses including HIV infection, severe tuberculosis, and viral infections (especially measles, varicella, and influenza) and in cases of inappropriately applied skin tests and perhaps concomitant administration of live virus vaccines (96,105). Up to 10% of immunocompetent children with culture-documented tuberculosis do not initially react to tuberculin, but most become reactive after several months (106). Repetitive tuberculin skin testing in previously sensitized children can result in increased reactions or booster phenomenon (106–108). Given these considerations, and because of unreliable interpretation and reporting or poor adherence to test reading, it is essential that parents are not allowed to interpret their children’s skin test results (109–111). C. Smears and Culture

Direct smears and acid-fast stains from clinical specimens, particularly sputum, are the easiest, least expensive, and most rapid procedure for obtaining preliminary information and establishing a presumptive diagnosis of tuberculosis. However, the relatively small number of mycobacteria that are characteristically present in children with tuberculosis may not be detected with smears, and sputum is rarely produced by children less than 10 years of age. Sputum smears alone are insufficient to diagnose or rule out childhood tuberculosis. Acid-fast stains and culture of gastric washings, obtained in lieu of sputum in children have a sensitivity less than 25% (112). Obtaining three consecutive early morning gastric aspirates for culture increases this sensitivity to 30% to 50% in children with pulmonary tuberculosis, and in infants the yield can be as high as 70% (113,114). If gastric aspirates are obtained correctly, they are more likely to yield the organism than are bronchial washings (115–117). In HIV-infected children, although the overall yield of cultures may be lower, gastric aspirates are more sensitive in children under five years of age and are equivalent to sputum in older children (114). Gastric aspiration should be performed early in the morning because the child awakens before the stomach empties itself of overnight accumulation of secretions swallowed from the respiratory tract. Induced sputum production with nebulized 5% saline in serial collections has been proposed as an alternative sample collection method in infants in an ambulatory setting. A small (5.6%) increase in yield compared with two or three consecutive gastric aspirates has been reported, with

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similar sensitivity in HIV-positive and HIV-negative children (118). However, this procedure requires appropriately trained staff and facilities that follow strict infection control procedures to reduce the likelihood of spread to other patients and health care personnel. Overall, the combination of acid-fast stains and culture of any sample with older patient age increases the likelihood of confirming the diagnosis of tuberculosis (119). Other body fluids and tissue specimens are not as helpful for diagnosing tuberculosis in children because the rate of positivity of stains and cultures is much lower. However, effusions (pleural, ascitic, pericardial, etc.) with a lymphocyte predominance and high protein content could suggest tuberculosis when Gram stains are negative and other bacterial etiologies have been ruled out. In practice, the difficulty of isolating M. tuberculosis from a child with tuberculosis disease should not greatly influence the approach to therapy. If the epidemiological, tuberculin skin test, clinical, and radiographic information are compatible with the diagnosis, then the child should be treated for tuberculosis, even if the cultures are negative. If the adult source case culture and susceptibility results are available, they can be used to guide antituberculosis chemotherapy. However, it is important to attempt to isolate M. tuberculosis from the child if the diagnosis is in question, no source case confirmation is available, the source case has drug-resistant M. tuberculosis disease, or the child has suspected extrathoracic tuberculosis. D. Serology and New Diagnostic Techniques

After years of investigation, the serologic diagnosis of tuberculosis in children has found little place in the current clinical practice. Available methods include enzyme-linked immunosorbent assays (ELISA) to detect antibodies to various purified or complex antigens of M. tuberculosis, particularly antibodies against antigen A60, but both the sensitivity and specificity of these tests are low and variable in children (120,121) and therefore inadequate to use under various clinical conditions. The detection of specific mycobacterial antigens has been evaluated in clinical samples of adults with tuberculosis, yielding high sensitivity and specificity (122,123), but data are not known for children. Gamma interferon (IFN-c) production in response to M. tuberculosis antigens is a target for the immunodiagnosis of tuberculosis disease currently undergoing evaluation in adults (124). The most promising approaches utilize enzyme-linked immunospot analysis, or IFN-c ELISA techniques, which, although highly specific, may not be applicable to children, in whom more studies are still needed (125–127). In England, a country with low prevalence of tuberculosis, INF-c responses in children were more prevalent to nontuberculous mycobacteria than to M. tuberculosis (128). In addition, these techniques require technically advanced equipment and expertise, not commonly available in resourcelimited countries and most areas where childhood tuberculosis is seen. The use of nucleic acid amplification, specifically the polymerase chain reaction (PCR) technique, for the diagnosis of tuberculosis in children is

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limited. Compared with a clinical diagnosis of pulmonary tuberculosis in children, sensitivity of PCR has varied from 25% to 83%, and specificity has varied from 80% to 100% (129–131). There seem to be no advantages to the use of PCR in smear negative respiratory samples (131). PCR may have a special role in the diagnosis of extrapulmonary and pulmonary tuberculosis in young children and immunocompromised patients, when the diagnosis is not established readily by clinical or epidemiological data, and when the yield of positive acid-fast smears of sputum, gastric aspirates, or other clinical specimens is low (132,133). A negative PCR result, however, does not eliminate tuberculosis as a diagnostic possibility. VI. Treatment A. General Principles

During the past decade, dramatic changes in the therapeutic approach to childhood tuberculosis have occurred as a result of large numbers of treatment trials for children and increased concern about the development of resistance to antituberculosis drugs. Newer regimens often called ‘‘shortcourse’’ chemotherapy because of treatment durations as short as six months are successful. The key to this approach, however, is not the short duration, but the intensive initial therapy with three or more antituberculosis drugs. There are several special considerations to keep in mind when treating children with tuberculosis. First, children usually develop tuberculosis disease as an immediate consequence of the primary infection, and they typically have closed caseous lesions with relatively fewer mycobacteria than those found in adults. Because the likelihood of developing resistance to any antimycobacterial drug depends primarily upon the size of the bacillary population, resistance that emerges during therapy, that is secondary drug resistance, is rare in children. Most resistance encountered in childhood is primary, i.e., already present when infection occurs. Second, children have a higher propensity than adults to develop extrapulmonary forms of tuberculosis, particularly disseminated disease and meningitis. It is important that antituberculosis drugs used in children penetrate a variety of tissues and fluids, especially the meninges. Third, the pharmacokinetics of antituberculosis drugs differs between children and adults. In general, children tolerate larger doses per kilogram of body weight and have fewer adverse reactions than adults (134). Although higher serum concentrations of the drugs are achieved in children, it is unclear whether they provide a higher therapeutic advantage. In general, young children with more severe forms of tuberculosis, or those with malnutrition, experience more significant hepatotoxic effects than less severely ill children treated with the same doses per kilogram of INH and rifampicin (RIF), especially if the dose of INH exceeds 10 mg/kg/day (135,136). Finally, most available dosage forms for antituberculosis drugs are designed for use in adults, and giving these preparations to children often involves crushing pills or making up suspensions that may be inadequately absorbed and cause diarrhea (137).

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Problems or difficulties in taking the several medications required should be anticipated and resolved, especially at the beginning of therapy, to avoid delays and interruptions of treatment. B. Antituberculosis Drugs for Children

The first-line drugs are bactericidal with the exception of pyrazinamide (PZA), which has a potent sterilizing activity, and ethambutol, which is bacteriostatic in vitro at 15 mg/kg but bactericidal at 25 mg/kg (Table 3). Infants and children tolerate antituberculosis drugs very well and adverse reactions are rare. INH is the mainstay of treatment of tuberculosis in children, because it is effective and familiar to most pediatricians. Although it is metabolized by acetylation in the liver, there is no correlation in children Table 3 Antituberculosis Drugs in Children

Drugs

Dosage forms

First-line drugs Isoniazida

Scored tablets: 100 mg, 300 mg; syrup: 10 mg/mLb a Rifampicin Capsules: 150 mg, 300 mg; syrup: formulated from capsulesc Pyrazinamide Scored tablets: 500 mg Streptomycin (IM) Vials: 1 g, 4 g Ethambutol Scored tablets: 100 mg, 400 mg Second-line drugs Ethionamide Kanamycin (IM) Cycloserine Para-amino salicylic acid a

Tablets: 250 mg Vials: 1 g Capsules: 250 mg

Twiceweekly Daily dose dose (mg/ kg/dose) (mg/kg)

Maximum dose

10–15

20–40

10–20

10–20

Daily: 300 mg; twice-weekly: 900 mg 600 mg

20–40

50–70

2g

20–40 15–25

20–40 50

1g 2.5 g

10–20 15

15–25

1g 1g

10–20 200–300

1g 10 g

Rifamate is a capsule containing 150 mg of isoniazid and 300 mg of rifampicin. Two capsules provide the usual adult (weight > 50 kg) daily dose of each drug. b Many experts recommend not using isoniazid syrup, as it is unstable and it is associated with frequent gastrointestinal complaints, especially diarrhea. c Marion Merrell Dow issues directions for preparation of this ‘‘extemporeaneous’’ syrup. Abbreviation: IM, intramuscular.

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between acetylation rate and either efficacy or adverse reactions (138). The doses of INH in regular use in the United States are high enough that drug concentrations are sufficient even in children who acetylate the drug very rapidly. The two major toxic effects of INH seen in adults, pyridoxine deficiency–associated peripheral neuritis and hepatotoxicity, are rare in children (139). Only in certain children—teenagers with inadequate diets, children from ethnic groups with low milk or meat intake, and breastfeeding babies—is pyridoxine supplementation recommended (140). Of children taking INH, 3% to 10% have transiently elevated liver transaminase levels, but clinically significant hepatitis is exceedingly rare (141). It is common to observe an elevation in serum liver enzymes of two to three times normal, and therefore discontinuation of the drugs is unnecessary if all other clinical findings are normal. Adolescents are more likely than younger children to experience hepatotoxicity (142). For most children, toxicity can be monitored using clinical signs and symptoms, and routine biochemical monitoring is unnecessary unless the child has underlying liver disease, is taking other hepatotoxic drugs, or has disseminated tuberculosis or meningitis. RIF is more effective against mycobacteria than any other drug except INH. Adverse reactions include hepatotoxicity, leukopenia, thrombocytopenia, flu-like syndrome, and hypersensitivity reactions, but they are extremely rare in children. Parents must be warned in advance about tears, saliva, urine, and stool turning orange as a result of a harmless metabolite. Although there is no commercially available formulation for young children in the United States, RIF is safe, effective, and routinely used in children (140). PZA plays a major role in intensive, short-course treatment regimens, exerting its maximum effect during the first two months of therapy (143,144). The adult dose of 30 to 40 mg/kg daily is well tolerated by children, results in adequate CSF levels (145), rarely produces toxicity, and appears to be effective. Pharmacokinetic studies of PZA in children are limited. In a study that included 23 children with active tuberculosis, PZA concentrations increased linearly with increasing oral doses, but incomplete or delayed absorption was more common in children than in adults, and the volume of distribution and median clearance were larger in children, with a resultant half-life shorter by approximately 40% in children (146). Hepatitis and hyperuricemia are exceedingly rare in children. Streptomycin is well tolerated by children. It is usually used in conjunction with INH and RIF in life-threatening forms of tuberculosis, and can be discontinued within one to three months if clinical improvement is documented. Ethambutol is used in combination with other antituberculosis drugs to prevent or delay the emergence of resistant strains. Ethambutol causes dose-related reversible optic neuritis or alterations in red/green color discrimination, and it is not routinely recommended for very young children in whom visual field and color discrimination tests are difficult or inaccurate. However, it can be used safely in children when periodic evaluation of visual acuity and color vision is performed during treatment, particularly for life-threatening or drug-resistant tuberculosis.

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Ocular toxicity is rare when used at recommended doses for a duration of two to three months. In a recent pharmacokinetic study of 14 children with active tuberculosis, delayed absorption and very low serum concentrations of ethambutol were observed using currently recommended doses (147). The second-line drugs (Table 3) are less commonly used, and indicated only in cases of drug-resistant tuberculosis or when patients do not tolerate first-line drugs. Ethionamide is well tolerated by children, who experience much less gastrointestinal distress than adults, but it can cause significant hepatitis. Ethionamide crosses the meninges well, and may be especially useful in cases of meningitis. Other antituberculosis drugs used in children include the aminoglycosides kanamycin, amikacin, and capreomycin, with specific activity against different mycobacterial strains. Cycloserine can cause significant mood changes and other neurologic complaints. Clofazimine and rifabutin are newer drugs used mainly in children with AIDS and Mycobacterium avium-intracellulare infections (148). The fluoroquinolones (ciprofloxacin and levofloxacin) have antituberculous activity and can be used in multidrug-resistant tuberculosis after weighing the potential risks and benefits in children (149). C. Specific Regimens Exposure

It is recommended to start treatment with INH alone in children under five years of age who have been exposed to potentially infectious adults with pulmonary disease. In these patients, severe tuberculosis may develop before the tuberculin skin test becomes reactive. After a minimum of three months of treatment after contact with the infectious case is broken (by chemotherapy or physical separation), the tuberculin skin test is repeated. If the second test is positive, infection is documented and treated for a total duration of nine months. If the result is negative, INH can be discontinued. HIV-infected children with significant exposure to tuberculosis are at higher risk for rapid progression of tuberculosis. Frequently they are also anergic, and therefore should be treated as if they had tuberculosis infection, for a total duration of nine months (98). Infection Without Disease

The treatment of children with asymptomatic tuberculosis infection to prevent the development of tuberculosis disease is an established practice. In infected children, the effectiveness of INH therapy has approached 100% and the effect has lasted for at least 30 years (150). Tuberculin-positive children with known contact to an infectious adult case are at the highest risk of developing disease, and should always be given treatment. Tuberculinpositive children without known contact also should receive therapy, especially those under five years of age and adolescents. In the United States, the American Academy of Pediatrics and the Centers for Disease Control and Prevention recommend a duration of nine months of therapy with

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INH in children with tuberculosis infection (98,140). In other parts of the world, WHO recommends a minimum of six months of INH therapy and regular follow-up. Short-course preventive therapy regimens have not been systematically studied in persons younger than 18 years of age. Due to the importance of treating latent M. tuberculosis in children, there is a need for data on well-tolerated, shorter regimens to ensure high rates of adherence to treatment. RIF can be used in children infected with INH-resistant M. tuberculosis. These drugs can be taken daily under self-supervision or twice weekly under direct supervision when compliance cannot be assured. Pulmonary Disease

A large number of clinical trials of antituberculosis drugs in children have been reported during the last few decades, focusing on shorter, more intense regimens and on improving adherence to treatment. Abernathy reported, in 1983, successful treatment of 50 children with tuberculosis using INH and RIF daily for one month, then twice weekly for eight months, a total duration of nine months, with a success rate of 100% (151). Several studies of six-month duration of antituberculosis therapy using at least three drugs in the initial phase, have reported a success rate greater then 98%, with less than 2% incidence of clinically significant adverse reactions (152–154). The most commonly used regimen is six months of INH and RIF supplemented during the first two months with PZA. This six-month, three-drug regimen is currently the standard therapy for presumed or confirmed drug-susceptible intrathoracic tuberculosis (pulmonary and/or hilar adenopathy) in children and adolescents (134,140). It is well tolerated, less expensive, and results in increased adherence to therapy and decreased development of drug resistance. Daily administration of three medications during the first two weeks to two months is preferable, followed by twice weekly administration under directly observed therapy (DOT) for the remaining duration, resulting in equivalent success rates. Although nine-month regimens of INH and RIF are effective in areas where drug resistance rates are low, it is not recommended given the tendency of patients to become noncompliant as the treatment duration is lengthened. When a source case is not identified or when the culture and/or susceptibility results are not available from the source case or the child, the standard initial regimen of INH, RIF, and PZA should be used. If the likely source case has risk factors for drug-resistant tuberculosis (such as residence in an area or country with high rates of drug resistance), a fourth antituberculosis drug should be added (155). The usual choice is ethambutol, which offers the advantage of oral administration, particularly in settings where using parenteral preparations represents a problem. Streptomycin is a second alternative but, because it has to be administered by intramuscular injection, is not the preferred choice for children. Unless confirmation of drug susceptibility is available, ethambutol or streptomycin should be continued for the total six months of treatment. In any case, PZA can be stopped after the first two months.

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Controlled clinical trials comparing treatment regimens for various forms of extrapulmonary tuberculosis are rare. In general, the six-month regimen using INH, RIF, and PZA initially is recommended for most forms of extrapulmonary tuberculosis in children. Exceptions include bone and joint disease, meningitis, and disseminated tuberculosis (140). Bone and joint tuberculosis may require a treatment duration of 9 to 12 months, especially if surgical intervention has not been performed. For meningitis and disseminated tuberculosis, most children are treated initially with four drugs (INH, RIF, PZA, and ethionamide or streptomycin) for the first two months, followed by INH and RIF for a total duration of no less than six months, usually 9 to 12 months. Drug-Resistant Tuberculosis

Although unknown in most developing countries, the rates of antituberculosis drug resistance are greater than 20% and as high as 80% in some areas of the world (156,157). In the United States, approximately 10% of M. tuberculosis isolates are resistant to at least one drug (158). Patterns of drug resistance among children with tuberculosis tend to reflect those found among adults in the same population. Certain epidemiological factors such as residence in a country or area with high rates of drug resistance, homelessness, and previous antituberculosis therapy, in the child or the adult source case, are clues to determining drug resistance in childhood tuberculosis. The treatment of drug-resistant tuberculosis in children must be guided by the drug susceptibility pattern of the isolate. Treatment regimens must include at least two bactericidal drugs to which the organism is susceptible to prevent secondary resistance from developing (159–161). Duration of therapy is usually 9 to 12 months if either INH or RIF can be used, and to 18 to 24 months if resistance to both drugs is present (162,163). RIF-resistant disease is more difficult to treat than INH-resistant disease. The usual treatment regimens include four to seven drugs administered daily under DOT, and should be managed by experts in tuberculosis. HIV-Related Tuberculosis

The principles of treatment of HIV-infected children are the same as those for non–HIV infected children. However, because of the complexity of HIV and tuberculosis chemotherapy schedules, drug interactions, toxicities, and resistance, these patients should be cared for by a specialist. In general, children with HIV infection who have been exposed to an adult with contagious tuberculosis should be treated as if they have tuberculosis infection with INH (or RIF if the organism is resistant to INH) for a total duration of nine months. Tuberculosis disease in these and patients with other with immunocompromising conditions should be treated with at least four drugs initially (INH, RIF, PZA, and either ethambutol or streptomycin) for two months, and subsequent modifications of the treatment regimen should be based on susceptibility testing whenever possible. For M. tuberculosis

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susceptible to INH, the initial two months of therapy can be followed by INH and RIF to complete a total duration of 9 to 12 months (164,165). For drugresistant M. tuberculosis, regimens should include a minimum of three drugs and up to six drugs with varying levels of activity, and the duration should be a minimum of 12 months, with clinical, microbiological, and radiographical monitoring to guide the exact duration of treatment. Children with HIV infection receiving antituberculosis therapy should be closely monitored for hepatotoxicity with baseline and serial liver function tests, as well as for other drug toxicities. Corticosteroids

Corticosteroids are beneficial in the management of tuberculosis in children when the host inflammatory reaction is contributing significantly to tissue damage or impairment of function. They should always be used under cover of appropriate antituberculosis drugs to prevent further dissemination of the disease. Corticosteroids can decrease mortality and long-term neurological sequelae in children with meningitis by decreasing brain edema, inflammation, and the occurrence of vasculitis (166). They also benefit children with significantly enlarged mediastinal lymph nodes that result in respiratory difficulty or bronchial obstruction, endobronchial disease, miliary disease, and pleural or pericardial effusions (167). A frequently used regimen includes prednisone (1–2 mg/kg/day) for four to six weeks with gradual taper over one to two weeks. Although there is no convincing evidence that one form of corticosteroid is more beneficial than others, some experts prefer dexamethasone for tuberculous meningitis. Directly Observed Therapy and Follow-Up

While receiving antituberculosis therapy, children should be examined monthly to monitor compliance, possible side effects, and success or failure of treatment. Routine laboratory testing is not necessary given the low rates of adverse reactions observed in children. Radiographic improvement of intrathoracic tuberculosis in children occurs very slowly, and frequent monitoring with chest radiographs is not usually necessary. Radiographic abnormalities may still be present at the time of completion of therapy, and therefore a normal chest radiograph is not a necessary criterion for stopping therapy. Noncompliance with drug therapy is a major problem in tuberculosis control because of the long-term nature of treatment. Many children with tuberculosis have few or no symptoms and do not benefit from the dramatic clinical improvement often seen in adults. Although a variety of methods have been used in the past to encourage adherence to treatment, DOT is considered the optimal method of drug administration by the CDC and WHO for all patients, particularly for those with drug-resistant tuberculosis. By ensuring patient compliance, DOT decreases the rates of drug resistance, relapse, and treatment failures. However, DOT requires that a health care worker observes the patient taking the medications at a time and place convenient for the patient, and therefore only few communities

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in the world may have the resources to provide DOT for children with tuberculosis. VII. Summary Despite the availability of curative therapy for disease and preventive therapy for infection, tuberculosis continues to occur in children at alarming rates throughout the world. In theory, all cases of childhood tuberculosis could be prevented if tuberculosis in adults could be controlled, and if basic principles of tuberculosis control were adhered to more completely. The control of childhood tuberculosis today and its eradication in the future represent a constant challenge for scientists, physicians, health care workers, epidemiologists, local health departments, and governments in both developing and developed nations. References 1. Dye C, Scheele S, Dolin P, Pathania V, Raviglione MC. Consensus statement. Global burden of tuberculosis: estimated incidence, prevalence, and mortality by country. WHO Global Surveillance and Monitoring Project. JAMA 1999; 282(7): 677–686. 2. Raviglione MC. The TB epidemic from 1992 to 2002. Tuberculosis (Edinb) 2003; 83(1–3):4–14. 3. World Health Organization. Treatment of Tuberculosis: Guidelines for National Programmes. 3rd ed. 2003:1–108. 4. Marais BJ, Gie RP, Schaaf HS, et al. The clinical epidemiology of childhood pulmonary tuberculosis: a critical review of literature from the pre-chemotherapy era. Int J Tuberc Lung Dis 2004; 8(3):278–285. 5. Starke JR, Taylor-Watts KT. Tuberculosis in the pediatric population of Houston, Texas. Pediatrics 1989; 84(1):28–35. 6. Raviglione MC, Snider DE Jr., Kochi A. Global epidemiology of tuberculosis. Morbidity and mortality of a worldwide epidemic. JAMA 1995; 273(3):220–226. 7. van Rie A, Beyers N, Gie RP, Kunneke M, Zietsman L, Donald PR. Childhood tuberculosis in an urban population in South Africa: burden and risk factor. Arch Dis Child 1999; 80(5):433–437. 8. Murray CJ, Styblo K, Rouillon A. Tuberculosis in developing countries: burden, intervention and cost. Bull Int Union Tuberc Lung Dis 1990; 65(1):6–24. 9. Salazar GE, Schmitz TL, Cama R, et al. Pulmonary tuberculosis in children in a developing country. Pediatrics 2001; 108(2):448–453. 10. Shingadia D, Novelli V. Diagnosis and treatment of tuberculosis in children. Lancet Infect Dis 2003; 3(10):624–632. 11. Walls T, Shingadia D. Global epidemiology of paediatric tuberculosis. J Infect 2004; 48(1):13–22. 12. Odhiambo JA, Borgdorff MW, Kiambih FM, et al. Tuberculosis and the HIV epidemic: increasing annual risk of tuberculous infection in Kenya, 1986–1996. Am J Public Health 1999; 89(7):1078–1082. 13. Range N, Ipuge YA, O’Brien RJ, et al. Trend in HIV prevalence among tuberculosis patients in Tanzania, 1991–1998. Int J Tuberc Lung Dis 2001; 5(5):405–412. 14. Public Health Agency of Canada. Pediatric tuberculosis in Canada. Canada Communicable Disease Report 29-16, 15 Aug 2003.

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15. Snider DE Jr., Rieder HL, Combs D, Bloch AB, Hayden CH, Smith MH. Tuberculosis in children. Pediatr Infect Dis J 1988; 7(4):271–278. 16. Ussery XT, Valway SE, McKenna M, Cauthen GM, McCray E, Onorato IM. Epidemiology of tuberculosis among children in the United States: 1985 to 1994. Pediatr Infect Dis J 1996; 15(8):697–704. 17. Centers for Disease Control and Prevention. Reported Tuberculosis in the United States, 2003–2004. Atlanta, GA: US Department of Health and Human Services. 18. Nelson LJ, Schneider E, Wells CD, Moore M. Epidemiology of childhood tuberculosis in the United States, 1993–2001: the need for continued vigilance. Pediatrics 2004; 114(2):333–341. 19. Rieder HL. Epidemiologic Basis of Tuberculosis Control. 1st ed. Paris: International Union Against Tuberculosis and Lung Diseases, 1999:4–46. 20. Mandalakas AM, Starke JR. Current concepts of childhood tuberculosis. Semin Pediatr Infect Dis 2005; 16(2):93–104. 21. Munoz FM, Ong LT, Seavy D, Medina D, Correa A, Starke JR. Tuberculosis among adult visitors of children with suspected tuberculosis and employees at a children’s hospital. Infect Control Hosp Epidemiol 2002; 23(10):568–572. 22. Nolan CM, Barr H, Elarth AM, Boase J. Tuberculosis in a day-care home. Pediatrics 1987; 79(4):630–632. 23. Leggiadro RJ, Callery B, Dowdy S, Larkin J. An outbreak of tuberculosis in a family day care home. Pediatr Infect Dis J 1989; 8(1):52–54. 24. Sanchez MA, Borja PC, Rubio Luengo MA, Peinado GA, Sola FC, Castillo Megias MC. Epidemic outbreak of tuberculosis in a primary and secondary school in Granada (Spain). An Pediatr (Barc) 2003; 58(5):432–437. 25. Corbett EL, Watt CJ, Walker N, et al. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med 2003; 163(9): 1009–1021. 26. Antonucci G, Girardi E, Raviglione MC, Ippolito G. Risk factors for tuberculosis in HIV-infected persons. A prospective cohort study. The Gruppo Italiano di Studio Tubercolosi e AIDS (GISTA). JAMA 1995; 274(2):143–148. 27. Daley CL, Small PM, Schecter GF, et al. An outbreak of tuberculosis with accelerated progression among persons infected with the human immunodeficiency virus. An analysis using restriction-fragment-length polymorphisms. N Engl J Med 1992; 326(4):231–235. 28. Chaisson RE, Slutkin G. Tuberculosis and human immunodeficiency virus infection. J Infect Dis 1989; 159(1):96–100. 29. Braun MM, Cauthen G. Relationship of the human immunodeficiency virus epidemic to pediatric tuberculosis and bacillus Calmette–Gue´rin immunization. Pediatr Infect Dis J 1992; 11(3):220–227. 30. Shah SR, Tullu MS, Kamat JR. Clinical profile of pediatric HIV infection from India. Arch Med Res 2005; 36(1):24–31. 31. Gutman LT, Moye J, Zimmer B, Tian C. Tuberculosis in human immunodeficiency virus-exposed or -infected United States children. Pediatr Infect Dis J 1994; 13(11):963–968. 32. Thomas P, Bornschlegel K, Singh TP, et al. Tuberculosis in human immunodeficiency virus-infected and human immunodeficiency virus-exposed children in New York City. The New York City Pediatric Spectrum of HIV Disease Consortium. Pediatr Infect Dis J 2000; 19(8):700–706. 33. Chan SP, Birnbaum J, Rao M, Steiner P. Clinical manifestation and outcome of tuberculosis in children with acquired immunodeficiency syndrome. Pediatr Infect Dis J 1996; 15(5):443–447.

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76. Zarabi M, Sane S, Girdany BR. The chest roentgenogram in the early diagnosis of tuberculous meningitis in children. Am J Dis Child 1971; 121(5):389–392. 77. Rieder HL, Snider DE Jr., Cauthen GM. Extrapulmonary tuberculosis in the United States. Am Rev Respir Dis 1990; 141(2):347–351. 78. Margileth AM, Chandra R, Altman RP. Chronic lymphadenopathy due to mycobacterial infection. Clinical features, diagnosis, histopathology, and management. Am J Dis Child 1984; 138(10):917–922. 79. Moore SW, Schneider JW, Schaaf HS. Diagnostic aspects of cervical lymphadenopathy in children in the developing world: a study of 1,877 surgical specimens. Pediatr Surg Int 2003; 19(4):240–244. 80. Dhammi IK, Jain AK, Singh S, Aggarwal A, Kumar S. Multifocal skeletal tuberculosis in children: a retrospective study of 18 cases. Scand J Infect Dis 2003; 35(11–12): 797–799. 81. Boukthir S, Mrad SM, Becher SB, Khaldi F, Barsaoui S. Abdominal tuberculosis in children. Report of 10 cases. Acta Gastroenterol Belg 2004; 67(3):245–249. 82. Chavalittamrong B, Talalak P. Tuberculous peritonitis in children. Prog Pediatr Surg 1982; 15:161–167. 83. Raina UK, Jain S, Monga S, Arora R, Mehta DK. Tubercular preseptal cellulitis in children: a presenting feature of underlying systemic tuberculosis. Ophthalmology 2004; 111(2):291–296. 84. Vaamonde P, Castro C, Garcia-Soto N, Labella T, Lozano A. Tuberculous otitis media: a significant diagnostic challenge. Otolaryngol Head Neck Surg 2004; 130(6):759–766. 85. Gokce G, Kilicarslan H, Ayan S, et al. Genitourinary tuberculosis: a review of 174 cases. Scand J Infect Dis 2002; 34(5):338–340. 86. Nemir RL. Perspectives in adolescent tuberculosis: three decades of experience. Pediatrics 1986; 78(3):399–405. 87. Marais BJ, Gie RP, Schaaf HS, et al. The natural history of childhood intrathoracic tuberculosis: a critical review of literature from the pre-chemotherapy era. Int J Tuberc Lung Dis 2004; 8(4):392–402. 88. Hertzog AJ, Chapman S, Herring J. Congenital pulmonary aspiration-tuberculosis; report of a case. Am J Clin Pathol 1949; 19(12):1139–1142 (illustration). 89. Kendig EL Jr., Rodgers WL. Tuberculosis in the neonatal period. Am Rev Tuberc 1958; 77(3):418–422. 90. Dormer BA, Harrison I, Swart JA, Vidor SR. Prophylactic isoniazid: protection of infants in a tuberculosis hospital. Lancet 1959; 2:902–903. 91. Kendig EL Jr. Prognosis of infants born of tuberculous mothers. Pediatrics 1960; 26:97–100. 92. Light IJ, Saidleman M, Sutherland JM. Management of newborns after nursery exposure to tuberculosis. Am Rev Respir Dis 1974; 109(4):415–419. 93. Kendig EL Jr. The place of BCG vaccine in the management of infants born of tuberculous mothers. N Engl J Med 1969; 281(10):520–523. 94. Snider DE Jr., Powell KE. Should women taking antituberculosis drugs breast-feed? Arch Intern Med 1984; 144(3):589–590. 95. Hesseling AC, Schaaf HS, Gie RP, Starke JR, Beyers N. A critical review of diagnostic approaches used in the diagnosis of childhood tuberculosis. Int J Tuberc Lung Dis 2002; 6(12):1038–1045. 96. Huebner RE, Schein MF, Bass JB Jr. The tuberculin skin test. Clin Infect Dis 1993; 17(6):968–975. 97. American Academy of Pediatrics Committee on Infectious Diseases. Update on tuberculosis skin testing of children. Pediatrics 1996; 97(2):282–284. 98. American Academy of Pediatrics Committee on Infectious Diseases. Screening for tuberculosis in infants and children. Pediatrics 1994; 93(1):131–134.

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99. Centers for Disease Control and Prevention. Screening for tuberculosis and tuberculosis infection in high risk populations. MMWR 1995; 44:19–34. 100. Mohle-Boetani JC, Miller B, Halpern M, et al. School-based screening for tuberculous infection. A cost-benefit analysis. JAMA 1995; 274(8):613–619. 101. Nemir RL, Teichner A. Management of tuberculin reactors in children and adolescents previously vaccinated with BCG. Pediatr Infect Dis 1983; 2(6):446–451. 102. Lifschitz M. The value of the tuberculin skin test as a screening test for tuberculosis among BCG-vaccinated children. Pediatrics 1965; 36(4):624–627. 103. Johnson H, Lee B, Doherty E, Kelly E, McDonnell T. Tuberculin sensitivity and the BCG scar in tuberculosis contacts. Tuber Lung Dis 1995; 76(2):122–125. 104. Hsu KH. Tuberculin reaction in children treated with isoniazid. Am J Dis Child 1983; 137(11):1090–1092. 105. American Thoracic Society CfDCaPIDSoA. Diagnostic standards and classification of tuberculosis. Am Rev Respir Dis 1990; 142:725–735. 106. Steiner P, Rao M, Victoria MS, Jabbar H, Steiner M. Persistently negative tuberculin reactions: their presence among children with culture positive for Mycobacterium tuberculosis (tuberculin-negative tuberculosis). Am J Dis Child 1980; 134(8):747–750. 107. Sepulveda RL, Burr C, Ferrer X, Sorensen RU. Booster effect of tuberculin testing in healthy 6-year-old school children vaccinated with bacillus Calmette–Gue´rin at birth in Santiago, Chile. Pediatr Infect Dis J 1988; 7(8):578–581. 108. Thompson NJ, Glassroth JL, Snider DE Jr., Farer LS. The booster phenomenon in serial tuberculin testing. Am Rev Respir Dis 1979; 119(4):587–597. 109. Asnes RS, Maqbool S. Parent reading and reporting of children’s tuberculin skin test results. Chest 1975; 68(suppl 3):459–462. 110. Kenney RD. Improving reporting of tuberculin test results in a community hospital pediatric clinic. J Pediatr 1988; 112(3):427–429. 111. Cheng TL, Ottolini MC, Baumhaft K, Brasseux C, Wolf MD, Scheidt PC. Strategies to increase adherence with tuberculosis test reading in a high-risk population. Pediatrics 1997; 100(2 Pt 1):210–213. 112. Klotz SA, Penn RL. Acid-fast staining of urine and gastric contents is an excellent indicator of mycobacterial disease. Am Rev Respir Dis 1987; 136(5):1197–1198. 113. Vallejo JG, Ong LT, Starke JR. Clinical features, diagnosis, and treatment of tuberculosis in infants. Pediatrics 1994; 94(1):1–7. 114. Berggren PI, Gudetta B, Bruchfeld J, Eriksson M, Giesecke J. Detection of Mycobacterium tuberculosis in gastric aspirate and sputum collected from Ethiopian HIV-positive and HIV-negative children in a mixed in- and outpatient setting. Acta Paediatr 2004; 93(3):311–315. 115. de Blic J, Azevedo I, Burren CP, Le Bourgeois M, Lallemand D, Scheinmann P. The value of flexible bronchoscopy in childhood pulmonary tuberculosis. Chest 1991; 100(3):688–692. 116. Toppet M, Malfroot A, Derde MP, Toppet V, Spehl M, Dab I. Corticosteroids in primary tuberculosis with bronchial obstruction. Arch Dis Child 1990; 65(11):1222–1226. 117. Bibi H, Mosheyev A, Shoseyov D, Feigenbaum D, Kurzbart E, Weiller Z. Should bronchoscopy be performed in the evaluation of suspected pediatric pulmonary tuberculosis? Chest 2002; 122(5):1604–1608. 118. Zar HJ, Hanslo D, Apolles P, Swingler G, Hussey G. Induced sputum versus gastric lavage for microbiological confirmation of pulmonary tuberculosis in infants and young children: a prospective study. Lancet 2005; 365(9454):130–134. 119. Merino JM, Alvarez T, Marrero M, et al. Microbiology of pediatric primary pulmonary tuberculosis. Chest 2001; 119(5):1434–1438.

