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 Prevention of Tuberculosis, Biggs emphatically stated that the only efficient alternative to a family unwilling to follow sanitary restrictions was ‘‘consignment of the consumptive to a hospital.’’ He predicted the need for publicly funded institutions to care for the ‘‘homeless, friendless and dependent, dissipated, and vicious consumptives (2).’’ Biggs was opposed at the time by the organized medical societies of New York City and the Academy of Medicine of New York. But despite that opposition, compulsory reporting of all TB cases became New York law in 1897. Home visiting as well as compulsory hospitalization when indicated was common in New York by 1903. Biggs also called for ‘‘free dispensaries’’ to provide constant medical supervision, free medicine, and free food for the treatment of ambulatory TB cases. He envisioned these dispensaries (clinics) to be the focal point of TB control, where all patients following their discharge from inpatient institutions were to be served. A hundred years later, this vision still continues to be central to TB control. Although it may now be difficult to understand organized medicine’s ardent opposition to such obvious control measures, one has to appreciate the profound influence of the theory of the universality of TB disease, which pervaded civilization at the turn of the century. With the heavy prevalence of active advanced cases and the prolonged course of the disease, even the most accomplished of physicians felt that ‘‘everyone had a little tuberculosis (3).’’ This attitude of powerlessness prevailed into the early 1920s. III. The Origins of the Tuberculosis Clinic Francine’s description of the outpatient routine instituted by Flick in 1900 is most prophetic of today’s focus upon carefully monitored outpatient care. Flick, then the first Director of the Phipps Institute in Philadelphia, insisted on patient appointments every two weeks, with a full chest examination every month. Preventive procedures including the use of spit cups and paper napkins were emphasized. Homevisits every twoweeks were considered essential because ‘‘left to themselves, those cases, many of whom are ignorant and careless, cannot or will not follow instructions however carefully laid down.’’

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Reflecting on the Phipps Institute’s commitment to research, Flick had observed: ‘‘To do exact scientific work in a dispensary was a new departure (4).’’ Unlike voluntary general medical clinics that were offshoots of charity concerns (later combined with the needs of medical education) (5), it is clear that TB dispensaries arose from a public health motive. In 1905, the founding of the U.S. National Association for the Study and Prevention of Tuberculosis began a militant endeavor to combat the disease through the provision of additional specialized facilities for the detection and control of TB. This early voluntary public health movement utilized the outpatient clinic as a source of information as well as a center for disease treatment and control. Whereas in 1905 there were only 20 TB clinics in the United States, by 1915 over 500 community-based clinics had been established. The maintenance of these clinics, as in the case of sanatoria, gradually came to be recognized as a necessary and appropriate TB control function of municipal and state governments under the direction of their public health departments (6). In reevaluating its status in 1924, the New York Association of TB clinics concluded that the clinic should not be an isolated service, but rather should become a part of a unified TB care program that included the sanatoria (7). As if anticipating today’s needs, Hawes, then Director of the Pulmonary Disease Clinic at the Massachusetts General Hospital, called for the TB clinic to be the ‘‘center of activity for all anti-TB work (8).’’ He wanted the clinics to be centrally located; be easily accessible to the poor; be open at hours convenient to the population served; provide evening services; offer food; examine all contacts of cases of active TB; and have close cooperation with private physicians. Despite this focus on clinic care, it was then generally accepted that patients with active TB should receive treatment in institutions because of the communicable nature of the disease as well as the perception of an improved potential for recovery (9). By 1915, within the United States, hospital and sanatorium beds had increased from 600 to over 30,000 (5). By 1942, despite a decrease in the number of patients documented as having the disease, the number of beds had risen to 97,726, with the increase driven by a gradual lengthening of patients’ time in the sanatoria (10). This increase in length of hospitalization time can be partially explained by a reinvigorated focus on ‘‘protective isolation.’’ Chadwick called for sanatoria to care for the incurables until death and to treat all others until they were noninfectious (11). ‘‘A bed for every case of contagious TB’’ was Chadwick’s goal. By the early 1940s, interest in, and financial support for, ambulatory clinic services had faded in the United States. TB control had become synonymous with sanatorium care. IV. The Impact of Effective Chemotherapy Although there were newspaper reports of patients dancing in the wards, the discovery of streptomycin, para-amino salicylic acid (PAS), and isoniazid did not bring the sanatorium era to a quick end. In 1953, one year after

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the dramatic effect of isoniazid had been demonstrated, Hayes of the College of Chest Physicians emphatically stated that all other measures (including antibiotics) were only supplements to the basic treatment of TB, which remained rest and time (12). His views were strongly supported by the American Trudeau Society’s Committee on Therapy (13). The 1957 studies of Wier et al. (14) and later D’Esopo et al. (15), demonstrating that active ambulation and exercise were not detrimental, eroded support for prolonged hospitalization. Simultaneously Robins et al. (16) from New York confirmed the outpatient effectiveness of drugs. That same year, Riley et al. published his initial report delineating the infectivity of patients with pulmonary TB and documenting the potential sanitary control of contaminated indoor air by the use of ultraviolet lights and air hygiene (17). In the United States, the stage was now set for the return of TB control to the outpatient setting. Unfortunately, with both the professional staff and most financial resources committed to sanatorium care, TB clinics in the United States had indeed languished. Reviewing 37 areas of the United States, Blomquist (18) reported that sputum examinations had not been performed on 50% of clinic patients within a six-month period. One-sixth of clinic patients were not under medical supervision. Overall, health department clinics were supervising only one-third of the known TB patients. This was also an era of renewed efforts by organized medicine to stave off government intervention in the field of medical care—a situation amplified by many TB patients seeking care from private physicians. This unanticipated shift in the care of TB, from sanatorium specialists to inexperienced and untrained primary care private physicians, raised TB control concerns still common today. In a perceptive editorial, McDermott highlighted the possibility for widespread harm that could arise from the injudicious use of chemotherapy by private physicians unfamiliar with the disease (19). In response, the U.S. Communicable Disease Center [now the Centers for Disease Control and Prevention (CDC)] restructured its Tuberculosis Branch and began assigning both administrative and physician personnel to state and large metropolitan health departments. The goal was to redirect local and state funds from outdated sanatorium district and inpatient facilities to specialized TB clinics, which were to be operated by government-sponsored health departments. At the time, there were relatively few such clinics (20). Although governmental funding waxed and waned in the United States over the next 20 years, the specialized TB clinic and program structure put in place during the 1960s remained firmly in place. V. Nonadherence and the Introduction of Directly Observed Treatment Central to the debate of general clinics versus specialized clinics was a growing recognition that many patients were noncompliant with treatment. In 1958, Fox highlighted that problem in a publication from Madras, India,

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which still stands today as a classic in TB control (21). A year later, in 1959, Breite tested urine samples collected from patients being treated with PAS by the New York Department of Health. He found that only 35% were taking their medication (22), demonstrating that noncompliance with treatment was a universal problem and not limited to resource-poor countries. A cascade of confirming reports quickly followed making nonadherence with therapy the central concern of all future TB control programs. Fox again led the way, establishing what remains as the basic tenet of today’s TB control—the need for supervised therapy (23). Although Fox’s original concept of supervised (directly observed) therapy relied on daily treatment, his British Medical Research unit in Madras, India, reported that giving the same drugs intermittently in higher doses could be equally effective (24). One year later, in 1965, breaking with his country’s ‘‘long tradition of seeking to identify those characteristics that would be predictive of noncompliance,’’ Sbarbaro began a long campaign to establish intermittent directly administered treatment as the centerpiece for the control of active TB within the United States (25), bypassing the traditional approach of waiting until a patient’s noncompliant behavior had been confirmed. Instead public health quarantine laws were used to immediately compel patient cooperation. Patients were offered the option of replacing compulsory quarantine within an institution with outpatient ‘‘chemical quarantine.’’ The treatment approach relied on high dosages of chemotherapy directly administered to the patient twice a week by a nurse or community worker, who could then verify that the patient was still under active and continuing treatment. In 1993, the CDC made directly observed therapy the standard of care for the United States (26).

VI. Preventive Treatment: Expanding the Role of Chemotherapy in the United States While most of the world’s attention remained focused on the treatment of active disease, in 1959 an entirely new approach to controlling TB was launched by the Arden House Conference under the auspices of the U.S. Public Health Service and the National Tuberculosis Association. An impressive panel of TB control experts recommended the eradication of TB through the expanded use of chemotherapy. ‘‘Preventive treatment’’— treatment aimed at sterilizing the reservoir of tubercle bacille within the human population and thereby preventing the emergence of disease—was to become the second cornerstone of TB control. This recommendation was unique and must be considered a landmark in public health. All resources were to be mobilized for the widespread application of chemotherapy at all levels within the community. The goal was to render all patients with active disease noncontagious, and, further, to minimize the possibility of reactivation of latent disease (27,28).

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Combined with this reliance upon chemotherapy as a universal public health measure was the recommendation that state and local health authorities assume responsibility for ensuring the adequate treatment and rehabilitation of all patients with TB. Thus in one stroke, a new benchmark for TB control was established within the United States, and it reestablished the focus on, and the philosophical basis for, the primacy of the specialized public health clinic in TB control. A subsequent report to the Surgeon General of the United States emphasized the need for communities to build up clinic-centered TB control programs (29). These specialized district-based TB clinics were envisioned as best able to meet the ethnic, educational, social, and behavioral patterns of all patients. In support of the recommendation, McDermott observed that such a nationwide campaign could bring order and solution to the problems inherent in the transfer of the care of TB from sanatorium specialists to private practitioners (30). Federal funds and personnel began to flow to local and state health departments from the CDC. With the funds came case-reporting requirements and the program standards that were to be met by each clinic. The era of TB control program accountability had begun (31). VII. The Tuberculin Skin Test Essential to this emphasis on prevention was the ability to identify who was, and who was not, infected with Mycobacterium tuberculosis. The tuberculin skin test—using a mixture of by-product antigens of TB metabolism—had begun to emerge as a pivotal tool in the United States’s effort to control TB during the late 1940s. The Arden House report (27) made tuberculin skin testing, which was initially used for epidemiological studies, the cornerstone for its new and expanded phase of TB control—preventive treatment. As background, in 1941, one large batch of the material, purified protein derivative-standard (PPD-S), produced by Florence Seibert had become the international standard against which all commercial products were standardized (32). Unfortunately, over the next 40 years, all commercial product standardization was performed in guinea pigs—a flawed protocol that resulted in the production and sale of many ineffective tuberculintesting products. This problem was corrected in 1980 after the U.S. Food and Drug Administration required that all tuberculin standardization be performed only in human populations (33). However, even under the most ideal circumstances, the test is neither 100% specific nor 100% sensitive. Following the Arden House report, there quickly followed a series of public health–control initiatives that relied upon the identification of an infected individual through a positive tuberculin test. In the early 1960s, the U.S. Centers for Disease Control launched its Child Centered Program, which was designed to identify adult active TB cases through the identification of infected children (34). However, the program was unsuccessful (35). Other skin testing and preventive treatment programs begun in those same

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years were somewhat more effective, and over the decades they have undergone continuing refinement. The progressive decline of TB rates in the United States led the CDC to publish a Strategic Plan to Eliminate Tuberculosis from the United States in 1989 (36). The plan emphasized the need for a vigorous management focus. In addition, it expanded the goals of TB control more extensively into the area of preventing infection and disease, especially in high-risk populations. Focusing only on high-risk groups, ‘‘targeted testing’’ was encouraged to identify and preventively treat persons at significant risk. Routine screening of healthcare and criminal justice institution personnel, strongly encouraged within the United States beginning in the late 1970s, was to continue (37). Tuberculin skin testing of persons at lower risk was discouraged (38). Unfortunately, increasing rates of HIV/acquired immune deficiency syndrome (AIDS), with its negating effect on the skin test and the continuing immigration of bacille Calmette–Gue´rin (BCG)-immunized individuals into the United States have combined to diminish the value of the traditional tuberculin test. VIII. Tuberculosis Control in Europe The concept of ‘‘prevention’’ did not originate with the Arden House report. It began 70 years earlier, when Koch proposed the use of his glycerin-extracted tuberculin (Koch’s lymph) as a preventive vaccine (39). Although the material was ineffective, the concept was not. Calmette and Gue´rin introduced BCG, a vaccine employing an attenuated strain of Mycobacterium bovis, into Europe in the early 1920s. Producing it required 231 serial passages through ox bile–containing media. Because freeze-drying did not exist, continuous serial passage through media was required to keep the original vaccine viable. Subsequent large batches of BCG intended for community prevention programs were created from aliquots taken at different periods of time from that central serial growth process. The result was products of varying immunologic potency and effectiveness. Methodological and geographical differences further complicated any conclusions that could be drawn from the heterogeneous group of reported vaccine trials. Mass BCG vaccination began around 1950 and was strongly supported by the United Nations International Children’s Emergency Fund (UNICEF) and the World Health Organization (WHO) as the only feasible TB control measure in developing countries. Due to the high variability of assessed protection in controlled field trials, the 1974 WHO Expert Committee on Tuberculosis recommended that BCG be included in the Expanded Programs on Immunization and given to newborn infants to protect them from tuberculous meningitis and other disseminated forms of the disease. Despite the difficulty of assessing tuberculin conversion and diagnosing pediatric cases among contacts of an index bacillary case, BCG remained a standard practice in national programs throughout Europe as the only protection for tuberculin-negative contacts.

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However, prior to the introduction of BCG, TB mortality had already peaked in Europe before the 19th century, coinciding with urbanization and industrialization. Thereafter, perhaps as a result of improved host defense mechanisms, and especially by reduced transmission, TB mortality consistently decreased, with exception of the periods of the two global conflicts. In the mid-1950s, at about the time the value of multiple-drug chemotherapy was discovered, mortality was close to 100 per 100,000 population. This is approximately 100 times higher than the mortality of HIV/AIDS today in Western Europe. After the Second World War, the concept of social medicine emerged, with control and eradication of the disease becoming the responsibility of political and administrative institutions. Appropriate funding for TB control measures was made available by law. The economically poor were admitted free of charge to TB dispensaries and wards, and home chemotherapy supported by a tracking system for noncompliant individuals was established by the TB dispensaries. In the 1960s, selected control measures were still controversial. Some countries were advocating mass population screening by X-ray examination and tuberculin testing. Diagnosis, when combined with sterilization by treatment of all forms of TB, was demonstrated to be effective in steadily reducing the prevalence and incidence of the disease in a prospective operational research study in the Kolı`n District of Czechoslovakia by Styblo et al. (40) and Krivinka et al. (41). During the intervening years, as a result of continuing improvement in social conditions combined with control measures centered on the diagnosis and home treatment of TB, with both activities being coordinated by public health dispensaries, the disease became relatively rare in the span of only two decades. TB institutions began to concentrate on new social and emerging respiratory diseases, losing their specific focus on TB. Public concern over TB infection rapidly diminished. TB control measures became less strict and public health control measures were largely ignored even by TB and chest specialists. The consequence was a progressive loss of knowledge of, and commitment to, the key pillars of diagnosis and treatment strategy among the professional community. This decline was further aggravated by the lack of an efficient tracking of defaulters by public health nurses. The result was a resurgence of microepidemics and resistance to anti-TB drugs. In the 1980s, two new factors emerged: increased immigration from high TB prevalence countries and the global HIV epidemic. In confined environments, such as prisons or hospitals, these two events fuelled epidemics of significant proportions (42,43). At the beginning of the 21st century, in many European countries, about 50% of TB cases were foreign born and a significant proportion of the total patients were coinfected with HIV. These new developments attracted attention from the media, concerned professionals, voluntary organizations, and ultimately governments. Within a few years, the European public health TB control systems were

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reactivated. Epidemics became progressively rare, and TB reporting continued to show a steady decline. IX. Tuberculosis Control in Developing Countries Sputum microscopy and standardized multiple-drug chemotherapy remain the foundation for TB control in developing countries. These powerful tools had provided a tremendous impetus to the successful treatment of individual patients in industrialized countries. By the late 1950s, Crofton (44) achieved near 100% success with two years treatment and soon ‘‘croftonians’’ spread to other countries advocating his treatment concepts. In the 1960s and 1970s, clinical trials coordinated by the British Medical Research Council under the landmark scientific direction of Wallace Fox and Dennis Mitchison, extensively improved the knowledge of TB drugs. With the discovery of the bactericidal activity of rifampicin against mycobacteria (45) and recognition of the sterilizing effects of pyrazinamide, the duration of chemotherapy was shortened to six months. However, short-course chemotherapy was generally not recommended in developing countries as treatment policy until the 1990s. On the operational side, in 1956, the results of the Madras study (46) were made available demonstrating equal effects of home and hospital treatment. The study revealed that hospitalization per se was insufficient to ensure patients’ adherence to treatment. Patient compliance was higher when the possibility to participate in social and working life was ensured. This required a network of dedicated treatment supervisors, which was then not available in developing countries. In 1964 and 1974, the Eight and Ninth Reports of the WHO Expert Committee on Tuberculosis emphasized the need for TB control programs and proposed recommendations for their implementation (47). In the introduction to his fundamental book on TB control published in 1979, Toman stated, ‘‘the control of tuberculosis has ceased to be a primarily technical problem . . . . Instead of the privileged few that could be served in the past by a small number of specialists available, anyone suffering from tuberculosis . . . may enjoy the benefits of this technology, provided that is adapted to the requirements of a country’s health program (48).’’ Unfortunately, 25 years after his publication, Toman’s predictions have still not been realized. The question of course is ‘‘Why?’’ TB has always been primarily a disease of the poor. In the 1980s, in economically poor countries and among the Western world’s marginalized ethnic minorities and ghettos of mega cities, TB continued as a significant problem. The application of long-course (12–18 months) regimens without either the appropriate supervision or the necessary laboratory facilities generated epidemiological chaos. Prior to 1991, with the notable exception of Brazil, Chile, Cuba, Sri Lanka, and a few other countries, most developing countries were still using long-course chemotherapy, which was then the

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so-called ‘‘standard’’ chemotherapy. The end result was the creation of large numbers of chronic TB patients continuing to spread their bacille to contacts at the rate of approximately 12 to 14 new infections per case per year (49). The results of the Kolı`n, Madras, and other operational studies clearly demonstrated that early detection and diagnosis, and appropriate chemotherapy, accompanied by public health measures to counsel and track patients, were not only able to cure and significantly reduce mortality, but also would have an epidemiological impact on the incidence of the disease. The key issue at that time was how to expand that technical knowledge and tools to the large majority of patients in developing countries. Why could it not be accomplished? In the Alma Ata conference on primary health care (1977), the ethical principles and the technical content of primary health care were agreed on by UNICEF and WHO. The primary health care model was to be based on (i) health service delivery at village and subdistrict levels, (ii) referral of advanced cases to secondary care units, (iii) health services delivery integrated with nutritional support for risk groups such as children and mothers, and (iv) basic hygiene consisting of clean water and sanitation. The two foremost leaders of public health, Halfdan Mahler, Director General of the WHO (and previously head of the TB Unit in WHO) and Jim Grant, Secretary General of UNICEF, had the vision and the charisma to launch public health campaigns supporting primary health care. During the 1980s, the primary health care strategy had a major impact on child mortality. However, it did not have the anticipated impact on diseases such as TB, which required long-term care and expensive multiple-drug regimens, along with relatively complex patient and program management systems. The majority of TB patients were ‘‘diagnosed’’ by poor-quality radiographs in advanced phases of the disease. Suspects were not confirmed by bacteriology, and patients were prescribed nonstandardized treatments (50). Most patients, especially in Asia, sought treatment from private clinics. The effect of this chaotic situation soon became apparent—‘‘man-made’’ sources of infection spread drug-resistant bacille to susceptible individuals. As a result, the annual number of TB cases began to increase. Households were, and continue to be, economically destroyed by TB, thereby contributing significantly to an increase in poverty. This grim picture can be attributed primarily to insufficient political support and the resultant lack of government funding. The so-called structural adjustment reforms within poor countries, launched in the name of financial sustainability, have actually produced sharp reductions of already meager government budgets and staff. Aid agencies have tried to compensate for government services failure by providing direct support for the implementation of specific projects. They have done remarkable work in some situations; however, rarely could they compensate for the lack of the sufficient government funding, staff, and infrastructure.