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120. Delacourt C, Gobin J, Gaillard JL, de Blic J, Veron M, Scheinmann P. Value of ELISA using antigen 60 for the diagnosis of tuberculosis in children. Chest 1993; 104(2):393–398. 121. Turneer M, Van Nerom E, Nyabenda J, Waelbroeck A, Duvivier A, Toppet M. 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 1994; 150(6 Pt 1):1508–1512. 122. Wadee AA, Boting L, Reddy SG. Antigen capture assay for detection of a 43-kilodalton Mycobacterium tuberculosis antigen. J Clin Microbiol 1990; 28(12): 2786–2791. 123. Sada E, Aguilar D, Torres M, Herrera T. Detection of lipoarabinomannan as a diagnostic test for tuberculosis. J Clin Microbiol 1992; 30(9):2415–2418. 124. Hill PC, Brookes RH, Fox A, et al. Large-scale evaluation of enzyme-linked immunospot assay and skin test for diagnosis of Mycobacterium tuberculosis infection against a gradient of exposure in The Gambia. Clin Infect Dis 2004; 38(7):966–973. 125. Pai M, Riley LW, Colford JM Jr. Interferon-gamma assays in the immunodiagnosis of tuberculosis: a systematic review. Lancet Infect Dis 2004; 4(12):761–776. 126. Scholvinck E, Wilkinson KA, Whelan AO, Martineau AR, Levin M, Wilkinson RJ. Gamma interferon-based immunodiagnosis of tuberculosis: comparison between whole-blood and enzyme-linked immunospot methods. J Clin Microbiol 2004; 42(2):829–831. 127. Lewinsohn DA, Gennaro ML, Scholvinck L, Lewinsohn DM. Tuberculosis immunology in children: diagnostic and therapeutic challenges and opportunities. Int J Tuberc Lung Dis 2004; 8(5):658–674. 128. Weir RE, Fine PE, Nazareth B, et al. Interferon-gamma and skin test responses of schoolchildren in southeast England to purified protein derivatives from Mycobacterium tuberculosis and other species of mycobacteria. Clin Exp Immunol 2003; 134(2):285–294. 129. Pierre C, Olivier C, Lecossier D, Boussougant Y, Yeni P, Hance AJ. Diagnosis of primary tuberculosis in children by amplification and detection of mycobacterial DNA. Am Rev Respir Dis 1993; 147(2):420–424. 130. Smith KC, Starke JR, Eisenach K, Ong LT, Denby M. Detection of Mycobacterium tuberculosis in clinical specimens from children using a polymerase chain reaction. Pediatrics 1996; 97(2):155–160. 131. Montenegro SH, Gilman RH, Sheen P, et al. Improved detection of Mycobacterium tuberculosis in Peruvian children by use of a heminested IS6110 polymerase chain reaction assay. Clin Infect Dis 2003; 36(1):16–23. 132. Leon ME, Perez Del Molino ML, Lado Lado FL, Pazo NM, Pardo F. Use of ligase chain reaction for the rapid diagnosis of lymph node tuberculosis. Scand J Infect Dis 2004; 36(10):724–726. 133. Mirza S, Restrepo BI, McCormick JB, Fisher-Hoch SP. Diagnosis of tuberculosis lymphadenitis using a polymerase chain reaction on peripheral blood mononuclear cells. Am J Trop Med Hyg 2003; 69(5):461–465. 134. American Thoracic Society CfDCaPIDSoA. Treatment of tuberculosis. Am J Respir Crit Care Med 2003; 167:603–662. 135. Ohkawa K, Hashiguchi M, Ohno K, et al. Risk factors for antituberculous chemotherapy-induced hepatotoxicity in Japanese pediatric patients. Clin Pharmacol Ther 2002; 72(2):220–226. 136. Donald PR, Schoeman JF, O’Kennedy A. Hepatic toxicity during chemotherapy for severe tuberculosis meningitis. Am J Dis Child 1987; 141(7):741–743. 137. Notterman DA, Nardi M, Saslow JG. Effect of dose formulation on isoniazid absorption in two young children. Pediatrics 1986; 77(6):850–852.

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12 Tuberculosis in the Elderly

PETER D. O. DAVIES

JEAN WOO

Tuberculosis Research, Cardiothoracic Centre and University Hospital Aintree (NHS) Trusts, Mercers, Liverpool, U.K.

Department of Community and Family Medicine, Division of Geriatrics, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, and School of Public Health, Prince of Wales Hospital, Shatin, Hong Kong, China

JOHN MOORE-GILLON Department of Respiratory Medicine, St. Bartholomew’s and Royal London Hospitals, London, U.K.

I. Introduction As with most aspects of tuberculosis (TB), there is an increasing disparity between the richest nations and the poorest. While life expectancy in some of the poorest countries decreases, life expectancy in most developed countries is increasing. TB in the elderly is therefore an increasing problem in the developed world, but may be diminishing in some parts of the developing world. As longevity increases in the richer nations TB in the elderly is likely to remain a continuing and even an increasing problem. Presenting symptoms and signs may be uncharacteristic, causing the diagnosis to be missed. Because of the relative frailty of the elderly, adverse reactions to medication are more common. It may be partly for these reasons that mortality from TB in the elderly is higher than any other age group except infants. Special care is therefore needed for the awareness of TB in the elderly and the different patterns of disease that may present. 345

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Also the management of chemotherapy in the elderly will require more careful monitoring than in younger patients. II. The Aging Population Comparison of census figures for the United States shows that the proportion of the population aged 75 years and older grew from 5.27% in 1990 to 5.9% in 2000 (1). The growth of older population in the United Kingdom for 1991 to 2001 over the age of 65 was from 13% to 16% and is projected to rise to 23% by 2031 (2). The mean age of the European population is expected to rise from 34.9 to 44.4 years over the next 20 years (3). In the meantime, the average life expectancy in many sub-Saharan African countries is declining due to the steady attrition by human immunodeficiency virus (HIV)/AIDS and its related opportunistic infections, particularly TB (4). III. Epidemiology Among the indigenous white populations of the developed countries of Europe and North America, TB is principally a problem of the older age groups (5). This is because those who are elderly now would have been alive at a time when TB was very prevalent. The great majority of those aged over 65 will therefore have been infected with the tubercle bacille (Fig. 1) (6). Rates of disease in the white population of developed countries are therefore

Figure 1 Histogram indicating the proportion of patients by age group infected with tuberculosis in developed countries. Source: From Ref. 5.

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highest in the elderly (Fig. 2) (7). In contrast, rates of disease in the African ethnic minority are highest in the 15- to 34-year age range (Fig. 2), but again highest in the elderly in the Indian subcontinent (ISC) ethnic group. It is also of interest that among the older white population, rates in males are three times those of females, but there is no difference in rates between the sexes in the ISC group. The excess rates among older white males have been observed since the 1940s (8). Although rates are highest in the elderly, successive surveys have shown a steady decline in rates for every age group of more than a decade (Fig. 3) (9). Although rates of disease may be higher in the elderly at a given point of time, an analysis of trends by age cohort first carried out by Andvord (10), but also repeated by Frost for the United States (11) and Springett (12) for England and Wales, has consistently shown that rates for all groups at whatever time they were born are highest in early adult life, but fall progressively for each age cohort (Fig. 4). All these data were based on mortality. The higher rates among the older population seen at any point in time are because these represent the declining rates at the tail end of an older group that has a higher rate than the population born more recently. Rates peak in early adult life, but thereafter decline with increasing age. Since the advent of chemotherapy, case rates have become a much more accurate way of determining TB incidence than mortality.

Figure 2 Rates and proportions of patients notified with tuberculosis by age and sex for all ethnic groups combined (A), the white group (B), the Indian subcontinent group (C), and the black African group (D). Source: From Ref. 7.

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Figure 3 Rates of tuberculosis by age and sex for three successive surveys carried out in England and Wales. Source: From Ref. 9.

More recent evidence, based on case rates rather than mortality, may indicate a change in this trend (Fig. 5) (13). Analysis of data from Hong Kong and the United Kingdom suggests that rates by each cohort have been rising since about 1980, suggesting that the risk of disease is now rising, rather than falling, with increasing age. Whether this is a real phenomenon or has some other explanation such as migration needs to be retested after a further lapse in time, but if true it indicates a worrying change in trends for TB in the oldest age groups of the developed world. It may mean that as many people are now living to extreme old age, further decline in immunity is rendering them uniquely susceptible to TB. IV. Decline in Immunocompetence with Increasing Age It is well established that immunity declines with age. This can be seen in a number of tuberculin skin test studies. One carried out in over 2700 individuals resident in homes for the elderly in Liverpool showed that skin test positivity steadily declined from 15% in those aged 70 years to 3% in the over 90 years (Fig. 6) (14). The increasing susceptibility of the elderly to cancers, autoimmune diseases, and any infection, including TB is also well documented. It is usually accepted that this must be due to a general decline in immunocompetence. The elderly undergo changes in their immunity characterized by lack of

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Figure 4 Rates of tuberculosis mortality by age for successive birth cohorts. Source: From Ref. 12.

regulation in proinflammatory cytokines and enzymes that control the expression of inflammatory mediators and reactive oxygen species. Most of the work has been carried out on mice rather than humans. Workers have shown that cytokine expression, responsible for interferon (IFN) gamma transcription, from CD4þ T-cells, is affected by the aging process. It was found that supplementing the diet of aging mice with vitamin E restored this expression (15). Common mucosal immune responses are depressed in aged mice. Again dietary supplementation with the antioxidant vitamin E restored both the mucosal immune and the systemic humoral immune response to mature adult levels. This supports the hypothesis that some aspects of immunosenescence are due to dysregulations in cellular functions and are not due to any irreversible defects in cellular components of the immune system (16). In summary, cytokine dysregualtion, particularly of interleukin 2 and IFN

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Figure 5 Rates of tuberculosis by age for successive birth cohorts for males in Hong Kong. Source: From Ref. 13.

Figure 6 Tuberculin skin positivity by age in residents in homes for the elderly. Source: From Ref. 14.

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gamma, both important in host defense against TB, is likely to occur in the elderly, but is apparently reversible with dietary supplementation (17). V. Tuberculosis in Special Situations A. Homes for the Elderly

Many workers have found that the prevalence of TB among older people residing in homes for the elderly is several fold higher compared with those living at home. For example, the rate among whites in South Africa from a 1988 survey was 798/100,000, compared with 16/100,000 in the general population (18), while a survey in Hong Kong, China, in 1993 showed a rate of between 1200/100,000 and 2600/100,000 compared with a rate of between 100/100,000 and 400/100,000 in the general elderly population (19). Reasons for the higher prevalence include factors predisposing to reactivation of latent TB as well as the risk of cross-infection in an institutional environment (Fig. 7) (20). In contrast, other studies have shown no such increased risk (Fig. 8) (14,21). Many of the current cohorts of elderly people may have an acquired infection in their early years before effective treatment or bacille Calmette–Gue´rin vaccine was available, and it is thought that TB

Figure 7 Tuberculin skin test positivity by length of stay in homes for the elderly in Little Rock, Arkansas, United States. Source: From Ref. 20.

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Figure 8 Tuberculin skin test positivity by length of stay in homes for the elderly in Liverpool, England. Because skin test positivity declines with age (Fig. 6) and age increases with length of stay, statistical adjustment must be made. This is represented by the cross-symbols. Source: From Ref. 14.

in the majority of elderly people is a result of reactivation. With immunosenescence, comorbid illnesses such as diabetes mellitus, renal failure or malignancy, and poor nutrition, all of which are more commonly encountered in the old age–home setting, the risk of reactivation is increased. In view of the increased risk, surveillance is particularly important. Standard methods of screening include testing of skin reaction to a standard dose of purified protein derivative (PPD) of tuberculin [Mantoux test (MT)], sputum smear and culture, and chest X-ray. In many countries, the MT is accepted as a screening test, a positive result being an indication of treatment for latent infection (22). However, the usefulness of the MT may vary depending on the population prevalence of TB. Conversion of the skin test from negative to positive may be a better indicator of infection, and could be a useful screening test, if the overall prevalence is not high on entry to the home, as in certain countries such as the United States. Where the general population prevalence is already high, chest X-ray and sputum examination remain the currently cheapest available method for screening. Therefore, there are no standard recommendations for surveillance of TB in old age homes, owing to the wide variation in TB prevalence in different countries. Some recommend regular MT among old age–home residents, with more aggressive treatment of a positive skin test in spite of the higher incidence of hepatotoxicity caused by antituberculous drugs (23). On the other hand, surveillance among old age homes in Hong Kong consists of chest X-ray on entry and at regular intervals, and more intensive investigation for contacts of confirmed cases of TB.

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From the point of view of infection control, preventive measures would include avoidance of overcrowding, ensuring optimal nutrition and health status, adequate ventilation, and provision of some single rooms for isolation. VI. Clinical Presentation Although many papers have been published on the difference in clinical presentations of TB between young and older adults, none can be described as comprehensive or definitive. Often the number of patients studied is small and the cutoff point for age is arbitrary. There is often no clear definition of what constitutes a case. There is a general consensus that the presentation in the elderly is ‘‘atypical’’ without any definition of what is ‘‘typical.’’ The term ‘‘atypical’’ is in any case best avoided in connection with TB, because it may be confused with the term used for mycobacteria other than Mycobacterium tuberculosis or environmental mycobacteria. Across papers, there is often disagreement between the common ways of presentation. An early paper from Buffalo, New York, looked at only 27 patients aged 60 years or more (mean 70 years) compared with 52 aged under 60 years (mean 51 years) and found that fever, anorexia, weight loss, and cough on presentation of the two groups were equal, but breathlessness and hemoptysis were commoner in the older group. On radiography, cavitatory lesions and lower-lobe infiltrates were commoner (24). In a comparison, a paper looking at 37 younger (mean age 42 years) and 35 elderly men (24) from Japan found that cough, fever, and fatigue were seen in both groups, but weight loss and lower lung field crackles were more frequent in the older group. Radiographic changes were seen more commonly in the middle and lower lung fields of the elderly group. In a mass survey, the authors found that only 23% of older men had had TB diagnosed by clinical services prior to the survey compared with 54% in the younger group (25). A study from Taiwan looked at 52 younger (mean age 28.2 years) and 62 elderly patients (mean 73.5 years). Cough, malaise, and weigh loss occurred equally in the two groups, but fever was commoner in the younger. The elderly had more extensive radiological changes and pleural reactions. Underlying disease was more often present in the elderly. The tuberculin skin test was more likely to be falsely negative in the elderly (26). A study from Belgium in 72 elderly and 73 younger patients with the cutoff point at 60 years (mean ages not given) showed similar presentation of symptoms and radiology except that night sweats were commoner in the younger group and breathlessness in the older (27). A study from Leeds, United Kingdom, of 96 patients aged 65 years and older compared with 127 younger patients showed the elderly to have more frequent lower-zone shadowing and miliary disease. The older patients were six times more likely to die from their disease and 20 times more likely to have the diagnosis made at autopsy rather than during life (28). A study from Vancouver Canada, on 142 younger patients (mean 42 years) and 76 elderly (mean 75 years) with a cutoff point at 64 years, showed that fever hemoptysis cough and night sweats were all commoner in the younger group. Skin test

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results were more likely to be negative in the older group and radiographically, only miliary disease was commoner in the elderly (29). A report from Edinburgh confirms the presence of miliary diseases in the elderly being more common than in the young, particularly cryptic miliary disease. The authors point out that mortality in this group was 50%. Although not clearly defined, cryptic miliary is taken to mean the steady deterioration of a patient with weight loss and malaise without clear radiographic evidence of disease (30). A recent study from Singapore looked at sputum culture-positive patients with pulmonary TB, who received early treatment compared with those who received late treatment. The early treatment group were significantly younger and more likely to show cavitation on the chest radiograph. Although not highlighting the difference in presentation, this study supports the commonly held opinion that the diagnosis is often delayed in the elderly (31). In a study from Hong Kong, patients were divided into older and younger groups at the age of 65 years. Among the symptoms, the elderly had less frequent hemoptysis but more frequent nonspecific complaints. No difference was found in cough, fever, dyspnea, weight loss anorexia, malaise, or chest pain. Chest radiography showed more extensive infiltration of both lungs in the elderly. This paper examined the biochemistry of the patients, but only albumin showed a significant difference being lower in the elderly (32). In conclusion, there appears to be no consistent difference in the way TB presents in the elderly compared with younger adults, except that, radiographically, the elderly more commonly have lower-zone shadowing and miliary disease (Table 1). VII. Mortality A survey of 1312 adult patients notified with TB in England and Wales from October 1978 to March 1979 found that 163 (12%) had died before they completed chemotherapy. A stepwise multivariate analysis found that there was a significant association between mortality and radiographic extent of disease, age, extent of cavitation, and positive smear result. Among white males, only 1% of those aged 15 to 34 died compared with 51% of those aged 75 years or more (33). A survey of mortality from England and Wales from 1974 to 1987 found that at the end of the period, mortality in those aged 75 years and over was 32% compared with 14% in those aged 55 to 74 years, 4% in those aged 35 to 54 years, and 1% in those aged 15 to 34 years. However, in contrast, the survey showed a consistent reduction in mortality in the 75þ age group over the 18 years studied (34). This improvement was not maintained over the next five years. Overall mortality in the 75þ age group actually increased mainly as a result of an increase in mortality from nonrespiratory disease (35). The most recent study of this population suggests some improvement in mortality. Mortality in the 75þ age group was reduced to 27% by 2001,

No difference

No difference

Increased in young

Abbreviation: LZ, lower zone.

32

31

30

29

28

27

26

No No differdifference ence Increased Increased in elderly in young

25

No difference

Fever

No difference

Cough

24

Reference

No difference

No difference

No difference

Increased in young

Increased in young

Night sweat

Decrease No in elderly difference

Increased in young

Increased in elderly

No difference No difference Increased in elderly

Increased in elderly

Increased in elderly

No difference

No difference

No difference

Hemoptysis

Breathlessness

Weight loss

Anorexia/ malaise

Table 1 Clinical Presentation in the Elderly in Nine Separate Studies

Cavities LZ infiltrates LZ infiltrates

X-ray

LZ infiltrates: miliary Negative Miliary in elderly Miliary cryptic Cavity in young More extensive in elderly

Negative in elderly

Skin test

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whereas mortality in the other age groups has remained static (36). The high incidence of mortality with and from TB in the elderly is a common finding across the world. In a study from Geneva, of 1911 consecutive postmortem examinations in a geriatric population, active TB was found in 60 (3%). Of these, 37 (62%) with a mean age of 85 years were diagnosed at postmortem; the mean age of those diagnosed in life was 80 years (37). A study from Yugoslavia showed increased postmortem diagnosis in an older group (mean age 60 years) compared with a mean age of 49 for those diagnosed in life. There were increased risk factors including alcoholism in the former group (38). A retrospective study of 2088 TB patients in Birmingham, United Kingdom, showed a 3.6% mortality. The median age at death was 66 years. Case fatality was higher in Caucasians than Asians, only half of which could be explained by age. The authors conclude that delay in diagnosis is the main contributory factor to death. TB is likely to be missed most frequently in elderly Caucasians (39). A study of 4340 TB patients from the Netherlands showed a 7% mortality at one year. Age was an important independent determining factor for mortality. The adjusted hazard ratio was 10 (95%, CI 3.5–28) for the 45- to 64-year group and 45 (CI 17–124) for the 65þ years age group (40). In Ghana, 80 patients showed that mortality was strongly related to increased age (p < 0.001) (41). A study in Baltimore, Maryland, United States, showed 24% mortality among 174 patients. Patients who died were older (mean age 62 years) compared with a mean age for all patients of 47 years and were more likely to have underlying medical conditions. The unusually high mortality rate in this paper is not explained. All were sputum smear positive and, therefore, probably had extensive pulmonary disease, but many patients were suffering from other conditions, particularly diabetes mellitus and renal failure (42). There is no doubt that the elderly have a considerably increased mortality for TB, even in the absence of other medical conditions. A mortality of 30% in those over the age of 70 years and perhaps 50% in those over the age of 80 appears to be common. Delay in diagnosis and more extensive disease or both are frequently cited as contributing. Miliary and disseminate disease is also more common in the elderly. VIII. Human Immunodeficiency Virus Infection The impact of the age-related decline in immunity upon the risk of reactivation of latent TB and upon the risk of progression to active disease in recently infected elderly individuals is discussed above. Infection with the human immunodeficiency virus (HIV) is likely to have an even greater influence upon such risks, and the rise in rates of HIV infection globally is having an ever-increasing effect upon TB rates worldwide (Chapter 13). The mortality associated with HIV/AIDS is such that HIV-infected individuals usually die before reaching old age. Only those elderly people who acquired the infection relatively recently will still be alive, and thus individuals with HIV/AIDS are uncommon in older populations. This

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low prevalence leads to delays in the diagnosis of HIV infection in the elderly (43,44). At least in developed countries, however, this situation is likely to change: the prevalence of HIV infection is increasing, the elderly represent a higher proportion of the population, and the availability of an effective antiretroviral treatment is prolonging the survival in HIV-infected individuals. Accordingly, clinicians are likely to encounter increasing number of cases of HIV/TB coinfection in the elderly (45). Laszlo et al. report successful treatment of disseminated TB in the presence of AIDS in an 81-year-old woman (46). Initial treatment with rifampicin, isoniazid, pyrazinamide, and ethambutol was followed by continuation phase rifampicin and isoniazid, and at this stage antiretroviral therapy was introduced. The authors comment that the TB/HIV combination therapy was well tolerated without significant side effects, and that the individual’s quality of life was good. Although there are indeed problems of increased drug toxicity in the elderly (see above), there is rapidly increasing experience of treatment of both HIV/TB coinfection and HIV infection in the elderly (47). Once the diagnosis is established, elderly patients should (where resources permit) be treated with antituberculous and antiretroviral medication in the same way as younger patients (Chapter 13). IX. Diagnosis In theory, making a diagnosis of TB in an elderly patient should follow exactly the same pathway as for a younger individual. A suggestive clinical history or findings on examination should lead to appropriate further investigations and establishment of the diagnosis, ideally with microbiological confirmation. In practice, matters may not be so straightforward. The difficulties in making a diagnosis of TB in an elderly patient are of several kinds. Studies of clinical presentations of the disease in the elderly (as discussed above) shows that there are few consistently observed differences between old and young, but at least some studies suggest fever and night sweats are less common in the elderly, while no studies suggest they are more common. Comorbid conditions are present far more frequently in the elderly than in the young; therefore, when symptoms such as cough and weight loss occur in an older person, they may more readily be attributed to these other conditions than to TB. As with the clinical features of TB, there is conflicting information (discussed above) about its radiological manifestations in the old versus the young. Where differences do seem to be indicated, they are in the direction of TB in the elderly having radiological changes that are less characteristic of TB. The tuberculin skin test is undoubtedly less helpful in the old than the young, and disseminated disease is more common. Finally, the age of the patient and the presence of other significant medical conditions will increase the risks associated with invasive diagnostic procedures such as bronchoscopy, mediastinoscopy, and other biopsies. This is perhaps not so much of a problem if the diagnosis is already strongly

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suspected: TB therapy can be given empirically. The real danger lies in the presumption that the elderly patient has another condition, usually malignant, and if their frailty is felt to preclude invasive sampling, the correct (and curable) condition of TB may be missed. Mortality from TB in the elderly will always be higher than in the young. The key to reducing rates toward those of the young lies in establishing the diagnosis earlier—too often it is made only after death, and with declining rates of postmortem examination in most countries, many cases (and probably increasing numbers of cases) are not being diagnosed at all. Even where the diagnosis is made before death, delay increases the chances of mortality and of spread to others. Clinicians responsible for the care of such individuals need to maintain a high index of suspicion for TB in any elderly patient with unexplained illness, and an awareness that ‘‘classic’’ symptoms, signs, and results of investigations are, on average, less likely to be present than in the young. In the presence of a continuing unexplained decline, it is sometimes appropriate to commence treatment even when the diagnosis is not confirmed and when such confirmation will not be forthcoming. X. Treatment A. Drug Toxicity

In general, adverse reactions to drugs increase with age as a result of agerelated physiological changes and the coexistence of many diseases requiring multiple drug therapy. This observation applies to antituberculous drugs, causing particularly isoniazid-induced hepatitis (48) and fatal fulminant hepatic necrosis. Pharmacokinetic Changes with Age

Isoniazid, rifampicin, pyrazinamide, and ethambutol are predominantly metabolized by the liver (49). Hepatic volume and blood flow decrease with age (50), and the rate of hepatic metabolism may be reduced for certain drugs (51,52). There are few studies on the effect of age on the pharmacokinetics of antituberculous drugs, and most studies are of single drugs in isolation in healthy elderly individuals. For isoniazid, the acetylator phenotype and half-life were not affected by age in one study (53), whereas in another study, a positive correlation was found between age and plasma isoniazid concentrations when corrected for sex and weight (54). No age-related changes in the pharmacokinetics of isoniazid given alone were observed in three studies (55–57). One study of rifampicin given alone did not show any difference in pharmacokinetic parameters between six elderly individuals and younger subjects (58). There are no reports on the influence of age on pharmacokinetic parameters for pyrazinamide or ethambutol given as a single drug in healthy elderly individuals. Only one study examined the effect of age on pharmacokinetic parameters of antituberculous drugs given in combination in hospitalized patients with tuberculosis (59). No differences in parameters

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for isoniazid, rifampicin, or pyrazinamide were observed with initial dosing. However, one month after therapy, the clearances for isoniazid and rifampicin at steady state among subjects aged 65 years and over were significantly lower compared to that at first dose, suggesting an interaction between the drugs. In this study, elevations in serum liver enzyme levels and other side effects were more common among these patients compared with younger patients. Protein Binding

Another factor that may affect the disposition of antituberculous drugs in elderly patients is protein binding. In general, acidic drugs bind to albumin, whereas basic drugs bind to a1-acid glycoprotein, although there are exceptions (60). In the elderly, chronic diseases or malnutrition result in lower serum albumin concentrations (61), whereas a1-acid glycoprotein increases with age (62). Therefore the free-drug concentration of acidic drugs may rise, whereas that of basic drugs may fall with age (63,64). In healthy individuals, isoniazid is little bound to serum proteins, while the percentage bindings for rifampicin and ethambutol are quoted as 57% to 80% and 6% to 30%, respectively (49). No protein binding data are available for pyrazinamide. The effect of age on the protein binding of antituberculous drugs has not been reported. Therefore in spite of the similar pharmacokinetic profile between young and elderly subjects described in the previous studies, there may still be a difference if free-drug concentration was determined. Although the relationship between free-drug concentration and toxicity or bactericidal effect has not been established, it is important to address this issue because dosage adjustment may be indicated with a view to minimizing toxicity. For example, in the study by Walubo et al. (59), patients aged 65 years and over have lower serum albumin concentrations compared with those below 65 years, and although the plasma drug concentrations were the same in both groups, more side effects were noted in the elderly group. It is possible that the free-drug concentrations were higher in the elderly group. Studies of the influence of age and disease on the percentage binding antituberculous drugs to individual serum proteins and the relationship of free-drug concentrations to toxicity are needed to clarify these issues. Toxic Metabolites

The role of potentially toxic metabolites of antituberculous drugs in contributing to the age-related increase in incidence of adverse effects is largely unexplored. Hepatotoxicity increases with age (64,65), even in those with no previous liver disease. However, it is unclear whether isoniazid, rifampicin, or metabolites of these drugs are responsible. Isoniazid is metabolized to isonicotinic acid either by direct hydrolysis or indirectly via acetylation to acetyl isoniazid and then hydrolysis. In the direct pathway, a metabolite hydrazine is formed, whereas in the indirect pathway, monoacetylhydrazine is formed. Both metabolites are hepatotoxic. The plasma half-life of monoacetylhydrazine is five times longer than that of isoniazid, resulting in greater accumulation following repeated doses (66). Rapid acetylators

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may be expected to have a greater incidence of hepatotoxicity because more monoacetylhydrazine will be formed; however, in these subjects, monoacetylhydrazine will also be more quickly acetylated to the less-toxic diacetylhydrazine, so that the risk of hepatic reaction during treatment with isoniazid is no greater in rapid than slow acetylators (66). Hydrazine is a potent hepatotoxin and also affects many metabolic processes in the body (67). The age-related reduction in acetylation rate (56) may result in a greater proportion of isoniazid being metabolized to hydrazine, particularly in slow acetylator phenotypes. Hydrazine has been detected in plasma of healthy male volunteers taking isoniazid 300 mg daily for two weeks (68). In patients on antituberculous therapy consisting of similar dosages of isoniazid, rifampicin, pyrazinamide, and ethambutol per kg body weight, the maximum concentration of hydrazine after the first dose was significantly higher in the elderly than in the young (69). The steady-state hydrazine concentration in one subject aged 72 years, who died of submassive liver necrosis eight days after initiation of antituberculous therapy, exceeded twice the mean
SD value for the group of elderly patients who did not develop hepatotoxicity (70). Drug Combination

The concomitant administration of several drugs may predispose to increased incidence of adverse side effects. It has been suggested that concomitant administration of rifampicin and isoniazid may produce more hepatotoxicity than isoniazid alone (71,72). Metabolic induction by rifampicin may result in increased production of hepatotoxic metabolites of isoniazid. However, pretreatment with rifampicin did not modify the metabolism of acetylisoniazid (73). On the other hand, it has been suggested that concomitant administration of rifampicin and isoniazid may result in increased levels of hydrazine, particularly among slow acetylators (74). It has been postulated that an age-related difference in the hepatic microsomal drug detoxification system may account for the high incidence of isoniazid–rifampicin-induced jaundice in children (72). By analogy, a similar change could also occur in the elderly, so that concomitant administration of rifampicin and isoniazid may partly account for the increased occurrence of hepatotoxicity in the elderly. However, randomized trials comparing two anti-TB chemotherapy regimens with or without rifampicin showed no difference in the incidence of symptomatic adverse reactions, but treatment was not satisfactory in some patients without rifampicin (75). Nonpharmacological Factors

Other nonpharmacological factors in the elderly may predispose to toxicity from antituberculous drugs. TB commonly presents in an advanced state in the elderly due to atypical presentation and difficulty in diagnosis (64), so that miliary TB, for example, is more common among older people (76). Therefore, there may be a higher probability of liver involvement by mycobacteria, predisposing to hepatotoxicity, even in the absence of chronic liver

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disease or alcoholism. Poor nutritional status may be another predisposing factor, particularly in the presence of infection. Drug metabolism and toxicity is affected by dietary intake (77). Thus the higher incidence of hepatotoxicity (3–22%) in patients in India compared to those in the United States (2–3%) may partly be explained by poor nutrition (77). Conclusion

In the treatment of TB in the elderly, the following factors should be considered in an effort to avoid toxicity: consideration of free-drug concentrations, disposition of potentially toxic metabolites, drug combinations, nutritional status, and hepatic involvement by the disease process. Available data on treatment regimens and adverse reactions may not apply to the sick elderly. Further studies on the above aspects are needed to determine whether dosage should be adjusted according to factors other than body weight, and whether the present combination therapy might be altered, with the omission of one of the potentially hepatotoxic drugs without affecting bactericidal activity or recurrence rate. Clinicians should also be more aware of these serious adverse effects, monitor such patients closely, and provide nutritional support if necessary. Moreover, cases of hepatotoxicity in the sick elderly were not mild transient biochemical abnormalities that permit continuation of drugs (66). As the absolute number of old people increases, together with the increasing incidence of TB in the elderly, such problems are likely to be encountered with increasing frequency. With further studies, more definite guidelines should be available on the use of antituberculous drugs in elderly patients, with a view to reducing adverse effects, particularly hepatotoxicity. XI. Preventive Therapy In the prevention of TB in older people, as well as general measures such as poverty reduction and provision of adequate health care, preventive therapy using antituberculous drugs has been advocated, because most cases arise as a consequence of reactivation of latent infection. It is thought that the treatment of latent infection would reduce the likelihood of active disease developing. The general principle is that persons who are at increased risk of TB would benefit, and therefore they should undergo tuberculin skin testing, and be given preventive therapy if the result is positive. Those screened in this way usually fall into the following categories: those with increased risk of exposure to infectious cases (recent close contact with known cases), those with increased risk of disease (from countries with high prevalence, those living in long-term care institutions, and the homeless), and those with increased risk of disease once infection has occurred (with HIV or on immunosuppressive therapy, end-stage renal disease, diabetes, silicosis, cancer, and malnutrition). The standard tuberculin test consists of 0.1 mL (five tuberculin units) of PPD administered intracutaneously in the volar aspect of the forearm.