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X. Advancing the Goals of Tuberculosis Control In the latter half of the 1980s, the disastrous impact of HIV on the natural history of TB became fully apparent. TB–HIV epidemics began ravaging communities, especially in sub-Saharan African countries. Clinicians were reporting unusual ‘‘children-like’’ forms of TB in adults, and epidemiologists documented significant increases in TB rates, with unprecedented peaks in young women. Thus the 1980s witnessed the two most disastrous events ever to strike at the heart of TB control: the TB–HIV epidemic and the epidemic of ‘‘man-made’’ drug-resistant infection. At the same time as HIV began to show its devastating impact in sub-Saharan Africa, the International Union Against Tuberculosis and Lung Disease (IUATLD)- and The Royal Netherlands Tuberculosis Association (KNCV)-supported ‘‘model’’ national programs were reporting unprecedented positive results. The national programs of Algeria, Benin, Coˆte d’Ivoire, Guinea, Malawi, Morocco, Mozambique, Nicaragua, Senegal, Tanzania, and Viet Nam achieved countrywide case detection of all forms of TB, full registration of patients under treatment, and routine monitoring of treatment by sputum microscopy. End-of-treatment cohort analyses demonstrated that in developing countries it was possible to achieve the same results countrywide as those obtained in industrialized countries. In 1991, WHO’s TB program, under its new director Kochi, combined a powerful analysis of the world TB situation with clear and direct objectives for the future (51). Termed the Global Tuberculosis Programme, it depicted the devastating impact of TB around the world in such a clear and forceful manner that it changed the public health focus of WHO, national governments, and leading voluntary organizations. Major programmatic deficiencies that had to be overcome were identified: inadequate treatment producing high rates of failure to therapy; inadequate resources for programs designed to face the challenges of the worldwide TB–HIV epidemic; and inadequate governmental commitment and insufficient funding for program management, microscopy laboratories, and drug supply. WHO’s vision called for improved systems of treatment management to become the basis of a new two-pronged attack on TB and pointed to the work of Styblo and the IUATLD, noting that it had clearly demonstrated the importance of patient management to the IUATLD successes in Africa. Acknowledging that adherence to dogmatic technical policies had often suppressed new and innovative approaches, WHO’s new policy focused principally on ‘‘management,’’ which would be measured by ‘‘rigorous cohort analysis’’ of the results and outcomes. Directly observed treatment and short-term regimens became central to the DOTS strategy. The first strategic approach was to develop, package, and spread the knowledge of the technical components of a successful TB program. In February 1991, staff from WHO and the Malawi national program (one of the IUATLD model programs) met in Lilongwe (Malawi) with Karel Styblo (then retired IUATLD Scientific Director) to learn the lessons

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from their successful management approach and to start developing a global framework for national TB programs. WHO initiated standardized treatment guidelines along with the provision of training materials for use at district and national levels. A network of TB experts visited an increasing number of countries twice each year, supporting them in the change from their old policies to the new DOTS approach. ‘‘DOTS’’ became the brand name of the modern TB strategy and encompassed the essential components of the new control strategy: diagnosis by sputum examination and case history, treatment by the standard short-course regimen, continuous supply of anti-TB drugs, and monitoring of treatment outcomes by cohort analysis and sputum examinations. Responding to the new threats to TB control, the WHO strategy was focused on strengthening country operations. Publications were directed to respond to country needs on ‘‘how to do it practically’’ instead of ‘‘how it should be done in theory.’’ This philosophy was, and is, reflected in WHO’s treatment guidelines. They are based on the best knowledge of epidemiology and technical tools, especially short-course chemotherapy, coupled to the operational experience gained in the ‘‘model programs.’’ WHO recommended that: (i) patient treatment be categorized by personal history and results of sputum smear microscopy, without culture and drug-resistance tests; (ii) treatment of smear-positive patients be directly supervised until the patient becomes smear negative; (iii) health staff performance be evaluated by their treatment results and by quarterly cohort analysis; (iv) two sputum smear–negative results, in two successive occasions, be required to declare a patient cured; and (v) treatment of HIV-infected patients be of the same duration as for the noninfected. District training materials and TB–HIV guidelines were developed to provide practical guidance to TB coordinators through program implementation. The second strategic approach was to reach out to an international network of supporting partners who had both technical competence and access to funding decision makers. Internationally, the publication of the articles on the cost-effectiveness of short-course chemotherapy summarized by Murray et al. (52,53) and the inclusion of TB care among the most costeffective interventions in the 1993 World Bank World Development Report triggered positive attention by donor agencies. WHO was then able to expand the TB partnership from the technical and advocacy agencies such as the IUATLD and KNCV, to bring in other development agencies [Norwegian Agency for Development Cooperation, German Leprosy Relief Association (GLRA), the Netherlands Cooperation, Canadian International Development Agency (Canada), Swedish International Development Cooperation Agency (SIDA) (Sweden), U.S. CDC, United States Agency for International Development, Sorro’s Sorros Open Society] all becoming members of the Coordination and Advisory Research Group, together with rotating memberships from high-prevalence countries. This partnership provided the political support for increased international funding and technical assistance to developing countries.

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The third strategic approach was to take advantage of opportunities as they emerged. For example, the cost-effectiveness studies of shortcourse chemotherapy expanded WHO’s involvement as a technical adviser to the large-scale projects supported by the International Development Association/World Bank in China, Bangladesh, Kyrgyzstan, and India. Recognizing that each country would have different operational needs, WHO began to actively assist countries in developing their own national manuals and management principles. This activity led to the development of a cadre of country and regional technical advisers, thereby strengthening WHO’s resources. Due to the renewed priority given to TB control, many developing countries began strengthening their programs with their best public health managers, with support staff from WHO and its partner agencies. In retrospect, it is clear that the combination of these three strategies was successful. Coordination among key stake holders, together with sound and country-based technical guidance, appear to be the main reasons why it became possible to expand modern TB control to the majority of developing countries in the 1990s. Funding for TB control increased sharply to reach the total aggregated expenditures of 850 million for 2002 and the planned budget of 1000 million for 2003 (54). There has been a longstanding debate over the value of a ‘‘vertical’’ (disease-specific programmatic planning and service delivery) versus a ‘‘horizontal’’ (all disease control efforts integrated at the primary care level) program approach to TB control. Disease-specific programs, such as Stop TB, have achieved a great deal through concentration of their expertise, commitments, and approaches. Such programs are not an alternative to a broader health system support, but provide added value when well integrated into national health development and sectoral strategy and plans. The approach involves three levels of the health infrastructure—national, regional, and district—which is necessary to ensure the technical quality of general health staff performance and to improve the management of disease-specific operations (including planning of drug supply, management of diagnostic practices, patient registration, and outcomes evaluation). The chain of service delivery, from national planning to counseling of patients and supervision of drug intake, is jeopardized by reorganization involving downsizing of government health staff. The DOTS approach is most effective when fully integrated in the management of services at community level, but should maintain a specific national budget to ensure support of the technical network (for diagnosis, treatment, registration, monitoring, and evaluation). Experience shows that the best approach involves adaptation to the local situation. XI. The Impact of Social Trends upon TB Control The upsurge in the number and clinical presentation of new cases of TB secondary to the advent of AIDS has brought intensified interest in controlling TB.

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Although the impact of war and natural disasters on TB rates has long been recognized, the role of immigration was generally ignored until more than 260,000 Indochinese refugees arrived in the United States during the period 1979–1980. At the time of entry into the United States, the prevalence of TB disease among this immigrant group was estimated to be 1128 per 100,000, followed by an after-entry annual incidence of new disease of 407 per 100,000. The comparison figure for overall incidence of TB within the United States was 11.3 per 100,000 (55). The progressive impact of these immigration trends on TB rates within Western industrialized countries has been startling. By 2003, foreign-born persons accounted for 53.3% of the total reported TB cases in the United States—up from 41.7% just five years earlier (56). Similar trends have been documented throughout Europe. The finding that drug-resistant organisms could be as infectious as nonresistant strains overturned a longstanding belief that such organisms were less contagious (57), and further heightened concerns over the impact of immigrants on TB control efforts. Inadequate and erratic supplies of drugs, difficulties in patient adherence with treatment, inconsistent governmental support for TB control, and over-the-counter availability of anti-TB drugs (some even counterfeit) had resulted in the emergence of resistant organisms in most low-income areas of the world: organisms that would immigrate into more developed countries. More recent studies have added additional challenges to TB control programs. Noble confirmed that patients might remain contagious for many weeks after the initiation of adequate treatment (58). Both Curtis and Mangura documented casual transmission among contacts (59,60). Behr reported that smear-negative patients do transmit the organism although at a lesser rate than smear-positive patients (61). An earlier study by the Madras British Medical Research Council had found that 40% of smear- and culture-negative patients with clinical and radiological findings suggestive of active TB progressed to confirmed clinically active disease within 30 months (62). XII. Conclusion Political leaders have a basic responsibility to protect the health of their people and it will take their strong and continuing commitment to maintain the management systems necessary to control the disease. The history of TB has repeatedly demonstrated that failure to do so has serious consequences. The United States’s Office of Technology Assessment concluded that the withdrawal of public health resources and the resultant dismantlement of that nation’s community TB control programs played a major role in the 1980s resurgence of TB within the United States (63). In response to the evolving challenges of TB control, the U.S. Institute of Medicine published a new road map toward the control and elimination of the disease within that country (64). The road, like the road in every country,