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The size of the indurated area is read 48 to 72 hours later. A diameter of 5 mm or more is considered positive for those with close contact with infected subjects, those with HIV, those with abnormal chest radiograph consistent with previous TB (fibrotic capacities > 2 cm2 of the upper lobe), or immunosuppressed subjects on 15 mg prednisolone or more daily for one month or more. A diameter of 10 mm or more is considered positive for those living in institutions, the homeless, those with comorbidities listed above, foreign-born persons recently arrived (less than five year earlier) from a country with a high prevalence of TB, and those with conversion on a tuberculin skin test (increase in induration of 10 mm or more within a two-year period). Newer blood tests based on the release of IFN gamma from T-lymphocytes in response to stimulation with M. tuberculosis PPD or the secreted antigen ESAT-6 are being developed. The diagnosis of latent TB infection requires that active TB be ruled out, before chemotherapy for latent infection is started. Preventive treatment regimens recommended are isoniazid (5 mg/kg body weight; maximum 300 mg) daily or 900 mg twice weekly for six to nine months and has been shown to reduce the incidence by 25% to 92% compared with placebo. The possibility of increased risk of hepatitis in the elderly remains a concern. Another regimen consists of rifampicin (10 mg/kg; maximum 600 mg) and isoniazid in combination for three or four months. Other regimens consisting of rifampicin for four months or a combination of rifampicin (5 mg/kg; maximum 300 mg) and pyrazinamide (15–20 mg/kg; maximum 2000 mg) cannot be recommended. Monitoring of liver enzymes is considered necessary by some. Other workers believe in clinical monitoring, encouraging the patient to report adverse effects because they occur to be sufficient. The existence of resistant organisms would also need to be considered in the choice of therapy. In general, the incidence of adverse effects from preventive therapy in the elderly will outweigh the potential benefit of disease prevention (78). It is well known that isoniazid and rifampicin may be hepatotoxic. Indeed, isoniazid prophylaxis for those over 35 years old is contraindicated due to the possibility of hepatic necrosis (79,80). In patients with TB, the risks are low among the current regiments in use (80) The majority of patients in studies of drug toxicity are middle aged (79), reflecting the higher incidence of TB in this age group in the last decade. However, in Hong Kong, despite the falling overall incidence of TB, the incidence of TB among the elderly has been rising (81). Thus the incidence and nature of adverse reaction described in the literature may not apply to this group of patients. We report an adverse reaction in an elderly woman, unusual both in its severity and the rapidity with which it caused death. XII. Case Reports A. Fatal Acute Hepatitis

An 85-year-old Chinese female presented with vague chest discomfort unrelated to exercise. Her exercise tolerance was five to six flights, and she did

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not have angina. She smoked one packet of cigarettes per day for 30 years. Five years before presentation, she had one episode of hemoptysis for which no cause was found. She lived with several members of her family, one of whom is a registered nurse, and was independent in all her activities of daily living. Examination showed a fit looking, although thin, woman weighing 30.3 kg. Apart from mild deafness and bilateral early cataracts, there were no other abnormalities. An electrocardiogram showed left bundle branch block. Chest X-ray showed soft shadows in the right upper zone and left apical pleural thickening. Sputum showed acid-fast bacille (AFB) on Ziehl–Neelsen (ZN) stain. The complete blood picture, renal, and liver functions were normal. Isoniazid (10 mg/kg), rifampicin (15 mg/kg), and ethambutol (25 mg/kg) were given daily. Two days later, the patient complained of general malaise and nausea in the immediate period after taking the drugs. The temperature, pulse, and blood pressure were normal. She was advised to take the three drugs separately during the day, in order to reduce the number of tablets that she had to swallow at any one time. Seven days later, the patient became worse and vomited the rifampicin capsules each time. On examination, she was apyrexic. The blood pressure had fallen from the previous value of 160/80 to 110/60, and the pulse was 100/min. The patient was also sweaty, and the blood glucose was found to be 1.0 mmol/L. Twenty milliliter of 50% glucose was given intravenously, and all the antituberculous drugs were stopped. One day after the drugs were discontinued, the patient became less alert and was noted to be jaundiced. Investigations showed that she had renal and liver function impairment, hypoglycemia, and a metabolic acidosis. The hypoglycemia required a continuous 10% dextrose infusion. Despite all supportive measures, the patient became comatose soon after admission, and died the next day. At postmortem, the pertinent macroscopic findings were limited to the lungs and liver. In each pleural cavity, 100 mL of bloodstained fluid was present. The lungs showed scattered pleural thickening as well as edema, emphysema, and a soft, 2.7-cm nodule in the apical portion of the right upper lobe. The liver appeared much softer, smaller, and paler than normal. Microscopy confirmed active pulmonary TB and extensive necrosis of liver cells, primarily mid-zonal in distribution with early confluence, indicative of acute submassive hepatic necrosis. There were numerous acidophilic (Councilman) bodies. There was a striking paucity of inflammatory cells associated with the extensive necrosis. Orcein stain was negative for hepatitis B viral antigen. There was no evidence of preexisting (chronic) hepatic disease. Discussion

Asymptomatic elevation of transaminases during isoniazid and rifampicin is well documented, occurring in one-fifth of all patients, and may return to normal even if treatment is continued (82). If jaundice occurs, the liver

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function tests quickly improve on cessation of the offending drug. The risk of overt hepatitis caused or exacerbated by isoniazid for those aged 55 years or more is estimated to be 7.7 per 1000 in those taking isoniazid for a full year (82). The mortality from hepatitis in one large series was 0.09%, and massive hepatic necrosis was seen in 0.03% of patients (79). There is no evidence to suggest that hepatotoxicity is increased in regimens containing both rifampicin and isoniazid (82). Thus, it is likely that the drug responsible for hepatic necrosis in this patient is isoniazid. The histopathology of isoniazid liver injury can range from acute hepatocellular damage resembling typical viral hepatitis to submassive and massive necrosis. The inflammatory response consists mainly of lymphocytes and plasma cells with relatively few eosinophils and neutrophils. Cholestasis can occur alone or as an associated feature. Some patients may show features of chronic hepatic injury with bridging necrosis, disruption of limiting plates, and fibrosis as in active hepatitis. Finally, cirrhosis can occur as a late event. The histological findings in our patient also fit into the above picture, and, typically, there are not many polymorphs and eosinophils. Although serum was not examined for the presence of hepatitis B surface antigen, orcein stain for viral antigen was negative. Moreover, if the presence of hepatitis B virus did contribute to the development of hepatic necrosis, one would expect to have an increased incidence of adverse effects to isoniazid in Southeast Asia, because the prevalence of hepatitis B surface antigenemia is about 10%. However, this has not been observed. This case possesses certain unusual features; previous observations suggest that most patients who became ill within the first eight weeks of therapy had milder and usually nonfatal disease (79). Such a rapid progression and fulminant course in a patient with no preexisting liver disease had not been reported in the literature. The first sign of a potentially serious adverse reaction was hypoglycemia, indicating severe liver failure even before the usual sign of jaundice, so that withdrawal of isoniazid was already too late. Isoniazid hepatotoxicity may be due to a hypersensitivity reaction. The evidence for and against such a reaction is conflicting (80). It has also been suggested that the mechanism of hepatotoxicity is a dose-related phenomenon. The agent responsible for hepatotoxicity is thought to be monoacetyl hydrazine, a product of acetylation and the hydrolysis of isoniazid. It was thought that Orientals, who have a higher proportion of fast acetylators, may have higher incidence of hepatotoxicity (79). However, this theory is untenable because fast acetylators convert monoacetyl hydrazine more rapidly to a nontoxic product, diacetyl hydrazine (83). This is borne out by the clinical observation that the incidence of hepatitis is the same in both fast and slow acetylators (84). It is known that the relative risk of developing isoniazid hepatotoxicity increases as a function of age (85), and, yet, there is no significant

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difference in pharmacokinetic parameters between young and elderly of the same acetylator phenotype (86). Therefore, the increased risk may be explained by possible increased binding of monoacetyl hydrazine to liver cells in the elderly or increased susceptibility of liver cells to the effect of monoacetyl hydrazine. Further experiments in aged animals and clinical surveys of adverse effects in the elderly population appear warranted. B. A 76-Year-Old Bangladeshi Man

A 76-year-old Bangladeshi man was admitted to hospital. Over the course of four months, he had weight loss and progressive weakness, and was now confined to bed. In the two weeks before admission, he had become confused. There was no history of cough, fevers, or sweats. He had been resident in the United Kingdom for 18 years, was a nonsmoker, had no significant past medical history, and had been fit and active until this present illness. On admission, he had a body mass index of 15.6 (weight 40 kg, height 1.60 m). Apart from this cachexia and his mild confusion, no abnormality was apparent on examination of the abdomen or of the cardiovascular, respiratory, and central nervous systems. His chest X-ray was normal. Laboratory investigations showed a normocytic anemia (Hb 9.0 g/dL) and normal white blood count (4.6  10), and erythrocyte sedimentation rate and C-reactive protein only slightly raised for age (35 mm/hr and 15 mg/dL, respectively). There was renal impairment (blood urea 16.6 mmol/L and serum creatinine 170 mol/L), and predominantly hepatocellular liver dysfunction: bilirubin 24 mmol/L (0–19 mmol), alkaline phosphatase 177 IU/L (35–125 IU/L), alanine aminotransferase 255 IU/L (<50 IU/L), aspartate aminotransferase 312 IU/L (<35 IU/L), gamma-glutamyl transpeptidase 160 IU/L (<50 IU/L). Serum albumin was low at 22 g/dL. Tuberculin skin testing (Heaf) was unreactive. On observation after admission, he was apyrexic, but it became apparent that he was abnormally breathless, and arterial blood gases confirmed hypoxia (PaO2 8.5 kPa; PaCO2 4.4 kPa). Electrocardiogram was normal, and echocardiography showed only mildly impaired left ventricular dysfunction. He was too frail to cooperate with formal respiratory function testing. In view of the unexplained hypoxia, he underwent computed tomographic pulmonary angiography and high-resolution computed tomographic (HRCT) scanning. There was no evidence of thromboembolic disease, but innumerable small nodules were apparent on HRCT, and there was a diffuse parenchymal abnormality of the liver. Review of the chest X-ray confirmed that no abnormality could be seen. A percutaneous liver biopsy was performed. Histological examination showed multiple granulomata with central necrosis, highly suggestive of TB. He was started on antituberculous medication with rifampicin, isoniazid, ethambutol, and pyrazinamide, and cultures from the liver biopsy subsequently confirmed fully sensitive M. tuberculosis. He made a slow but steady recovery to normal health.

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Apart from the weight loss, there were no features in the clinical presentation suggestive of TB, and, in particular, there was no fever, no sweats, and a negative tuberculin skin test, and the chest X-ray was normal. This case is thus not one of classic miliary TB (miliary shadowing was absent on the chest X-ray) but rather of cryptic disseminated TB. Such presentations are not confined to the elderly, but are commoner than in the young (29,30). It is particularly important that the negative tuberculin test is not regarded by clinicians as precluding a diagnosis of TB. It is negative in a significant proportion of cases of active disease even in the young (87) and skin test positivity rates decline in the elderly (14,88). In this case, despite the paucity of findings on clinical examination, there were clear indications of multiorgan involvement by a disease process: abnormalities of liver biochemistry, abnormal renal function, and unexplained hypoxia. Appropriate imaging followed by an invasive diagnostic test allowed the diagnosis to be established, with a very satisfactory clinical outcome. XIII. Conclusions TB in the elderly is an increasing problem in the developed world and in some parts of the developing world. It requires a high index of suspicion for the diagnosis because presentation may often be uncharacteristic. Care must be taken during therapy because adverse events are much more frequent than in the younger patient, and a change of therapy may be required. The mortality in the elderly remains high, some of which is probably due to late diagnosis, and this could be improved if awareness of a possible diagnosis could be made more widely known. References 1. http://www.censusscope.org/us/chart_age.html (accessed 28/7/04, no date for update). 2. http://www.statistics.gov.uk/cci/nugget.asp?id¼763 (updated 24/6/04, accessed 28/ 7/04). 3. http://www.stats.govt.nz/domino/external/web/prod_serv.nsf/0/ce9f1956abbe70f3 cc256d4e007370a1?OpenDocument (accessed 28/7/04). 4. Davies PDO. The increase in tuberculosis. Ann Med 2003; 35:235–243. 5. Reider HL. Epidemiology of tuberculosis in Europe. Eur Resp J 1995; 20(suppl 8): 205–325. 6. Sudre P, ten Dam G, Kochi A. Tuberculosis: a global overview of the situation today. Bull World Health Org 1992; 70:149–159. 7. Rose AMC, Watson JM, Graham C, et al. Tuberculosis at the end of the 20th century in England and Wales: results of a national survey in 1998. Thorax 2001; 56:173–179. 8. Springett VH. An interpretation of statistical trends in tuberculosis. Lancet 1952; 1:521–525. 9. Medical Research Council. Cardiothoracic Epidemiology Group. National survey of notifications of tuberculosis in England and Wales in 1988. Thorax 1992; 47:770–775.

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10. Andvord KF. What can we learn by studying tuberculosis by generations? 1930 Norsk Mag. Laegevidensk 1930; 91:642–660. 11. Frost WH. Age selection of mortality from tuberculosis in successive decades. Am J Hyg 1939; A30:91–96. 12. Springett VH. A comparative study of tuberculosis mortality rates. J Hyg 1950; 48:361–395. 13. Tocque K, Bellis MA, Tam CM, et al. Long-term trends in tuberculosis: comparison of age-cohort data in Hong Kong and England and Wales. Am J Resp Crit Care Med 1998; 158:484–488. 14. Nisar M, Williams CSD, Ashby D, Davies PDO. Tuberculin screening of residential homes for the elderly. Thorax 1993; 48:1257–1260. 15. Daynes RA, Enioutina EY, Jones DC. Role of redox imbalance in the molecular mechanisms responsible for immunosenescence. Antioxid Redox Signal 2003; 5:537–548. 16. Enioutina EY, Visic VD, Daynes RA. Enhancement of common mucosal immunity in aged mice following their supplementation with various antioxidants. Vaccine 2000; 18:2381–2393. 17. Jones DC, Manning BM, Daynes RA. A role for the peroxisome proliferationactivated receptor alpha in T-cell physiology and ageing immunology. Proc Nutr Soc 2002; 61:363–369. 18. Morris CD, Nell H. Epidemic of pulmonary tuberculosis in geriatric homes. S Afr Med J 1989; 75:197. 19. Woo J, Chan HS, Hazlett CB, et al. Tuberculosis among elderly Chinese in residential homes: tuberculin reactivity and estimated prevalence. Gerontology 1996; 42:155–162. 20. Stead WW, Lofgren JP, Warren E, Thomas C. Tuberculosis as an endemic and nosocomial infection among the elderly in nursing homes. N Eng J Med 1985; 312:1483– 1487. 21. Perez-stable EJ, Flaherty D, Schecter G, Slutkin G, Hopewell PC. Conversion and reversion of tubrculin reactions in nursing home residents. Am Rev Respir Dis 1988; 137:801–804. 22. Yoshikawa TT. Tuberculosis in aging adults. J Am Geriatr Soc 1992; 40:178–187. 23. Zevallos M, Justman JE. Tuberculosis in the elderly. Clin Geriatr Med 2003; 19(1):121–138. 24. Katz PR, Reichman W, Dube D, Feather J. Clinical features of pulmonary tuberculosis in young and old veterans. J Am Geriatr Soc 1987; 35:512–515. 25. Umeki S. Comparison of younger and elderly patients with pulmonary tuberculosis. Respiration 1989; 55:75–83. 26. Tsai S-Y, Huang M-S, Hwang J-J, et al. Comparison of pulmonary tuberculosis in younger and elderly patients. Kaohsiung J Med Sci 1991; 7:107–114. 27. Van den Brande P, Demetdts M. Pulmonary tuberculosis in the elderly: diagnostic difficulties. Eur J Med 1992; 14:224–229. 28. Teale C, Goldman JM, Pearson SB. The association of age with presentation and outcome of tuberculosis: a five-year survey. Age Aging 1993; 22:289–293. 29. Korzeniewska-Kosela M, Krysl J, Muller N, Black W, Allen E, FitzGerald JM. Chest 1994; 106:28–32. 30. Sime PJ, Chilvers ER, Leitch AG. Miliary tuberculosis in Edinburgh—A comparison between 1984–1992 and 1954–1987. Respir Med 1994; 88:609–611. 31. Chin NK, Kumarashinge G, Lim TK. Efficacy and the conventional diagnostic approach to pulmonary tuberculosis. Singapore Med J 1998; 39:241–245. 32. Chan CHS, Woo J, Or KKH, Chan RCY, Cheung W. The effect of age on the presentation of patients with tuberculosis. Tuberc Lung Dis 1995; 76:290–294.

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33. Humphries MJ, Byfield SP, Darbyshire J, et al. Deaths occurring in newly notified patients with pulmonary tuberculosis in England and Wales. Br J Dis Chest 1984; 78:149–158. 34. Nisar M, Davies PDO. Current trends in mortality from tuberculosis in England and Wales. Thorax 1991; 46:438–440. 35. Doherty MJ, Spence DPS, Davies PDO. Trends in tuberculosis in England and Wales: the proportion of deaths from non-respiratory disease is increasing in the elderly. Thorax 1995; 50:976–979. 36. Martineau A, Lowey H, Tocque K, Davies PDO. Case fatality from tuberculosis by age and site in England and Wales. Int J Tuberc Lung Dis 2004; 8:732–742. 37. MacGee W. The frequency of unsuspected tuberculosis found post-mortem in a geriatric population. Z Gerontol 1989; 22:311–314. 38. Zafran N, Heldal E, Pavlovic S, Vuckovic D, Boe J. Why do our patients die of active tuberculosis in the era of effective chemotherapy? Tuberc Lung Dis 1994; 75:329– 333. 39. Bakhshi SS, Hawker J, Ali S. Tuberculosis mortality in notified cases from 1989– 1995 in Birmingham. Publ Health 1988; 112:165–168. 40. Borgdoff MW, Veen J, Kalisvaart NA, Nagelkerke N. Mortality among tuberculosis patients in the Netherlands in the period 1993–1995. Eur Respir J 1998; 11: 816–820. 41. Lawn SD, Acheampong JW. Pulmonary tuberculosis in adults: factors associated with mortality at a Ghanaian teaching hospital. West Afr J Med 1999; 18: 270–274. 42. Fielder JF, Chaulk CP, Dalvi M, Gachuhi R, Comstock GW, Sterling TR. A high tuberculosis case-fatality rate in a setting of effective tuberculosis control: implications for an acceptable treatment success rates. Int J Tuberc Lung Dis 2002; 6:1114–1117. 43. Wallace JI, Paauw DS, Spach DH. HIV infection in older patients: when to suspect the unexpected. Geriatrics 1993; 48:61–70. 44. Newcomer VD. Human immunodeficiency virus infection and acquired immunodeficiency syndrome in the elderly. Arch Dermatol 1997; 133:1311–1312. 45. Manfredo R. HIV infection and advanced age: emerging epidemiological, clinical and management issues. Ageing Res Rev 2004; 3:31–54. 46. Laszlo A, Gianelli S, Laurencet F, Krause KH, Janssens JP. Successful treatment of disseminated tuberculosis and acquired immunodeficiency syndrome in an 81-yr-old woman. Scand J Infect Dis 2003; 35:420–422. 47. Gebo KA, Moore RD. Treatment of HIV infection in the older patient. Expert Rev Anti Infect Ther 2004; 2:733–743. 48. Mackay AD, Cole RB. The problems of tuberculosis in the elderly. Q J Med 1984; 212:497–510. 49. Holdiness MR. Clinical pharmacokinetics of the antituberculous drugs. Clin Pharmacokinet 1984; 9:511–544. 50. Wynne HA, Cope LH, Mutch E, Rawlins MD, Woodhouse KW, James OF. The effect of age upon liver volume and apparent liver blood flow in healthy men. Hepatology 1989; 9:297–301. 51. Bach B, Hausen JM, Kampmann JP, Rasmussen SN, Skovsted L. Disposition of antipyrine and phenytoin correlated with age and liver volume in man. Clin Pharmacokinet 1981; 6:389–396. 52. Castleden CM, George CF. The effect of ageing on the hepatic clearance of propranolol. Br J Clin Pharmacol 1979; 7:49–54. 53. Weber WW, Hein DW. Clinical pharmacokinetics of isoniazid. Clin Pharmacokinet 1979; 4:401–422.

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54. Iselius L, Evans DA. Formal genetics of isoniazid metabolism in man. Clin Pharmacokinet 1983; 8:541–544. 55. Advenier C, Saint-Aubin A, Gorbert C, Houin G, Albengres E, Tillement JP. Pharmacokinetics of isoniazid in the elderly. Br J Clin Pharmacol 1980; 10: 167–168. 56. Kergueris MF, Bourin M, Larousse C. Pharmacokinetics of isoniazid: influence of age. Eur J Clin Pharmacol 1986; 30:335–340. 57. Paulsen O, Nilsson LG. Distribution of acetylator phenotype in relation to age and sex in Swedish patients. Eur J Clin Pharmacol 1985; 28:311–315. 58. Advenier C, Gobert C, Houin G, Bidet D, Richelet S, Tillement JP. Pharmacokinetics studies of rifampicin in the elderly. Ther Drug Monit 1983; 5:61–65. 59. Walubo A, Chan K, Woo J, Chan HS, Wong CL. The disposition of antituberculous drugs in plasma of elderly patients. II. Isoniazid, rifampicin and pyrazinamide. Methods Find Exp Clin Pharmacol 1991; 13:551–556. 60. Kremer JMH, Wilting J, Janssen LHM. Drug binding to human alpha-1-acid glycoprotein in health and disease. Pharmacol Rev 1988; 40:1–47. 61. Woodford-Williams E, Alvarez AS, Webster D, Landless B, Dixon MP. Serum protein patterns in ‘‘normal’’ and pathological ageing. Gerontologia 1964; 10:86–99. 62. Verbeek RK, Cardinal JA, Wallace SM. Effect of age and sex on the plasma binding of acidic and basic drugs. Eur J Clin Pharmacol 1984; 24:91–97. 63. Upton RA, Williams RL, Kelly J, Jones RM. Naproxen pharmacokinetics in the elderly. Br J Clin Pharmacol 1984; 18:207–214. 64. Umeki S. Age-related changes in the manifestations of tuberculosis. Implications for drug therapy. Drugs Aging 1991; 1:440–457. 65. Riska N. Hepatitis cases in isoniazid treated group and in a control group. Bull Int Union Tuberc 1976; 51:203–208. 66. Gangadharam PRJ. Isoniazid, rifampicin and hepatotoxicity. Am Rev Resp Dis 1986; 133:963–965. 67. Back KC, Thomas AA. Aerospace pharmacology and toxicology. Ann Rev Pharmacol 1970; 10:396–397. 68. Blair LA, Tinoco RM, Brodie MJ, et al. Plasma hydrazine concentrations in man after isoniazid and hydralazine administration. Human Toxicol 1985; 4:195–202. 69. Walubo A, Chan K, Woo J, Chan HS, Wong CL. The disposition of antituberculous drugs in plasma of elderly patients. I. Isoniazid and hydrazine metabolite. Methods Find Exp Clin Pharmacol 1991; 13:545–550. 70. Woo J, Chan HS, Walubo A, Chan K. Hydrazine: a possible cause of isoniazidinduced hepatic necrosis. J Med 1992; 23:51–59. 71. Lees AW, Allan GW, Smith J, Tyrrell WF, Fallon RJ. Toxicity of rifampicin plus isoniazid and rifampicin plus ethambutol therapy. Tubercle 1971; 52:182–190. 72. Centers for Disease Control. Adverse drug reactions among children treated for tuberculosis. MMWR 1980; 29:589–591. 73. Jenner PJ, Ellard GA. Isoniazid-related hepatotoxicity: a study of the effect of rifampicin administration on the metabolism of acetylisoniazid in man. Tubercle 1989; 70:93–101. 74. Sarma GR, Immanuel C, Kailasam S, Narayana ASL, Venkatesan P. Rifampininduced release of hydrazine from isoniazid. Am Rev Respir Dis 1986; 133: 1072–1075. 75. Chan CHS, Or KKH, Cheung W, Woo J. Adverse drug reactions and outcome of elderly patients on antituberculosis chemotherapy with and without rifampicin. J Med 1995; 26:43–52. 76. Farer LS, Lowell LM, Meador MP. Extrapulmonary tuberculosis in the United States. Am J Epidemiol 1979; 109:205–217.

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13 Tuberculosis–HIV Coinfection: Epidemiology, Clinical Aspects, and Interventions

KATHLEEN R. PAGE and RICHARD E. CHAISSON Johns Hopkins University Center for Tuberculosis Research, Baltimore, Maryland, U.S.A.

PETER GODFREY-FAUSSETT Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, U.K.

I. Introduction The human immunodeficiency virus (HIV) epidemic has had an enormous impact on tuberculosis (TB) worldwide. With the spread of HIV, incidence of TB rose dramatically both in endemic countries as well as in those with previously declining rates. By lowering host immune responses to mycobacteria, infection with HIV heightens the susceptibility to TB infection and the risk of progression to active disease. Because atypical clinical presentations and other concurrent infections are common, the diagnosis of TB is often delayed in HIV-infected individuals. On the other hand, in countries with a high prevalence of coinfection, increased awareness and clinical suspicion lead to many patients being started on anti-TB treatment without bacteriologic confirmation. Incidence rates of TB have risen to a greater extent than prevalence rates in settings with a high prevalence of HIV, suggesting that the duration of disease prior to diagnosis is shorter among coinfected patients in these settings (1). Common social risk factors such as poverty and crowded living situations place coinfected patients at a high risk for primary TB infection. All these factors, together with an accelerated course of disease, render HIV-infected patients with TB at high risk for death. In fact, 371

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coinfected individuals have a higher mortality than those with TB alone, and, in turn, TB accounts for the majority of deaths in HIV-infected individuals. The unique features of TB in HIV-infected patients will need to be more specifically addressed by TB control programs, particularly in countries with a high burden of HIV and TB. The collaboration between programs aimed at addressing HIV and TB control programs has been inadequate in many settings. However, there has been renewed interest in establishing coordinating bodies at national and district levels to carry out joint activities in the fight against TB and HIV. Expansion of educational and treatment programs addressing dual infection within the existing infrastructure and framework for HIV and TB care is an initial step toward decreasing the burden of disease. The wider availability of antiretroviral (ARV) therapy in resource-limited settings will greatly impact not only the overall prognosis of people living with HIV, but also the motivation for timely diagnosis and treatment. A basic step in the response to the overlapping TB and HIV epidemics is improving the case detection of TB among individuals infected with HIV, as well as providing HIV testing and counseling for all patients with TB. The treatment of latent TB infection (LTBI), which has been highly successful in preventing TB reactivation among HIV-infected people in developed countries, is gaining greater acceptance in resource-limited settings, although the optimal approach for safely administering preventive therapy in TB-endemic areas is complex and remains under investigation. Given the relatively limited experience with ARV therapy in settings with endemic TB, the next few years will be instrumental in devising and evaluating feasible and effective strategies to address the overlapping epidemics. II. Risk of Tuberculosis in Persons with HIV Infection As was evident by the resurgence of TB in the United States with the spread of HIV, the risk of TB is markedly increased in patients infected with HIV. Between 1953 and 1984, cases of TB in the United States were stably decreasing at a rate of 5% per year. With the spread of HIV, new cases of TB began to rise, peaking in 1992 at 26,673 new cases that year (2). A number of studies have described an increased incidence of TB with HIV infection, but the magnitude of the effect varies widely. This is because the risk of TB in HIV-infected patients is affected by the prevalence of active and latent TB, the degree of immunosuppression from HIV, and the accessibility to treatment for LTBI. One of the first studies to report the risk of TB in HIV-infected individuals was performed by Selwyn et al. (3) in the era prior to the advent of highly active antiretroviral therapy (HAART). HIV-seropositive and seronegative intravenous drug users in New York City were followed over a two-year period. Of 49 HIV-infected subjects, seven who had a positive (
5 mm induration) tuberculin skin test and one with a negative tuberculin test developed TB [7.9 cases per 100 person-years (PYRs) of observation].

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These findings suggested that at least seven out of the eight patients who developed TB had preexisting infection and developed TB after endogenous reactivation. During the study period, 11% of the seropositive individuals developed a positive tuberculin skin test, suggesting that there were a large number of infectious cases in this population. In the same cohort of patients, the risk of TB was high not only among HIV-infected subjects with a positive tuberculin skin test (9.7 cases per 100 HIV-infected subjects), but also in those who were anergic (6.6 cases per 100 HIV-infected subjects) (4). Studies in areas endemic with TB have shown that the tuberculin skin test may be a poor predictor of infection among patients with HIV. A prospective cohort study of Rwandan women of childbearing age found that the incidence of TB was 2.5% per year (5). The risk ratio for TB among HIV-infected women was 22.9 compared to HIV-negative women. Although having a positive tuberculin skin test was associated with an increased risk of TB among HIV-infected women (risk ratio ¼ 3), 9 out 17 HIV-infected women with active TB had a negative tuberculin skin test. Among these women, six out of nine had the tuberculin skin test performed at the time of diagnosis or after initiation of therapy for TB, whereas the other three had been tested before the onset of symptoms. However, no study has shown that treatment of LTBI in anergic HIV-infected individuals patients decreases the incidence of TB or improves the rate of mortality (6,7). This may be explained by the high rates of TB reinfection in highly endemic settings. The risk of TB among HIV-infected individuals depends to a large extent on the prevalence of TB in the community. For example, prospective follow-up of HIV-infected injecting drug users in Baltimore showed an annual rate of TB of only 0.22% (8). In contrast, a prospective study conducted in 23 hospital infectious disease units in Italy found that the 12-month rate of TB among 2760 HIV-infected subjects (72% injecting drug users) was 2.2% (9). Some areas of Africa have incident rates of TB higher than 10 per 100 PYRs in HIV-infected individuals (10). In Europe, there is a north-to-south gradient in TB rates among HIVinfected individuals, which reflects the increased prevalence of TB in the south. The percentage of AIDS patients with TB increases from 5.6% in Northern Europe, to 11.8% in Central Europe and 25% in the south (11). Regional differences in the risk of TB are also evident in the United States. In a large prospective cohort study of HIV-infected persons in six cities in the United States (New York, Newark, Detroit, Chicago, Los Angeles, and San Francisco), the overall rate of TB was 0.7 per 100 PYRs (12). In multivariate analyses, place of residence was strongly associated with increased incidence of TB [relative risk (RR) for Eastern sites ¼ 3.3 compared to Midwest and Western sites]. Rates of TB were also higher among subjects with a positive tuberculin skin test (4.5 per 100 PYRs) and for those who developed a new positive tuberculin test (5.4 per 100 PYRs). A recent analysis of global TB trends by Corbett et al. (13) showed marked geographic variability in the rates of TB among HIV-infected patients.

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Using information from published literature and data collected by World Health Organization (WHO), Joint United Nations Programme on HIV/AIDS (UNAIDS), the U.S. Census Bureau, and the Centers for Disease Control and Prevention (CDC), the authors estimated that 9% of all TB cases worldwide are attributable to HIV. Rates of TB attributed to HIV ranged from 1.1% in the Western Pacific, to 5.9% in the Americas, to a disturbing 31% in Africa. Despite a low incidence of TB, 26% of cases in the United States were attributed to HIV. This finding reflects the vulnerability of certain subpopulations to infection with both TB and HIV. In Spain, for example, TB and HIV are strongly associated with injection drug use, whereas, in the United States, the rates of both infections are disproportionately higher in certain ethnic groups. Although the proportion of coinfected individuals is lower in Asia than in Africa, the absolute numbers of coinfected people exceed two million. In India, for example, only 3.4% of TB is attributed to HIV, but it is second only to South Africa in absolute numbers of coinfected individuals. It is predicted that in India the HIV epidemic will result in an additional 200,000 case of TB per year (14). A study conducted in Northern Thailand showed a dramatic increase in the odds ratio for the association of HIV and TB over the course of a decade, with an increase in the proportion of TB cases attributable to HIV from 3.5% in 1990 to over 60% by 1998 (15). From the studies cited, it is evident that no single figure can convey the risk of TB in persons with HIV infection. There are at least four factors that can affect the incidence of TB: (i) the prevalence of latent infection with Mycobacterium tuberculosis in the population represented by the cohort, (ii) the likelihood of exposure to an infectious case, (iii) the degree of immunosuppression, and (iv) the use of preventive therapy (treatment of latent infection). A key determinant that operates through all these factors is the extent to which infections with HIV and TB cosegregate within particular groups or communities. For example, intravenous drug users may have higher rates of exposure to infectious cases as well as be more likely to be infected with HIV. Immigrants from countries with a high prevalence of HIV are also more likely to have latent infection with M. tuberculosis, and may also continue to have higher rates of exposure than the surrounding community. III. Prevalence of HIV Infection Among Patients with Tuberculosis Beginning in 1988, a systematic sampling of the prevalence of HIV infection in newly reported TB cases in the United States was undertaken by the CDC in 14 urban TB clinics. The median seropositivity rate in 4301 persons with suspected or confirmed TB was 3.4%. The rates varied widely, ranging from 0% to 46%, with the highest rate reported in New York City (46%), followed by Newark (34%), Boston (27%), Miami (24%), and Baltimore (13%) (16). In the United States, the prevalence of HIV among patients with TB peaked in 1992. In New York, the proportion of patients with TB coinfected with HIV declined from 33.6% in 1992 to 14.6% in 2001. National trends

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showed that despite more comprehensive testing for HIV, the prevalence of HIV among patients with TB decreased from 15% in 1993 to 9% in 2001 (17). Some of the decline may have been due to increased efforts to control TB among persons infected with HIV, increased access to ARV therapy, and a proportionate increase in TB among foreign-born individuals. In fact, there is great variability in HIV rates among certain subpopulations and ethnic groups. For example, a recent study reported an exceedingly high prevalence of HIV (80%) among injection drug users with TB in New York City (18). Globally, there are significant geographic differences in the prevalence of HIV infection among patients with TB. The prevalence of HIV in patients with TB correlates with population rates and ranges from 1% in the Western Pacific Region, to 14% in industrialized countries, and 38% in Africa (13). In Southern Africa, where prevalence rates of HIV are greater than 20%, over 60% of patients with TB are also infected with HIV (19). In areas of Asia, HIV prevalence among TB patients is rising fast (16). Worldwide, 13% of all TB deaths occur in coinfected individuals, with an aggregate case fatality rate of 40% in HIV-infected TB cases. Wide variation in TB death rates between countries, from 9 per 100,000 in Brazil to 139 per 100,000 in South Africa, can be predominantly explained by differences in HIV infection rates (13). IV. Influence of HIV Infection on the Pathogenesis of Tuberculosis HIV is the strongest risk factor known for the development of TB. The deleterious effect of HIV reflects the importance of cell-mediated immunity in the containment of TB. In the vast majority of immunocompetent individuals infected with M. tuberculosis, the bacilli are contained in pulmonary granulomas, leading to LTBI. LTBI is an asymptomatic infection with a low bacillary burden, which is kept at bay by host immune responses. Reactivation is thought to result from changes in immune response rather than enhanced mycobacterial virulence. Successful containment of TB infection is dependent on the induction of a type 1 adaptive immune response characterized by the production of interferon-gamma (IFN-c) by CD4 T-cells for activation of macrophages and subsequent destruction of intracellular bacilli (20). TB develops either by progression of recently acquired infection or reactivation of latent TB. In areas of low prevalence of TB, it is generally thought that most cases arise from latent infections, because few new infections are occurring (21). The risk of disease following infection with M. tuberculosis increases dramatically in patients with HIV coinfection, from 10% per lifetime in immunocompetent hosts to 10% per year in coinfected patients (3). Mathematical modeling suggests that in areas of high prevalence of TB, new infection with rapid progression is a major contributor to the incidence of TB in HIV-infected patients (22).

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It has been speculated that HIV-infected patients are more likely to acquire TB infection after exposure to TB (23). Although this concept is unsubstantiated, it has been clearly demonstrated that after infection with M. tuberculosis, there can be rapid progression to clinical disease in HIVinfected persons (23). In situations where groups of HIV-infected persons are exposed to patients with infectious TB, explosive outbreaks can occur. For example, in a residential care facility for HIV-infected persons in San Francisco, 11 of 35 (35%) residents exposed developed active TB within 120 days (23). DNA fingerprinting confirmed that the same strain of M. tuberculosis infected the 11 patients. HIV-infected patients appear to have a higher risk of reinfection, probably because of an impaired capacity to mount long-lasting protective immune responses. Reinfection with drug-resistant organisms has been demonstrated by restriction fragment length polymorphism (RFLP) analysis among HIV-infected persons being treated for TB (24). A study of recurrent TB in South African mineworkers showed that in settings with a high risk for TB, HIV-infected patients are vulnerable to reinfection (25). A cohort of 326 mineworkers who had successfully completed treatment for pulmonary TB was followed for a median of 25 months. The rate of recurrence was 16 per 100 PYRs in HIV-positive patients and 6.4 per 100 in HIV-negative patients. DNA fingerprinting performed on 39 recurrent samples showed that HIV infection was a risk factor for recurrence, due to its association with reinfection, but not relapse, of TB. However, the applicability of these findings to other populations may be limited given the exceedingly high prevalence of TB in this setting and the presence of silicosis as a strong susceptibility factor. In addition to reinfection, relapse is also a major cause of recurrent disease. A review of 47 prospective studies of recurrent pulmonary TB revealed that recurrence rates for both HIV-infected and -uninfected persons were strongly associated with the duration of treatment (26). This association suggests that a large proportion of recurrences are due to relapses and is supported by RFLP data from a subset of studies showing that 62% of recurrent cases in HIV-infected individuals were due to relapse. Population-based application of DNA fingerprinting over a five-year period in San Francisco demonstrated that prior to the intensification of TB control measures, the rates of clustered cases were particularly high in HIV-infected persons (27). This could result from social circumstances, HIV-induced immunosuppression, or both. Several cross-sectional studies, however, have shown that HIV-infected individuals with pulmonary TB are less likely than HIV-negative patients to transmit M. tuberculosis to close contacts (28,29). A cohort study of household contacts of individuals with pulmonary TB in the Dominican Republic showed that 54% of contacts of HIV-positive individuals had a positive tuberculin skin test compared to 70% of contacts of HIV-negative persons (30). Possible explanations for the decreased contagiousness of HIV-infected individuals may include a lower sputum bacillary burden; decreased duration of smear positivity

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due to rapid progression and earlier presentation to medical care; weakened cough with more severe disease; or greater social isolation. Because M. tuberculosis is a virulent pathogen even in the normal host, TB tends to occur relatively early in the course of HIV infection. This is supported by the findings of several groups that HIV-seropositive patients with TB tend to have higher CD4 counts than patients with opportunistic infections such as Pneumocystis jiroveci pneumonia (PCP) (31,32). A recent retrospective cohort analysis of 20,503 mineworkers with known dates of HIV seroconversion and diagnosis of TB showed that the risk of TB doubled within the first year of HIV infection, before any significant expected declines in CD4 count (33). No increased risk was found during the seroconversion interval, a period of significant immunosuppression. The effect of HIV on TB early in the course of HIV infection has important implications regarding the timing of ARV therapy. In countries with low prevalence of TB, initiation of ARV therapy in patients with relatively preserved immune function (CD
350) is controversial and has not been proven to be clinically beneficial (34,35). However, in TB endemic areas, early ARV therapy or more effective use of isoniazid preventive therapy may be warranted to curtail the effect of HIV on TB (19). V. Influence of Tuberculosis on the Course of HIV Infection Experimental evidence shows that TB increases HIV replication (36,37) and enhances susceptibility to viral infection at the cellular level (38). Elevation of proinflammatory cytokines such as tumor necrosis factor (TNF) (39–42) or enhanced macrophage expression of chemokine receptor 5 (43) with TB infection may upregulate HIV replication in vivo. Epidemiologic data regarding the effect of TB on HIV progression has been inconsistent. An intriguing small trial of a TNF-blocking agent (etanercept) used in conjunction with standard chemotherapy for the treatment of active TB in HIV-infected patients with CD4 counts >200 resulted in a 25% increase in CD4 count after one month of therapy (p ¼ 0.1) but no change in HIV viral load (36). A few small studies have shown increased viral load (37,38,44) and decreased CD4 count (45) from baseline in HIV-infected individuals, suggesting faster progression of HIV in patients with TB. However, data from two studies show that a high viral load and low CD4 count precede the onset of TB infection, implying that rapid TB is a marker of more advanced HIV disease rather than the cause of accelerated progression (46,47). No significant difference in viral load or CD4 counts were detected in 111 HIV-infected patients during the treatment of active TB (48). A number of retrospective studies have shown worsened survival in HIV-infected patients with TB (49–51). The largest prospective cohort study to evaluate the impact of TB on survival of HIV-infected individuals demonstrated a significant effect of TB on survival in patients with CD4

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counts above 200 (relative hazard for death was 3), but no significant effect on individuals with more advanced immunosuppression (52). Although one study reported that treatment of LTBI delayed the onset of opportunistic infections (53), most studies have not shown a survival benefit in HIV-infected patients treated for LTBI (7,42,54,55). In brief, TB may accelerate the progression of HIV, and the impact of coinfection may be particularly significant for patients who are not receiving ARV therapy. Nonetheless, the most important intervention in controlling HIV progression is ARV therapy, which is becoming more widely available with the implementation of collaborative international efforts. VI. Diagnosis of Tuberculosis Infection and Disease The approach to diagnosing TB in the setting of HIV infection is essentially the same as used in persons without HIV. However, delays in diagnosis may be more common in HIV-infected patients because atypical clinical presentations such as disseminated disease and unusual findings on chest radiography are common. On the other hand, HIV-infected patients may be more likely to attend health care for reasons other than TB, and in settings with a high prevalence of HIV, the awareness of TB as the most important cause of morbidity should encourage earlier diagnosis and treatment. Although TB has become more stigmatized in many communities through its association with HIV, a study in Zambia did not suggest that patients were more likely to delay seeking care for their cough if they held stigmatizing attitudes to TB and HIV (56). The sensitivity of diagnostic tests such as the tuberculin skin test and of other immunology-based assays is also reduced in patients with HIV. Smear-negative pulmonary TB can lead to significant delays in therapy, especially in patients with atypical presentations. Finally, the broad differential diagnosis in patients at risk for opportunistic infections can complicate the diagnostic algorithm of TB. A. Tuberculin Skin Testing and Anergy Testing

The tuberculin skin test may show little or no reaction in persons with advanced HIV infection, particularly in populations with a low prevalence of TB. However, in earlier stages of the infection, reactivity may be maintained. The ability to respond to tuberculin is an indicator of the status of cell-mediated immunity, which in turn is an indicator of the stage of HIV infection. Nonetheless, even in advanced HIV disease, up to 50% of patients with confirmed TB have a reactive tuberculin skin test (57). In a study reported by Markowitz et al. (58), the prevalence of positive (
5 mm induration) tuberculin skin tests decreased progressively as the CD4 count declined. The relationship between CD4 cell count and the presence of tuberculin reactivity is shown in Figure 1. In addition, the rate of reactivity to mumps and Candida skin test antigens was related to the CD4 count. Stated conversely, the prevalence of anergy increased

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Figure 1 Tuberculin skin test reactions in persons with HIV infection and differeing CD4+ lymphocyte counts compared with an HIV-uninfected control group. Source: From Ref. 58.

with decreasing CD4 counts, as shown in Figure 2. It should be noted, however, that the prevalence of anergy was 42% among non–HIV-infected injecting drug users and 12% among homosexual/bisexual men. Chin et al. (59) described the results of serial skin testing using Candida and mumps antigen as well as tuberculin in a cohort of HIV-infected subjects. Of the subjects who had no reaction to any of the three antigens, 30% reacted to mumps or Candida when tested a year later, thus reverting from being anergic to being reactive, counter to what would be expected as HIV infection progressed. These same investigators also examined the results of mumps antigen tests in 50 subjects who had a false-negative tuberculin test after a previous positive test. The mumps antigen was reactive in

Figure 2 Proportion of HIV-infected subjects with anergy defined as failure to react to tuberculosis, mumps, and candida antigen. Source: From Ref. 58.

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39% of the subjects when the tuberculin test was falsely negative. Given the unreliability of anergy testing, the authors concluded that anergy testing should not be used to make individual decisions concerning the validity of a negative tuberculin skin result. In a study by Johnson et al. from Haiti (60), HIV-infected adults were more likely to have no reaction to tuberculin, but 65% had reactions of 5 mm or greater induration, similar to the 70% of HIV-seronegative adults who had a 10 mm or greater reaction. To sum up, these studies illustrate that tuberculin skin testing retains some clinical value in the presence of HIV infection. In particular, in HIV-infected individuals, tuberculin skin reactions 5 mm or greater provide strong evidence of TB infection. However, negative skin test reactions have a low negative-predictive value. Because of the frequency of blunted skin test responses, or anergy, it is recommended by the American Thoracic Society (ATS) and the CDC that a reaction of 5 mm or greater induration to five tuberculin units of purified protein derivative (PPD) be regarded as indicative of TB infection in HIV-infected persons (61,62). The validity of a 5-mm cutoff is suggested by the finding that the risk of TB is substantially increased in persons with reaction sizes 5 mm or greater compared with the risk in persons with an 1to 5-mm reaction. As reported by Markowitz et al. (12), the rate of TB in a cohort of HIV-infected subjects who had 0-mm reaction was 0.5 cases per 100; with reactions of 1 to 4 mm, the rate was 0; with 5 to 9 and 10 to 19 mm, the rates were 2.4 and 2.5, respectively; and for reactions 20 mm or greater, the rate was 5.4. B. Clinical Features of Tuberculosis

TB may occur relatively early in the course of HIV infection. However, the clinical manifestations of TB in patients with HIV partly depend on the severity of immunosuppression (31,32,63). In a series reported by Markowitz et al. (12) in which HIV-infected subjects were followed prospectively, the median CD4 lymphocyte count within six months before the diagnosis of TB was 144, with a range of 2 to 543. The degree of immunosuppression was not as severe as in patients who develop infections such as PCP or disseminated Mycobacterium avium complex disease. The clinical diagnosis of TB in HIV-infected patients is complicated by the broad differential diagnosis of pulmonary disease in HIV and atypical presentations with extrapulmonary manifestations in patients with HIV. All patients with suspected pulmonary TB should have sputum smear microscopy. However, sputum smears are often negative in HIVinfected patients with pulmonary TB, especially in the absence of cavitary disease. Patients who have had at least two negative sputum smears but continue to cough despite an adequate course of antibiotic therapy for bacterial pneumonia should be further evaluated with chest radiography. The radiographic findings of pulmonary TB in patients with HIV are varied and may not be easily distinguished from other conditions unless interpreted within the clinical context. For example, most patients with

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cavitary disease are sputum-smear positive, so that the presence of cavities and repeated negative sputum smears may be indicative of another disease. Furthermore, failure to respond to standard antibiotic therapy for bacterial pneumonia in patients with abnormal radiographs is suggestive of TB. Although both TB and PCP can cause interstitial infiltrates, PCP is characterized by a dry rather than productive cough and a greater degree of dyspnea. Whereas patients with high CD4 counts display features of TB similar to those in HIV-negative individuals, the clinical presentation of TB among patients with advanced HIV disease tends to be atypical (32). Clinical reports have emphasized that TB in advanced HIV is frequently disseminated, with unusual radiographic manifestations, lymph node involvement, and low rates of tuberculin skin test reactivity. Low CD4 counts have been clearly correlated with an increased frequency of extrapulmonary TB, positive blood cultures for M. tuberculosis, and intrathoracic adenopathy on chest radiographs (32). Conversely, pleural effusions are more frequent in persons with CD4 counts of 200 or more. In a prospective study of 1130 HIV-infected individuals, 31 developed TB over a mean follow-up period of 53 months. Of these, 16 (52%) had only pulmonary involvement, seven (23%) only extrapulmonary disease, and eight (26%) had both pulmonary and extrapulmonary sites of disease (12). In a cross-sectional study of 1171 patients from Brazil with TB, of whom 47% were HIV coinfected, HIV infection was twice as frequent in extrapulmonary cases than in exclusively pulmonary forms (64). In a prospective study of consecutive patients admitted with TB to a district hospital in Malawi, 547 out of 686 (80%) patients were coinfected with HIV. HIV coinfected patients were slightly more likely than HIV-uninfected patients to have smear-negative pulmonary disease (45% vs. 38%) and extrapulmonary TB (33% vs. 27%), but these differences were not statistically significant (65). A variety of extrapulmonary manifestations of TB have been noted in HIV-infected patients. These include central nervous system (CNS) involvement with brain abscesses, tuberculomas, and meningitis, bone (including vertebral) disease, pericarditis, gastric TB, tuberculous peritonitis, and scrotal TB. In addition, M. tuberculosis has been cultured from the blood as well as bone marrow. However, despite the increased frequency of extrapulmonary forms of TB in persons with HIV infection, pulmonary disease tends to predominate in most series (12,31,32,57). C. Radiographic Findings

Unusual findings on chest radiographs of HIV-infected patients with TB are common. Lower lung zone and diffuse infiltrates are often seen, cavitation is less frequent, and intrathoracic adenopathy more common in patients with HIV infection (32,66,67). Atypical findings on chest radiography can be difficult to differentiate from other causes of pulmonary disease such as community-acquired pneumonia or PCP. However, in conjunction with clinical criteria, chest radiography plays an important role in assisting the

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diagnosis of TB, particularly in patients who are smear negative. Abnormal chest radiographic findings in HIV-infected patients with a chronic cough (three weeks or longer) and repeatedly negative sputum smears who have not improved with antimicrobial therapy for community-acquired pneumonia are suggestive of TB. Certain characteristics such as intrathoracic lymphadenopathy, night sweats, weight loss, or close contact with an active case may heighten the suspicion of TB. Small et al. (68) followed the radiographic course of treated pulmonary TB in persons with HIV infection, and noted that, in general, there was rapid improvement with little residual scarring after completion of therapy. However, many patients who had radiographic worsening had new superimposed diseases other than TB. Worsening pulmonary infiltrates during treatment for TB can also be seen in patients with advanced HIV, who initiate ARV therapy (69,70). Rapid improvement in immune function can lead to an enhanced inflammatory response against M. tuberculosis, which manifests as a temporary clinical and radiographic deterioration. Therefore, the differential diagnosis for HIV-infected patients not responding adequately to TB therapy includes therapeutic failure due to drug resistance or noncompliance, the immune reconstitution syndrome, or the presence of another pulmonary process. D. Bacteriologic Examinations

As in HIV-uninfected individuals, the most sensitive method for detection of mycobacteria in HIV-infected patients is culture, which has the added advantage of allowing for drug-sensitivity testing. However, conventional culture techniques on solid media can take as long as eight weeks to isolate a mycobacterial species. The time to detection of growth can be greatly shortened by the use of automated or semiautomated liquid culture systems, which rely on radiometric or nonradiometric indicators of mycobacterial growth. Unfortunately, because of high operational costs and slow turnover, mycobacterial culture methods are not readily available worldwide, and most developing countries rely exclusively on sputum smears. Although the proportion of positive sputum cultures in patients with pulmonary TB is approximately the same in HIV-infected and uninfected individuals, sputum smears are less sensitive. Various studies have shown that sputum smears may be negative in over half of all HIV-infected patients with culture-proven TB. Because the diagnostic yield of sputum smears depends to some extent on cavitation, the sensitivity may be lower in patients with advanced immunosuppression who are less likely to have cavitary pulmonary lesions. The number of bacilli in the sputum of HIV-infected individuals may be lower than in the sputum of HIV-negative persons (71), but repeat testing of multiple sputum samples can increase the diagnostic yield of smears (72,73). Common causes of false-negative sputum smears include problems in sputum collection or processing, and inadequate examination of the sputum sample. Fluorochrome staining may allow for rapid scanning of smears under low magnification by facilitating the identification of bacilli, which will fluoresce bright yellow after staining with phenolic auramine or

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auramine rhodamine. In a study conducted in India, fluorochrome staining improved the detection of bacilli in the sputum of HIV-infected patients with pulmonary TB from 29% with Ziehl–Neelsen stain to 45% (74). Sputum concentration through centrifugation may improve the detection of acid-fast bacilli (AFB) in the sputum. In one study, the sensitivity of smears from sputum of HIV-infected patients increased from 39% to 50% after concentration, but there was little clinical benefit when concentrated smears were compared to direct microscopy supported by clinical judgment (75). The utility of sputum induction or bronchoscopy has not been well established. A study by Miro et al. (76) did not show a significant contribution from cultures and smears performed on samples obtained by bronchoscopic alveolar lavage (BAL). In another study by Kennedy et al. (77), one-third of patients with culture-confirmed TB and negative sputum smears had positive smears on samples obtained by BAL. However, in this study, only 63% of BAL cultures were positive, compared to 91% of sputum cultures. For patients who cannot produce sputum spontaneously, sputum induction has a similar diagnostic yield to bronchoscopy (78). Because smear-negative TB has a poor prognosis in HIV-infected patients (79,80), several algorithms have been developed to facilitate early diagnosis. In areas with high prevalence of HIV and TB, the presence of cough for more than three weeks, in the absence of significant shortness of breath, is suggestive of pulmonary TB (81). The presence of cervical lymphadenopathy or chest pain, and failure to improve after a course of antibiotic therapy for community-acquired pneumonia, increases the likelihood of TB (81). A high index of suspicion should be maintained in HIV-infected patients with atypical radiographic findings, such as diffuse infiltrates or intrathoracic lymphadenopathy, or even normal findings. In one study, 21% of patients with culture-confirmed TB and negative smears had normal or slightly abnormal radiographs (82). In another study conducted in Tanzania, clinical and subclinical TB were commonly diagnosed among ambulatory HIV-infected individuals who were screened for TB with clinical examination, chest radiography, sputum cultures and acid-fast stains, and blood cultures (83). Of particular concern was that 10 out of the 20 patients diagnosed with TB were asymptomatic and had normal radiography, and that seven of these cases were detected only by mycobacterial culture. Further studies are needed to evaluate the role of mycobacterial culture in excluding active TB among patients with HIV living in TB-endemic areas, particularly in settings offering isoniazid monotherapy for the treatment of LTBI. Given the high frequency of extrapulmonary TB in HIV-infected individuals, specimens from any site should be examined for mycobacteria and culture. Potential high-yield sources include lymph nodes, bone marrow, urine, and blood (84). E. New Tests Nucleic Acid Amplification

The utility of nucleic acid amplification (NAA) tests for the diagnosis of TB depends on the clinical situation and the prevalence of TB and

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nontuberculous mycobacteria. The test has good sensitivity and specificity in respiratory specimens that are smear positive for AFB, but the sensitivity drops in smear-negative samples (85). In non–HIV-infected individuals, NAA tests appear most useful in excluding TB in smear-positive cases from low TB prevalence areas. A positive NAA in smear-negative cases may reduce diagnostic delays and potentially avoid invasive workups, but the relatively high rates of false-positive results may limit its use in this setting. Currently, the only FDA-approved use for NAA is as an adjunct to cultures of AFB-positive respiratory specimens. The CDC has issued guidelines for the use of NAA tests, advocating selective testing on smear-positive and negative sputums to enhance diagnostic certainty (86). The utility of NAA tests in the rapid determination of drug resistance remains to be well established. NAA tests have not been extensively validated in HIV-infected individuals. A study evaluating the performance of an NAA test [enhanced M. tuberculosis direct (E-MTD)] as a diagnostic test in health care centers in the United States and Switzerland showed slightly lower sensitivity and similar specificity for HIV-infected patients compared to uninfected individuals (87). For the 339 patients enrolled, the overall sensitivity and specificity of the NAA compared to a combination of culture results and clinical diagnosis (‘‘gold standard’’) was 85.9% and 97.8%, respectively. In 31 patients infected with HIV, the same values were 80% and 97.7%, respectively. In an evaluation of the performance of E-MTD in the sputum of Texan prison inmates (85), 10 out of 12 smear-negative cases were positive by E-MTD. Two of these were from HIV-infected patients in whom the diagnosis of TB prior to culture results could have obviated the need for invasive diagnostic procedures. The role of NAA tests in the diagnosis of TB in HIV-infected patients with negative smears deserves further examination. It should be noted, however, that despite the appeal of rapid diagnostic testing with NAA, the complex nature of the test precludes their practical use in most areas endemic for TB. T Cell–Based Assays

The first T-cell–based assay to be FDA approved for clinical use was an enzyme-linked immunosorbent assay–based test quantifying IFN-c in plasma after stimulation of whole blood with PPD (QuantiFERON1-TB Gold). A multicenter study of 1226 HIV-negative individuals from the United States reported comparable agreement between the tuberculin skin test and this IFN-c release assay (j ¼ 0.60) (88). However, concordance was highest in patients with a negative tuberculin skin test, and a subsequent study evaluating the assay in an area with high prevalence of TB found that it performed poorly compared to the tuberculin skin test (j ¼ 0.35). Among HIV-infected patients, the agreement between the two tests was even lower (j ¼ 0.23) (89). Furthermore, because the antigenic proteins used for stimulation (PPD) are present in other nonpathogenic mycobacteria, the specificity of the assay for M. tuberculosis may be limited.

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The discovery of region of difference 1, a genomic segment present in M. tuberculosis but absent from most other mycobacteria, led to the isolation of antigenic gene products unique to M. tuberculosis. A new enzyme-linked immunospot (ELISPOT) assay for the diagnosis of TB quantifies the number of IFN-c–secreting T-cells after stimulation with two antigens, culture filtrate protein (CFP)-10 and early secretory antigenic target (ESAT)-6, which are specific for M. tuberculosis. Clinical studies (90) and outbreak investigations (91–93) have shown that the ESAT-6 and CFP10 stimulation assay is more specific than the tuberculin skin test in bacille Calmette–Gue´rin (BCG)vaccinated individuals. The sensitivity for latent and active TB appears to be comparable to that of the tuberculin skin test and is also affected by immune function (94,95). A cross-sectional study conducted in Zambia and in the United Kingdom evaluated the effect of HIV infection on the performance of the ESAT-6/CFP10 T-cell assay (96). In this study, the ELISPOT assay was performed in blood samples from 50 patients with active TB (39/50 coinfected with HIV), 75 healthy Zambians (21/75 HIV infected), and 40 healthy United Kingdom residents (33/40 BCG vaccinated). The ESAT-6/CFP10 ELISPOT was positive in 100% of HIV-negative patients with TB and in 90% of coinfected patients. All healthy U.K. residents had a negative ESAT-6/CFP10 test, whereas 69% of healthy Zambians had positive results, suggesting a high prevalence of LTBI in this setting. Fewer HIVinfected Zambians without active TB had ESAT-6-/CFP10-specific cells (43%), but the impact of HIV was less on this assay than on the PPD-based ELISPOT or tuberculin skin test. In a prospective study of 293 African children with suspected TB (97), results from the ESAT-6/CFP10 ELISPOT and the tuberculin skin test were compared to final clinical and microbiologic diagnoses. Overall, the sensitivity of the ELISPOT was significantly higher than that of the tuberculin skin test (83% vs. 63%). In HIV-infected children, the sensitivity of the tuberculin skin test was low (36%), but the sensitivity of the ELISPOT remained high (73%). These studies suggest that despite being an immunologic assay, the ESAT-6/CFP10 ELISPOT may be more useful than the tuberculin skin test in the diagnosis of active and latent TB in HIV-infected individuals. However, the feasibility of performing this relatively expensive, laboratory-based assay in the developing world may limit its utility in areas with the highest prevalence of TB and HIV coinfection. VII. Treatment of Tuberculosis in Patients with HIV As in HIV-negative individuals, the successful treatment of TB in patients coinfected with HIV is based on a four-drug therapy induction phase, under proper case management including DOT, followed by a continuation phase with two drugs. In spite of similar responses to therapy, patients with HIV

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have a higher overall mortality and are at a higher risk for TB reinfection than patients without HIV. Concurrent opportunistic infections, drug interactions, and immune reconstitution can complicate the care of patients coinfected with HIV and TB. A. Efficacy and Outcome of Therapy

There is substantial information from both retrospective and prospective studies, indicating that treatment regimens that include isoniazid and rifampicin for six months supplemented by pyrazinamide and ethambutol (or streptomycin) for the first two months are effective in treating HIV-infected patients with TB (98–102). Sputum conversion, time to clinical improvement, and resolution of radiographic abnormalities occur as rapidly in HIV-infected patients as in those without HIV (98–102). However, despite adequate responses to TB therapy, high mortality rates in HIV and TB coinfected patients are well documented (100,103, 104). Mortality is higher in the first weeks or months after the diagnosis of TB and occurs more frequently in patients with advanced HIV. An autopsy study from South Africa suggested that most of the early mortality was caused by TB, whereas among those patients who died more than a month after starting treatment, other causes were usually identified (104). In outbreaks of multidrug-resistant TB (MDR-TB), deaths among HIV-infected patients often occurred within 16 weeks of exposure, and the rate was greater than 50%, showing an accelerated progression of disease (105). The presence of concurrent opportunistic infections may contribute to the high mortality of HIV-infected patients with TB. In areas with limited diagnostic capabilities, HIV-infected patients are often misdiagnosed as having TB and treated inappropriately. An autopsy study of 180 HIVinfected and 84 HIV-negative African children dying of respiratory illnesses showed that TB was present in one-fifth of all cases, and that approximately half of the patients with TB had other pulmonary processes such as pyogenic pneumonia, PCP, or cytomegalovirus infection (106). A review of 50 studies of HIV-infected patients with TB showed a high case fatality rate in coinfected patients, especially those with negative sputums and extrapulmonary disease. Autopsy data revealed high rates of opportunistic infections, which may have been misdiagnosed or occurred concurrently with TB (107). Probably as a result of multiple infections in patients with HIV, treatment with cotrimoxazole decreases mortality in HIV and TB coinfected patients who are not receiving ARV therapy. In a prospective study of HIV-seropositive individuals (average CD4 count 317) with smear-positive TB, treatment with cotrimoxazole decreased the risk of death by 46% (13.8 vs. 25.4 per 100 PYRs) (108). A cohort study conducted in Malawi in HIV-infected patients diagnosed with TB also showed a decrease in case fatality rate after the implementation of cotrimoxazole prophylaxis (109). Whether this intervention will have the same effect in areas with different patterns of resistance and prevalence of opportunistic infections remains to be determined.

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B. Duration of Therapy

Recommendations on the length of therapy for drug-susceptible pulmonary TB are similar for HIV-infected and -uninfected individuals. In a study in Zaire (99), it was shown that relapse rates after isoniazid and rifampicin administration for six months were similar in HIV-infected and -uninfected controls, and that prolongation of therapy to 12 months reduced relapse rates, but did not affect mortality in HIV-infected patients. A prospective study comparing outcomes in HIV-infected and HIV-negative individuals in Haiti showed equal rates of relapse in HIV-infected and noninfected patients with TB after six months of isoniazid, rifampicin, pyrazinamide, and ethambutol followed by isoniazid and rifampicin for four months. Death rates from nontuberculous causes were higher in HIV coinfected patients (100). Retrospective analysis of 188 patients with recurrent TB in Florida did not show an association between recurrence and HIV infection. In a meta-analysis conducted from 1970–1999 of 47 prospective studies of recurrent TB, recurrence appeared to be highly associated with the length of therapy (26). In patients with HIV, the relative rate (RR) of recurrence for treatment duration of two to three months versus a duration of seven months or more was 4.6. Based on data from a prospective study in HIVnegative individuals, where therapeutic failure was associated with a slow bacteriologic response and cavitation (110), current CDC guidelines for the treatment of drug-susceptible TB recommend prolongation of therapy to nine months in patients with cavitary disease or positive mycobacterial cultures after two months of therapy, regardless of HIV status (111). In studies where DNA fingerprinting is used to distinguish relapse from reinfection, the proportion of recurrences that are due to reinfection tend to increase with HIV infection and in areas with higher TB incidence (26). Given the predisposition to reinfection TB in HIV-infected patients, a study conducted in Haiti (112) evaluated the effect of post-therapy isoniazid on the prevention of recurrent TB. In this study, 142 HIV-infected patients and 91 HIV-negative patients were randomized to one year of post-therapy isoniazid. After a follow-up period of 24 months, HIV-infected individuals were found to have higher recurrence rates than HIV-negative people (4.8 vs. 0.4 per 100 PYR). In HIV-infected individuals, posttreatment isoniazid decreased rates of recurrence from 7.8 to 1.4 per 100 PYRs, and had an even greater effect on patients with symptomatic HIV at the time of TB diagnosis, but there was no effect on overall survival. Current WHO guidelines for the treatment of drug-susceptible pulmonary TB in HIV-infected patients recommend as the preferred regimen two months of four-drug initiation-phase therapy (isoniazid, rifampicin, pyrazinamide, and ethambutol), followed by four months of continuation-phase therapy with rifampicin and isoniazid (113). A sixmonth continuation-phase rifamycin-sparing regimen containing ethambutol and isoniazid may be considered in patients whose adherence cannot be closely monitored.

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With the exception of pyrazinamide-associated hepatotoxicity, HIVinfected patients are generally more likely to experience side effects from first-line anti-TB medications. In a retrospective review of 430 patients receiving treatment for TB, HIV infection was associated with an increased risk for adverse drug reactions, especially with the use of rifampicin (114). Dermatologic reactions are common in HIV-infected individuals receiving isoniazid and rifampicin (115). The use of thiacetazone has been linked with severe mucocutaneous hypersensitivity and toxic epidermal necrolysis in HIV-infected patients, and should be avoided in this population (116). In patients receiving anti-TB medications and ARV therapy concomitantly, the rates of adverse drug reactions are high, probably due to overlapping toxicities. A retrospective study of HIV-infected patients receiving treatment for TB reported 167 adverse drug events in 99 (54%) of 183 patients (44% of whom were taking ARVs) (117). The most common side effects noted were peripheral neuropathy (21%), rash (17%), and gastrointestinal symptoms (10%). Peripheral neuropathy occurred most commonly in patients prescribed isoniazid and neurotoxic ARVs such as stavudine and didanosine. Elevations in transaminases (five times or more the upper limit of normal) occurred in 6% of patients. Most side effects occurred within the first two months of TB therapy. Adverse events led to the interruption or discontinuation of therapy in 34% of patients. D. Relapse and Drug Resistance

In general, it appears that HIV infection does not dramatically increase rates of relapse after successful therapy for TB. A review of nine TB treatment trials in HIV-infected and noninfected patients performed before 2001 revealed relapse rates in HIV-infected patients ranging from 0% to 10%, compared to 0% to 3.4% in HIV-negative individuals (118). Although there appeared to be an increased relapse rate with HIV infection, differences in study design, follow-up period, patient enrollment, and therapeutic intervention may have confounded the results. Direct comparison of relapse between HIV-infected and -uninfected individuals has not shown an increased risk associated with HIV (25,119,120). Relapse after TB therapy appears to be more strongly associated with drug resistance and cavitary disease in both HIV-infected (25) and -uninfected (110) individuals. However, HIV-infected patients have high rates of acquired rifamycin resistance when treated with intermittent therapy during the induction phase of therapy. Tuberculosis Trials Consortium Study 23, a single-arm trial of twice-weekly rifabutin-based therapy for the treatment of TB in HIV-infected patients, was prematurely suspended due to the occurrence of acquired rifamycin resistance in the five patients with therapy failure. Characteristics associated with acquired resistance included randomization to twice-weekly therapy during the initial two months of therapy and to CD4 counts below 60 (121). Based on these findings, the CDC issued a warning against the use of intermittent regiments in HIV-infected patients

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with CD4 counts below 100 (122). Retrospective studies confirm that HIV infection is a risk factor for rifamycin resistance (123), especially in patients with severe immunosuppression (124). The reason for the high rates of acquired resistance in HIV-infected patients treated with intermittent induction therapy is unclear, and data on malabsorption of anti-TB medication in patients with HIV is inconclusive (125–127). E. Concomitant Antiretroviral Therapy

The simultaneous treatment of HIV and TB poses significant challenges with regard to overlapping drug toxicities, drug interactions, medical compliance with complicated regimens, and the potential for immune reconstitution syndrome. Nonetheless, high rates of opportunistic infections and death in HIV-infected patients with TB, particularly in those with advanced immunosuppression, necessitates therapy for both conditions. Drug Interactions

A crucial aspect of treatment with ARV and anti-TB medications is the management of drug interactions. The induction of the P450 cytochromes (CYP450) by rifamycins and the non-nucleoside reverse transcriptase (NNRTI) efavirenz, and the inhibition of CYP450 by most protease inhibitors and delavirdine, can lead to significant alterations in the levels of drugs that metabolized CYP450 by these pathways. Therefore, concurrent use of potent CYP450 inducers such as rifampicin can lead to subtherapeutic levels of protease inhibitors or NNRTIs and ARV treatment failure. Nucleoside reverse transcriptases (NRTIs) are not significantly affected by alterations in the CYP450 system. Of the rifamycins, the most potent inducer of CYP450 is rifampicin, followed by rifapentine, and then rifabutin. Rifampicin decreases the levels of most protease inhibitors (except ritonavir) by 75% to 95%, whereas rifabutin reduces protease inhibitor levels by 20% to 40%. Rifampicin can be used in select situations (Table 1), but in general, rifabutin is preferred for patients taking protease inhibitors. However, protease inhibitors, especially ritonavir, lead to marked decrease in rifabutin metabolism, which can result in supratherapeutic rifabutin levels and high rates of toxicity. Therefore, rifabutin doses must be decreased when used concomitantly with protease inhibitors (except with saquinavir). In contrast, rifabutin doses must be increased in the presence of efavirenz. Although some experts have recommended increasing the dose of efavirenz to 800 mg daily when used with rifampicin, recent data suggests that dose adjustments may not be necessary (128). In a recent clinical trial conducted in Thailand, 84 HIV-infected patients with TB receiving rifampicin (450 mg/day if less than 50 kg and 650 mg/day if more than 50 kg) were randomized to 600 mg/day or 800 mg/day of efavirenz (129,130). Median plasma efavirenz levels were comparable between the two groups, as were virologic and immunologic outcomes 48 weeks after initiating ARV therapy. A recent report of nine patients treated with 800 mg/day of

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Table 1 Dose Adjustments with Concomitant Use of Rifamycins and Antiretrovirals Antiretroviral

Rifabutin " dose adjustment

NRTI Protease inhibitors Saquinavir

None

Yes, but rarely used alone

None

Possible if regimen includes ritonavir Only if sole PI or in combination with saquinavir. Do not use with low-dose ritonavir No

Ritonavir #

Decrease dose substantially (150 mg three times per week)

Lopinavir/ ritonavir # Atazanavir #

Decrease dose (150 mg three times a week) Decrease daily dose (150 mg daily or 300 mg intermittent)

Use of rifampicin "

No

Indinavir # Nelfinavir # Amprenavir # NNRTI Efavirenz "

Nevirapine Delavirdine

Increase dose (450–600 mg daily or 600 mg intermittent) None Do not use

Yes at 600 or 800 mg/day (127–129) Possibly (131–133) No

Note: Dosage adjustments for coadministration of antiretrovirals and rifabutin or rifampicin. Recommendations are for the usual combination of two or three NRTIs with either one NNRTI or PI (may be ritonavir-boosted). Drug interactions between rifamycins and more complex regimens (e.g., dual PI, PI, and NNRTI) are not well studied, and dosing should be individually tailored. # denotes CYP450 inhibitor; " represents CYP450 inducer. Abbreviations: PI, protease inhibitor; NRTI, nucleoside reverse transcriptase; NNRTI, nonnucleoside reverse transcriptase; CYP450, P450 cytochromes.

efavirenz and rifampicin showed that most patients (78%) were unable to tolerate high doses of efavirenz due to toxicity, which included CNS disturbances and hepatitis (131). These findings suggest that efavirenz can be used effectively with rifampicin at regular doses. The first-line ARV regimen recommended in many developing countries includes nevirapine in combination with two NRTIs. Nevirapine does not appear to affect rifampicin plasma levels, but several small studies have shown marked reductions in plasma levels of nevirapine ranging from 31% to 58% after rifampicin administration (132,133). However, the clinical significance of this alteration is unclear because the lowest trough concentration of nevirapine exceeds by more than 40 times the median infective dose (IC50) of wild-type HIV. An observational study of 36 HIV-infected

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patients with TB who received rifampicin (600 mg daily) and nevirapine (400 mg daily) as part of their therapy showed that all patients were cured of TB and 74% of patients achieved undetectable viral loads, a response rate similar to the range found in clinical studies including nevirapine (134). Given the high therapeutic index of nevirapine, it is likely that reductions in serum concentration of the drug by rifampicin have no clinical implication and that nevirapine can be effectively used at standard doses in combination with rifampicin. Furthermore, concomitant use of nevirapine and rifampicin has not been associated with increased hepatotoxicity (135). In patients taking complex CYP450-inducer and -inhibitor combinations (such as efavirenz, protease inhibitors, and rifabutin), it is difficult to accurately predict drug metabolism, and monitoring drug levels may be informative. However, despite numerous interactions, every effort should be made to include rifamycins in the treatment of TB. Non–rifamycin-based regimens have inferior outcomes and higher relapse rates (100,118,136), and require streptomycin for the entire course. Immune Reconstitution Syndrome

Another concern in the treatment of HIV-infected patients with TB is the common occurrence of paradoxical worsening associated with immune reconstitution upon initiation of ARV therapy. In some studies, over 30% of HIV-infected patients with active TB clinically deteriorate when started on ARVs (69,70). Immune reconstitution syndrome usually occurs within six weeks of ARV initiation in patients with low initial CD4 counts (<50) that rise more than two-fold over a short period of time. Clinical manifestations are typical of an enhanced inflammatory response to M. tuberculosis with the improvement of immune function, which manifests as high fevers, lymphadenopathy, and respiratory compromise. There is no data from randomized trials regarding the best management of immune reconstitution syndrome in patients with TB. For mild cases, the use of nonsteroidal anti-inflammatory agents is appropriate. Steroids are commonly used in more severe presentations, at doses of approximately 1 mg/kg/day, tapered very slowly over the course of weeks to months. Although immune reconstitution can be very symptomatic and can complicate medical compliance as well as the assessment of drug toxicities, it is rarely life threatening and discontinuation of ARVs is not recommended. Some authorities have advocated delaying the initiation of ARV therapy in patients diagnosed with active TB until the completion of two months of TB therapy. However, in a study by Dean et al. (117), 39% of patients with CD4 counts below 100 who were not receiving ARV therapy developed an opportunistic infection during treatment for TB. Despite high rates of adverse drug reactions in patients with advanced HIV and TB, ARV therapy is associated with reductions in AIDS-defining illnesses and mortality (117,137). Therefore, ARV therapy should not be delayed in individuals with CD4 counts below 100.