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will encounter the occasional pothole. Periodic shortages of fuel—the funding needed for success—will undoubtedly occur. But the Institute’s road map is optimistic, comprehensive, and a clear statement that with continued dedication, both the United States and we as a world society can reach the end of that road—the elimination of TB. Santayana’s often-quoted observation—those who do not remember the past are condemned to repeat it—continues to ring true (65). History has shown us that effective TB control is a never-ending process—adapting to new knowledge, new technology, and new social challenges. But basic to all TB control programs is the understanding that TB is a disease, not only of the individual, but also of society. References 1. Meachen GN. A Short History of Tuberculosis. London: John Bale and Sons, 1936. 2. Biggs H. The administrative control of tuberculosis. First Annual Report of the Henry Phipps Institute for the Study, Treatment and Prevention of Tuberculosis, University of Penn., 1903:169. 3. Long ER. A half century of medical progress in the control of tuberculosis. Am Rev Tuberc 1954; 70:383–390. 4. Francine AP. Pulmonary Tuberculosis, Its Modern and Specialized Treatment. Philadelphia: J.B. Lippencott Co., 1906. 5. Davis MM, Warner AR. Clinics, Hospitals, and Health Centers. 1st ed. New York: Harper and Brothers Publishers, 1927. 6. White WC. The official responsibility of the state in the tuberculosis problem. JAMA 1915; 65:512–514. 7. Association of Tuberculosis Clinics in the City of New York, Dispensary Control of Tuberculosis. Sixteenth Annual Report, Yearbook, 1924. 8. Hawes JB. Tuberculosis and the Community. Philadelphia: Len and Febiger, 1922. 9. Elliot JH. The evolution of dispensary control of tuberculosis, historical aspects. Am Rev Tuberc 1937; 36:577–591. 10. National Tuberculosis Association, Tuberculosis Hospital and Sanatorium Directory, New York, 1942. 11. Chadwick HD, Pope AS. The Modern Attack on Tuberculosis. New York: The Commonwealth Fund, 1942. 12. Hayes EW. They stumble who run. Dis Chest 1953; 23:102–104. 13. Committee on Therapy. Bed rest in the treatment of tuberculosis. A statement by the Committee on Therapy. Am Rev Tuberc 1954; 69:1069–1070. 14. Wier JA, Taylor R, Fraser R. The ambulatory treatment of patients hospitalized with pulmonary tuberculosis. Ann Int Med 1957; 47:762–773. 15. D’Esopo ND, Rodman M, Delabarre EM. Results of chemotherapy without rest therapy; first program report, pilot study VII. Trans 15th Conf on the Chemotherapy of Tuberc, 1956:60. 16. Robins AB, Abeles H, Chaves AD, Aronsohn MA, Breuer J, Widelock D. The drug treatment of non-hospitalized patients with tuberculosis. Am Rev Tuberc Pul Dis 1957; 75:41–52. 17. Riley RL, Wells WF, Mills CC, Nyka W, McLean RL. Air hygiene in tuberculosis; quantitative studies of infectivity and control in a pilot ward. Am Rev Tuber Pul Dis 1957; 75:420–431. 18. Blomquist ET. The non-hospitalized tuberculosis patient. Am J Public Health 1956; 46:149–155.

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19. McDermott W. The enlarging role of the general practitioner in tuberculosis therapy. J Chronic Dis 1955; 2:234–236. 20. Seggerson J. Early history of the CDC TB Division 1944–1985. Division of Tuberculosis Elimination, National Centers for HIV, STD and TB Prevention. TB Notes 2000; 1:1–7. 21. Fox W. The problem of self-administration of drugs: with particular references to pulmonary tuberculosis. Tubercle 1958; 39:269–274. 22. Breite MJ. Urine test for the detection of PAS in ambulatory tuberculosis patients. Am Rev Tuberc Pul Dis 1959; 79:672. 23. Fox W. Self-administration of medicaments: a review of published work and a study of the problems. Bull Int Union Tuber 1962; 32:307–331. 24. Tuberculosis Chemotherapy Centre, Madras. A concurrent comparison of intermittent (twice-weekly) isoniazid plus streptomycin plus PAS in the domiciliary treatment of pulmonary tuberculosis. Bull World Health Organ 1964; 31:247–271. 25. Bayer R, Wilkinson D. Directly observed therapy for tuberculosis: history of an idea. Lancet 1995; 345:1545–1548. 26. Advisory Council for the elimination of tuberculosis. Initial therapy for tuberculosis in the era of multidrug resistance: recommendations of the Advisory Council for the Elimination of Tuberculosis. Morb Mortal Wkly Rep 1993; 42:RR/7. 27. Long ER. Foreword to Arden House Conference Recommendations. Am Rev Resp Dis 1960; 81:481. 28. National Tuberculosis Association. TB Control, the Big Push Ahead, Treatment is the Tool. New York: National Tuberculosis Association, 1960. 29. United States Department of Health, Education and Welfare. The Future of Tuberculosis Control, A Report to the Surgeon General of the Public Health Service by a Task Force on Tuberculosis Control. Public Health Service Publication No. 1119, December, 1963. 30. McDermott W. Tuberculosis chemotherapy as a public health measure. Am Rev Resp Dis 1960; 81:579–581. 31. Centers for Disease Control. A strategic plan for the elimination of tuberculosis in the United States. Morb Mortal Wkly Rep 1989; 39(suppl S-3):1–25. 32. Seibert FB, Glenn JT. Tuberculin purified protein derivative preparation and analysis of a large quantity for standard. Am Rev Tuberc 1941; 44:9–35. 33. Sbarbaro JA, Campbell CC, Comstock GW, et al. Skin test antigens; proposed implementation of efficacy review. Department of Health, Education and Welfare; Food and Drug Administration, Federal Register, Vol. 42, No. 190, September 30, l977:52674–52723. 34. US Dept of Health, Education, and Welfare. Public Health Service. A ChildCentered Program to prevent tuberculosis. Public Health Service Publication. No. 1280, March, 1963. 35. Edwards PQ, Ogasawara FR. Phasing out the child-centered TB program. NTRDA Bulletin, November, 1971. 36. World Health Organization, Technical Report Series 552, Tuberculosis control, 1974. 37. World Health Organization, Technical Report Series 652, BCG vaccination policies, 1980. 38. American Thoracic Society and Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent infection. Am J Repir Crit Care Med 2000; 161:5221–5247. 39. Koch R. Weitere mitteilungen uber ein heilmittel gegen tuberculose. Dtsch Med Wochenschr 1890; 16:1029–1032. 40. Styblo K, Dankova D, Drapela J, et al. Epidemiological and clinical study of tuberculosis in the district of Kolin, Czechoslovakia. Bull Wld Hlth Org 1967; 37:819–874.

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41. Krivinka R, Drapela J, Kubik A, et al. Epidemiological and clinical study of tuberculosis in the district of Kolin, Czechoslovakia. Bull Wld Hlth Org 1974; 51:819–874. 42. 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. 43. Stead WW. Control of tuberculosis in institutions. Chest 1979; 76(Suppl 6):797–800. 44. Crofton J. Tuberculosis undefeated. Brit Med J 1960; 5200:679–687. 45. Pallanza R, Arioli V, Furesz S, Bolzoni G. Rifampicin: a new rifamycin. Arzneim Forsch 1967; 17:529. 46. Tuberculosis Chemotherapy Centre, Madras. Current comparison of home and sanatorium treatment of pulmonary tuberculosis in South India. Bull Wld Hlth Org 1959; 21:51–144. 47. World Health Organization, Technical Report Series 290, Tuberculosis Control, 1964. 48. Toman K. Tuberculosis Case-Finding and Chemotherapy, Questions and Answers, World Health Organization, Geneva, 1979. 49. Styblo K. Epidemiology of Tuberculosis. VEB Gustav Fisher Verlag Jena, 1984:109. 50. Uplekar MW, Shepard DS. Treatment of tuberculosis by private general practitioners in India. Tubercle 1991; 72:284–290. 51. Kochi A. The global tuberculosis situation and the new control strategy of the World Health Organization. Tubercle 1991; 72:1–6. 52. Murray CJL, De Jonghe E, Chum HG, Nyangulu DS, Salomao, Styblo K. Cost effectiveness of chemotherapy for pulmonary tuberculosis in three sub-Saharan African countries. Lancet 1991; 338:1305–1308. 53. Murray C, Styblo K, Rouillon A. Tuberculosis, Disease Control Priorities in Developing Countries. Oxford Medical Publication, Oxford University Press Inc., New York, 1993:233–259. 54. World Health Organization, Global Tuberculosis Control Report, WHO, Geneva, 2004. 55. Centers for Disease Control. Tuberculosis among Indochinese refugees–an update. Morb Mortal Wkly Rep 1981; 30:603–606. 56. Centers for Disease Control. Trends in Tuberculosis–United States, 1998–2003. Morb Mortal Wkly Rep 2004; 53:209–214. 57. Snider DE, Kelly GD, Cauthen GM, Thompson NJ, Kilburn JO. Infection and disease among contacts of tuberculosis cases with drug-resistant and drug-susceptible bacilli. Am Rev Respir Dis 1985; 132:125–132. 58. Noble RC. Infectiousness of pulmonary tuberculosis after starting chemotherapy. Am J Infect Control 1981; 9:6–10. 59. Curtis AB, Ridzon R, Vogel R, et al. Extensive transmission of Mycobacterium tuberculosis from a child. New Engl J Med 1999; 341:539–1540. 60. Mangura BT, Napolitano EC, Passannante MR, McDonald RJ, Reichmann LB. Mycobacterium tuberculosis miniepidemic in a church gospel choir. Chest 1998; 113:234–237. 61. Behr MA, Warren SA, Salamon H, et al. Transmission of Mycobacterium tuberculosis from patients smear-negative for acid-fast bacilli. Lancet 1999; 353:444–449. 62. Hong Kong Chest Service/Tuberculosis Research Centre; Madras British Medical Research Council: A study of the characteristics and course of sputum smearnegative pulmonary tuberculosis. Tubercle 1981; 62:155–167. 63. US Congress, Office of Technology Assessment (OTA), the Continuing Challenge of Tuberculosis. Washington, D.C.: US Government Printing Office, 1993:OTA-574. 64. Institute of Medicine (U.S.). Committee on the Elimination of Tuberculosis in the United States. Ending Neglect: The Elimination of Tuberculosis in the United States. Geiter L, ed. Division of Health Promotion and Disease Prevention. Washington, D.C.: National Academy Press, 2000. 65. Santayana G. The Life of Reason I, ‘‘Reason in Common Sense,’’ 1905. Dictionary of quotations, collected and arranged and with comments by Bergen Evans. Aventel Books, New York, 1978:511.