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As ARV therapy becomes widely available in countries with a high prevalence of TB, immune reconstitution syndrome in patients treated for HIV and TB will be common. Distinguishing this syndrome from progressive TB (treatment failure), new opportunistic infections, or drug toxicity in countries with limited diagnostic capabilities will be challenging. Impact of Antiretroviral Therapy on Tuberculosis Control

ARV therapy decreases the risk of TB by preserving immune function. Multiple observational studies have documented a significant reduction in TB among individuals taking ARV therapy (19,138–141). A European multicenter observational cohort of more than 7000 patients showed a decrease in TB from 1.8 cases per 100 to 0.3 cases over a period of five years, which was associated with the introduction of HAART and changes in CD4 counts (139). Likewise, an observational study of 1360 Italian patients followed for a mean duration of 104 weeks showed that triple combination ARV therapy was associated with a reduced risk of TB (relative hazard 0.08) (138). The beneficial effect of HAART is also evident in countries with high rates of TB. The incidence of TB was reduced by more than 80% in South African patients (n ¼ 264) who received HAART in phase III clinical trials compared to 770 non-HAART recipients (2.4 cases per 100 PYR vs. 9.7 cases per 100 PYR). The benefit of HAART was greatest in patients with WHO stage 3 or 4 and in those with CD4 counts of less than 200, but had no effect in patients with CD4 counts over 350 (140). Nonetheless, the incidence of TB among those taking HAART was still greater than that found among the HIV-negative population. The impact of ARV therapy on TB at a population level is contingent on the timing, degree of coverage, and compliance with ARV therapy (19). Extrapolation from available data suggests that: (i) the median survival after HIV infection is nine years, (ii) TB incidence increases by a factor of 2.1 as CD4 counts fall below 200, (iii) TB risk is reduced to pre-HIV infection levels with ARV therapy, and (iv) survival after HIV infection increases from 10.2 years to 19.2 years with ARV. Even based on these optimistic assumptions, mathematical modeling predicts that with complete coverage of ARV therapy initiated when CD4 counts fall below 200, the incidence of TB would only decline by 22%. Significant reduction of TB (70%) would require early initiation of ARV therapy at a CD4 count of 500 in conjunction with treatment of latent TB (19). The significant rates of TB seen even among patients on HAART in high-incidence settings such as South Africa suggest that the impact of ARV therapy at a population level could be even less, and it is even possible that it will exacerbate the TB epidemic because patients are surviving much longer than in its absence. VIII. Tuberculosis and HIV in Children Because of the difficulties in diagnosing TB in children, surveillance data on the incidence and prevalence of TB among children infected with HIV is

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scarce. However, as in adults, the risk of TB is significantly increased in HIV-infected children. Incident case rates of pediatric TB in the United States suggest a 100-fold increased risk of TB in HIV-infected children compared to children of comparable ages who are not HIV seropositive (142). Data from international studies show high rates of HIV among children with TB and a poor prognosis for coinfected children. In a retrospective study of 118 culture-proven children with TB in South Africa, 48% of children were HIV-infected and hospital mortality was higher in HIVinfected than in HIV-negative children (17.5% vs. 11.4%) (143). A prospective cohort study in Ethiopia of children with TB reported that HIV-positive children were younger, more underweight, and had a six-fold higher mortality than HIV-negative children (144). Despite good adherence to therapy, the cure rate for HIV-positive children was only 58%, compared to 89% in the HIV-negative group. Despite similar clinical presentations, mortality rates for children infected with HIV and TB in Cote d’Ivoire were significantly higher than in children with TB alone (23% vs. 4%) (145). An important factor that complicates the medical care of all children with TB is the challenge of reaching a definitive diagnosis. Sputum samples are difficult to obtain and cultures of gastric aspirate samples, which can be positive in approximately 50% of HIV-negative children who have TB, are cumbersome and not widely available in low-resource settings (146). The clinical suspicion of TB in HIV-infected children can be confounded by the frequent presence of preexisting fever, pulmonary symptoms, and generalized failure to thrive. An important finding in the cohort study of Ethiopian children with TB was the significant delay in the diagnosis of TB in HIV-infected children, many of whom had sought medical attention several times before being tested and treated (144). In this study, the tuberculin skin test was less sensitive and chest radiography less specific in HIV-infected children with TB, underscoring the importance of maintaining a high index of suspicion in this population. Because pediatric TB usually results from primary infection rather than reactivation disease, linking the ill child to an adult with confirmed pulmonary TB is an important diagnostic clue. An important issue in pediatric TB among children with HIV is the safety and effectiveness of BCG vaccination. The protection conferred by BCG against tuberculous meningitis and miliary TB varies widely, but a meta-analysis suggests that the overall protection in HIV-negative children is approximately 80% (147). However, there are no studies to date powered to evaluate the effectiveness of the vaccine to protect HIV-infected children. The safety of the vaccine depends on the degree of immunosuppression of the recipient. Administration of BCG to HIV-infected neonates is associated with relatively low rates of complications because immune suppression takes several months to develop (148). However, at least 30 cases of disseminated BCG infection have been reported in HIV-infected children and adults (149). Because diagnosis of disseminated BCG requires specialized laboratory facilities, this likely represents a significant underassessment of the disease. In a retrospective study of all mycobacterial isolates

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from children with HIV infection in a hospital in South Africa, the Danish Mycobacterium bovis BCG strain was isolated from 5 out of 49 patients (150). Clinically, the most common presentation of BCG disease in these patients was the presence of axillary adenitis ipsilateral to the vaccination site. Children with BCG disease had advanced AIDS, but all had been asymptomatic when vaccinated at birth. Disseminated BCG disease with positive mycobacterial cultures appears to be rare after BCG vaccination even in children with HIV. No mycobacterial isolates were recovered from mycobacterial blood cultures of 229 BCG-vaccinated HIV-positive children admitted to a hospital in Malawi (151), and of six positive mycobacterial isolates from blood cultures in 387 HIV-positive children hospitalized in Zambia, only one was identified as M. bovis BCG (152). Current WHO guidelines recommend that in countries where the risk of TB is high, live attenuated BCG vaccine should be administered to all infants, regardless of HIV status or exposure, unless there is symptomatic evidence of HIV infection. In areas where the risk of TB is low, BCG should be withheld from children with known or suspected HIV (153). IX. Tuberculosis Caused by Multidrug-Resistant Organisms In settings with high prevalence of MDR-TB, HIV can potentiate the problem of resistance. The increased susceptibility of HIV-infected patients to infection with M. tuberculosis and the rapid progression of active disease can magnify the spread of resistant strains. Furthermore, shared epidemiologic risk factors for infection with HIV and MDR-TB, such as injection drug use and hospitalization, contribute to the increased prevalence of MDR-TB among HIV-infected individuals. Outbreaks of TB caused by MDR-TB have occurred in hospitals and clinics, and have predominantly involved HIV-infected patients (154). In a multi-institutional outbreak in New York City, 86% of 267 patients with identical RFLP were HIV infected (155). The largest reported nosocomial outbreak of MDR-TB reported in Europe occurred among 117 HIVinfected patients in two large hospitals in Milan (156). In a similar outbreak at an HIV referral treatment facility in Buenos Aires, 68 HIV-positive individuals were infected with a single strain of MDR-TB. The one-year survival in HIV-positive patients infected with MDR-TB was markedly reduced (5/68) compared to those infected with susceptible strains of M. tuberculosis (92/148) (157). These incidents highlight the importance of high-quality hospital infection control programs, especially in institutions caring for HIV-infected individuals. Prior therapy for TB is a strong risk factor for MDR-TB, regardless of HIV status. An observational, prospective study conducted in Italy found that prevalence rates of MDR-TB among HIV-infected individuals were significantly higher in previously treated cases (12.5%) than in new cases (2.6%) (158). Molecular typing and drug susceptibility testing of M. tuberculosis

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isolates from 157 patients in Haiti showed that the only risk factor associated with MDR-TB was a history of prior TB therapy (159). In fact, HIV-infected patients were less likely to have received therapy in the past and to have resistant isolates (6.4%) compared to individuals without HIV (14%). In a study of 709 culture-positive cases from Mozambique, HIV-infected individuals were more likely to have resistance to isoniazid and streptomycin than HIV-negative persons [odds ratio (OR)2.3], but they were also more likely to have a prior history of TB therapy (OR 2.3). Among all patients, drug resistance was most highly associated with prior therapy (OR 4.5) (160). However, in patients with a first episode of TB, MDR-TB may be associated with HIV infection. In a study from Thailand (161), the prevalence of MDR-TB was significantly higher in HIV-infected patients without a history of prior TB therapy than in HIV-negative individuals (5.2% vs. 0.4%). HIVinfected persons were more likely to have other epidemiologic risk factors for TB such as lower socioeconomic status and injection drug use. In Lima, Peru, MDR-TB was documented in 43% of HIV-positive and 3.9% of HIV-negative patients. MDR-TB in HIV-infected individuals was not associated with prior therapy, but HIV-infected individuals with TB showed a higher frequency of visits to clinics frequented by patients with TB, which may have increased their degree of exposure to contagious cases (162). Other factors that may increase the likelihood of antibiotic resistance among HIV-infected TB patients include increased rates of recent infections and altered drug metabolism. For example, higher MDR-TB rates over the last decade increase the likelihood that new infections, which are more common among HIV-infected individuals, are caused by drugresistant organisms. Furthermore, the high rates of rifamycin resistance in patients treated with intermittent rifabutin suggest that HIV-infected patients may have a higher predisposition to developing drug resistance, possibly from drug malabsorption, altered metabolism, or drug interactions. There is no substantiating evidence, however, that HIV infection alone predisposes to the development of MDR-TB. Rather, the link between HIV and MDR-TB appears to be fueled primarily by an increased susceptibility to TB, which can have a great impact in areas with high prevalence of MDR-TB. Global trends in the spread of resistant strains show that the magnitude of effect of HIV on MDR-TB is closely related to the preexisting rates of MDR-TB. Africa, for example, has a relatively low burden of MDR-TB, despite being the epicenter of the TB–HIV epidemic, with over 70% of the coinfected cases seen worldwide. The recent initiation and regulated use of rifampicin in Africa may explain the low rates of MDR-TB seen in this region so far. In contrast, the impact of HIV on countries with high rates of MDR-TB has been dramatic, even at a relatively low prevalence of HIV. Particularly concerning are the rising rates of HIV in some Eastern European countries, where rates of MDR-TB are greater than 10% (163–165). In Latvia, for example, the prevalence of HIV among MDRTB cases increased from 0% to 5.6% just over the course of three years

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(166). In the prison systems of Russia and Azerbaijan, the prevalence of MDR-TB is over 20%. Overcrowded living conditions, poor ventilation, and rising rates of HIV could lead to catastrophic consequences (167). Other regions such as India and China, which together harbor 39% of the world’s incident cases of TB, are worrisome due to the absolute number of potential cases with the spread of HIV and MDR-TB (165). Because of the possible delays in determination of drug resistance in areas where there is a high prevalence of MDR-TB, empiric therapy should be based on prevailing resistance patterns (Chapter 14). Once drug susceptibility results are known, regimens can be appropriately tailored. At least two agents to which the organisms are thought to be susceptible should be used. Treatment regimens for patients with MDR-TB have not been well studied, but experience from the National Jewish Center has shown that the overall cure rate among immunocompetent patients with MDR-TB was 56% (168). A national program in Peru for the treatment of MDR-TB with a standardized regimen of directly observed administration of kanamycin, ciprofloxacin, ethionamide, pyrazinamide, and ethambutol achieved cure rates of 55% of all those who completed therapy (169). A community-based approach with individualized regimens for MDR-TB resulted in 83% cure rates at the completion of therapy (170). X. Treatment of Latent Tuberculosis Infection HIV infection markedly increases the risk of TB reactivation in patients with latent infection. Individuals with HIV and a positive tuberculin reaction have a 10% per year risk of active TB, compared to a 10% lifetime risk in HIV-negative tuberculin reactors. The accelerated progression from latent TB to active disease in HIV-positive persons has put in question the efficacy of the DOTS strategy alone to control the TB epidemic (171). Although DOTS is instrumental in the treatment of active cases and the reduction of drug resistance, it has become apparent that additional measures, such as the prevention of TB reactivation or more intensive case finding, also need to be addressed in areas with high rates of HIV infection. Several studies have shown a reduction in the risk of active TB after treatment of LTBI in HIV-infected individuals (172), especially in those with positive tuberculin skin tests and low CD4 counts (18,173). The length of the protective effect is unclear, and there appears to be no benefit in overall mortality after treatment of LTBI, perhaps due to a high mortality from other opportunistic infections in patients without access to ARV therapy. Two meta-analyses (6,7) of a total of five randomized controlled trials performed in the United States, Africa, and Latin America prior to 1998 (53,174–178) showed that treatment with isoniazid significantly reduced the risk of TB [RR 0.57 (7) and 0.58 (6)], but did not affect mortality [RR 0.93 (7) and 0.94 (6)]. Treatment of latent tuberculosis infection (TLTBI) was not beneficial in tuberculin-negative adults with HIV. The maximum mean follow-up for these studies was 33 months (range 4–33

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months), and all patients were treated with isoniazid for six months, except for one study, which extended therapy to 12 months. Given the practical difficulties with long-term therapy, several randomized studies have evaluated the efficacy of short-course therapeutic regimens for TLTBI in HIV-infected persons (55,179,180). In the largest of these trials (179), 1583 HIV-positive persons with a positive tuberculin skin test were randomized to isoniazid and pyridoxine for 12 months or rifampicin and pyrazinamide for two months. After a mean follow-up period of 37 months, it was concluded that the efficacy and safety was similar between the two regimens, but that compliance was better with the rifampicin and pyrazinamide regimens (80% vs. 69% completion rates). These findings were hailed as a significant step toward improved LTBI control. A number of subsequent studies evaluated the long-term effects of different therapeutic modalities for LTBI in HIV-infected individuals. A randomized controlled trial of 1053 HIV-positive Zambian adults compared the effects of isoniazid for six months, rifampicin and pyrazinamide for three months, or placebo. Isoniazid and pyrazinamide had a similar protective effect (RR 0.55) over an average follow-up of three years. There was no effect on overall mortality or HIV progression, and the protective effect diminished significantly over time. A study of 2728 HIV-infected Ugandans randomized to placebo, isoniazid for six months, isoniazid plus rifampicin for three months, or isoniazid plus rifampicin and pyrazinamide for three months again confirmed the efficacy of TLBI in reducing the risk of TB (RR 0.67) but not of mortality (54). In this trial, rifampicin-containing regimens were more effective than isoniazid alone (RR 0.46) and provided longer protection (up to three years) compared to isoniazid (protection waned 18 months after completion of therapy). A significant setback to the effort of shortening LTBI therapy occurred when the two-month regimen of rifampicin and pyrazinamide was introduced to the general public. Numerous studies of rifampicinand pyrazinamide-containing regimens for LTBI in HIV-infected individuals (54,55,178–180) did not detect significant adverse drug reactions. In 2000, the ATS and the Centers for Disease Control and Prevention stated that a two-month regimen of daily rifampicin and pyrazinamide was an acceptable alternative to TLTBI in HIV-negative persons (61). Following the release of these guidelines, however, severe and fatal hepatotoxicity in 48 HIV-negative individuals treated for LTBI with rifampicin and pyrazinamide were reported (181). Several randomized and observational studies have confirmed that, although equally effective, treatment of LTBI with rifampicin and pyrazinamide in HIV-negative individuals results in more hepatotoxicity than isoniazid (182–186), with rates ranging from 6.9% (185) to 13% (182). Based on these findings, the CDC has now issued a recommendation against the use of rifampicin and pyrazinamide in HIVnegative individuals and a warning for HIV-positive persons (184). Detailed analysis of the original trial of daily rifampicin and pyrazinamide did not demonstrate increased hepatotoxicity (187). The reason for

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the discrepancy between HIV-positive and -negative individuals remains unclear. Although release of new therapies to the general population often unmasks adverse drug reactions that were not detected in clinical trials due to sample size and selection criteria, the persistent dichotomy in hepatotoxicity among HIV-negative and -positive individuals is intriguing. Furthermore, use of rifampicin and pyrazinamide in the treatment of active TB has not resulted in a similar hepatotoxic profile (186). Speculation that rifampicin and pyrazinamide hepatotoxicity may be immune mediated, and therefore attenuated in HIV-positive individuals, or that there is reduced bioavailability of the medication in patients with HIV has not been conclusively proven (188). Current CDC recommendations for the prevention of active TB in HIVinfected individuals focus on the treatment of tuberculin-positive patients (61). The guidelines advocate the screening of all patients for LTBI upon diagnosis of HIV, and yearly screening for those at risk for new infection. Because the tuberculin skin test loses sensitivity with progressive immunosuppression, induration of 5 mm or more is considered positive in HIV-infected individuals. Anergy testing has no proven utility in the evaluation of TB (189). However, in patients with immune reconstitution following ARV therapy, repeat testing should be considered (111,190). Furthermore, HIV-infected individuals who are close contacts of persons with infectious TB should be treated for TLTBI regardless of tuberculin skin test (TST) status (111). Subgroup analyses of prospective, randomized trials in HIV-negative persons indicate that the maximal beneficial effect of isoniazid is achieved by nine months of therapy (61). Because there are no randomized trials evaluating the efficacy of extended therapy for HIV-infected persons, the nine-month course of isoniazid is therefore recommended by CDC for both HIV-negative and -positive individuals (61). The WHO recommendations for resource-poor settings are to use a six-month course of isoniazid, because this regimen was studied in intention-to-treat analyses in both Zambia and Uganda (176,178). Four months of rifampicin may be an appropriate alternative, but requires special attention to multiple drug interactions with ARV agents. This regimen is not recommended by the WHO, due to concerns that unsupervised therapy might lead to additional cases of rifampicin resistance. Substitution of rifampicin with rifabutin has not been specifically studied in LTBI but has been recommended by the CDC, given the efficacy of rifabutin in active TB (61,191). Despite the lack of evidence of hepatotoxicity from rifampicin and pyrazinamide in HIV-positive individuals, this regimen should generally be avoided. A major concern with the widespread implementation of therapy for LTBI in countries with high rates of TB is the inadvertent treatment of active TB with isoniazid monotherapy and the development of drug resistance. In addition to clinical history and physical examination, in areas with high rates of TB, the UNAIDS/WHO recommends chest radiography for asymptomatic individuals with HIV prior to the implementation of therapy for LTBI, in order to rule out active TB (192). Given the high cost and limited access to chest radiography in many settings, this recommendation may

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not be feasible in resource-limited settings. A study conducted in Botswana demonstrated that chest radiography in asymptomatic HIV-infected individuals prior to initiation of isoniazid preventive therapy contributed to high attrition from the program (18%) and detected active TB only in 0.2% (1 out of 563) of asymptomatic patients who were screened (193). On the other hand, a smaller study from Tanzania, where HIV-infected individuals were screened for active TB with sputum smear, sputum culture, and chest radiography, found that 10 out of 20 patients had asymptomatic disease with normal radiographic findings (83). These subclinical cases were only detected with sputum smear (3 out of 10) or sputum culture (7 out of 10). Several other small observational studies have also shown that in areas with high TB rates, asymptomatic HIV-infected individuals may have subclinical TB that is not detected by chest radiography (82,194–196). Given the complexities in balancing the potential benefit of treating LTBI and the risk of promoting drug resistance, careful evaluation of the practical experience and long-term outcomes in sites providing LTBI therapy will be essential to understand the feasibility and impact of this intervention. In summary, treatment of LTBI in HIV-infected individuals with a positive tuberculin skin test decreases the risk of progression to active TB. The effect of TLTBI may wane over time, perhaps due to reinfection in endemic areas, but there is no evidence from randomized trials that longer or repeated courses of therapy are effective. The lack of effect of TLTBI on mortality in HIV-infected patients underscores the urgent need for ARV therapy, to prevent death from other opportunistic infections. Although treatment of LTBI in patients with HIV is not routine in most countries, increasing awareness of the importance of this issue in global TB control will likely result in greater availability of TLTBI in countries with high rates of TB and HIV. Further studies on new short-course regimens for LTBI, improved delivery systems, and the timing and length of therapy are required. XI. Programs and Interventions Infection with HIV has caused a dramatic change in the history of TB. Infection with HIV accelerates the course of TB, leads to higher mortality in coinfected patients, and increases the lifetime risk of progression to active TB. A large number of the two billion people thought to have LTBI live in areas with high HIV prevalence, where infection with HIV renders LTBI a literal time bomb for TB. As a consequence of the rapid progression, case fatality rates are much higher in coinfected patients than in those with TB only, with the majority of fatalities occurring before treatment is started or in the first month of therapy. In HIV-infected patients, TB therapy is often complicated by biologic factors such as adverse drug reactions and the immune reconstitution syndrome, as well as socioeconomic barriers such as stigma poverty, and poor access to medical care. So what has been learnt in the past decade regarding TB and HIV care, which can help improve the lives of coinfected individuals? With

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regard to TB, the success of many industrialized nations in controlling the resurgence of TB with the advent of HIV demonstrates the importance of DOT, thorough contact investigations, and treatment of LTBI. The dramatic shift in the prognosis of HIV-infected patients from a terminal illness to a chronic disease with excellent quality of life speaks volumes on the success of HAART (197). The issue at hand is how these interventions, which have been hugely successful in industrialized nations, should be applied globally, and what modifications will be necessary to address the different needs of the developing world. The main problem is one of magnitude and resources. The United States, with all its wealth, has tackled a problem of miniscule proportions compared to that faced by other nations. Whereas the estimated number of HIV-infected individuals with TB in the United States is less than 1 per 100,000, many sub-Saharan countries have rates over 200 per 100,000 people (13). This means the widespread implementation of the DOTS strategy, ARV therapy, and treatment of LTBI will require global political commitment and resources. Furthermore, in areas with high rates of TB and HIV where case fatality rates are high, reinfection with TB is common, and many patients are undiagnosed, additional measures such as active case finding for TB and voluntary screening for HIV may be necessary to fully address the overlapping epidemics. As an initial step toward attaining widespread treatment of TB and HIV, it may be useful to utilize already existing programs for TB control. As part of a WHO initiative to combat TB, most developing countries have functional DOTS programs in place. The success of the DOTS strategy lies not only in the direct supervision of therapy, but also on the standardization of TB diagnostics and therapeutic regimens, which can be implemented locally, and, importantly, on sustained political commitment that ensures uninterrupted drug supplies and outcome monitoring. Many have argued that these principles may help direct the upcoming global delivery of ARV therapy (198), whereas others have responded that the enthusiasm for DOT in HIV care may be premature (199). Extrapolating from the TB experience, DOT for HIV could theoretically decrease the emergence of drug resistance, and increase the chances for therapeutic success. Delivery of ARV therapy through a DOT community program in Haiti was very successful, with high rates of adherence and viral load suppression (200). Expansion of ARV therapy in Malawi has been modeled at a national level after the DOTS strategy, which has been successful in controlling TB in developing countries (201). Malawi has an effective DOTS TB control program, which delivers care to 27,000 patients per year based on a simple algorithm of sputum smear microscopy for diagnosis and standardized treatment regimens recommended by the WHO. In a similar fashion, simple criteria based on a positive HIV serology test and clinical staging of HIV as classified by WHO have been developed to assess eligibility for ARV therapy. To ensure rapid countrywide expansion, Malawi has adopted a standardized first-line ARV regimen (stavudine, lamivudine, and nevirapine), with

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alternative second-line regimens offered at specialized centers. As with TB therapy, family members and guardians are educated to encourage the adherence to and compliance with therapy. Finally, the government has adopted a system to monitor ARV therapy and ensure uninterrupted supplies of drugs. Despite the complexity of a public health intervention of such magnitude, it is hoped that the lessons learnt from the TB control programs will facilitate the delivery of urgently needed lifesaving ARV therapy on a large scale. In 2004, WHO developed a policy on collaborative TB/HIV activities, which provides guidance on 12 internationally accepted interventions to decrease the joint burden of TB and HIV (202). The policy does not call for the institution of new disease control programs, but rather it promotes enhanced collaboration between existing TB and HIV programs. The objectives of the policy are to establish mechanisms of collaboration that will decrease the burden of TB in people living with HIV and decrease the burden of HIV in patients with TB. The recommendations can be implemented by TB and HIV programs, nongovernmental organizations, community-based organizations, or the private sector, with the overall supervision of national TB and HIV programs. The 12 specific recommendations are summarized below. It should be noted that given the relatively short experience in addressing the HIV/TB epidemic in developing countries, the evidence supporting collaborative HIV/TB programs is limited and many recommendations are based primarily on expert opinion. 1.

2.

To set up a joint coordinating body for TB/HIV activities effective at all levels Until recently, TB and HIV programs have been largely managed separately. However, the significant overlap of the two diseases necessitates that coinfected patients have access to comprehensive care for both HIV and TB. The joint coordinating bodies would be responsible for ensuring coherence of communications about TB/HIV, training and promoting the participation of health care workers and the community in joint HIV/TB activities, mobilization of resources for joint activities, and collection of data to monitor the effectiveness of collaborative programs. To conduct surveillance of HIV prevalence among patients with tuberculosis WHO has recommended three key methods for surveillance of HIV among TB patients: periodic surveys (cross-sectional surveys among groups of TB patients); sentinel surveys (using TB patients as a sentinel group for HIV); and data from the routine HIV testing and counseling of TB patients. The surveillance method adopted should reflect the underlying HIV and TB epidemic rate in a particular country and the availability of resources for widespread or targeted screening.

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4.

5.

6.

7.

To carry out joint TB/HIV planning For establishing successful and systematic collaborations and avoiding competition for the same resources, TB and HIV programs need joint planning of activities. In particular, joint strategies should include the training of health care workers on HIV/TB issues, the design of TB/HIV advocacy activities and communication programs, the enhancement of community involvement in collaborative activities, and operational research to determine efficient means of implementing joint activities. To monitor and evaluate collaborative TB/HIV activities An essential component of further collaborative strategies is the formal evaluation of those recently implemented. WHO calls for a core set of indicators and data collection tools based on WHO guidelines for monitoring HIV and TB activities. To establish intensified tuberculosis case finding Timely diagnosis and treatment of TB in people living with HIV increases the chance of survival, improves the quality of life, and reduces the transmission of TB to the community. Studies have shown that intensified TB case finding with simple questionnaires can be achieved at little additional cost to existing health services. In a study conducted at a HIV voluntary counseling and testing (VCT) center in Haiti, all patients reporting a cough at presentation were evaluated for pulmonary TB. Of 241 patients evaluated for cough, 76 (32%) were diagnosed with pulmonary TB (203). In South Africa, 438 HIV-infected individuals (mostly women) were actively screened for TB, 49% had a positive tuberculin skin test, and further evaluation of these patients revealed that 11% had active TB (204). To introduce isoniazid preventive therapy Although several studies have shown a reduction in the risk of active TB after treatment of LTBI in HIV-infected persons (18,174,205), a reduction in mortality has not been conclusively demonstrated (6,7). Furthermore, the feasibility of widespread treatment of LTBI in developing countries has not been established. Particularly concerning is the development of isoniazid-resistant M. tuberculosis if active TB is not carefully excluded prior to preventive therapy with isoniazid. WHO recommends that information about LTBI therapy be provided to people living with HIV and that therapy be available for individuals in whom active TB has been safely excluded. To ensure tuberculosis infection control in health care and congregate settings Health care workers (206), prisoners, and military personnel (207) are at increased risk of TB, particularly in the setting of HIV. Measures to reduce TB transmission in congregate settings should include the early recognition, diagnosis, and

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9.

10.

11.

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treatment of TB suspects, isolation of patients with pulmonary TB, maximization of natural ventilation, and, in some instances, the utilization of ultraviolet irradiation. To provide HIV testing and counseling for patients with tuberculosis An important intersection between HIV and TB care is the screening for HIV in patients with TB (208). A majority of patients seeking care for TB do not know their HIV serostatus, and there is evidence from descriptive studies that HIV surveillance among patients with TB can provide useful information about epidemic trends and facilitate timely medical care. Anonymous HIV testing in patients with TB in London showed an HIV seroprevalence of 11.4% (209). In a study from Malawi, 1019 TB patients were offered voluntary counseling and testing for HIV. The majority of patients (964, 91%) underwent HIV testing and the overall seroprevalence rate was 77%. HIVinfected patients were given cotrimoxazole and had a lower adjusted relative risk of death (0.81) than a control group of patients who were neither tested for HIV nor treated with cotrimoxazole (210). WHO recommends that HIV testing and counseling be offered to all TB patients where HIV prevalence among patients with TB is more than 5%, and that all TB control programs provide HIV testing or establish active referrals to HIV testing centers. Informed consent must be obtained prior to testing and confidentiality maximally protected. To introduce HIV prevention methods Measures to reduce sexual, parenteral, and vertical transmission of HIV are essential components of HIV care. WHO recommends that as part of an integrated TB/HIV care approach, TB control programs implement HIV prevention strategies for their patients, including the provision of condoms, screening and treatment of sexually transmitted diseases, utilization of sterilized injection and surgical equipment, referral to drug-dependence services for intravenous drug users, and referral of HIV-positive pregnant women to centers that provide therapy to prevent mother-to-child transmission of HIV. To introduce co-trimoxazole preventive therapy Several trials have shown a reduced mortality among HIVinfected patients with TB treated with co-trimoxazole (109,210– 212). The administration of co-trimoxazole by TB/HIV programs to people living with HIV who have active TB is feasible and safe, and is strongly encouraged by the WHO. To ensure HIV/AIDS care and support Access to health care for HIV-positive individuals is a basic human right and a crucial component of any HIV intervention. TB control programs must establish a referral linkage with HIV programs to provide comprehensive care and support for patients

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with TB co-infected with HIV. Directly observed ARV therapy modeled after TB control programs have been successfully used in small-scale interventions of HIV therapy (200,213). To introduce antiretroviral therapy Studies show that despite a relatively high risk of adverse drug reactions and immune reconstitution, in patients with TB and advanced HIV, ARV therapy should not be delayed unnecessarily, due to a high mortality from other opportunistic infections without improvement in immune function. Given that in some areas of Africa, 60% of TB patients have HIV (mostly untreated) (19), many patients receiving TB therapy through DOT programs may meet the criteria for treatment with ARVs during the first few months of TB therapy. Coadministration of TB therapy and ARV therapy through established DOT programs may facilitate a patient’s introduction to ARV therapy, especially, during the period of highest risk of complications. However, there are conflicting opinions and scarce data about the effectiveness of this strategy (198,199,213). At a minimum, TB/HIV programs must establish mechanisms to provide ARV therapy to HIV-infected patients with TB, who meet WHO treatment criteria. Simple algorithms should be developed to address drug toxicity, drug interactions, and the immune reconstitution syndrome.

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113. WHO. Treatment of tuberculosis: guidelines for national programmes. WHO/ HTM/TB/2004.313, 2003. 114. Yee D, Valiquette C, Pelletier M, Parisien I, Rocher I, Menzies D. Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active tuberculosis. Am J Respir Crit Care Med 2003; 167:1472–1477. 115. Kuaban C, Bercion R, Koula-Shiro S. Current HIV seroprevalence rate and incidence of adverse skin reactions in adults with pulmonary tuberculosis receiving thiacetazone-free antituberculosis treatment in Yaounde, Cameroon. Cent Afr J Med 1998; 44:34–37. 116. Nunn P, Kibuga D, Gathua S, et al. Cutaneous hypersensitivity reactions due to thiacetazone in HIV-1 seropositive patients treated for tuberculosis. Lancet 1991; 337:627–630. 117. Dean GL, Edwards SG, Ives NJ, et al. Treatment of tuberculosis in HIVinfected persons in the era of highly active antiretroviral therapy. AIDS 2002; 16:75–83. 118. El-Sadr WM, Perlman DC, Denning E, Matts JP, Cohn DL. A review of efficacy studies of 6-month short-course therapy for tuberculosis among patients infected with human immunodeficiency virus: differences in study outcomes. Clin Infect Dis 2001; 32:623–632. 119. Connolly C, Reid A, Davies G, Sturm W, McAdam KP, Wilkinson D. Relapse and mortality among HIV-infected and uninfected patients with tuberculosis successfully treated with twice weekly directly observed therapy in rural South Africa. AIDS 1999; 13:1543–1547. 120. Narita M, Hisada M, Thimmappa B, et al. Tuberculosis recurrence: multivariate analysis of serum levels of tuberculosis drugs, human immunodeficiency virus status, and other risk factors. Clin Infect Dis 2001; 32:515–517. 121. Vernon A, Burman W, Benator D, Khan A, Bozeman L. Acquired rifamycin monoresistance in patients with HIV-related tuberculosis treated with once-weekly rifapentine and isoniazid. Tuberculosis Trials Consortium. Lancet 1999; 353:1843–1847. 122. CDC. Acquired rifamycin resistance in persons with advanced HIV disease being treated for active tuberculosis with intermittent rifamycin-based regimens. Morb Mortal Wkly Rep 2002; 51:214–215. 123. Sandman L, Schluger NW, Davidow AL, Bonk S. Risk factors for rifampinmonoresistant tuberculosis: a case-control study. Am J Respir Crit Care Med 1999; 159:468–472. 124. Nettles RE, Mazo D, Alwood K, et al. Risk factors for relapse and acquired rifamycin resistance after directly observed tuberculosis treatment: a comparison by HIV serostatus and rifamycin use. Clin Infect Dis 2004; 38:731–736. 125. Peloquin CA, Nitta AT, Burman WJ, et al. Low antituberculosis drug concentrations in patients with AIDS. Ann Pharmacother 1996; 30:919–925. 126. Sahai J, Gallicano K, Swick L, et al. Reduced plasma concentrations of antituberculosis drugs in patients with HIV infection. Ann Intern Med 1997; 127:289–293. 127. Taylor B, Smith PJ. Does AIDS impair the absorption of antituberculosis agents? Int J Tuberc Lung Dis 1998; 2:670–675. 128. Sheehan N, Richter C, Koopmans P, Burger D. Efavirenz is not associated with subtherapeutic EFV concentrations when given concomitantly with rifampin. 6th International Workshop on Clinical Pharmacology of HIV Therapy, Quebec, 2005. 129. Manosuthi W, Kiertiburanakul S, Sungkanuparph S, et al. Efavirenz 600 mg/day versus efavirenz 800 mg/day in HIV-infected patients with tuberculosis receiving rifampicin: 48 weeks results. AIDS 2006; 20:131–132.

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146. Starke JR. Diagnosis of tuberculosis in children. Pediatr Infect Dis J 2000; 19:1095–1096. 147. Colditz GA, Brewer TF, Berkey CS, et al. Efficacy of BCG vaccine in the prevention of tuberculosis. Meta-analysis of the published literature. JAMA 1994; 271:698–702. 148. Moss WJ, Clements CJ, Halsey NA. Immunization of children at risk of infection with human immunodeficiency virus. Bull World Health Organ 2003; 81:61–70. 149. Talbot EA, Perkins MD, Silva SF, Frothingham R. Disseminated Bacille CalmetteGuerin disease after vaccination: case report and review. Clin Infect Dis 1997; 24:1139–1146. 150. Hesseling AC, Schaaf HS, Hanekom WA, et al. Danish Bacille Calmette-Guerin vaccine-induced disease in human immunodeficiency virus-infected children. Clin Infect Dis 2003; 37:1226–1233. 151. Archibald LK, Kazembe PN, Nwanyanwu O, Mwansambo C, Reller LB, Jarvis WR. Epidemiology of bloodstream infections in a Bacille Calmette-Guerin-vaccinated pediatric population in Malawi. J Infect Dis 2003; 188:202–208. 152. Waddell RD, Lishimpi K, von Reyn CF, et al. Bacteremia due to Mycobacterium tuberculosis or M. bovis, Bacille Calmette-Guerin (BCG) among HIV-positive children and adults in Zambia. AIDS 2001; 15:55–60. 153. WHO. Core information for the development of vaccine policy, 2002 update. WHO/V&B/02.28, 2002. 154. Coronado VG, Beck-Sague CM, Hutton MD, et al. Transmission of multidrugresistant Mycobacterium tuberculosis among persons with human immunodeficiency virus infection in an urban hospital: epidemiologic and restriction fragment length polymorphism analysis. J Infect Dis 1993; 168:1052–1055. 155. Frieden TR, Sherman LF, Maw KL, et al. A multi-institutional outbreak of highly drug-resistant tuberculosis: epidemiology and clinical outcomes. JAMA 1996; 276:1229–1235. 156. Moro ML, Gori A, Errante I, et al. An outbreak of multidrug-resistant tuberculosis involving HIV-infected patients of two hospitals in Milan, Italy. AIDS 1998; 12:1095–1102. 157. Ritacco V, Di Lonardo M, Reniero A, et al. Nosocomial spread of human immunodeficiency virus-related multidrug-resistant tuberculosis in Buenos Aires. J Infect Dis 1997; 176:637–642. 158. Vanacore P, Koehler B, Carbonara S, et al. Drug-resistant tuberculosis in HIVinfected persons: Italy 1999–2000. Infection 2004; 32:328–332. 159. Ferdinand S, Sola C, Verdol B, et al. Molecular characterization and drug resistance patterns of strains of Mycobacterium tuberculosis isolated from patients in an AIDS counseling center in Port-au-Prince, Haiti: a 1-year study. J Clin Microbiol 2003; 41:694–702. 160. Mac-Arthur A, Gloyd S, Perdigao P, Noya A, Sacarlal J, Kreiss J. Characteristics of drug resistance and HIV among tuberculosis patients in Mozambique. Int J Tuberc Lung Dis 2001; 5:894–902. 161. Punnotok J, Shaffer N, Naiwatanakul T, et al. Human immunodeficiency virusrelated tuberculosis and primary drug resistance in Bangkok, Thailand. Int J Tuberc Lung Dis 2000; 4:537–543. 162. Campos PE, Suarez PG, Sanchez J, et al. Multidrug-resistant Mycobacterium tuberculosis in HIV-infected persons, Peru. Emerg Infect Dis 2003; 9:1571–1578. 163. Dye C, Espinal MA, Watt CJ, Mbiaga C, Williams BG. Worldwide incidence of multidrug-resistant tuberculosis. J Infect Dis 2002; 185:1197–1202. 164. Dehne KL, Khodakevich L, Hamers FF, Schwartlander B. The HIV/AIDS epidemic in Eastern Europe: recent patterns and trends and their implications for policy-making. AIDS 1999; 13:741–749.

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181. CDC. Fatal and severe hepatitis associated with rifampin and pyrazinamide for the treatment of latent tuberculosis infection. Morb Mortal Wkly Rep 2001; 50: 289–291. 182. McNeill L, Allen M, Estrada C, Cook P. Pyrazinamide and rifampin versus isoniazid for the treatment of latent tuberculosis: improved completion rates but more hepatotoxicity. Chest 2003; 123:102–106. 183. Jasmer RM, Saukkonen JJ, Blumberg HM, et al. Short-course rifampin and pyrazinamide compared with isoniazid for latent tuberculosis infection: a multicenter clinical trial. Ann Intern Med 2002; 137:640–647. 184. CDC. Update: adverse event data and revised American Thoracic Society/ CDC recommendations against the use of rifampin and pyrazinamide for the treatment of latent tuberculosis infection. Morb Mortal Wkly Rep 2003; 52: 735–739. 185. Priest DH, Vossel LF Jr., Sherfy EA, Hoy DP, Haley CA. Use of intermittent rifampin and pyrazinamide therapy for latent tuberculosis infection in a targeted tuberculin testing program. Clin Infect Dis 2004; 39:1764–1771. 186. van Hest R, Baars H, Kik S, et al. Hepatotoxicity of rifampin-pyrazinamide and isoniazid preventive therapy and tuberculosis treatment. Clin Infect Dis 2004; 39: 488–496. 187. Gordin FM, Cohn DL, Matts JP, Chaisson RE, O’Brien RJ. Hepatotoxicity of rifampin and pyrazinamide in the treatment of latent tuberculosis infection in HIV-infected persons: is it different than in HIV-negative persons? Clin Infect Dis 2004; 39:561–565. 188. Saukkonen J. Rifampin and pyrazinamide for latent tuberculosis infection: clinical trials and general practice. Clin Infect Dis 2004; 39:566–568. 189. Slovis BS, Plitman JD, Haas DW. The case against anergy testing as a routine adjunct to tuberculin skin testing. JAMA 2000; 283:2003–2007. 190. Girardi E, Palmieri F, Zaccarelli M, et al. High incidence of tuberculin skin test conversion among HIV-infected individuals who have a favourable immunological response to highly active antiretroviral therapy. AIDS 2002; 16: 1976–1979. 191. McGregor MM, Olliaro P, Wolmarans L, et al. Efficacy and safety of rifabutin in the treatment of patients with newly diagnosed pulmonary tuberculosis. Am J Respir Crit Care Med 1996; 154:1462–1467. 192. WHO. Preventive therapy against tuberculosis in people living with HIV. Wkly Epidemiol Rec 1999; 74:385–398. 193. Mosimaneotsile B, Talbot EA, Moeti TL, et al. Value of chest radiography in a tuberculosis prevention programme for HIV-infected people, Botswana. Lancet 2003; 362:1551–1552. 194. Greenberg SD, Frager D, Suster B, Walker S, Stavropoulos C, Rothpearl A. Active pulmonary tuberculosis in patients with AIDS: spectrum of radiographic findings (including a normal appearance). Radiology 1994; 193:115–119. 195. Swaminathan S, Paramasivan CN, Kumar SR, Mohan V, Venkatesan P. Unrecognised tuberculosis in HIV-infected patients: sputum culture is a useful tool. Int J Tuberc Lung Dis 2004; 8:896–898. 196. Palmieri F, Girardi E, Pellicelli AM, et al. Pulmonary tuberculosis in HIV-infected patients presenting with normal chest radiograph and negative sputum smear. Infection 2002; 30:68–74. 197. Palella FJ Jr., Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med 1998; 338:853–860.

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14 Diagnosis and Treatment of Multidrug-Resistant Tuberculosis

MICHAEL LEONARD RICH Partners in Health, Division of Social Medicine and Health Inequalities, Brigham and Women’s Hospital, Boston, Massachusetts, U.S.A.

I. Introduction The goals of tuberculosis (TB) control programs are to cure patients with disease due to infection of Mycobacterium tuberculosis, prevent the development of new cases, and prevent the emergence of drug resistance. Nevertheless, drug-resistant TB is bound to appear in even the best-run programs. There is considerable evidence that drug resistance has emerged and is on the upsurge in many parts of the world (1). This chapter focuses on the care of patients with drug-resistant TB and examines the origins, prevention, diagnosis, and impact of drug resistance on TB control. II. History Resistance to anti-TB agents was first documented in the 1940s, when patients who initially responded to monotherapy with streptomycin, the only available medication at the time, relapsed with disease that was clearly resistant to the drug (2–4). By 1950, the manufacturer recognized that the administration of streptomycin alone caused most cases of TB to become resistant to it after two to four months of therapy (5). It was later documented that strains with acquired resistance did not revert to a susceptible 417

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phenotype, even after the drug in question was no longer administered. Unless new anti-TB drugs were administered and/or localized lesions surgically resected, the disease took its course, leading too often to early death. Soon it was determined that para-aminosalicylic acid (PAS) given in combination with streptomycin prevented or postponed the development of resistance. This finding eventually led to the principle of treatment with multiple drugs at the same time. New anti-TB drugs have been developed, and today regimens for multidrug-resistant tuberculosis (MDR-TB), defined as resistance to at least isoniazid and rifampicin, often consist of four to six anti-TB agents (6). Today, with timely and appropriate therapy (including, when appropriate, resectional surgery), MDR-TB can be cured. Although not all programs and studies have reported favorable results, promising cure rates of 66% to 100% have been documented in countries with low [United States (7–9), Canada (10), New Zealand (11), the Netherlands (12), Denmark (13)] as well as high [South Korea (14), Turkey (15), Hong Kong (16), Peru (17), Bangladesh (18), and Latvia (19)] TB burdens. III. Mechanisms of Resistance The terms mono-, poly-, and multidrug resistance have been traditionally used in the Western medical literature. Monoresistance is defined as resistance to only one anti-TB agent; polyresistance is defined as resistance to more than one anti-TB agent but not to both isoniazid and rifampicin; and multidrug resistance as resistance to at least isoniazid and rifampicin. Mycobacteria achieve drug resistance through three basic mechanisms: (i) the creation of a lipid-rich cell wall that can reduce the permeability of drugs; (ii) the production of enzymes that degrade or modify compounds, rendering them useless; and (iii) spontaneous chromosomal mutations of key drug targets (20). The third mechanism, the development of drug resistance in M. tuberculosis through random genetic mutations, is considered the most significant. In any large population of M. tuberculosis bacille, there are naturally occurring mutants; there is no mobile resistance factor (i.e., no plasmid mechanism) as seen with gram-negative rods. The mutations are unlinked and occur at low but predictable frequencies in the range of one mutation per 106 to 109 replications. In clinical practice, acquired resistance occurs when the patient is originally infected with a drug-susceptible strain and, through inadequate therapy, develops resistance. Inadequate therapy may be due to patient noncompliance, physician error (suboptimal dosing, insufficient number of active agents, noncompliance with established guidelines, or absence of guidelines), lack of access or stock-outs of medications, poor drug absorption, or the organizational failure of the TB control program. Patient nonadherence is often considered the most common cause of acquired drug resistance (21); however, it has also been argued that the noncompliant patient’s contribution to acquired resistance is minimal (22–24). In fact, the organizational failure of TB programs, lack of available drugs, and

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physician error are likely to be the significant contributors to acquired resistance. Once the patient’s bacterial population is resistant to a single drug, any subsequent inadequate treatment (i.e., treatment regimens that may have only one or two effective agents) may cause further acquired resistance. The result is that strains resistant to one or two agents can become sequentially resistant to several agents if the initial resistance is not recognized and addressed. When drug resistance develops, patients may transmit resistant strains to others who then present with preformed or ‘‘primary’’ drug resistance. If drug-susceptibility testing (DST) is done before the start of the patient’s first TB treatment, any resistance documented is primary resistance. If additional resistance is found when DST is later repeated and genetic testing confirms that it is the same strain, it can be concluded that the strain has acquired resistance. If either DST or genetic testing is not available, it is impossible to distinguish acquired resistance from primary resistance. Therefore, in most settings around the world, acquired resistance is not distinguishable from primary resistance. IV. Cross-Resistance There is well-known cross-resistance between some of the antibiotics used to treat TB. Resistance mutations to one anti-TB drug may confer resistance to some or all members of its drug family and, less commonly, to members of different antibiotic families. For example, resistance to the aminoglycoside kanamycin is associated with high cross-resistance to the similar aminoglycoside amikacin (25,26). In contrast, cross-resistance between the aminoglycosides kanamycin and streptomycin is generally low (27,28). TB isolates that are resistant to kanamycin at high doses may be resistant to capreomycin, a nonaminoglycoside (peptide antibiotic). The cross-resistance between lower and higher generation fluoroquinolones does not appear complete (29–35); however, the clinical implications of this are not yet fully understood. There is partial cross-resistance between isoniazid and thiacetazone (36,37), and isoniazid and ethionamide (38–42). There is almost complete cross-resistance between rifampicin and rifabutin (43–46). V. Pathogenicity, Transmissibility, and Drug Resistance Resistant strains of TB have traditionally been considered less pathogenic, also referred to as less virulent (i.e., less likely to result in a progressive disease in persons infected with such strains). This assumption was primarily based on the observation by Cohn et al. that virulent strains of M. tuberculosis, when selectively bred in the laboratory for high-level resistance to isoniazid, became significantly less capable of producing infection in animal models (47). The technique used to select these particular mutants was

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associated with the loss of catalase enzyme activity by the bacille; the catalase was either a direct or a surrogate indicator of attenuated virulence (48). Some studies have attempted to compare the transmissibility of MDRTB and drug susceptible strains. A small cluster study by Garcia-Garcia et al. (49) examined 25 MDR-TB cases and revealed that drug-resistant strains had a decreased propensity to cluster. Clustering is associated with recent transmission, and less clustering could be explained either by decreased ability of the MDR-TB strains to infect individuals (decreased transmissibility), or by decreased ability of the strains to cause disease once the individual has been infected (decreased pathogenicity). A study by Burgos et al. demonstrated, in the context of an effective TB program in San Francisco, that strains, which were resistant to isoniazid either alone or in combination with other drugs, were less likely to result in secondary cases than were drugsusceptible strains (50). However, there is substantial evidence that MDR-TB strains are not always less pathogenic or transmissible (51). There are many examples of normal hosts who, once infected with strains resistant to isoniazid, develop serious, even lethal, disease. The classic study is the 1996 report on the multi-institutional spread of the notorious ‘‘strain W’’ in New York City in the early 1990s. This study provides insight into the nature of isoniazid resistance and virulence (52). Contrary to traditional assumptions, the ‘‘W’’ strain is catalase positive and grows rapidly in both culture medium and animals despite mutations at the katG locus (48). Furthermore, epidemiological data from the field confirms that resistance is not always accompanied by decreased transmission. Snider et al. performed a retrospective case control analysis to compare the likelihood of contact infection by patients with drug-susceptible versus drug-resistant strains. They observed that overall tuberculin skin-test conversion rates were comparable for young, high-risk persons whether they were contacts of susceptible or resistant cases (33.6% and 39.8%, respectively). Among those who had contact with drug-resistant cases with prior treatment, the risk of conversion was even higher (49%), presumably reflecting extended periods of exposure. In addition, the attack rate of active infection did not differ statistically whether the patient was in contact with a drug-susceptible or a drug-resistant case [6 of 252 (2.38%) vs. 4 of 239 (1.67%), respectively] (53). Even if MDR-TB is less transmissible or less pathogenic, MDR-TB cases can nevertheless generate more secondary cases than pan-sensitive strains because they remain infectious for longer, owing both to the lower cure rates and to the fact that treatment is often inadequate. Furthermore, it is highly likely that the relative fitness of MDR-TB strains is heterogeneous, with some strains being less and others more fit. Through mathematical modeling, Cohen and Murray (54) demonstrated that, even when the average fitness of MDR-TB strains is lower, a small subpopulation of a relatively fit strain may eventually outcompete both the drug-sensitive strains and the less-fit MDR-TB strains. Blower and Chou (55) have used models to show

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that, even when MDR-TB strains are less fit (and thus less transmissible and/ or less pathogenic) than pan-sensitive strains, hot zones for MDR-TB can emerge. They concluded that MDR-TB levels are driven by case-finding rates, cure rates, and amplification probabilities, rather than by just strain fitness. Overall, there is a preponderance of evidence indicating that current drug-resistant strains can produce progressive disease in both normal and immunosuppressed contacts. New studies examining transmission patterns in urban settings (56–61) and nosocomial transmissions (62–66) have reported unexpectedly high rates of recently transmitted disease among MDR-TB patients. These studies underscore the point that the transmissibility of MDR-TB should not be dismissed, and indicate that the treatment of active MDR-TB cases and investigation of the contacts of MDR-TB patients should be a high priority. A. Impact of Drug Resistance on Tuberculosis Control

Many areas of the world are recording alarmingly high MDR-TB rates. The World Health Organization (WHO) estimates that 50 million people are infected with strains resistant to at least one first-line anti-TB agent (67). Estimates of the worldwide incidence of MDR-TB are not well characterized. One WHO study (68) estimated the incidence in year 2000 to be 273,000 (95% CI 180,000–400,000) cases. The mathematical model from the study estimated that 3.2% of all TB cases diagnosed worldwide are drug resistant. A 2004 WHO/IUALTD report on the global scope of MDR-TB confirms that many areas of the world are facing epidemics of drug-resistant TB. The report states that the percentage of retreatment cases in a national TB program is an indicator of program performance, and multivariate analysis indicates that the proportion of cases being retreated was significantly associated with mono-, poly-, and multidrug resistance (1). More discussions of the dynamics of drug resistance in the world can be found in Chapter 32. MDR-TB is clearly already endemic and is threatening to undermine recent gains in some settings with excellent national TB control programs (e.g., Peru) as well as in settings where TB programs are currently being expanded (e.g., India). Once MDR-TB strains are well established in a population, short-course chemotherapy (SCC) will fail to cure a growing proportion of TB patients. The WHO category II retreatment regimen, when used in MDR-TB cases, has been documented to be successful in a very low percentage of patients—on an average, 29% in data from six different countries (69). Close to 30% of MDR-TB cases that are deemed cured with SCC under WHO outcome definitions later relapse (70). Furthermore, there is evidence that challenging drug-resistant strains with SCC actually amplifies already-existing resistance to first-line drugs, known as the ‘‘amplifier effect of short-course therapy (71,72).’’ Most MDR-TB cases in the world are resistant to three or four drugs (1), the repeated use of categories I and II treatment regimens in patients with drug-resistant TB has most certainly played a role.

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Incidence rates of MDR-TB as high as 14.2% in new cases have been reported in some areas (1). Blower and Chou (55) determined that MDRTB prevalence can be three times greater than its incidence; their model indicates that some areas will develop prevalence rates of MDR-TB as high as 40%. These alarming prevalence rates are not just theoretical and have in fact been seen in settings such as Tomsk, Russia, where 530 (40.6%) of the 1302 registered prevalent smear-positive TB cases had multidrug-resistant strains in 2001 (Pasechnikov AD. Medical Director Tomsk Project, Partners In Health, Tomsk, Russia. Personal communication, 2003). Some authors have proposed using certain cutoff points (e.g. 1.5% MDR-TB in new cases) where MDR-TB should be considered less of a program priority (73). However, the cutoff point for when universal SCC will lead to treatment failure in a significant proportion of patients, and thus compromise DOTS program performance, remains unclear. The author of this chapter believes that good TB control programs should not let MDR-TB go unchecked and untreated in any circumstance. The interaction between MDR-TB and HIV is addressed later in this chapter; however, it is worth mentioning that there have been numerous outbreaks with documented dismal outcomes for coinfected individuals (74). Prompt diagnosis and treatment of coinfected patients may decrease these outbreaks and improve outcomes. There is a reason to believe that HIV will have a similar effect on MDR-TB as it has on fueling the TB epidemic in general. Because MDR-TB is not readily contained by national borders, hospital walls, or prison bars, the full impact of the outbreaks that have been documented worldwide are yet to be fully felt. A universal strategy that includes appropriate treatment of all TB patients may be the best way to prevent resistance from overwhelming TB control efforts. This requires the coordination of many partners and is described in more detail in Chapter 33 on programmatic MDR-TB management (DOTS-Plus Programs). VI. Preventing the Evolution and Transmission of Drug Resistance Although there is no known way to completely prevent mutations that give rise to drug resistance, adequate TB treatment can minimize the selection of resistance in both treatment-naive patients and those undergoing retreatment (75). Assurance of top-notch adherence to appropriate regimens is essential, as is the prevention of exposure to MDR-TB strains through proper infection-control measures. The role of the bacille Calmette–Gue´rin (BCG) vaccine and of preventive therapy in preventing MDR-TB is less clear. A. Appropriate Regimens

Using multiple drugs for TB treatment is now the accepted standard of care. Appropriate regimens for drug-susceptible TB are described in Chapter 8 of this book. For drug-resistant TB, a regimen based on reliable DST and

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a review of treatment history is the gold standard of care. When MDR-TB is not suspected, a regimen that includes only first-line medications is appropriate while awaiting DST. If there is a possibility of primary resistance, a more ample regimen that includes both first- and second-line drugs is indicated. Empirical and definitive regimens are discussed in more detail in the treatment section of this chapter. Inappropriate regimens can lead not only to poor outcomes, but also to amplification or acquired drug resistance (76). The use of multiple courses of first-line drugs despite repeated treatment failures has resulted in loss of susceptibility to all first-line drugs. This amplification effect has been documented in a research by Farmer et al. in Peruvian patients (77) and by Rigouts and Portaels in Rwandan patients (78). B. Assurance of Adherence

A treatment regimen is effective only if it is taken correctly. Resistance can emerge if a patient takes only a reduced (ineffective) dose or omits one or more drugs (75). Treatment completion rates for pulmonary TB are most likely to exceed 90% when treatment is based on a patient-centered approach incorporating directly observed therapy (DOT) with multiple enablers and enhancers (79,80). DOT also appears to be cost-effective when compared to self-administered therapy, although cost-effectiveness data is limited (80). C. Exposure Prevention and Infection Control

Adequate infection control requires a number of complementary interventions and is discussed elsewhere in this book. Special considerations should be included for MDR-TB suspects and documented MDR-TB patients. Implementing infection control measures is a high priority in preventing the spread of MDR-TB. D. Bacille Calmette–Gue´rin Vaccination

Some experts advocate BCG vaccination for those who have not had the vaccination, are tuberculin skin test negative, and will have unavoidable contact with MDR-TB patients in the future. For example, in two large MDR-TB treatment projects administered by Partners In Health, care providers who fit these criteria are vaccinated. However, not all experts are in agreement with this approach. The debate is focused around the uncertain efficacy of BCG; the fact that BCG makes the tuberculin test uninterpretable and therefore limits identification of new infections and the option for chemoprophylaxis; and questions of whether persons will accept the ulcer and subsequent scarring that result from the BCG vaccine (81). A study that compared the utility of BCG vaccination with postexposure chemoprophylaxis with pyrazinamide and ciprofloxacin found that vaccination was favored by a small margin, provided the efficacy of the vaccine was greater than 26% (82).

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The pros and cons of secondary prevention for contacts of MDR-TB patients are discussed in Chapter 10, Treatment of Latent TB Infection. VII. Multidrug-Resistant Tuberculosis Diagnosis Early identification and appropriate treatment of MDR-TB cases will interrupt the transmission cycle, prevent death, and limit morbidity. The only way to confirm MDR-TB diagnosis is to perform DST on cultures and demonstrate resistance to at least isoniazid and rifampicin. A. Identification of Multidrug-Resistant Tuberculosis Patients

Assuming adequate resources and technical capacity, in order to assure identification of MDR-TB cases, all patients should be tested for susceptibility to at least H, R, ethambutol (E), and streptomycin (S) prior to treatment initiation. If drug resistance is found, testing of a full panel of second-line drugs and the first-line drug pyrazinamide (z) may be indicated. For patients who are initially tested as pan-susceptible, a repeat DST is indicated if they have persistently positive acid-fast bacille smear or culture or clinical progression of TB while on therapy. Rapid tests for resistance are becoming the standard of care in most areas with the resources to do so. Often, rapid tests are used to identify resistance to either isoniazid and rifampicin, or only rifampicin. Currently there are many options for rapid drug-susceptibility testing, including genetic tests to identify the gene (rpoB) associated with rifampicin resistance as a surrogate marker of MDR-TB, utilization of bacteriophage-based assays (e.g., FASTPlaque-TB1) to identify growing mycobacteria in the presence of isoniazid or rifampicin, and a number of liquid or solid media that report susceptibility profiles in just a few weeks [radiometric semiautomated BACTEC1 system (Becton Dickinson, Franklin Lakes, New Jersey, U.S.A.); nonradiometric automated systems of Mycobacterial Growth Indicator Tube or MGIT1 (Becton Dickinson, Franklin Lakes, New Jersey, U.S.A.); Bacti-Alert1 (Organon Technika Co., Durham, North Carolina, New Jersey, U.S.A.); colorimetric methods including TK Medium1, alamar blue methods, microscopic observation direct susceptibility methods; and others]. Some of these diagnostics have not yet been field-tested comprehensively in low-resource settings and further standardization studies are needed for many of the newer techniques for drugs other than isoniazid and rifampicin. More information on rapid DST is presented in Chapter 2. In some areas, resources to perform DST may be limited. In such settings, only patients with suspected MDR-TB should have their sputum sent for culture and DST. Figure 1 lists the categories of patients for whom DST is a priority, in descending order of higher-to-lower risk. Patients in whom treatment is failing or has recently failed under DOT and with rifampicin in the continuation phase may have extremely high MDR-TB rates (see

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Figure 1 Groups of patients for targeted drug susceptibility testing in low-resource areas. Abbreviations: DST, drug-susceptibility testing; SCC, short-course chemotherapy; MDR, multidrug-resistant.

Section VIII.D. on standardized regimens for a more detailed discussion of the probability of having MDR-TB after failing a first-line drug regimen). In addition, close contacts of MDR-TB patients are very likely to have MDRTB and DST profiles similar to that of the index case (also see Section VIII. C. ‘‘Choice of Empiric Treatment Regimen’’ for a more lengthy discussion on the probability of a contact case having MDR-TB). DST is strongly recommended for all TB/HIV coinfected patients, because unidentified MDR-TB is especially lethal in this population. It is likely that HIV patients in some settings have an increased risk of developing

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drug resistance (83,84) but other surveillance data indicate that globally, HIV is not an independent risk factor for drug-resistant TB (1). More MDR-TB epidemiological surveillance in HIV-infected patients is needed to fully assess whether drug-resistance rates are growing in coinfected patients. B. Drug-Susceptibility Testing

Reliable and valid DST is essential for optimal MDR-TB treatment. Many regional laboratories are only able to perform susceptibility testing for four first-line drugs: H, R, E, and S. Pyrazinamide-susceptibility testing is especially challenging and cannot be done using conventional methods based on solid media. Typically, second-line drug susceptibility is tested in specialized centers or supranational reference laboratories (SRLs). Regular quality control of results is required in all laboratories. In general, susceptibility testing for second-line anti-TB drugs is not as simple as testing for some first-line drugs, partly because critical drug concentrations defining resistance are much closer to the minimal inhibitory concentrations in the former than in the latter. Nonetheless, reasonably consistent, clinically validated criteria for drug resistance testing were determined almost 50 years ago, for the proportion method on Lowenstein-Jensen medium for kanamycin, capreomycin, viomycin, D-cycloserine, ethionamide, and PAS (Laszlo A. World Health Organization, Geneva. Personal communications, 2004). Guidelines for DST on second-line drugs are also available (85,86). There has been much debate, some of it unfounded, on the reliability (the ability of the results to be consistently reproducible) of second-line DST. Kim et al. have recently speculated that in a survey of SRLs, criteria for the second-line drug resistance are so different as to preclude any possibility of concordance (87). Ignored is the fact that different methods use different criteria; a finer data analysis indicates that most of the surveyed SRLs were fairly consistent in the drug-resistance criteria used in the proportion method on L.J and Middlebrook 7H10, 7H11 media, in addition to being consistent with what is recommended in the literature (85,86). Nonetheless, it is true that proficiency metrics equivalent to those obtained for first-line drug testing are not available for second-line drug testing. Without such data, little can be said about the reliability of second-line DST. Fortunately a proficiency-testing exercise among SRLs to evaluate the reproducibility of DST is currently under way (87). Even if the reliability for anti-TB DST is determined to be adequate under standardized testing methods, the validity (the correlation between testing resistant and the lack of clinical efficacy of a drug) for many drugs is not well characterized. More studies to better determine the clinical usefulness of pyrazinamide, ethambutol, and second-line DST are needed. In summary, while many uncertainties exist about the reliability and validity of DST, these do not negate the usefulness of in vitro susceptibility testing for anti-TB drugs; many treatment facilities and programs have obtained adequate outcome results with regimens based on first- and

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second-line DST (6). Any DST results should be interpreted with care, taking into consideration local resistance prevalence, the patient’s drug history, and the quality of the testing laboratory. The need persists for improving and better understanding the methodologies presently in use. C. Prior Anti-TB Treatment History

Although DST is an important component in identifying the patient with drug resistance, the use of a good medical history, which includes all previous anti-TB treatments, outcomes of treatments, and DST patterns of contacts, can also help identify patients with drug resistance. The treatment history and contact history should always be used together with the DST results to help determine whether a drug may be effective against the infecting strain in a patient. This is further discussed below in Section VIII. ‘‘Multidrug-Resistant Tuberculosis Treatment.’’ VIII. Multidrug-Resistant Tuberculosis Treatment A thorough treatment history, knowledge of local drug resistance patterns, and reliable DST results are key inputs in designing an appropriate MDRTB treatment regimen. Patients harboring strains resistant to both isoniazid and rifampicin (MDR-TB) are at a high risk for treatment failure and acquired resistance if they are not promptly placed on adequate regimens. Definitive randomized or controlled trials have not been performed on patients with different drug-resistance patterns. In fact, to date there have been very few randomized trials directly comparing two MDR-TB treatment regimens in blinded controlled studies. Regimen design is thus based on a mixture of nonideal evidence, general principles, extrapolations, and expert opinions (86). A. Principles of Treatment and Medications

Second-line drugs for the treatment of MDR-TB are more toxic, not as efficacious, and must be administered for longer periods of time than their first-line counterparts. It is recommended that treatment be supervised by a physician specialized in drug-resistant TB, although treatment programs that depend on highly trained nurses and health promoters have also been successful (17,88). The main consideration lies in the choice between a standardized regimen, where all patients in a specific group receive the same regimen and DST is not done for all individuals; or individualized regimens, where treatment is based on each patient’s DST profile (an empiric regimen is used while awaiting DST results). The following is a list of general principles for the treatment of MDR-TB patients using either a standardized or an individualized approach:



Early detection and prompt initiation of treatment are critical factors in ensuring successful outcomes. Treatment regimens should take into consideration the patient’s treatment history. If a patient has taken a drug for an extended

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period of time (generally defined as longer than one month) with persistently positive smears or cultures, the patient’s TB should be considered resistant to that drug even if DST reports indicate susceptibility. Care providers should take into consideration local treatment practices and the history of drug availability in the population, including commonly used drugs and first- and second-line drugresistance patterns. Treatment regimens should consist of at least four effective drugs, and preferably five. When the susceptibility pattern is unknown, or drug efficacy unclear for whatever reason, as many as six or seven drugs may be used. Recently, a study from Latvia (19) showed that the use of five or fewer drugs for three months or more was an independent predictor of poor outcome. In the initial phase of treatment, drugs are administered for six to seven days per week, usually twice a day (to lessen the side effects). In later phases, the drugs are generally given six days a week; however, some programs have given drugs in later phases of treatment, five times a week. When possible, pyrazinamide and ethambutol should be given daily if they are included in the treatment regimen, because the high peaks attained in once-a-day dosing may be more efficacious. Once-a-day dosing is acceptable for other second-line drugs depending on patient tolerance, but data on the relative efficacy of once-a-day dosing versus twice-a-day dosing with some drugs is unclear. Drug dosage should be determined by a patient’s weight, and highend doses are suggested (Table 1). Some drugs (thioamides, cycloserine, and PAS) should be introduced at lower doses and increased over 3 to 10 days. If available, pharmacokinetic studies (drug serum level testing) can be performed to determine the optimal dosing for maximal serum concentrations in the therapeutic range and to avoid levels above the therapeutic range that may be more likely to cause side effects. An injectable agent (an aminoglycoside or capreomycin) should be used for a minimum of six months and the treatment with other drugs should last for 24 months (see below for more discussion on length of injectable agent and treatment). DOT should be used for all patients for the entire duration of treatment. Strong patient support and aggressive management of side effects should be available. The use of drugs that have demonstrated in vitro resistance is not recommended (assuming the laboratory testing is accurate), especially when alternative medicines are available. An exception may be in patients whose strain tests resistant to low level isoniazid but is susceptible to high concentrations (greater than 1.0 mg/mL) (Text continues on page 433.)

Pyrazinamide (Z)

Rifampicin (R)

Isoniazid (H)

Drug name (abbreviation)

Side effects

Common: hepatitis (10–20% Description: bactericidal; have elevated of inhibits mycolic acid synthesis transaminases), peripheral most effectively in dividing neuropathy (dose-related; cells; hepatically metabolized. increased risk with Dose: 4–6 mg/kg/day malnutrition, alcoholism, diabetes, concurrent use of AG or ETO). Less common: gynecomastia, rash, psychosis, seizure Common: orange-colored bodily Description: bactericidal; secretions, transient inhibits protein synthesis by transaminitis, hepatitis, GI blocking mRNA transcription distress. and synthesis; hepatically Less common: cholestatic metabolized. jaundice Dose: 8–12 mg/kg/day Common: arthritis/arthralgias, Description: bactericidal; hepatotoxicity, hyperuricemia, mechanism unclear; effective abdominal distress. in acidic milieu (e.g., cavitary Less common: impaired diabetic disease, intracellular control, rash organisms); hepatically metabolized, renally excreted. Dose: 30–40 mg/kg/day

Description and adult dose

Table 1 Antituberculosis Medications and Their Side Effects

(Continued )

Monitoring: baseline SGOT and bilirubin, repeat if symptoms (jaundice, fatigue, anorexia, weakness, or nausea and vomiting for more than three days) Monitoring: baseline and monthly SGOT; uric acid can be measured if arthralgias, arthritis, or symptoms of gout are present. Comments: usually given once daily, but can split dose initially to improve tolerance

Monitoring: consider baseline and monthly SGOT, especially if age greater than 50. Comments: give with pyridoxine 50 mg/day if using large dose or if patient is at risk for peripheral neuropathy (diabetes, alcoholism, HIV, etc.)

Monitoring requirements and comments

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Aminoglycosides: amikacin (AMK), kanamycin (K), streptomycin (S); Polypeptides: capreomycin (CM), viomycin (VM)

Ethambutol (E)

Drug name (abbreviation)

Side effects

Monitoring requirements and comments

Monitoring: baseline and Common: generally well Description: bacteriostatic at monthly visual acuity and red/ tolerated. conventional dosing (15 mg/ green color vision test when kg); inhibits lipid and cell wall Less common: optic neuritis, GI dosed at greater than 15 mg/ distress, arthritis/arthralgia metabolism; renally excreted. kg/day (more than 10% loss is Dose: 25 mg/kg, consider considered significant) (89); decreasing to 15 mg/kg once regularly question patient patient is culture negative about visual symptoms Common: pain at injection site, Monitoring: baseline and then Description: bactericidal; biweekly creatinine, urea, and proteinuria, serum electrolyte aminoglycosides inhibit serum potassium more disturbances. protein synthesis through frequently in high-risk Less common: cochlear disruption of ribosomal patients. If potassium is low, ototoxicity (hearing loss, dose function; less effective in check magnesium and related to cumulative and peak acidic, intracellular calcium. Baseline audiometry concentrations, increased risk environments; polypeptides and monthly monitoring in with renal insufficiency, may appear to inhibit translocation high-risk patients (high-risk be irreversible), nephrotoxicity of the peptidyl-tRNA and the patients ¼ elderly, diabetic, or (dose related to cumulative initiation of protein synthesis; HIV-positive patients, or and peak concentrations, renally excreted. patients with renal increased risk with renal Dose: 15–20 mg/kg/day insufficiency). insufficiency, often Comments: observe for irreversible), peripheral problems with balance; neuropathy, rash, vestibular increase dosing interval or toxicity (nausea, vomiting, reduce dose and monitor vertigo, ataxia, nystagmus), serum drug concentrations as eosinophilia. Ototoxicity

Description and adult dose

Table 1 Antituberculosis Medications and Their Side Effects (Continued )

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(Continued )

needed to control side effects. Electrolyte disturbances are more common in patients receiving CM (90) Monitoring: no laboratory Description: bactericidal; DNA- Common: generally well Fluoroquinolones: monitoring requirements. tolerated, well absorbed. gyrase inhibitor; renally ciprofloxacin (CPX), ofloxacin Comments: do not administer Less common: diarrhea, excreted. (OFX), levofloxacin (LFX), with antacids, sucralfate, iron, dizziness, GI distress, Dose: ciprofloxacin 1500 mg/ moxifloxacin (MFX), zinc, calcium, or oral headache, insomnia, day; ofloxacin 800 mg/day; gatifloxacin (GFX) potassium and magnesium photosensitivity, rash, levofloxacin 750 mg/day; replacements; LFX, MFX, vaginitis, psychosis, seizure moxifloxacin 400 mg/day; GFX have the most activity (CNS effects seen almost gatifloxacin 400 mg/day against Mycobacterium exclusively in elderly) tuberculosis; data on long-term safety and tolerability are limited on MFX and GFX, thus LFX is currently the preferred fluoroquinolone (86) Monitoring: consider serum Common: neurologic and Cycloserine (CS) Description: bacteriostatic; drug monitoring to establish psychiatric disturbances, alanine analogue; interferes optimal dosing. including headaches, with cell-wall proteoglycan irritability, sleep disturbances, Comments: give 50 mg of synthesis; renally excreted. pyridoxine for every 250 mg of aggression, and tremors. Dose: 500–1000 mg/day CS (to lessen neurological Less common: psychosis, adverse effects) peripheral neuropathy, seizures (increased risk of CNS effects with concurrent use of ethanol, H, ETO, or other centrally acting medications), hypersensitivity potentiated by certain diuretics, especially loop diuretics

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Para-aminosalicylic acid (PAS)

Thiamides: ethionamide (ETO), prothionamide (PTO)

Drug name (abbreviation) Description: may be bactericidal or bacteriostatic depending on susceptibility and concentrations attained at the infection site; the carbotionamide group, also found on thioacetazone, and the pyridine ring, also found on H, appear essential for activity (91); hepatically metabolized, renally excreted Dose: 500–1000 mg/day Description: bacteriostatic; disrupts folic acid metabolism (thought to inhibit the biosynthesis of coenzyme F in the folic acid pathway); hepatic acetylation, renally excreted Dose: consult manufacturer’s recommendations

Description and adult dose

Side effects

Monitoring requirements and comments

Common: GI distress (nausea, Monitoring: no laboratory vomiting, diarrhea), monitoring requirements hypersensitivity, Comments: some formulas of hypothyroidism (especially enteric coated granules need to when taken with ETO). be administered with an acidic Less common: hepatitis, food or beverage (i.e., yogurt electrolyte abnormalities. or acidic juice) Drug interactions: Decreased INH acetylation, decreased R absorption in nongranular preparation, decreased B12 uptake

Monitoring: consider baseline Common: GI distress (nausea, and monthly SGOT vomiting, diarrhea, abdominal Comments: may split dose or pain, loss of appetite), give at bedtime to improve dysgeusia (metallic taste), tolerability; ETO and PTO hypothyroidism (especially efficacies are considered when taken with PAS). similar; PTO may cause fewer Less common: arthralgias, GI side effects (92) dermatitis, gynecomastia, hepatitis, impotence, peripheral neuropathy, photosensitivity

Table 1 Antituberculosis Medications and Their Side Effects (Continued )

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Isoniazid use was associated with better survival rates in patients with strain W of MDR-TB that was susceptible to higher isoniazid concentrations on susceptibility testing (94). A full assessment of DST reliability and clinical correlation for some first-line and most second-line anti-TB drugs has not yet been achieved. Nonetheless, regimens should include at least four drugs thought to be efficacious based on DST and/or the patient’s treatment history. The newer rifamycins have high levels of cross-resistance to rifampicin and should be considered ineffective if DST indicates rifampicin resistance. Amikacin should be considered ineffective if kanamycin tests resistant, and vice versa. Pyrazinamide can be used for the entire duration of treatment if it is thought to be efficacious. Many MDR-TB patients have chronically inflamed lungs, which theoretically produce the acidic environment in which pyrazinamide is active. Analysis of patient cohorts should follow internationally recommended case registration and outcome definitions (95).