17 Tuberculosis Control Interventions: A Stepwise Approach

ANTONIO PIO Public Health and Respiratory Disease, Mar del Plata, Argentina

I. Concepts of Tuberculosis Control, Elimination, and Eradication Tuberculosis (TB) control may be defined as a combination of interventions that interfere in the natural relationship between human beings and tubercle bacilli in order to reverse a situation of increasing or stable epidemiologic indicators or to accelerate a declining trend. In any setting, the goal or general purpose of the TB control program is an improvement of the community health through a reduction of the infection, morbidity, and mortality from TB and the prevention of mycobacterial drug resistance. The TB problem can be considered controlled when the epidemiologic indicators come down to a level at which TB is no longer a public health problem for the country as a whole, although some subsets of the population may retain high transmission and disease rates (1,2). An objective is a quantified goal set within a time period. An incidence rate of less than 10 cases per 100,000 population might be taken as the epidemiologic objective to be reached by any country in order to consider that the TB problem is controlled. This is the criterion used by World Health Organization (WHO) to categorize the most advanced countries by progress in the implementation of TB control interventions (3). 501

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Countries with low morbidity should maintain or realign their interventions toward ‘‘elimination’’ of TB. Two conventional definitions of elimination have been adopted. For the Netherlands, TB can be considered eliminated when the incidence of smear-positive pulmonary TB has fallen below one per million population, or the prevalence of tuberculous infection in the general population has fallen below 1% and continues to decrease (4). For the United States, TB elimination would be reached when the incidence of any form of TB (smear-positive, smear-negative, extrapulmonary) is less than one per million population (5). The ultimate objective of global efforts to combat TB would be ‘‘eradication,’’ namely, a permanent reduction to zero of the worldwide incidence of disease caused by tubercle bacilli; at this point, ongoing intervention measures would no longer be needed because transmission of infection would have ceased in an irreversible manner (6). However, with the presently available technical interventions and tools, eradication of TB cannot be achieved in a foreseeable future. II. Overview of Tuberculosis Control Interventions Realistic epidemiologic objectives for TB control depend on knowledge of the effectiveness or impact of the interventions to be implemented. An intervention is implemented through a specific or nonspecific measure to control or eliminate a health problem. ‘‘Specific interventions’’ are those that are purposely intended for TB control. They are as follows:
Case management
bacille Calmette–Gue´rin (BCG) vaccination
Chemoprophylaxis Control or eradication of bovine TB can also be considered as a specific intervention, which is an integral part of the programs for the control of zoonoses under the responsibility of the ministries related to rural economic affairs. Nonspecific interventions are those that are not directly intended to control TB but to control general or other health problems that constitute a risk factor for TB. There are two categories of nonspecific interventions. They are as follows:
Prevention of risk factors for transmission of infection.
Prevention of risk factors for progression of infection into disease. III. The Global Stop TB Strategy A health program is the organization of services and articulation of managerial activities to control a health problem. A program for effective TB control, called DOTS, was developed in the early 1990s by WHO, other

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international cooperation agencies, and nongovernmental organizations (NGOs). These institutions established the Stop TB Partnership in 2001 from a previous less defined ‘‘Stop TB Initiative,’’ and developed a global program to accelerate the expansion of the DOTS strategy and improve the quality of the TB control services (7). Despite a remarkable progress made in global TB control over the last decade, in 2005 an analysis of the foreseeable trends of the problem suggested that DOTS alone was not sufficient to achieve the 2015 TB-related Millennium Development Goals (MDG) and there was a need for a new strategy to be built on, and to go beyond DOTS, to address the major constraints to achieving the TB control goals (8). The new Stop TB strategy has six components. They are as follows: 1.

2.

3.

4.

5.

6.

Pursue high-quality DOTS expansion and enhancement through the reaffirmation of the long-standing framework of TB control (9,10): political commitment at national and local levels with increased and sustained financing to support TB control; laboratory networks for sputum smear microscopy, and phased introduction of culture and drug-susceptibility testing; standardized short-course chemotherapy with a major focus on patient support to ensure adherence to treatment; national drug management systems that guarantee regular supply of quality-assured drugs; and a system to monitor program performance and evaluate achievement of TB-related epidemiological MDGs. Address TB/HIV, multidrug-resistant TB (MDR-TB), and other special challenges. HIV and TB programs need to rapidly scale up collaborative activities in all relevant settings. Programmatic management of drug-resistant TB should be an integral part of the national TB control program. Risk groups, such as household contacts, prisoners, migrants, and displaced populations need focused attention. Contribute to health system strengthening with active participation in efforts to improve policies, human resources, management, and service delivery; and to extend TB care to standardized care of respiratory diseases at primary health care facilities. Engage all care providers in TB case detection, diagnosis, and treatment, such as government health facilities inside and outside the ministry of health, social security, NGOs, large private companies, and private clinics. The public–private mix will help increase access and equity in TB care provision. Empower people with TB and communities through communication, advocacy, and social mobilization to help improve care, reduce stigma, and enhance political commitment. Enable and promote research, both operational research to continuously improve program performance and biomedical research to develop new diagnostic tools, drugs, and vaccines.

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Case management comprises case finding, diagnosis and treatment. Case finding is always active (and never passive); this is because the identification of persons with respiratory symptoms among the patients attending the outpatient health units involves an active effort by the health care services. Although case finding should always be regarded as a dynamic action, there are two different programmatic approaches: one is the systematic examination of any patient with respiratory symptoms defined as a TB suspect who spontaneously attends a primary health care service; another is the screening for TB in high-risk groups such as household contacts, prison and mental hospital inmates, immigrants or refugees from high TB prevalence areas and HIV-positive individuals. The fundamental diagnostic method in limited resources settings is the direct sputum smear examination and the central treatment approach is short-course chemotherapy provided under supervision by a health worker or someone accountable to a health worker. Case management is the most effective, feasible and affordable intervention for TB control in all situations. It can produce an important impact on the TB problem through the prevention of mortality and the gradual reduction of the risk of infection and the subsequent incidence of morbidity (11). V. Case Management Impact on the Risk of Infection Transmission of tubercle bacilli is sustained in the population when every infectious case (source of infection) generates one or more new infectious cases. Effective case management reduces almost immediately the infectiousness of smear-positive pulmonary patients and thereby interrupts transmission. From the beginning of the 20th century until the Second World War the risk of infection declined by 3% to 5% per year in the industrialized countries of Europe and North America. The reduction was attributed to the gradual improvement of hygiene and socioeconomic conditions (better nutrition, education, and housing) and also to isolation in sanatoria of many patients with infectious TB. After effective anti-TB chemotherapy was introduced in 1947, the annual decrease of the risk of infection jumped almost suddenly to a range between 10% and 13% in those countries, and has generally been maintained at this rate until now. This decline rate is an indication of the maximum that can be achieved under the best conditions in an industrialized country. In comparison with the control interventions for other diseases (e.g., measles immunization), the effectiveness of the TB case management intervention is rather modest: it can prevent only from 10% to 13% of new infections which can be expected in one year, which means that 87% to 90% of them cannot be prevented. This modest effectiveness is explained by the fact that the great majority of new infections take place before the source of infection is diagnosed and treated. However, keeping an annual 10% decrease rate, the risk of infection is halved every seven years (12).

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The best-implemented case management intervention in developing countries should not be expected to reach the same level of effectiveness observed in the industrialized countries. The basic diagnostic method used in most health units of developing countries is sputum smear microscopy, which, on its own, does not detect pulmonary TB cases as early as when it is used in combination with other diagnostic methods such as radiology and sputum culture, as is a normal practice in industrialized countries. Another factor is the limited utilization of health facilities in developing countries as shown in the average number of 0.5 visits per person per year, while this ratio is usually between six to eight visits per person per year in the industrialized countries. The expectation is that the case management intervention can lead to an annual decrease of 5% to 7% in the risk of infection in developing countries. If an annual reduction of 5% is constantly maintained, the risk of infection will be halved in a 15-year period (13). However, to be effective, the case management intervention should be implemented with a high level of coverage and technical quality. The minimum optimal coverage estimated to have a significant impact on the TB transmission is to detect 70% of the incidence of sputum smear-positive pulmonary cases and to cure 85% of them (14). These have been adopted as the global strategic objectives for case detection and cure by the World Health Assembly and endorsed by the international cooperation agencies (15). The impact on the risk of infection will be lower if there is a rapid increase in the prevalence of HIV infection (16) or in situations of social disruption and acute material deprivation (wars, civil unrest, drought, displacement of large population groups) (17). The trend of the risk of infection is the most sensitive indicator to assess the progress in achieving the TB control epidemiologic objectives. However, in developing countries the prevalence of environmental mycobacteria infection and the high coverage of BCG vaccination in children are important obstacles to accurate measurement. VI. Case Management Impact on Morbidity Incidence The impact of the case management intervention on the overall TB morbidity incidence may be less than its impact on the risk of infection. The incidence is a mixture of cases evolving from recent infections (which are influenced by current trends in the level of the risk of infection) and cases resulting from reactivation of old infections (which are not influenced by the current risk of infection). In the last 50 years in the western European countries, while the risk of infection decreased at an annual rate of 10% to 13%, the TB incidence (all forms in all age groups) decreased at an annual rate of 5% to 7%. The fall in incidence of smear-positive pulmonary TB in children and young adults in these countries was almost parallel to the fall in the risk of infection and it was greater than the incidence decline in older age groups (18). The median age of TB patients has steadily increased as the infected population segments become increasingly older. However, in the evaluation of the fully implemented DOTS intervention in Peru, the overall rate of