B. Drugs Used in Drug-Resistant Tuberculosis Treatment

First- and second-line drugs were introduced in Chapter 8 on tuberculosis treatment. Table 1 is a summary of anti-TB drugs and their mechanism of action, metabolism, recommended dosing, common side effects, and monitoring requirements. Note that rare side effects and drug–drug interactions are available from other sources (96). Drugs not included in Table 1 but applicable in some situations of high resistance include clofazimine, amoxicillin-clavulanate, and clarithromycin (6,86). Although these agents have been successfully used against other mycobacterial infections and may have some proven in vitro activity against M. tuberculosis, their clinical efficacy in MDR-TB treatment has not been established. Thioacetazone is not commonly used for MDR-TB because of its modest anti-TB activity, potential for life-threatening toxicity in HIV-infected patients, and crossresistance to thioamides. Linezolid, an expensive new antibiotic, has recently gained attention as a possible new anti-TB agent because of its promising in vitro activity against M. tuberculosis; however, clinical effectiveness in humans has not been proven (97). The safety of using linezolid for extended periods of time has also not been well studied. C. Choice of Empiric Treatment Regimen

Patients are started on an empiric regimen when DST results are not available. With a few exceptions, most patients deemed to have a high probability of drug-resistant disease should immediately be placed on an empiric regimen as soon as adequate specimens are obtained for culture and DST, in order to prevent clinical deterioration and transmission to contacts. Consideration may be given to waiting for DST results if the laboratory uses a

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rapid method with a turnaround time of under two weeks, and the patient is clinically very stable. The empiric regimen should be based on the patient’s treatment history, local prevalence of drug resistance, and the DST profiles of any known contacts. In patients who have previously received anti-TB treatment, obtaining a detailed clinical history is crucial. Every effort should be made to supplement the patient’s recall with objective records from previous health-care providers. A detailed treatment history can help suggest which drugs are likely to be ineffective. The probability of acquired drug resistance increases with the amount of time that a drug is administered; while some clinicians use a lower limit of one month as the minimum administration time before drug resistance can develop, in fact there is no lower limit. In the case of inadequate regimen administration, drug resistance can develop within weeks or even days, as has been documented in case reports of patients with drug allergies (98). Further indications of acquired drug resistance may be found by examining the bacteriological data. In particular, evidence of clinical or bacteriological treatment failure during a period of regular drug administration is highly suggestive of drug resistance. As Stewart and Crofton wrote in 1968, ‘‘failure while under treatment with the relevant drug must indicate that the drug is no longer suppressing the growth of the patient’s bacille (99).’’ The clinical role of DST patterns of the community or local patient populations is the same for empiric regimens as for standardized regimens and is explained below in Section VIII. D. ‘‘Standardized Regimens.’’ Close contacts of MDR-TB patients who develop active disease have the same drug-resistant disease in over two-thirds of cases; they should be started on empiric regimens based on the index patient’s DST pattern. A review of literature searching for any study that examined more than 100 contacts of MDR-TB patients (Table 2) reveals that most of the contacts that developed active disease had drug-resistant forms. Concordance between the index case and the contact may be lower in the case of resistance to drugs other than isoniazid and rifampicin because

Table 2 Rates of MDR-TB Among Contacts of MDR-TB Patients

Study Kritski et al. (61) Schaaf et al. (100) Teixeira et al. (101) Schaaf et al. (102) Bayona et al. (103)

Country

Number of contacts

Brazil South Africa Brazil South Africa Peru

218 149 133 119 945

Percentage of patients (%) with MDR-TB (no. of TB case/total no. with active TB) 62 83 83 75 84

(8/13) (5/6) (5/6) (3/4) (35/42)

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additional resistance can develop over time in the strain of either the index or the contact patient, often due to inadequate therapy after the time of transmission of infection. This may result in decreased confidence in the ability to predict the exact DST pattern of a contact’s isolate from that of the index case. Therefore, the empiric regimen should be designed based on the treatment histories of both the index and the contact cases (in relation to when the exposure took place) and on the DST of the index case. As with all empiric treatments, the regimen should be adjusted once the DST of the contact case becomes available. More studies on the relationship of DST patterns between the index case and the contact are needed. The number of drugs required to effectively treat MDR-TB ranges from three to seven, depending on the drugs and the patient. A literature review of MDR-TB treatment programs reveals that all reported cohorts were treated with four to six drugs (6). The WHO and the Green Light Committee for Second-line Drug Access in MDR-TB Treatment advocate the use of at least four drugs considered to be efficacious (Cegielski P, Personal Communications, 2004). Because in vitro susceptibility does not correlate perfectly with clinical efficacy, when designing an empiric regimen, treatment often comprises as many as six or seven drugs, at least initially, to ensure that at least four are effective. For example, during the notorious outbreaks of MDR-TB in New York City in the 1980s, an initial regimen of seven drugs was used in order to ensure adequate antimicrobial coverage while awaiting DST studies (104). Many practitioners adhere to the principle that the best opportunity to cure a patient is the current course of treatment (the likelihood of cure decreases with successive courses of treatment). Rather than reserving effective drugs ‘‘just in case’’ the current course of treatment fails, these experts will use every known drug with potential efficacy against a patient’s multidrug-resistant bacille (105). D. Standardized Regimens

It has been proposed that certain groups of patients can be treated with standardized regimens that do not depend on individualized DST, especially in resource-poor settings without laboratory capacity. In the past, WHO and the International Union Against Tuberculosis and Lung Disease (IUATLD) recommended that all retreatment cases receive the same regimen, referred to as category II retreatment regimen (106,107). WHO has recently acknowledged that enforcing one universal retreatment regimen is not a good medical practice; retreatment therapy must be tailored to the specific patient or group of patients. A revised WHO publication Treatment of Tuberculosis: Guidelines for National Programs, Third Edition (108), introduces the use of specially designed regimens for patients who fall into the WHO diagnostic category IV (drug-resistant cases). These ‘‘Category IV regimens’’ can be standardized or individualized, and are now considered to be part of the WHO DOTS strategy. This section explains the design of standardized category IV regimens, and the following section explains the individualized strategy.

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Although DST may not be needed for every patient in standardized regimen strategies, it still plays an important role. First, drug resistance surveys are needed to identify groups of patients who are at increased risk for MDR-TB. Nationwide surveys, for example, may not reflect DST patterns of specific groups of patients: the DST patterns of all previously treated patients lumped together may be very different from the DST patterns of only those in whom standardized SSC failed. Furthermore, there may be community outbreaks of MDR-TB with DST patterns very different from those represented in national surveys. Standardized MDR-TB treatment regimens can be used in individuals if they come from a group with a very high probability of having MDR-TB. For example, patients in whom category II treatment fails (chronic cases) in well-run TB control programs almost always have MDR-TB (109,110) and this group, in most instances, can enter standardized treatment regimens without individual confirmation of resistance. However, surveillance DST in this group should still be performed, as it will both confirm that this practice is justified and aid in the design of the specific standardized regimen to be used. Whether failures of WHO category I treatment can routinely enter a standardized MDR-TB treatment regimen is often unclear and depends on a number of factors. The MDR-TB rate in these patients may be related to the drugs used in the continuation phase as well as to the level of DOT. In many TB control programs, category I regimen failures that use isoniazidrifampicin in the continuation phase have high MDR-TB rates, ranging from 62% to 88% in published studies (111–113). It has been speculated that if isoniazid-rifampicin and strict DOT are used in the continuation phase, the presence of MDR-TB is the main plausible cause of failure. Much lower rates of MDR-TB (22–33%) are reported if isoniazid-ethambutol or isoniazid-thioacetazone is used or if DOT was not part of the continuation phase (76,114–116). However, the above observations do not always hold true. A recent study from Vietnam reported a very high rate of MDR-TB (80%) of failures in category I treatment with unsupervised HE in the continuation phase (117). The high MDR-TB rates among the category I failures in this cohort may have been a result of high rates of primary resistance (both isoniazid resistance and MDR-TB) and past medical practices in the country. Therefore, when using standardized MDR-TB treatment regimens, drug-resistance survey data are necessary to confirm that the population of patients who will receive the standardized regimen is very likely to have MDR-TB. The surveillance data in these groups will need to be repeated periodically. The second setting where DST will be needed is in groups with low or moderate rates of MDR-TB, including patients who relapse, who return after default, and, sometimes in patients with failure of category I or III treatment regimens. It may be more difficult (if not impossible) to find a single retreatment regimen that does not deny isoniazid and rifampicin to a large percentage of these patients who would in fact benefit from these

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drugs, or unnecessarily expose patients to toxic second-line drugs. The logical solution for these groups of patients with low or moderate MDR-TB rates, but high enough so that the routine use of the WHO category II regimen may be not completely safe, is to test susceptibility to at least rifampicin and isoniazid. This will differentiate patients who can be treated with first-line drugs from those requiring regimens with second-line drugs (WHO category IV regimens). The development of a quick, accurate, and inexpensive test to identify patients with MDR-TB would greatly aid the strategy described above. The unavailability on a widespread basis of such a test remains a major obstacle in the treatment of drug-resistant TB and good TB control throughout the world. Until such tests are available locally, DST can be done in a laboratory at a distance, in a regional or central laboratory, or even overseas, if transportation and communications are adequate. Experience in the use of standardized regimens for large cohorts is limited. There have only been three reports to date, from Peru, Korea, and Bangladesh. Given the low rate of successful outcomes, the programmatic strategies used in the Peruvian and Korean studies may have been insufficient. The Peruvian study had a cure rate of 48% (and in patients with confirmed MDR-TB, the failure rate was 32.2%), which can be attributed in part to regimen design and programmatic problems. A significant percentage of patients (estimated to be 16% in a similar group of patients, unpublished results) were on two or fewer effective drugs because the standard regimen relied heavily on ethambutol and pyrazinamide, both of which had been used extensively in these patients in the past. The injectable drug, which was one of the most bactericidal agents in the regimen, was used for only three months. Other reasons for the program’s limited success include the relatively low dosage of ciprofloxacin (1000 mg/day), the untenable costs to the patients of ancillary medicines to treat side effects, and inadequate (low-to-moderate) social support. The late identification of MDR-TB (most patients were not identified until after failure of category II treatment) may have also contributed to the poor outcomes (110). The low cure rates in the Korean study are attributable in part to a high default rate (28.9%), likely due to the self-administration of most of the regimen and a lack of supportive measures to help patients to adhere to treatment (118). The Bangladesh study documented the best success to date in the use of a standardized regimen, reporting a cure rate of 69%. However, the cohort was small, with only 58 patients, and it is unclear whether the seven-drug standardized regimen used for the cohort will be successful in other settings, especially because it included three first-line drugs (18). Data from one prospective randomized trial, which would probably be impossible to conduct today for ethical reasons (119), compared a wholly empiric treatment approach with individualized regimens based on pretreatment DST. Between 1967 and 1969, 619 patients in Hong Kong were randomized to one of three strategies: (i) a standard empiric regimen of isoniazid, streptomycin, and PAS; (ii) the same empiric regimen followed by

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individualized regimens based on conventional susceptibility testing results; and (iii) rapid-susceptibility testing followed by fully individualized regimens. In all arms, susceptibility testing was performed for isoniazid, streptomycin, and PAS at the start of treatment. In the individualized arms, ethionamide, pyrazinamide, and cycloserine were substituted for any drug to which in vitro resistance was demonstrated. The study reported on cultures at months 10, 11, and 12. In the standard arm that ignored susceptibility testing results, the percentage of culture-negative patients was 40% in those with resistance to three drugs. The percentage of culture-negative patients who were resistant to three drugs in the two individualized arms increased to more than 88% in both arms. There were no statistical differences in patients resistant to one or two drugs at the start of treatment between the three arms, but the numbers in the study were small for these groups. Despite their low success in some settings and the limited data on their efficacy, standardized regimens are thought to be both feasible and cost-effective for MDR-TB treatment (110). There is no reason to believe that carefully designed and well-supported standardized regimens will not result in cure rates equal to those from individualized regimens, provided the ancillary measures to ensure adherence to and completion of treatment are comparable. In summary, for programs that plan to use only standardized regimens, DST will still be necessary for surveillance (to identify groups of patients with high MDR-TB rates) and for individual patients who come from populations with low-to-moderate MDR-TB rates. Care should be taken to design a standardized regimen that will cover most patients with at least four effective drugs, and adequate support should be given throughout the duration of treatment. E. Designing an Individualized Regimen

The design of individualized regimens is more straightforward than the design of regimens without reference to DST. Nonetheless, here too there are some cautionary points. To begin, the treating physician should be thoroughly trained in the interpretation of DST results so as to avoid making classic management errors such as adding only one drug to a failing regimen. Such errors can be disastrous, both for the patient and for TB control efforts. DST results should complement rather than invalidate other sources of data about the likely efficacy of a specific drug. For example, if a history of prior anti-TB drug use suggests that a drug is likely to be ineffective, this drug should not be relied on as one of the four core drugs in the regimen even if the strain tests susceptible to it in the laboratory. Alternatively, if the strain is resistant to a drug in the laboratory, but the patient has never taken the drug and resistance to it is extremely uncommon in the community, laboratory error or the limited specificity of DST for some second-line drugs may be a factor. Due to the turnaround time necessary for DST, the patient in question may already have received months of an empiric treatment regimen by the

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time results become available. The possibility of further acquired resistance during this time must be considered. If there is a high probability of acquired resistance to a drug after the specimen that gave the DST result was obtained, this drug should not be counted as one of the four drugs in the core regimen. Some laboratories may report that a strain has a low or intermediate level of resistance to a certain drug. There is very little clinical evidence to support this sort of designation, particularly if the patient previously received the drug as part of DOT. Finally, effective DST interpretation requires a high level of confidence in the laboratory performing the tests. In the case of inconsistent results or unclear evidence about drug effectiveness, one should follow the dictum ‘‘use the medicine, but do not depend on it for success (120).’’ In short, individualized regimens need to be designed, whenever possible, with at least four medications thought or documented to be efficacious. This may entail a regimen with more than four drugs if the efficacy of one or more of the drugs is unclear or in doubt for any of the reasons discussed above. Table 3 lists suggested regimens for various DST patterns, with the caveat that definitive randomized or controlled studies have not been performed among patients with different resistance patterns. The given regimens assume accessible, reliable, and accurate DST for pyrazinamide, and no chance of acquired resistance to additional agents after the DST specimen that gave the DST results was collected. If DST for pyrazinamide is not performed, it cannot be depended upon as being an effective drug in the regimen. In such situations, regimens from Table 3 that assume it to be resistant should be used. Some clinicians would add pyrazinamide to those regimens because a significant percentage of patients could benefit from the drug. F. The Standardized vs. Individualized Debate

Sections VIIII. C. ‘‘Choice of Empiric Treatment Regimen,’’ VIIII. D. ‘‘Standardized Regimens,’’ and VIII. E. ‘‘Designing an Individualized Regimen’’ described the basic strategies of MDR-TB management, with the two main models being a standardized or an individualized approach. Their respective strengths and weakness have been discussed in other publications, but much of the debate is speculative. It is often stated that individualized treatments are more effective, but if standardized regimens are well designed, there is no reason to think the two cannot obtain equivalent efficacy. Although often regarded as requiring less technical capacity, standardized regimens may nevertheless need to be adjusted due to side effects, and some DST capacity will still be necessary. Furthermore, while it is assumed that the cost of standardized treatment regimens is lower, this may not be true if cure rates for a standardized regimen are low, which will result in greater long-term costs due to additional resistance and ongoing generation of new cases. Both strategies confer similar levels of toxicity, and default rates under either strategy will be high if excellent patient

R, E, and fluoroquinolones R, Z, and fluoroquinolones H, E, fluoroquinolones, plus at least 2 mo of Z H, Z, fluoroquinolones, plus an injectable agent for at least the first 2–3 mo H, E, fluoroquinolones, plus an injectable agent for at least the first 2–3 mo R, fluoroquinolones, plus an oral second-line agent, plus an injectable agent for the first 2–3 mo

H and Z

H and E

R

H, E, Z (S)

R and Z (S)

R and E (S)

R, Z, and E

Suggested regimenb

H (S)

Pattern of drug resistance

18

18

18

12–18

9–12

9–12

6–9

Minimum duration of treatment (mo)

Table 3 Suggested Regimens for Drug-Resistant Tuberculosisa

A fluoroquinolone may strengthen the regimen for patients with extensive disease. A longer duration of treatment should be used for patients with an extensive disease. A longer duration of treatment should be used for patients with an extensive disease. An injectable agent may strengthen the regimen for patients with an extensive disease. A longer course (6 mo) of the injectable agent may strengthen the regimen for patients with an extensive disease. A longer course (6 mo) of the injectable agent may strengthen the regimen for patients with an extensive disease. A longer course (6 mo) of the injectable agent may strengthen the regimen for patients with an extensive disease.

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Z, E, injectable agent (for at least first 6 mo), fluoroquinolones, plus two or more oral second-line agents

H-R (S) and E or Z

24

18–24

One oral second-line agent is sufficient if E and Z susceptibility is well ascertained. Two oral second-line agents should be used in an extensive disease, or if the DST result is questionable (i.e., reported susceptibility to E or Z despite a history of these agents being used in a failing regimen). Surgery, when available, can be considered. Only the first-line agents is used to which the patient is susceptible. Alternative injectable agent is used if S resistance is present. More than two oral second-line agents should be used in an extensive disease or if resistance to E and Z is present or suspected. Surgery, when available, can be considered.

Notes: Injectable agents: streptomycin, amikacin, kanamycin, capreomycin, and viomycin. Oral second-line agents: ethionamide or protionamide, cycloserine, and p-aminosalicylic acid. In cases of very high resistance where four-drug regimens cannot be formed, alternative oral agents may include clarithromycin, amoxicillin/clavulanate, linezolid, and/or clofazimine. a Adapted from Ref. 121. b Assumes further acquired resistance is not a factor and laboratory results are reliable. Abbreviations: H, isoniazid; R, rifampicin; E, ethambutol; Z, pyrazinamide; S, streptomycin.

Z, E, injectable agent (for at least first 6 mo), fluoroquinolones, plus one or two oral second-line agents

H-R

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support systems are not in place. Standardized regimens may not be possible in areas or countries where large-scale use of second-line anti-TB agents have been used; finding a single regimen in such situations, which adequately treats all MDR-TB cases is not always feasible. Designing standardized regimens for MDR-TB is more feasible in countries with very low prior use of second-line anti-TB drugs. G. Monitoring the Patient

The systematic and careful monitoring of treatment response (including side effects) is an integral part of the treatment of drug-resistant TB. To establish the baseline mycobacterial burden, sputum specimens for semiquantitative smear and culture should be obtained weekly during the initial part of treatment until conversion is reached (122). The weekly evaluation helps determine when patient isolation can be suspended and allows for an accurate assessment of the treatment response. However, programs with very limited laboratory capacity may choose to perform smear and culture monthly until conversion occurs. After conversion, smear and culture should be performed at least every other month while treatment continues. After treatment, smear and culture should be performed twice yearly for two years and thereafter whenever the patient has symptoms suggestive of active TB. Conversion to a negative smear and culture occurs, on an average between one and two months (17). Persistence of positive smear or culture past three months after initiating a new regimen should prompt an evaluation of the regimen and the patient’s adherence. DST should be repeated on a new specimen. Although bacteriological examination is the main indicator of response to treatment, the patient should also be monitored for weight gain, decrease of cough, absence of fever, and overall clinical progress. Chest radiograph should also be done every three to six months, though radiological signs of improvement will often lag behind bacteriological and clinical indicators. Computerized axial tomography (CAT) scans better identify cavities that can go unappreciated on chest radiographs. CAT scans should be done for all patients for whom surgical intervention is considered. DOT is an essential part of the treatment strategy. Clinical and laboratory monitoring for adverse effects depends on the drugs used in the regimen and should be performed according to the information provided in Table 1. Any comorbid conditions, such as diabetes, HIV, liver disease, alcoholism, etc., may require closer monitoring for side effects. The frequency of adverse effects in 818 patients from five different MDR-TB treatment programs that used DOT is reported in a study by Nathanson et al. (123) who found that only 2% of patients had to stop treatment completely because of adverse events. Frequent medical encounters with the care provider are essential. H. Completion of the Injectable Agent (Intensive Phase)

The recommended duration of the injectable agent is guided by smear and culture conversion. The injectable should be continued for a minimum of

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six months and most practitioners prefer to use the injectable for at least four to six months after the patient first becomes and remains smear or culture negative. It is advisable to use an individualized approach and review the patient’s cultures, smears, X-rays, and clinical status before stopping the injectable agent. Injections are often extended if extensive lung damage is present. If there is a high level of drug resistance, stopping the injectable could place the patient at risk for failure or early relapse; the injectable can be continued, under extreme circumstances it can be used throughout the entire treatment. Intermittent therapy with the injectable agent can be considered for patients who have been on the injectable for a prolonged period of time or when the risk of toxicity becomes a problem. Successful outcomes have been achieved with intermittent dosing (three times a week) of the injectable agent after an initial period of two to three months of daily therapy. However, a high percentage of patients in these cohorts also underwent surgery, which may have contributed to their successful outcomes (9,124). I. Length of Treatment

The optimal duration of MDR-TB therapy has not been definitively determined. Generally, it is recommended that treatment lasts for at least 18 to 24 months past culture conversion. In addition to bacteriological results, clinical and radiographic data may be used to determine total treatment duration; treatment for a full 24 months may be indicated in patients with extensive pulmonary damage. The newer generation fluoroquinolones may allow shorter regimens, but to date evidence is lacking and regimens of less than 18 months are generally not recommended. Surgical intervention may also allow shortening of the regimens to less than 18 months in some cases; excellent outcome results from one U.S. treatment center are reported with the use of treatment for 15 to 18 months past conversion when adjuvant surgery was used (9). J. Surgery in MDR-TB Treatment

The role of resectional surgery in the management of MDR-TB has not been established through randomized studies. Surgery as an adjunct to chemotherapy for patients with resectable localized disease appears to be beneficial when skilled thoracic surgeons and excellent postoperative care are available (see Chapter 15) (9,125–129). Surgical resection cannot be performed in patients with extensive bilateral disease. Although collapse therapy—including thoracoplasty, artificial pneumothorax, and pneumoperitoneum—is commonly used in some parts of the world, the author of this chapter prefers resectional therapy, based on the vast body of experience garnered during the 20th century. There are no clinical trials that directly compare resection to collapse therapy or thoracoplasty; however, case series have shown resectional surgery to be effective and safe under proper conditions (9,130,131).

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In settings with limited surgical capacity, patients who remain smear positive or are resistant to a high number of drugs usually take priority, because they can die without such intervention. General criteria for surgery are localized pulmonary disease, adequate cardiopulmonary reserve, and optimal medical therapy for at least two months. In addition, surgery is often indicated for severe hemoptysis and other pulmonary complications. Even with successful resection, an additional 12 to 18 months of chemotherapy should be given, using the principles of MDR-TB treatment regimen design. Currently, most resource-limited countries do not have adequate trained staff and materials or postoperative care to perform surgery on MDR-TB patients routinely. Attempting to carry out a surgery without adequate expertise, technical capacity, and postoperative care can result in high morbidity and mortality. In addition, surgery should never take the place of, or take priority over, a good chemotherapy program for drug-resistant TB. K. Immune Modulation

For a number of reasons, immune modulation or immunotherapy of the host is an attractive option in the treatment of MDR-TB. First, cure rates could be improved in difficult-to-treat cases. Second, chemotherapeutic regimens might be shortened if adjuvant immunotherapy reduces the time to cure (132). The cytokine c-interferon has shown the most encouraging results, although most of the studies have been done in patients with a poor chance of recovery by conventional treatment methods (133–137). Interleukin-2 has also been employed, with equivocal results (138). Although these modalities are attractive, the evidence to date does not justify their routine use, and further investigation in the area of immune modulation is needed. L. Management of Ultimate Failures

Treatment with second-line drugs is often a patient’s last hope for a cure; unfortunately, treatment is not always effective. There is no simple definition for MDR-TB treatment failure. Individualized therapy often consists of a cycle of treatments; if there is no effect, a new plan should be formulated after careful assessment. Often new drugs are added and adjunctive options, most commonly surgery, are entertained. A single drug should never be added to a failing regimen; if treatment is failing, the best option is to design a new regimen with at least four effective agents. Given the limited number of known anti-TB agents, a wholly new four-drug regimen is often unattainable for patients in whom a regimen of second-line drugs is failing. In these cases, the new regimen should include as many new or potentially efficacious agents as possible. The health-care provider should make an extra effort to ensure that patients are taking all their medicines; if care included DOT, the DOT worker should be interviewed. In cases of noncompliance, the contributing conditions should be corrected (i.e., aggressive management of adverse effects) and the response to subsequent therapy observed before treatment failure is declared.

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Although there is no simple definition of treatment failure, there may come a time when it becomes clear that the treatment is not going to work. Signs indicative of treatment failure include persistent positive smears or cultures past the eighth month of treatment; extensive and bilateral lung disease with no option for surgery; high-grade resistance with no option for adding additional agents; and deterioration in clinical condition, which usually includes weight loss and respiratory insufficiency. The presence of these conditions indicates that cure is highly unlikely. A number of supportive measures can be implemented once the decision to suspend the therapy has been made. Supportive measures include pain control, relief of respiratory insufficiency with oxygen, ongoing nutritional support, and hospitalization or hospice care. Infection control measures should be continued. Some patients can set up home conditions with sufficient space and ventilation along with reliable access to food and other necessities (139). Family members and friends who visit the patient can be provided with personal respirators. When these requisites are in place, there is little risk of further spread. Sanatoria designed for ultimate failures of MDR-TB treatment regimens can also be used for end-of-life care. Continuing second-line agents when treatment has failed is not recommended, as the side effects may add to the suffering at the end of a patient’s life as well as lead to the possible development of extremely resistant stains that can be transmitted to others. Some experts abandon the less-tolerated and expensive second-line agents, and continue the patient on a maintenance program of drugs such as isoniazid, rifampicin, and/or ethambutol (despite the presence of resistance to them) (140). However, there is no firm evidence that this will result in suppression of the bacteria or improve quality of life. In fact, these agents also carry risks of toxicity. Therefore, the author of this chapter recommends to discontinue all TB medications when no hope for cure remains and to aggressively offer the support measures described above. M. Drug Adjustment in Renal Insufficiency

Renal insufficiency due to long-standing TB infection or previous aminoglycoside use is not uncommon. Great care should be taken in administering second-line drugs to patients with renal insufficiency, and the dose and/ or the interval between doses should be adjusted as shown in Table 4. Sodium salt formulations of PAS may result in an excessive sodium load and may precipitate congestive heart failure in patients with preexisting heart disease; these formulations should be avoided in such patients. Formulations of PAS that do not include sodium salt (e.g., Jacobus PASER1) can be used without the hazard of sodium retention (120). IX. Drug-Resistant Tuberculosis and HIV (and Other Immunosuppressive States) HIV and other immunosuppressive conditions make MDR-TB treatment more difficult because of increased drug toxicity, drug–drug interactions,

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Table 4 Adjustment of Anti-tuberculosis Medications in Patients with Renal Insufficiencya

Drug

Change in frequency?

Recommended doseb and frequency for patients with creatinine clearance < 30 mL/min or for patients receiving hemodialysis

Isoniazid Rifampicin Pyrazinamide Ethambutol Streptomycin Capreomycin Kanamycin Amikacin Ciprofloxacin Ofloxacin Levofloxacin Moxifloxacin Gatifloxacin Cycloserine Ethionamide p-Aminosalicylic acid

No change No change Yes Yes Yes Yes Yes Yes Yes Yes Yes No change Yes Yes No change No change

300 mg/day, or 900 mg 3/week 600 mg/day, or 600 mg 3/week 25–35 mg/kg 3/week (not daily) 15–25 mg/kg 3/week (not daily) 12–15 mg/kg 2–3/week (not daily)c 12–15 mg/kg 2–3/week (not daily)c 12–15 mg/kg 2–3/week (not daily)c 12–15 mg/kg 2–3/week (not daily)c 1000–1500 mg 3/week (not daily) 600–800 mg 3/week (not daily) 750–1000 mg 3/week (not daily) 400 mg/day 400 mg 3/week (not daily) 250 mg/day, or 500 mg/dose 3/weekd 250–500 mg/day 4 g 2/day

a

The recommended doses are taken from the official joint statement of the American Thoracic Society (ATS), the Centers for Disease Control and Prevention (CDC), and the Infectious Disease Society of America (IDSA) on the Treatment of Tuberculosis (86), except ciprofloxacin, ofloxacin, moxifloxacin, and gatifloxacin, for which doses are determined from extrapolating data on the recommended renal adjusted doses (89) and to use as close to standard doses as possible to optimize the bactericidal effect of these drugs. b To take advantage of the concentration-dependent bactericidal effect of many anti-tuberculosis drugs, standard doses are given unless there is intolerance. For patients on hemodialysis, the medications should be given after hemodialysis on the day of hemodialysis. Data currently are not available for patients receiving peritoneal dialysis. Until data become available, begin with doses recommended for patients receiving hemodialysis and verify adequacy of dosing, using serum concentration monitoring (86). c Caution should be used with injectable agents in patients with renal function impairment because of an increased risk of both ototoxicity and nephrotoxicity (93). d The appropriateness of 250 mg/day doses has not been established. There should be careful monitoring for evidence of neurotoxicity; if possible, measure serum concentrations and adjust regimen accordingly (86).

and malabsorption. HIV has already impacted the TB epidemic both by clinical management and by increasing the number of cases. The devastating consequences of the collision of HIV and MDR-TB cannot be underestimated: numerous studies report dismal outcomes for coinfected patients (63,141–144). The relationship between HIV infection and drug-resistant TB is not wholly clear. Data collected by the WHO/IUATLD Global Project

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on Anti-Tuberculosis Drug Resistance suggests that HIV infection is not an independent risk factor for drug-resistant TB (1), whereas other data suggests that HIV patients have an increased rate of TB drug resistance (84,145–147). There are multiple reports of outbreaks associating MDRTB and AIDS in New York City (64,148,149) as well as in other parts of the world (150–152). These outbreaks are often associated with delayed diagnosis, extended infectious periods, poor infection control practices, and delayed initiation of appropriate therapy. The development of rifampicin resistance has been associated with HIV therapy. In a case-control study, prior rifabutin use (commonly used as Mycobacterium avium prophylaxis), antifungal therapy, and diarrhea were each independently associated with rifampicin monoresistance (153). Given the dire consequences of unaddressed MDR-TB in HIV patients, DST is essential for all coinfected individuals, especially in settings where drug resistance is common. Prompt diagnosis and initiation of appropriate therapy clearly reduce mortality: in a number of studies, survival rates were significantly improved if therapy with at least four drugs with in vitro activity was started within one month of diagnosis (144,154,155). In addition, the timely initiation of antiretroviral therapy (ART) for HIV is extremely important. In Peru, outcomes were greatly improved in a cohort of MDR-TB/HIV patients who were started on ART as compared to an earlier cohort of patients who did not have an access to ART (Mitnick C. Personal communication, 2004). Patients with other immunosuppressive diseases (diabetes mellitus, vasculitis, long-term corticosteroid therapy, or cancer) are also at risk for poor outcomes if they develop active MDR-TB. Diabetes may have a similar effect as HIV in fueling TB (156). X. Factors Associated with Good Treatment Outcomes A wide range of outcomes—cure rates ranging from 38% to 100%—have been reported by MDR-TB treatment programs (6). Although few formal randomized, controlled studies have been performed, a number of factors appear to be associated with better MDR-TB treatment outcomes. The three most important factors that result in positive outcomes are (i) early diagnosis and treatment initiation, (ii) provision of an adequate regimen with a sufficient number of effective drugs, and (iii) provision of extensive treatment support, especially in the management of side effects. Early diagnosis and prompt entrance into an adequate treatment regimen with second-line drugs are the most critical factors. In particular, cycling patients through repeated ineffective first-line treatment courses is associated with worse outcomes because of increased lung damage and decreased drug efficacy. Furthermore, delays in initiating therapy often result in chronic, cachectic patients who have difficulty tolerating second-line drugs, further increasing the likelihood of poor outcomes. The second critical factor to ensure better outcomes is to treat patients before resistance patterns worsen. Mitnick et al. demonstrated that

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resistance to ethambutol and pyrazinamide is associated with poorer outcomes (17). Inability to use an injectable (Mitnick C. Personal communication, 2004) or a quinolone (9) is also associated with worse outcomes. Patients in whom a second-line drug-containing regimen failed may be very difficult to cure (Mitnick C. Personal communication, 2004). Therefore, weak retreatment regimens that have suboptimal cure rates should be avoided. While the optimal number of drugs in a retreatment regimen has not been determined, WHO as well as the author of this chapter advocates for at least four drugs (and preferably five at the start of treatment) to which the patient’s isolate is considered to be susceptible, with a continuation phase of three to four drugs (108). Third, extensive treatment support for the MDR-TB patient, including DOT and aggressive side-effect management, is crucial. Although there is ongoing debate about the necessity of DOT in regular TB treatment, these arguments do not hold for MDR-TB. MDR-TB treatment is very difficult and toxic, and patients need full accompaniment throughout treatment to ensure the best outcomes. A number of other factors may improve patient outcomes, including surgical interventions (discussed in Section VIII. J. ‘‘Surgery in MDR-TB Treatment’’), drug-level monitoring, patient support groups (157), patient incentives, social support, patient and family education, and nutritional supplementation. The influence of these factors on improving cure rates has not been documented. XI. Summary The incidence and prevalence of MDR-TB are alarmingly high in many areas of the world and exist in all regions worldwide (1). Because MDR-TB knows no borders, even areas where MDR-TB is under control are vulnerable (158). MDR-TB patients are largely overlooked in many parts of the world, despite the fact that highly effective treatment has been available for over 40 years. To prevent the situation from worsening and to provide much-needed treatment to the hundreds of thousands of prevalent MDR-TB cases, massive financial, technical, and human resources must be mobilized. Within the past decade, WHO has begun to systematically address drug-resistant TB through a strategy known as DOTSPlus (159–161). MDR-TB treatment programs must have adequate protocols and guidelines, qualified personnel, access to microbiological laboratories, constant and reliable supplies of medicines, ability to treat side effects, and well-established nutritional and psychosocial support systems (161). DOT should be used throughout the treatment (161,162). Regimens consisting of multiple drugs, which are generally more difficult to take, must be administrated for 18 to 24 months. Resectional surgery may be required for certain patients. The convergence of the AIDS and TB epidemics further challenges treatment and infection-control efforts.

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148. Frieden TR, Sterling T, Pablos-Mendez A, et al. The emergence of drug-resistant tuberculosis in New York City. N Engl J Med 1993; 328(8):521–526. 149. Coronado VG, Beck-Sague CM, Hutton MD, et al. Transmission of multidrugresistant Mycobacterium tuberculosis among persons with immunodeficiency virus infection in an urban hospital: epidemiologic and restriction fragment length polymorphism analysis. J Infect Dis 1993; 168(4):1052–1055. 150. Cohn DL, Bustreo F, Raviglione MC. Drug-resistant tuberculosis: review of the worldwide situation and the WHO/IUATLD Global Surveillance Project. Clin Infect Dis 1997; 24(S1):S121–S130. 151. Davies GR, Pillay M, Wilkinson D, et al. Emergence of multidrug-resistant tuberculosis in rural South Africa. Int J Tuberc Lung Dis 1998; 2(11):S327. 152. Ritacco V, Di Lonardo M, Reniero A. Nosocomial spread of human immunodeficiency virus-related multidrug-resistant tuberculosis in Buenos Aires. J Infec Dis 1997; 176(3):637–642. 153. Ridzon R, Whitney CG, McKenna MT, et al. Risk factors for rifampicin monoresistant tuberculosis. Am J Respir Crit Care Med 1998; 157(6 Pt 1):1881–1884. 154. Iseman MD, Huitt GA. Treatment of multidrug-resistant tuberculosis. In: Bastian I, Portaels F, eds. Multidrug-resistant Tuberculosis. London: Kluwer Academic Publishers, 2000:179. 155. Kenyon TA, Ridzon R, Luskin M, et al. A nosocomial outbreak of multidrugresistant tuberculosis. Ann Int Med 1997; 127:32–36. 156. Ponce-de-Leon A, Garcia-Garcia L, Garcia-Sancho MC, et al. Tuberculosis and diabetes in southern Me´xico. Diabetes Care 2004; 27(7):1584–1590. 157. Achu J, Sweetland A. Guia SES para Tratamiento y Manejo de la Tuberculosis Multidrogo Resistente. Lima, Peru: Socios En Salud, 2004. 158. Griffith DE. The United States and worldwide tuberculosis control: a second chance for Prince Prospero [editorial]. Chest 1998; 113(6):1434–1436. 159. Iseman MD. MDR-TB and the developing world—a problem no longer to be ignored: the WHO announces ‘‘DOTS Plus’’ strategy [editorial]. Int J Tuberc Lung Dis 1998; 2(11):867. 160. World Health Organization. Guidelines for Establishing DOTS-Plus Pilot Projects for the Management of Multidrug-Resistant Tuberculosis (MDR-TB). Geneva, Switzerland (WHO/CDS/TB2000.279), 2000. 161. World Health Organization, Guidelines for the management of drug-resistant tuberculosis. World Health Organization, Geneva, Switzerland (WHO/HTM/TB/ 2006.361), 2006. 162. Iseman MD, Cohn DL, Sbarbaro JA. Directly observed treatment of tuberculosis. We can’t afford not to try it. N Eng J Med 1993; 328(8):576–578. 163. Heifets LB, Cangelosi GA. Drug susceptibility testing of Mycobacterium tuberculosis: a neglected problem at the turn of the century. Int J Tuberc Lung Dis 1999; 3(7):564–581. 164. World Health Organization, The 3x5 Initiative. http://www.who.int/3by5/en/ (accessed December 2004). 165. Kim JY, Mate K, Rich ML, Mukherjee JS, Bayona J, Becerra MC. From Multidrugresistant tuberculosis to DOTS expansion and beyond: Making the most of a paradigm shift. Tuberculosis 2003; 83:59–65.