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decline in incidence of pulmonary TB was around 6% per year from 1996 to 2000, without any discernible difference in the declining rate among the different age groups (19). Therefore, a measurable epidemiologic objective of the TB control program is to achieve an annual decrease of 4% to 6% of the incidence of smear-positive pulmonary TB, at least in the population below 30 years of age. This indicator is only valid in a country or region where the extent and intensity of the case finding and reporting activities are stable and the prevalence of risk factors remains constant. A well-planned and implemented program may achieve much less than a 4% annual decrease in morbidity in areas with rapidly increasing prevalence of HIV infection or with acute material deprivation. The reduction in the annual incidence of TB meningitis in children less than five years of age can be much higher than the reduction in the incidence of the smear-positive pulmonary TB in adolescents and young adults because of the combined effect of the case management and BCG vaccination interventions. In Peru, the incidence of TB meningitis in children less than five years of age decreased at an average annual rate of 15% between 1992 and 2000 (20). VII. Case Management Impact on Case Fatality and Mortality Before the advent of anti-TB chemotherapy, 50% to 60% of patients with smear-positive pulmonary TB died within the first two years after diagnosis. With current chemotherapy, more than 95% of HIV-negative patients and more than 70% of HIV-positive patients who do not receive highly active antiretroviral therapy can be cured of TB if properly treated. The prevention of mortality due to TB is also very high in HIV-infected patients who receive effective antiretroviral therapy. A striking impact of first line chemotherapy on case fatality and mortality may be expected, for instance a 20% or more reduction in a two-year period, if there is:
a rapid transition from self-administered treatment to an effective organization of DOT in all new patients;
a low prevalence of people coinfected with HIV and tubercle bacilli; or if the prevalence is high, and highly active antiretroviral drugs are available for treating all AIDS patients; and
a low prevalence of chronic cases and MDR cases who are not cured with first-line regimens. In the past three decades mortality from TB decreased in western European countries at a rate of 5% to 8% per year. In the common situation where implementation of DOT is gradual and there is a lack of drugs for second-line treatment, it can be expected that the annual mortality (all ages, all forms) will show only a modest decrease of 2% or less per year in areas with low prevalence of HIV infection. The annual decrease can be

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up to 5% in the young age groups and in very well implemented programs. On the other hand, either no decrease or even an increase may occur in areas with high prevalence of HIV infection if antiretroviral therapy is not available. The case fatality is increasing in older age groups in some industrialized countries because TB is often associated with other significant chronic diseases (21). VIII. Specific Tuberculosis-Control Interventions Other than Case Management Whereas interrupting the chain of transmission through effective case management has the highest priority in any TB control program, other specific control interventions such as BCG immunization and treatment of latent TB infection are important measures at specific stages of the TB epidemic. Both of these interventions reduce the progression from infection to disease and they should be used in specific population groups. IX. Bacille Calmette–Gue´rin Immunization BCG immunization is only effective when administered to individuals not yet infected with the tubercle bacilli, i.e., those who are tuberculin-negative. However, BCG does not prevent the infection. Its protective mechanism is to enhance the cell-mediated immune response to prevent the infection from progressing to disease. In particular BCG prevents the haematogenous dissemination of tubercle bacilli during the primary infection and therefore it prevents the serious forms of miliary TB and meningitis. For this reason, WHO recommends mass BCG vaccination of children for countries with a high risk of infection through a single dose at birth. Multiple repeat doses are not recommended (22). This vaccination contributes little to the prevention of postprimary bacteriologically positive pulmonary TB and therefore cannot substantially interfere in the transmission of infection (see Chapter 19). Mass BCG vaccination in children is not justified in countries with a low and steadily declining risk of infection where the incidence of serious BCG complications may outweigh the risk of TB disease. The International Union Against Tuberculosis and Lung Disease (IUATLD) has suggested criteria on which, if an efficient notification system is in place, it may be recommended to shift from mass BCG vaccination in children to selective vaccination of special groups or individuals at increased risk of TB infection, for instance, when the average annual notification of smear-positive TB is less than 5 per 100,000, or the average annual risk of infection is less than 0.1% (23). X. Chemoprophylaxis Chemoprophylaxis, also called ‘‘preventive therapy,’’ can be primary, secondary, or tertiary. Isoniazid is the usual drug of choice for chemoprophylaxis. ‘‘Primary chemoprophylaxis’’ is the administration of isoniazid (INH) to

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tuberculin-negative individuals to prevent infection with tubercle bacilli. The efficacy of the primary chemoprophylaxis has not been well documented, although it is likely that it provides some protection during the period in which the individual taking the INH is exposed to infection. Primary chemoprophylaxis is used in some developing countries for practical rather than preventive reasons. INH is prescribed to all contact children without prior tuberculin test to simplify the operational procedures of contact control. INH is also prescribed as chemoprophylaxis for all HIV-positive individuals where tuberculin tests are not feasible. ‘‘Secondary chemoprophylaxis,’’ also called ‘‘treatment of latent infection,’’ is the administration of INH (or other drugs) to tuberculinpositive individuals to prevent the progression of the infection into disease. Secondary chemoprophylaxis is effective in reducing from 70% to 80% the incidence of TB during the medication period. A lower protective effect remains during five or more years after the medication has been completed (see Chapter 10). In theory, ‘‘systematic mass secondary chemoprophylaxis’’ to all the tuberculin-positive population would be an effective intervention to control TB. However, it is not feasible to organize the periodic tuberculin test of the whole population, the chest X-ray examination of all the tuberculin-positive individuals to identify the cases of TB disease (who should receive combined chemotherapy), the supervision of the INH intake and the surveillance of the adverse reactions. ‘‘Selective secondary chemoprophylaxis’’ is a recommended intervention at any step of TB control to be applied to contact children of smear-positive TB cases and HIV-positive individuals, if they can easily be examined to rule out the presence of active TB and monitored for drug intake and adverse reactions (24). The indications for this kind of chemoprophylaxis are broader in countries or areas committed to eliminate TB because the risk of infection is low and rapidly decreasing, so that most cases of TB are caused by endogenous reactivation. In these settings secondary chemoprophylaxis can be extended to persons who are tuberculin positive and have evidence of recent infection (converters), old healed TB, diabetes, health staff in frequent contact with TB patients, and persons with prolonged corticosteroid treatment or other immunosuppressive therapy. There are other groups which can benefit from secondary chemoprophylaxis, but they are of lower priority for the TB control program or require especially tailored measures for different reasons. They include persons who are unlikely to comply with the INH medication (alcohol and other drug addicts), persons with a higher risk of neurological or hepatic adverse reactions (the elderly), and, in general, individual groups in which the chemoprophylaxis is not expected to have a community benefit in relation with the overall TB problem (for instance, gastrectomized patients). In institutional groups of high TB prevalence, such as in prisons, psychiatric hospitals, and nursing homes, and in professional groups (workers

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exposed to silica dust), it is possible, where resources permit, to organize systematic tuberculin and radiological examinations and the supervision of INH intake as a preventive therapy to a large number of individuals, at least for certain high-risk groups such as close contacts of smear-positive pulmonary TB and HIV-positive people. ‘‘Tertiary chemoprophylaxis,’’ or post-treatment prophylaxis, is preventive treatment aimed at decreasing the risk of TB recurrence after completion of treatment in HIV-positive individuals. These individuals have a higher rate of recurrent TB than the non-HIV-infected individuals. XI. Nonspecific Tuberculosis-Control Interventions A. Preventing Risk Factors for Infection

The most important factor associated with the risk of infection with Mycobacterium tuberculosis is the prevalence of sputum smear-positive cases. The risk is reduced through early diagnosis and effective treatment, i.e., the case management intervention. Other factors influencing transmission of infection are the concentration of infectious particles in the air and the duration of exposure. However, no public health interventions have proven effective in reducing or eliminating airborne transmission of TB in the general population. Nevertheless, reduction of poverty and related improvement of living conditions, such as good ventilation and avoidance of crowding in households, working places and public buildings most probably contribute to TB control in high prevalence TB settings. In high risks areas, such as TB hospital wards and TB laboratories, various environmental control methods can be used to reduce the concentration of infectious particles in the air, reduce exposure in the laboratory, and prevent patient-to-health worker and patient-to-patient transmission (see Chapter 36). Patients who are hospitalized with MDR-TB should be placed in a separated, well-ventilated area where the possibility of contact with other patients is minimal. It is essential that patients with MDR-TB be completely separated from TB patients with a positive or unknown HIV status. B. Preventing Progression from Infection to Disease

In most persons the life-time risk of progression of an infection with M. tuberculosis into active TB is estimated to be from 5% to 10% if infection has occurred in childhood. The risk of developing disease is greatest in the first year following infection. Many risk factors that favor the progression from infection to disease are not alterable and cannot be targets for public health measures, for instance, genetic characteristics (blood group and other genetic traits). HIV infection is the most important risk factor that can be controlled by public health programs. Other controllable risk factors are malnutrition, diabetes, silicosis, tobacco smoking, and alcohol and other drug addictions. The control of these problems may have a significant impact on TB in the

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general population if the frequency of the association of the particular risk factor with the TB incidence is high. HIV infection is associated with the greatest risk of reactivation, a risk nearly 10-fold greater than in HIVnegative persons. Even among patients receiving effective antiretroviral therapy, the risk of TB is still twice that of persons without HIV infection. It may not be possible to control TB without controlling HIV infection in HIV high-prevalence countries (see Chapter 38). XII. A Stepwise Approach to Implementation of Tuberculosis-Control Interventions The implementation of the six components of the new Stop TB Strategy will be better accomplished through a careful stepwise approach. This complex process requires sustained political commitment, continuous investment of human and material resources, and continuous monitoring and evaluation. A sequence of four steps to implement the Stop TB Strategy can be put forward as an example for consideration and adaptation by countries depending on their epidemiological situation, the health system infrastructure and the program priorities. The stepwise approach is a sequential logical order based on feasibility and efficiency criteria that should be borne in mind in the organization of services and the planning of activities addressed to achieve the objectives of the case management intervention, which is the central intervention of the Stop TB Strategy. Each step includes activities of several or all the six components of the Strategy. The activities in subsequent steps build on the programmatic achievements in earlier steps that should be maintained. In a general outline, Step 1 is addressed to achieving high cure rates for new and retreatment cases presenting for diagnosis within the Ministry of Health (MOH) health facilities, including contribution to infrastructure strengthening, empowerment of patients and communities served by the MOH and promotion of operational research. BCG immunization is included in this step. In Step 2, case finding and patient management is extended to all public and private health care providers, the HIV/TB collaboration is intensively pursued, and TB control for high-risk groups and special situations is organized. Selective chemoprophylaxis is also included, in particular for household contact children and HIV-positive individuals. Contribution to health systems strengthening, empowerment of patients and communities, and operational research are extended from the public to the private sector. In Step 3, while maintaining the gains of previous steps, the main focus is addressed to solving the problem of chronic and MDR-TB cases. Finally, in Step 4, the Strategy will promote full integration of TB care with the case management of other respiratory diseases, as an important contribution to health system strengthening. When the main objectives and targets of one step have been achieved, the program moves to the next step. However, progress in DOTS implementation

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has been variable in the past. Even within the same country, there may be rapid improvement in some regions and very slow progress in others, so that some regions are still in Step 1 while others are involved in Step 2 activities. Flexibility is needed in determining the sequence of the steps. If the program confronts serious obstacles in one step—for instance, difficulty in ensuring the 85% treatment success intended in Step 1 because of the heavy case fatality due to high prevalence of TB/HIV coinfection—it may opt to move to the following step. Steps may also overlap. For instance, in settings with a high proportion of retreatment cases and high levels of MDR-TB, as in parts of Eastern Europe and China, the management of MDRTB may need to be addressed simultaneously with Step 2 activities (see Chapter 32). A. Step 1. Achieving the Strategic Objective of 85% Treatment Success in Ministry of Health Units

In Step 1, the overriding priorities are: (i) adequate diagnosis and classification in patients presenting with symptoms in the National Tuberculosis Control Program units; (ii) regular supply of drugs and laboratory materials; (iii) organization of communication, advocacy, and social mobilization activities to ensure adherence of patients to chemotherapy such as DOT (iv) organization of the information system in the health units and the districts, thus allowing for monitoring and evaluation of program performance; and (v) organization of operational research to improve MOH program performance. Although case finding and treatment must be developed together, the first step to be taken in any inefficient TB program is to achieve the strategic objective of 85% cure rate in all diagnosed cases. In this phase, there are important epidemiological reasons for prioritizing treatment over case detection. In general, it makes no sense to expand case-finding activities if a large proportion of detected cases will not be cured because there is no capacity to deliver adequate treatment regimens to patients and to ensure their adherence. On the contrary, premature expansion of case finding before treatment facilities are in place may result in treatment failure and emergence and transmission of drug-resistant strains. Failure to achieve cure in treated patients has been identified as the most critical deficiency of TB control programs (25). DOT is only one of a range of measures aimed at promoting treatment adherence and completion. The patients should be placed at the center of case-holding activities taking care of their needs, looking for potential difficulties in advance, considering incentives or enablers and taking action against default (26). The reasons for focusing on the MOH units in Step 1 are as follows:


The organization of the case management intervention in the MOH units provides a foundation for expansion because it is easier for the MOH to overcome obstacles and solve problems in its own structure over which it has administrative authority.

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The MOH staff has experience in putting into practice new official guidelines if properly trained, supervised, and supplied.
The extensive MOH infrastructure provides a test for the DOTS intervention in a variety of situations, which may present different challenges and provide lessons that can be applied later to nonprofit NGO health units and fee-for-service public health facilities (such as the hospitals in China).
The MOH experienced staff can help other agencies to implement proper patient supervision and support.
The MOH laboratories can provide training, supervision, and microscopy quality assurance to other ministries, social security, NGOs, and private laboratories.
The successful implementation of DOTS in the MOH units lends credibility to the intervention.

Complementing the case management intervention, high BCG immunization coverage in infants should be pursued in Step 1. B. Step 2. Achieving the Strategic Objective of 70% Case Finding

In Step 2, the focus of the program is to expand efficiently the case-finding activities by involving all the entities that provide primary health care services (government services outside the MOH jurisdiction, social security agencies, nonprofit NGOs health units, health services of private companies for their workers, and families and private clinics), mobilizing the communities in support of the TB control interventions and gradually expanding the diagnostic laboratory facilities for cultures. An essential requirement of Step 2 is to ensure the Step 1 objectives in every new public or private health unit in which the TB strategy is introduced, i.e., 85% treatment success rate, regular supply of drugs, good quality microscopy, and implementation of the TB information system. In this Step the collaboration between TB and HIV control programs should be strengthened. The case management intervention of Step 2 is complemented with the organization of chemoprophylaxis for some priority groups, such as household contact children and HIV-positive individuals. The expansion of case finding can be accomplished in many directions, which should be undertaken through gradual substeps. The priority order may vary from country-to-country and from region-to-region within one country. As an example, the following sequential directions for expanding case finding can be considered: Expansion of the case detection capacity of the MOH units are as follows:
Enlarging the laboratory capacity to perform microscopy; the target is to introduce microscopy into all the MOH laboratories that are not using this technique.

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Implementing systematic identification of TB suspects among patients attending MOH outpatient services. Addressing intensive screening activities among identified priority high-prevalence groups, such as household contacts and HIVpositive persons.

Expansion of DOTS to institutional health services outside the MOH are as follows:






Organizing DOTS in the government health services which are not under the direct MOH responsibility: armed forces, security forces, prisons, welfare institutions for the elderly and the homeless, hospitals and health centers run by the Ministry of Education. Establishing TB services at refugee and displaced population camps. Introducing DOTS into the social security, nonprofit NGO, health units, and health services of large private companies (oil, mining, agriculture).

Promotion of Community Participation

In some countries the core of TB control activities was developed and implemented by NGOs with official support. Everywhere, community volunteers, development groups and nongovernmental health organizations have an important role to expand access to effective TB diagnosis and treatment. They contribute through the identification and referral of TB suspects, support to patients throughout treatment, including direct observation of the drugs intake, defaulter tracing, and educational initiatives. The community can also provide opportunities to link TB and HIV/AIDS preventive and care activities. Community contributions should be closely coordinated with the local health units to secure a comprehensive TB control package, in particular access to laboratory facilities and drugs, regular reporting, instruction, and supervision (see also Chapter 22). Development of Guidelines on Case Diagnosis in Specific High-Risk Groups

Special efforts should be addressed to case finding among identified highrisk individuals and congregate settings, such as HIV-positive individuals, immigrants, prisoners, diabetics, mental hospital patients, health staff, and workers exposed to a silica dust environment. Risk groups are obviously country specific. Involving the Private Clinics and Practitioners

For a number of countries, the involvement of private doctors and clinics in TB case finding, diagnosis, and treatment control is of low priority because the proportion of cases detected and treated by them is very minor in comparison with the total incidence. However, in many countries, including high burden countries, such as India, Indonesia, and Vietnam, the private sector plays a major role in TB case management (see Chapter 39).

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After a widespread quality-assured microscopy network has been established and the case finding and treatment activities have been extended throughout the whole health infrastructure, the program should consider providing culture services for the diagnosis of TB. This is especially the case in countries with a high proportion of retreatment cases among all cases and high rates of MDR-TB. Culture is considerably more sensitive than microscopy. It is considered to be the gold standard for the diagnosis of TB; it is required for the diagnosis of MDR-TB and is of particular importance for the diagnosis of TB in children and HIV-positive patients. This improvement calls for an important investment in building laboratories at central and regional levels, acquiring equipment, training personnel, organizing internal and external quality assurance, and maintaining a regular supply of culture media and materials. However, this must not lead to neglect of microscopy services. On the contrary, smear microscopy remains the backbone of diagnostic services in high-prevalence TB countries, because of the following reasons:
It allows immediate diagnosis of the most important sources of infection, which are the priority for treatment
It can be reliably implemented in laboratories of peripheral health centers and district hospitals in developing countries
It requires less strict laboratory biosafety measures
It does not demand an extensive system for the transport of specimens
It is less expensive and requires less training time than culture C. Step 3. Addressing the Management of Multidrug-Resistant Cases

Step 3 is crucial in countries facing high levels of MDR-TB, but also appropriate in countries with a well performing TB control program and a relatively limited MDR-TB problem. The new Stop TB Strategy advocates care and cure for all TB patients, including those with drug-resistant strains. However, it should be stressed that it makes no sense to introduce a complicated and expensive program component to manage MDR-TB (also termed DOTS-Plus), without first addressing the causes of MDR-TB. In general, a prerequisite for the programmatic management of MDR-TB is a strong DOTS program that does not produce drug resistance (see also Chapter 32). The framework for managing MDR-TB within the context of TB control programs requires the following:
Sustained political commitment to TB control, including the financial and human resources to provide quality diagnosis and care to MDR-patients
A rational country-specific case-finding intervention, including quality assured culture and drug-susceptibility testing

Component 1 of the Stop TB strategy Organization of adequate treatment delivery in patients diagnosed with TB in MOH units (target: 85% treatment success) High coverage of BCG immunization in infants Components 2 and 4 of the Stop TB strategy Expansion of case finding to reach at least 70% detection of smear (+) cases incidence. Intensification of HIV/TB collaboration. Case finding among risk groups and special situations Chemoprophylaxis to household children contacts and HIV-positive individuals Sub-steps in case finding Main focus Sub-step a Expansion of microscopy capacity of MOH units Sub-step b Case finding among outpatients, household contacts and HIV (+). Expansion of DOTS intervention to institutional health services outside the MOH: other ministries (prison sector), social security, and NGOs Sub-step c Promotion of community participation Sub-step d Development of country-specific guidelines on risk-group management, including screening and tailored treatment delivery Sub-step e Involving the health services of private companies, private clinics and practitioners Sub-step f Provision of quality assured laboratory services for culture and DST Component 2 of the Stop TB strategy Programmatic management of drug-resistant tuberculosis Component 3 of the Stop TB strategy PAL: Integration of TB case finding and treatment with case management of adult respiratory diseases

Step 1

Notes: Activities of Components 3, 5, and 6 are present in all the steps. These steps may overlap or may need restructuring based on the specific epidemiological and programmatic situation. Abbreviation: MOH, Ministry of Health; BCG, bacille Calmette–Gue´rin; PAL, practical approach to lung health; DST, drug susceptibility test.