15 Surgical Treatment of Pulmonary Tuberculosis

MIKHAIL I. PERELMAN Sechenov Moscow Medical Academy, Moscow, Russia

I. Historical Background Three distinct periods may be identified in the development of surgical methods for the treatment of pulmonary tuberculosis. A. First Period

This covers the 18th and the first half of the 19th century. The object of surgical operations was the draining of abscesses: ‘‘Ubi pus—ibi evacua’’ (Hippocrates, fifth to fourth centuries, B.C.). First reports of draining of tuberculous cavities in the lungs go back as far as the 18th century (1). The results of these operations were poor. It was only in 1844 that Hastings diagnosed and Storks successfully drained a cavity in the superior lobe of the left lung (2). For the next almost 40 years, there were no further reports of surgery being used in the treatment of pulmonary tuberculosis. B. Second Period

This lasted from the 1880s to the mid-1940s. During this period, collapsotherapy methods were developed. At the beginning of the second period, the ineffectiveness of draining of tuberculous cavities had been demonstrated. Surgery was carried out on 459

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extremely ill patients. During operations, major difficulties arose over the localization of cavities. The operation was often complicated by pneumothorax and hemorrhage, and in the postoperative period, bronchial fistulae developed. Bronchogenic dissemination and septic infection of the wound in the thoracic wall were frequently observed. For these reasons, cavernostomy (opening of the cavity) was very rarely used. More attention was paid to ways and means of reducing the size of the lung affected by tuberculosis. They were based on theoretical assumptions, experimental findings, and clinical observations of the beneficial effect of exudative pleurisy and spontaneous pneumothorax on the course of the tuberculous process. In 1882, Forlanini published work on the treatment of pulmonary tuberculosis by provoking artificial pneumothorax (3). However, only the development of radiographic methods using X-ray examination and the introduction of the manometer as a working tool made the procedure more or less safe and useful for physicians and tuberculosis specialists. The role of surgeons consisted of the correction of pneumothorax by destroying pleural adhesions. In 1910 to 1912, Jacobeus (4) developed thoracoscopy and an effective operation for closed cauterization of pleural adhesions (Fig. 1). The principle of breaking down adhesions during treatment of some patients through artificial pneumothorax is still of importance nowadays, with the use of videothoracoscopy and state-of-the-art instrumentation. Where pneumothorax could not be used, efforts concentrated on reducing the volume of the affected lung by means of rib resection. Spengler (5) was the first to employ the term ‘‘extrapleural thoracoplasty.’’ Friedrich (6) removed eight ribs (from the second to the ninth inclusive) in a single

Figure 1 Schematic representation of pleural adhesions and cauterization using Jacobeus method.

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operation. The success of the operation outstripped expectations: 16 years later the patient was in a satisfactory condition and working. However, the operation was very traumatic for those patients who were weakened by tuberculosis. Postoperative mortality reached 30% to 50%. Sauerbruch (7) introduced considerable improvements to thoracoplasty. He began to use a limited rib resection technique and double-step operations. Postoperative mortality declined to 10% to 15%. Further study of thoracoplasty showed that for limited procedures, a good clinical effect could be obtained with considerable saving of operations (8). Before the outbreak of the Second World War, thoracoplasty had become the basic surgical tool for the treatment of cavernous pulmonary tuberculosis. Where the pleural cavity has been obliterated, extrapleural pneumolysis (partial separation of a lung from the thoracic wall with parietal pleura in order to collapse the part of the lung in which the cavity is present) with plombage of the extrapleural cavity or extrapleural pneumothorax was employed instead of pneumothorax and thoracoplasty (9,10). Other operations proposed included interventions on the phrenic nerve (11), intercostal nerves, and cavity drainage (12). However, they were of limited usefulness and did not play any significant part in the general effort to contain tuberculosis. C. Third Period

This period in the development of surgical methods for treating pulmonary tuberculosis has seen progress in surgical techniques and the development of effective antituberculosis drugs. These factors led to successful use of lung resection and pneumonectomy and to improved results from other methods of surgical treatment for pulmonary tuberculosis. The first successful pneumonectomy for the treatment of tuberculosis was reported in 1933 by Lilienthal (13), and the first lobectomy was reported by Freedlander (14). During the Second World War, pulmonary resection came to be used much more widely for tuberculosis. The most experienced of the specialists involved were Overholt and Woods (15) and Sweet. Their reports were discussed at the 26th Annual Meeting of the American Association of Thoracic Surgeons in 1946. Good postsurgical results were obtained in half of the patients. Nevertheless, reservations continued to be expressed about pulmonary resection. However, at the 28th Annual Meeting of the American Association of Thoracic Surgeons in 1948, a radical improvement in the outcomes of operations was reported. This was as a result of using pulmonary resection in combination with streptomycin treatment. The introduction of antituberculosis drugs based on isoniazid led to even better results in pulmonary resection. Much larger cohorts of patients could now be provided with effective surgical care. In the early 1950s, pulmonary resection came to be widely used and gradually became the method of choice for surgical treatment of pulmonary tuberculosis.

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Figure 2 Number of operations for tuberculosis in the Russian Federation from 1993 to 2004.

In the industrialized countries of Europe and North America and in Australia and Japan, the need for, and number of, operations fell considerably because the spread of tuberculosis declined, and rifampicin was introduced in medical practice from 1966. In the Russian Federation, on a backdrop of high tuberculosis morbidity and frequency of seriously advanced chronic forms, there is still a call for surgical treatment as a necessary and widely used treatment method. The number of operations for pulmonary tuberculosis in Russia for the period 1963–2004 is given in Figure 2.

II. Indications for Surgery Surgical operations are indicated for pulmonary tuberculosis patients in the following circumstances:  Inefficacy of chemotherapy, particularly where multidrug resistance is widespread (16–24).  Irreversible morphological changes of the lungs, bronchi, pleurae, lymphatic nodes, caused by the tuberculosis process.  Life-threatening tuberculosis complications and sequelae with clinical manifestations that possibly lead to undesirable effects (25–27). Surgical treatment is most often used in cases of tuberculoma and fibrotic-cavitary pulmonary tuberculosis, more rarely in fibrosis of the lungs, tuberculous empyema of the pleurae, caseous necrotic lesions of the lymph nodes, and caseous pneumonia.

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Complications and sequelae of the tuberculosis process for which surgical intervention is indicated may include       

pulmonary hemorrhage, spontaneous pneumothorax and pyopneumothorax, nodular-bronchial fistula, bronchiectasis with suppuration, broncholith (bronchus calculus), pneumofibrosis with hemoptysis, and pachypleuritis or pericarditis with the impairment of the respiratory and blood circulation functions.

Most surgical operations for tuberculosis are elective. However, a directly life-threatening condition must sometimes be eliminated, with indications for operations as possibly urgent or to be carried out immediately. Possible indications for urgent operations are  

a tuberculous process that worsens rapidly despite a backdrop of intensive chemotherapy, and repeated pulmonary hemorrhage.

Possible indications for immediate operations are  

profuse pulmonary hemorrhage, and tension pneumothorax.

Figure 3 Focal tuberculosis with limited S-2 lesion of the left lung after five months of treatment for infiltrative tuberculosis. Fragment from longitudinal tomogram.

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Indications for elective lung resection and the selection of a time frame for the operation are determined individually for patients already under treatment with combination chemotherapy. Treatment normally lasts until chemotherapy shows a positive clinical response. Clinical deterioration constitutes grounds for discussing whether to undertake surgical intervention (17). In most patients who have limited tuberculosis lesions, there is no laboratory-determined bacterial discharge after four to six months of treatment, but the absence of radiographically demonstrated regression of serious lesions may occasionally constitute grounds for minor pulmonary resection. In Russia, about 12% to 15% of patients identified for the first time as having active tuberculosis present indications for surgery (Fig. 3). In cases of tuberculoma (size more than 3 cm), early resection of the lung will prevent a progressive tuberculous process, shorten the period of treatment, and permit full rehabilitation of the patient at the clinical, occupational, and social levels (Fig. 4). In some cases, the operation avoids the frequent errors in differential diagnosis of tuberculoma and peripheral lung cancer. In patients with advanced fibrotic-cavitary tuberculosis, successful treatment by chemotherapy may be the exception to the rule. Unfortunately,

Figure 4 Pulmonary tuberculomas. (A) Major tuberculoma with central decay cavity in the superior lobe of the right lung. Tomogram view from the front. (B) Tuberculoma with decay cavities in the superior lobe of the left lung. Computed tomogram. (C and D) Cross-section of specimens from operation. (E) Histotopographic section. Van Gizon staining.

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Figure 5 Fibrotic-cavitary tuberculosis with large cavern in the superior lobe of the left lung. X-ray of lungs in frontal projection.

this group includes a large number of patients with contraindications for surgical treatment. According to our findings, surgical treatment is possible in only 15% of such patients (Figs. 5–7). In cases of fibrotic tuberculosis and pulmonary damage through caseous pneumonia, which are also of importance to the treatment approach, they are contraindications rather than indications for surgical treatment (Fig. 8).

Figure 6 Fibrotic-cavitary tuberculosis with large cavern in superior lobe of the right lung and dissemination in left lung. Computed tomogram.

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Figure 7 Fibrotic-cavitary tuberculosis with destruction of right lung. (A) X-ray of lungs in frontal projection. (B) Histotopographical section of the removed lung.

In cases of multidrug-resistant tuberculosis (MDR-TB), if lung resection is practicable, it is an alternative to protracted chemotherapy by second-line drugs and can supplement drug therapy where it is ineffective. When preparing the patient for operation, it is important to bring his/her general condition to the best possible level, reduce or eliminate

Figure 8 Fibrotic tuberculosis of the inferior lobe of the right lung. Computed tomogram.

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Figure 9 Multiple cavities in the superior lobe of the left lung following caseous pneumonia. Computed tomogram.

the tuberculous discharge limit the process, and repress nonspecific flora. With all surgical intervention relating to tuberculosis, combination chemotherapy is used in both the pre- and the postoperative periods. At the same time, pathogenetic, desensitizing, and immune therapies are also administered, as well as treatment for concomitant conditions. Where specially indicated, hemosorption, plasmapheresis, and parenteral administration of nutrition are also carried out. During the postoperative period, some patients necessitating prolonged care should be sent to a sanatorium or convalescent home. It is best to carry out the operation in the remission phase, which is determined by clinical, laboratory, and X-ray data. It should also be borne in mind that excessively protracted preparation of the patient for an operation is often harmful. It can lead to increased drug resistance and to the next spike in the tuberculosis process. Clinical experience also shows that where waiting for an operation is prolonged, the patient often refuses the intervention.

III. Contraindications In most cases, contraindications to the surgical treatment of tuberculosis patients depend on how extensive the process has been. Frequent contraindications for surgery are also the poor general state of the patients, advanced age, and impairment of respiratory, circulatory, liver, and kidneys functions. If these disorders are to be assessed, there must be a multidisciplinary approach to the patient.

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It should be borne in mind that in many patients, after the basic site of the infection has been removed, functional signs improve and sometimes even become normal. This is most often the case with caseous pneumonia, pulmonary hemorrhage, and chronic empyema of the pleura with wide bronchopleural fistula. IV. Types of Operation Various kinds of surgical intervention are practiced for tuberculosis of the lungs, pleura, intrathoracic lymph nodes, and bronchi:          

lung resection, pneumonectomy, thoracoplasty, extrapleural plombage, operations on the cavity (drainage, cavernotomy, and cavernoplasty), videothoracoscopic sanitation of the pleural cavity, thoracostomy, pleurectomy and decortication of the lung, removal of intrathoracic lymph nodes, operations on the bronchi (occlusion, resection and bronchoplasty, and reamputation of the stump), and elimination of pleural adhesions for correction of artificial pneumothorax.

Separate consideration should be given to endoscope removal of granulations or broncholiths in bronchoscopy and X-ray endovascular occlusion of the bronchial arteries in case of pulmonary hemorrhage. Operations to the nerves and major arteries, as separate interventions in their own right, are not practiced nowadays. All operations involving the thoracic wall, lungs, pleura, intrathoracic lymph nodes, and bronchi are carried out under general anesthesia with endotracheal or endobronchial intubation and artificial ventilation of the lungs. A. Lung Resection and Pneumonectomy

Pulmonary resection is an operation of varying extent. In tuberculosis patients, the so-called minor, or conservative, resections are mostly used. In such operations, a portion of the lung is removed (segmentectomy, wedge, and marginal and planar resection). Still less invasive is precision resection (high-point resection) proposed by the author. This is when a group of foci, tuberculoma or cavity, are removed with a very small layer of pulmonary tissue. The technical execution of most minor resections is greatly facilitated by the use of a surgical stapling instrument and application of machine stitching with tantalum staples. Precision resection is done by spot electrocoagulation or a neodim laser. Ligatures are applied to relatively major vascular and bronchial branches (28,29).

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Removal of one lobe (lobectomy) or two lobes of the lung (bilobectomy) is usually done for serious, advanced fibrotic-cavitary tuberculosis with one or more cavities in a single lobe of the lung. Lobectomy is also carried out for caseous pneumonia, major tuberculomas with major foci in a single lobe, fibrosis of a lobe of the lung, and scarring stenosis of the lobar bronchus. If the remaining portion of the lung turns out to be insufficient to fill the entire pleural cavity, pneumoperitoneum is also used in order to raise the diaphragm. Sometimes, to reduce the size of the relevant half of the ribcage, the posterior segments of the upper three or four ribs are resected. Resections of lungs, particularly minor resections, can be done from both sides. However, a distinction is drawn between operations in series with time intervals of three to five weeks and one-off interventions. Minor resections of lungs are well tolerated by patients and they are very effective. The majority of patients undergoing surgery are cured of tuberculosis. Pneumonectomy is chiefly carried out in extensive unilateral lesions including polycavernous process in a single lung, fibrotic-cavitary tuberculosis with bronchogenic dissemination, giant cavity, caseous pneumonia, and cicatricial stenosis of the main bronchi. In an extensive lesion of the lung, complicated by an empyema of the pleural cavity, pleuropneumonectomy is indicated, i.e., removal of the lung with its purulent pleural sac (30). Pneumonectomy is often the only possible type of operation; it is an absolutely indicated and effective operation. B. Thoracoplasty

This operation consists of resection of ribs on the side where the lung lesion is present. The volume of the relevant half of the rib cage is thus reduced, and the elastic tension of the lung tissue falls. Respiratory excursions of the lungs are reduced following damage to the integrity of ribs and to respiratory muscle function. Thereafter, immobile osseous tissue regenerates from the remaining rib periosteum. In a collapsed lung, the absorption of toxic products is reduced, and conditions are created for collapsing the cavern and the development of fibrosis. In this way, thoracoplasty with its mechanical effect leads to certain biological changes that help recovery during tuberculosis (Fig. 10). After thoracoplasty, occasionally the cavity will close up through scarring or the formation of a dense encapsulated caseous focus. More often it turns into a narrow cleft with an epithelialized internal wall. In many cases, the cavity simply collapses, but remains lined by granular tissue with foci of caseous necrosis. Naturally, the preservation of such a cavity may be the source of exacerbation, and it may progress in varying periods following the operation. Thoracoplasty is performed as a rule when there are contraindications to lung resection. Operations are carried out when the tuberculosis process is in a stable phase for small- and medium-sized cavities, if there is no clearly expressed fibrosis in the lung tissue and the cavern walls. Hemorrhage from a cavity can be an indication for immediate surgery. In patients

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Figure 10 Left-side seven-rib thoracoplasty. Volume of the left lung considerably reduced. X-ray of lungs in frontal projection.

with residual pleural cavities, where there is chronic pleural empyema and bronchopleural fistula, thoracoplasty in combination with muscular plasty (thoracomyoplasty) is invariably an effective operation. Thoracoplasty is well tolerated by the young and the middle aged. The indications for it are limited after the age of 55 to 60 years. More often, a one-off thoracoplasty operation is performed, involving the resection of the rear segments of the upper five to seven ribs. Ribs are removed down to one or two ribs lower than the lower edge of the cavity (based on the front-to-back X-ray). For large caverns with superior lobe localizations, the upper two to three ribs must be almost entirely removed. A compressing bandage is held in place for 1.5 to 2 months following the operation. One possible complication following thoracoplasty is atelectasis of the lung on the side where the operation was performed. As part of preventive efforts, it is essential to check the expectoration of sputum and to perform sanitation of the bronchial tree by fibrobronchoscopy when needed. C. Operations on Cavities

For draining, a catheter is inserted into a cavity by puncturing the thoracic wall. The catheter is used for constant aspiration of the cavity contents via a special suction pump system. Medicines are periodically injected into the cavity. Using a thin drainage catheter (microirrigator), a fairly protracted period for sanitation of the cavern by the local use of drugs is possible.

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Figure 11 Chronic tuberculous empyema (left) with thick and dense pleural sac walls. Computed tomogram.

In favorable cases, patients show clear clinical improvement. The contents of the cavity become progressively more fluid, transparent, and assume a serous character, with tubercle bacille disappearing from the cavity contents. The cavity becomes smaller, but does not usually heal up. Drainage is therefore more often used as an auxiliary method before another operation: resection, thoracoplasty, or cavernoplasty.

Figure 12 Chronic tuberculous empyema. (A) Surgical specimens of the removed pleural sac. Impressions from the ribs can be observed on the parietal pleura. (B) Removed pleural sac with thick walls opened up. Its content is made up of caseous masses, pus, and fibrin.

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Thoracostomy performed in patient with tuberculous pleural empyema.

Opening up and open treatment of cavities (cavernotomy) is used for large and giant cavities with rigid walls, when other operations are contraindicated—either because the process is extensive or because of the poor functional state of the patient. Before the operation is performed, it is essential to determine accurately the localization of the cavity using computerized tomography. For four to five weeks after the operation, open local treatment takes place, using tamponades with drugs. The cavity is treated with low-frequency ultrasound or lasers. The walls of the cavity are gradually cleansed, bacterial discharge is stopped, and the level of intoxication is reduced. In the second stage of surgical treatment, the cavity is closed up by thoracoplasty, myoplasty, or by a combination of the two, i.e., thoracomyoplasty. With proper cleaning of a solitary cavity where Mycobacterium tuberculosis is not present in the contents, a single-stage operation is possible: cavernotomy with cavernoplasty. For this purpose, the cavity is opened up, its walls are curetted and treated with antiseptics, and the lips of the draining bronchi are sutured, followed by suturing of the lung cavity. The cavity can also be sealed by muscle grafting on the pedicle (cavernomyoplasty). Simple cavernoplasty is sometimes possible when there are two cavities located close to one another. During the operation, they are joined up as a single cavity. Single-stage cavernoplasty is a clinically effective operation, which is well tolerated by patients. Videothoracoscopic cleansing of the pleural cavity consists of mechanical removal from the pleural cavity of pus, caseous masses, and fibrin mesh deposits. Accumulations of pathological content are eliminated, and the cavity is washed out with antituberculosis drugs and antiseptics. This cleansing is, as a rule, simply a continuation of diagnostic videothoracoscopy.

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Figure 14 Posttuberculous stenosis of the left main bronchus. (A) Bronchogram with distinctly appearing stenosis. (B) Diagram of superior lobectomy with resection of main bronchus and bronchial anastomosis. (C) Postoperative bronchogram. Bronchial lumen restored.

After examining the pleural cavity through an optical thoracoscope hooked up to a monitor, a location for a second thoracoport is selected. Through this port an aspirator, forceps, and other instruments for sanitation are introduced into a pleural cavity. When the work has been completed through the thoracoports, two drains are inserted to provide constant aspiration. D. Pleurectomy and Lung Decortication

This kind of operation is performed in tuberculosis patients with chronic empyema, pyopneumothorax, or chronic exudative pleuritis (Fig. 11). The operation consists of removal of the whole sac, with its content of pus, caseous material, and fibrin (Fig. 12). The thickness of the walls of this

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Figure 15 Silicone extrapleural plombage following operation for cavernous tuberculosis of the superior lobe of the left lung. X-ray of lungs in frontal projection.

sac, which consists of the parietal pleura and surface overlying the visceral pleura, can exceed 2 to 3 cm. This operation is sometimes called ‘‘empyemectomy,’’ emphasizing its radical nature in pleural empyema. In many patients suffering from empyema and concomitant lung lesion, the empyema sac is removed at the same time as lung resection. In some cases, it may be necessary to remove the entire lung together with the pus-filled pleural sac (pleuropneumonectomy). After removal of the sac containing the empyema and fibrin, the lung expands to fill the corresponding half of the thoracic cavity. Respiratory function steadily improves. Unlike the case with thoracoplasty, pleurectomy with decortication of a lung is a restorative operation. Thoracostomy consists in the resection of segments of two to three ribs, with the empyema cavity being opened up at the same time. The edges of the skin are sutured to the deeper layers of the wound. A ‘‘window’’ (Fig. 13) is formed in the thoracic wall. This can be used for undertaking open treatment of the pleura by washing out and tamponading the cavity, treating it with low-frequency ultrasound and laser irradiation. Thoracostomy used to be widely employed as a first step in tuberculosis empyema before thoracoplasty. Nowadays, however, indications for thoracostomy have narrowed down. E. Operations on Bronchi

Cutting and suturing of the bronchi in an affected lobe of the lung leads to obturation atelectasis. As a result, conditions are ripe for reparatory processes in the area of a cavity, and closure of the bronchial lumen helps stop the secretion of bacteria. However, the clinical effectiveness of operations,

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Figure 16 Tuberculosis of intrathoracic lymph nodes. (A) Paratracheal caseousnecrotic node from right side, causing ‘‘superior vena cava syndrome.’’ Removal of node eliminated intoxication and brought vein flow back to normal. X-ray of lungs in frontal projection (detail). (B) Superior lobe of the right lung with lung component of primary complex and large caseous-necrotic lymph node. Arrow indicates nodule-bronchial fistula. Photo of surgical specimen. (C) Caseous-necrotic mediastinal node. X-ray of left-lung frontal projection (detail). (D) Paratracheal caseous-necrotic node on the left. X-ray of lungs in the side view (detail). (E) Caseous-necrotic node in posterior mediastinum, showing pressure on esophagus. Removal of node eliminated intoxication and restored normal passage of esophagus. Esophagogram in a left side view.

designed to create obturation atelectasis, is often rather poor due to recanalization of the bronchus. For this reason, they are used sparingly, only when special indications dictate. Of far greater significance is bronchial resection with application of bronchial anastomosis (31). This is indicated for patients with posttuberculosis stenosis of the main bronchus, broncholiths, or bronchonodular fistula. Excision of the affected segment of the bronchus and reestablishment of bronchial permeability allow preservation of the whole lung or part of it in many patients (Fig. 14).

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Table 1 Indications for Basic Pulmonary Tuberculosis Operations Minor pulmonary resections (segmentectomy, marginal, wedge, and precision resections) Lobectomy

Pneumonectomy, pleuropneumonectomy

Thoracoplasty

Thoracomyoplasty

Cavernoplasty

Pleurectomy, decortication Removal of caseous lymph nodes Cavern draining Cavernotomy

Pulmonary tuberculosis of limited extension: cavity, conglomerate foci, tuberculoma

Cavitary or fibrotic-cavitary tuberculosis with foci in a single lobe. Multiple cavities in a single lobe (destroyed lobe). Tuberculoma with a decay and intralobar dissemination. Fibrosis of the lobe. Caseous pneumonia with involvement of a single lobe Fibrotic-cavitary tuberculosis with dissemination. Destroyed lung. Multiple cavities in a single lung. Post-tuberculous stenosis of the main bronchus with involvement of the lung—primary or secondary. Caseous pneumonia with lesion in more than one lobe. Fibrotic-cavitary tuberculosis with chronic pleural empyema One-sided fibrotic-cavitary tuberculosis with small cavity in the superior lobe and moderate focal dissemination or fibrotic alterations to other segments of the lungs. Residual cavern following draining or cavernotomy Tuberculous empyema with bronchopleural fistula and involvement of the lung together with contraindications for pleuropneumonectomy. Tuberculous empyema, with or without bronchopleural fistula, following lung resection Cleansed large or giant cavern in the superior lobe or the sixth segment with dissemination (Mycobacterium tuberculosis not appearing in sputum or in cavern swabbings) Pachypleuritis. Chronic empyema with nonextensive tuberculous lesion of the lung Chronic disease. Pressure on bronchus. Rupture of caseous masses in bronchi. Large-size nodes Large or giant cavity with clinical X-ray signs of active tuberculosis Large or giant cavity in the superior lobe or the sixth segment

The use of extrapleural silicone plombage (Fig. 15) is a relatively new operation for cavernous tuberculosis of the lungs. We began using this method sometimes for collapsotherapy instead of the more old-fashioned plombage materials. Long-term outcomes of this kind of operation have yet to be studied.

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Figure 17 Pulmonary hemorrhage. Catheter introduced into wide right bronchial artery. Its branches are expanded and form an area of hypervascularization. The right pulmonary artery is contrasted through arterioarterial anastomoses (its lower contour line is indicated by arrows). Bronchial arteriogram of the right lung in front view.

Figure 18 Subcutaneous emphysema of the neck and face of a patient with tension pneumothorax. Photo taken after aspirated drainage of pleural cavity.

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Figure 19 X-rays of tension pneumothorax. (A) Tension pneumothorax from the right with complete lung collapse and leftwards displacement of mediastinum. (B and C) Tension pneumothorax from the left with rightwards displacement of mediastinum. (D) Tension pneumothorax with complete collapse of lung and rightwards displacement of mediastinum. Computed tomogram. F. Lymphadenectomy

These operations are performed mainly in children, less frequently in adolescents, and very seldom in adults. For ongoing chronic primary tuberculosis, caseous necrotic lymph nodes at the root of the lung and the mediastinum are often a source of intoxication and spread of tuberculosis infection. A simultaneous tuberculosis involvement of the bronchi, with penetration of caseous matter into the bronchial lumen with bronchonodular fistula, and

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Bullous emphysema at the top of the lung. Photo taken during operation.

the formation of bronchial calculi (broncholiths) are all occasionally reported. The size of the affected nodes, their topography, degree of calcification, and possible complications, all vary widely (Fig. 16). Surgical removal of caseous necrotic lymph nodes is a very effective operation. The range of complications is minimal and the short- and long-term results are good (32). When there is a need for intervention from both sides, it can be done either simultaneously or in successive operations. Table 1 shows the different indications for the basic operations in patients with pulmonary tuberculosis. Emergency operations on complications from pulmonary tuberculosis are very rarely reported in clinical practice. However, they are of great importance because they may constitute a last chance for saving a patient’s life. With pulmonary hemorrhage, along with pulmonary resection, pneumonectomy, or collapsotherapy interventions, an X-ray endovascular operation may be extremely effective. It consists of the catheterization of the bronchial artery, bronchial arteriography (Fig. 17), and subsequent occlusion of the artery with special materials introduced through a catheter. When tension pneumothorax occurs, there must be an immediate aspirational drainage of the pleural cavity. This eliminates the direct threat of death (Figs. 18 and 19). In the case of cavity rupture or pulmonary bubbles, the wisdom of surgical intervention on the lung can then be assessed. V. Conclusion At the present time, the mortality after minor lung resections stands at less than 1%, whereas tuberculosis cure rates amount to 93% to 95%. Mortality following lobectomy is 2% to 3% and following pneumonectomy it is 7% to

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8%. The postoperative convalescence time, where recovery proceeds smoothly, varies from two to three weeks (after minor resections) to two to three months (following pneumonectomy). Functional results after minor resections and lobectomy are usually good. Fitness for work is reestablished in a period of two to three months. After pneumonectomy, functional test results among people in younger- and middle-age groups are usually fully satisfactory. In people from the more elderly groups, results are worse and physical effort needs to be limited. Patients suffering from MDR-TB also suffer from infections and other postoperative complications that are not as a rule due to the drug resistance itself, but to many other factors. Of crucial importance are the long duration of the illness, the fact that the destructive process is extensive and complicated, that immunity has been weakened, operations are complex, and drugs are poorly tolerated. In striving to improve the outcome of tuberculosis treatment, especially among seriously advanced forms of disease, it is important to explore the possibility of surgery, where there are the appropriate indications, and to operate on patients at the right time. Where a conservative approach to treatment of pulmonary tuberculosis patients is not sufficiently effective, it is advisable to consult a thoracic surgeon. References 1. Barry E. A treatise on consumption of the lungs. Dublin, 1726. 2. Hastings J, Storks R. A case of tuberculous excavation of the left lung treated by perforation of the cavity through the walls of the chest. London Med Gaz 1844; 5:378. 3. Forlanini C. A contribuzione della terapia chirurgica della tisi [Contribution to the surgical treatment of tuberculosis]. Gazz Osped 1882; 68:537. 4. Jacobeus C. Ueber Laparo-und Thoracoscopy [On laparoscopy and thoracoscopy]. Beitr Klin Tuberk 1912; 25:185. 5. Spengler C. Chirurgische und klimatische Behandlung der Lungenschwindtsucht [Surgical and climatic treatment of pulmonary tuberculosis]. Bremen: Verh Naturforsch, 1890. 6. Friedrich P. Weitere Fragestellungen und Winke fur Brustwand-Lungen-Mobilisierung [Further questions and trends in thoracic wall and lung mobilization]. Dtsch Zschr Chir 1909; 100:181. 7. Sauerbruch F. Die chirurgische Behandlung der Lungentuberkulose [The surgical treatment of pulmonary tuberculosis]. Munch Med Wchnschr 1921; 9:261. 8. Bogoush LK, ed. Surgical Management of Pulmonary Tuberculosis. Moscow: Medizina, 1979:296 (in Russian). 9. Graf W. Ueber die thoracoplastische Totalausschaltung des Spitzenoberfeldbereichs der Lunge und die klinische Auswertung des extrapleuralen Selektivpneumothorax und Oleothorax [On the complete thoracoplastic closure of the upper areas of the lung and clinical assessment of extrapleural selective pneumothorax and oleothorax]. Dtsch med Wchnschr 1936; 62:632. 10. Schlange H. Kongress der Deutschen Gesellschaft fur Chirurgie zu Berlin [Congress of the German Association for Surgery, Berlin]. Int Zbl Tbk-Forsch 1907; 2:38. 11. Stuertz C. Kunstliche Zwerchfellaehmung bei schweren chronischen einseitigen Lungenerkrankungen [Artificial diaphragmatic breathing in serious chronic one-sided lung diseases]. Dtsch med Wschr 1911; 37:2224.

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12. Monaldi V. Tentativi di aspirazione endocavitaria nelle caverne tubercolari del polmone [Endocavity aspiration trials in pulmonary tuberculosis caverns]. Lotta Tuberc 1938; 9:910. 13. Lilienthal H. Pneumonectomy for sarcoma of lung in tuberculous patient. J Thorac Surg 1933; 2:600. 14. Freedlander S. Lobectomy in pulmonary tuberculosis. J Thorac Surg 1935; 5:132. 15. Overholt RH, Woods FM. The prone position in thoracic surgery. J Internat Coll Surg 1947; 10:216. 16. Iseman M. Treatment of multidrug-resistant tuberculosis. New Engl J Med 1993; 329:784. 17. Perelman MI. Pulmonary Resection for Tuberculosis. Novosibirsk: USSR Academy of Science, 1962:372 (in Russian). 18. Perelman MI. Surgery of tuberculosis. World J Surg 1997; 21:557. 19. Perelman MI, ed. Surgery of Pulmonary Tuberculosis. Surgery of Tuberc. [abstr]. Moscow International Conference, September 17–19, 1997. 20. Pomerantz M, Madsen L, Goble M, Iseman M. Surgical management of resistant mycobacterial tuberculosis and other mycobacterial pulmonary infections. Ann Thorac Surg 1991; 52:1108. 21. Pomerantz M, Brown J. The surgical management of tuberculosis. Semin Thorac Cardiovasc Surg 195; 7:108. 22. Treasure RL, Seaworth BJ. Current role of surgery in Mycobacterium tuberculosis. Ann Thorac Surg 1995; 59:1405. 23. Rizzi A, Rocco G, Robustellini M, Rossi G, Della-Pona S, Massera F. Results of surgical management of tuberculosis: experience in 206 patients undergoing operation. Ann Thorac Surg 1995; 59:896. 24. Zaleskis R. The role of surgical methods in tuberculosis treatment. Probl Tuberc 2001; 9:3. 25. Reed CE, Parker EF, Crawford FA. Surgical resection for complications of pulmonary tuberculosis. Ann Thorac Surg 1989; 48:165. 26. Repin YuM. [Surgery of Aggravated Forms of Pulmonary Tuberculosis]. Leningrad: Medizina, 1984:230. 27. Worthington MG, Brink JG, Odell JA, et al. Surgical relief of acute airway obstruction due to primary tuberculosis. Ann Thorac Surg 1993; 56:1054. 28. Cooper DJ, Perelman MI, Todd TR, Ginsberg RJ, Patterson GA, Pearson FG. Precision cautery excision of pulmonary lesions. Ann Thorac Surg 1986; 41:51. 29. Perelman MI. Precision techniques for removal of lesions from the lungs. Surgery 1983; 11:12 (in Russian). ˜ hest Surg 30. Brown J, Pomerantz M. Extrapleural pneumonectomy for tuberculosis. N Clin North Am 1995; 5:289. 31. Watanabe Y, Murakami S, Iwa T. Bronchial stricture due to endobronchial tuberculosis. Thorac Cardiovasc Surgeon 1988; 36:27. 32. Freixinet J, Varela A, Lopez L, Caminero J, Rodriguez de Castro F, Serrano A. Surgical treatment of childhood mediastinal tuberculous lymphadenitis. Ann Thorac Surg 1995; 59:644.

SECTION III: CONTROL OF TUBERCULOSIS—BASIC PRINCIPLES AND TOOLS

16 History of Tuberculosis Control

JOHN A. SBARBARO

SERGIO SPINACI

University of Colorado Health Sciences Center, University Physicians, Inc., Denver, Colorado, U.S.A.

Global Malaria Programme, World Health Organization, HIV/AIDS, Tuberculosis and Malaria Cluster, Geneva, Switzerland

I. Introduction Treatment is the centerpiece of all tuberculosis (TB) control efforts— adequate and complete treatment that renders the patient permanently noncontagious and unable to transmit the organism to others. The history of TB control dates from 2700 B.C. when the Chinese first began to treat TB, albeit ineffectively, with the dung of animals (1). Efforts to treat TB continued throughout the millennia as each new generation of physicians developed new, although equally unsuccessful, treatments. However, TB control is more than just the treatment of individual patients. It involves an organized and ongoing effort by society to protect its members from acquiring the infection; prevent the infection from progressing to disease and then to death; and minimize the social and economic impact of the disease on the entire community. Thus, before the identification of the TB bacille in 1882, systematic TB control efforts were not possible. Although the opening of the first sanatorium by Hermann Brehmer in 1859 reduced the opportunity for transmission to others, this benefit to the community depended on patients voluntarily accepting institutionalization. Prior to 1882, all sanatoria had been private ventures for patients able to 483

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afford their services. However, that was to change once the airborne transmission of the bacille was fully recognized. The establishment of publicly funded sanatoria and clinics was then only a matter of time. II. Compulsory Isolation and the Beginnings of TB Control in the United States Five years after the identification of the tubercle bacille, in 1887, Hermann Biggs of New York City pioneered the first documented effort to establish an effective and scientifically based TB control program. He chastised New York’s sanitary officials for their slowness in taking rational action against an infectious disease. In his first report to the Henry Phipps Institute for the Study, Treatment, and P