Step 4

Step 3

Step 2

Main focus

Steps

Table 1 Stepwise Approach to Implementing the Interventions for Tuberculosis Control Outlined in the New Stop TB Strategy in Developing Countries

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Main contents

Impact objective

Abbreviation: BCG, bacille Calmette–Gue´rin.

Interventions for TB control To maintain an annual 5% reduction in Case management Stepwise approach in the implementation of the Stop TB the risk of infection until reaching an Strategy incidence level of
10 TB cases per (see Table 1 ) BCG immunization Mass BCG vaccination of infants with a single dose at or soon 100,000 population after birth Chemoprophylaxis Selective secondary chemoprophylaxis: children <5 yr in contact with smear (þ) cases and HIV (þ) persons Preventing risk factors Basic measures to reduce health workers and patients exposure for TB infection to TB infection in hospitals, laboratories, prisons, and other high-risk facilities Intensified collaboration between TB and HIV Preventing risk factors Responsibility of programs other than TB for progression of Prevention of malnutrition: Tobacco smoking control infection into disease Interventions for TB elimination Case management Intensive use of all diagnostic methods: microscopy, culture, molecular To intensify measures to further methods on sputum and other samples, such as bronchial lavage reductions in the risk of infection until Systematic case finding in symptomatics, contacts, and identified reaching an incidence level of
1 smear high-risk groups, often including immigrants, refugees, prisoners, positive TB case, or
1 TB case, any HIV (þ), health care workers, homeless, and drug addicts form, per 1 million population Chemoprophylaxis Broad indications of secondary chemoprophylaxis to high-risk individuals and groups BCG immunization Selective BCG to restricted high-risk groups Preventing risk factors Isolation of suspected and diagnosed TB patients for TB infection Administrative, environmental, and personal respiratory protections in hospitals and laboratories Prevention and control of HIV/AIDS, diabetes, alcoholism and Preventing risk factors other drug addictions, silicosis and tobacco smoking for progression of infection into disease

Interventions

Table 2 Overview of Specific and Nonspecific Interventions and the Objectives for the Control and Elimination of TB

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A rational setting-specific treatment intervention, that includes the early identification and treatment of side effects An uninterrupted supply of quality assured second-line drugs to treat MDR-TB An information system designed for monitoring and evaluation of MDR-treatment programs.

D. Step 4. Integrating TB Care with the Case Management of Respiratory Diseases

Step 4 of the DOTS intervention is to integrate the case management of TB with the case management of the most frequent respiratory diseases [Practical Approach to Lung Health or (PAL), see Chapter 43] at primary health care facilities (27). Case management of TB implies that TB patients are identified among the many patients presenting with cough and other respiratory symptoms. TB is present in only a small fraction, generally less than 10%, of patients classified as TB suspects because they have had cough and expectoration for two weeks or more. The approach aims to improve the quality of TB diagnosis when microscopy is negative and at the same time to standardize the case management of other respiratory diseases with a focus on asthma, chronic bronchitis, chronic obstructive pulmonary disease, and acute respiratory infections including pneumonia. Wrong or insufficient treatment for these conditions is common in most low- and middle-income countries. PAL is also essential in countries and regions with a high prevalence of HIV infection, because respiratory infections are the most common clinical manifestations of AIDS. Concerted approaches to TB and lung health require strengthening the district health system through clinical guidelines on diagnosis, treatment, and referral together with managerial support by training, logistics, and supervision. XIII. Summary Table 1 presents a synopsis of the stepwise approach to implementing interventions for TB control in the new Stop Tuberculosis Strategy in developing countries. Table 2 gives an overview of specific and nonspecific interventions and the objectives for the control of TB in high prevalence countries and the elimination of TB in low prevalence countries. References 1. World Health Organization. WHO Expert Committee on Tuberculosis, Ninth Report. Technical Report Series 552. World Health Organization: Geneva, 1974. 2. Enarson DA. World tuberculosis control: how far have we to go? Int J Tuberc Lung Dis 2000; 4(12):S219–S223. 3. World Health Organization. Global Tuberculosis Control: Surveillance, Planning, Financing. World Health Organization: Geneva, Publication WHO/CDS/TB/ 2002.295, 2002.

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4. Styblo K. The elimination of tuberculosis in The Netherlands. Bull Int Union Tuberc Lung Dis 1990; 65(1):49–55. 5. Centers for Disease Control. A Strategic Plan for the Elimination of Tuberculosis in the United States. MMWR 1989; 38(suppl 3). 6. Goodman RA, Foster KL, Trowbridge FL, et al. Global disease elimination and eradication as public health interventions. Bull World Health Organ 1998; 76(suppl 2): 1–162. 7. Stop TB Partnership and WHO. The Global Plan to Stop Tuberculosis. World Health Organization: Geneva, Publication WHO/CDS/STB/2001.16, 2001. 8. Raviglione MC, Uplekar MW. The new Stop TB strategy of WHO. Lancet 2006; 367:952–955. 9. Stop TB, World Health Organization. An expanded DOTS framework for effective tuberculosis control. Int J Tuberc Lung Dis 2002; 6(5):378–388. 10. Stop TB Partnership. The Global Plan to Stop TB 2006–2015. World Health Organization: Geneva, Publication WHO/HTM/STB/2006.35,2006. 11. Broekmans JF. Control interventions and programme management. In: Porter JDH, McAdam KPWJ, eds. Tuberculosis, Back to the Future. New York: John Wiley and Sons, 1994:171–192. 12. Styblo K. Recent advances in epidemiological research in tuberculosis. Selected Papers (The Hague) 1980; 20:19–91. 13. Styblo K. Overview and epidemiologic assessment of the current global tuberculosis situation with an emphasis on control in developing countries. Rev Infect Dis 1989; 11(suppl 2):S339–S346. 14. Styblo K, Bumgarner JR. Tuberculosis can be controlled with existing technologies: evidence. Tuberculosis Surveillance Research Unit (The Hague). Prog Report 1991; 2:60–72. 15. Veron LJ, Blanc LJ, Suchi M, et al. DOTS expansion: will we reach the 2005 targets? Int J Tuberc Lung Dis 2004; 8(1):139–146. 16. Corbett EL, Watt CJ, Maher D, et al. The growing burden of tuberculosis. Global trends and interactions with the HIV epidemic. Arch Intern Med 2003; 163: 1009–1021. 17. Barr RG, Menzies R. The effect of war on tuberculosis: results of a tuberculin survey among displaced persons in El Salvador. Tubercle Lung Dis 1994; 75:251–259. 18. Rieder H. Epidemiologic Basis of Tuberculosis Control. Paris: International Union Against Tuberculosis and Lung Disease, 1999:87–92. 19. 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. 20. Carranza MT. Meningoencefalitis tuberculosa en menores de 5 an˜os. Peru, 1993–2000. Tuberculosis en el Peru, Informe. Ministerio de Salud. Lima, Peru, 2000: 69–76. 21. Fielder JF, Chaulk CP, Dalvi M, et al. A high tuberculosis case fatality rate in a setting of effective tuberculosis control: implications for acceptable treatment success rates. Int J Tuberc Lung Dis 2002; 6(12):1114–1117. 22. Fine PEM, Carneiro IAA, Milstien JB, et al. Issues relating to the use of BCG in immunization programmes. A discussion document. World Health Organization: Geneva. Publication WHO/V&B/99.23, 1999:29–31. 23. International Union against Tuberculosis and Lung Disease. Criteria for discontinuation of vaccination programmes using Bacille Calmette Guerin (BCG) in countries with low prevalence of tuberculosis. Tubercle Lung Dis 1994; 75:179–181. 24. Harris A, Maher D, Graham S, et al. TB/HIV: A Clinical Manual. World Health Organization: Geneva, Publication WHO/HTM/TB/2004.329, 2004:199–203.

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25. Grzybowski S, Enarson DA. The fate of cases of pulmonary tuberculosis under various treatment programmes. Bull Int Union Tuberc 1978; 53(1):70–75. 26. Maher D, Gupta R, Uplekar M, et al. Directly observed therapy and treatment adherence. Correspondence. Lancet 2000; 356:1031–1032. 27. World Health Organization. Practical approach to lung health. A primary health care intervention for the integrated management of respiratory conditions in people of five years of age and over. World Health Organization: Geneva. Publication WHO/ HTM/TB/2005.351, 2005.

18 The Laboratory Network in Tuberculosis Control in High-Prevalence Countries

ADALBERT LASZLO

ISABEL N. DE KANTOR

Mycobacteriology Laboratory Consultant, Ottawa, Ontario, Canada

Tuberculosis Consultants Panel, World Health Organization, Buenos Aires, Argentina

RICHARD URBANCZIK Tuberculosis Consultants Panel, World Health Organization/International Union Against Tuberculosis and Lung Disease, Scho¨mberg, Germany

I. The Concept of Diagnosis in Tuberculosis Control Diagnosis, one of the fundamental objectives of the National Tuberculosis Program (NTP), relies in the majority of disease-endemic countries (DECs) on the direct smear microscopic examination of sputum to identify highly infectious cases of smear-positive pulmonary tuberculosis (PTB). The estimated worldwide detection rate of new smear-positive PTB under DOTS was 53% of the estimated total incidence in 2004 (1). The ‘‘specificity’’ of sputum smear microscopy is surprisingly high, i.e., 98% or more, considering the number of different mycobacterial species so far described (2–6). Due to this very high specificity, and taking into account expectorated sputum specimens only, ‘‘positive predictive value’’ [acid-fast bacilli (AFB) seen on smears graded
1þ are very probably Mycobacterium tuberculosis complex] seems to exceed 90% in different regions. This is possibly related to a much lower sputum smear positivity in persons with pulmonary disease provoked by mycobacteria other than tubercle bacilli (such as Mycobacterium avium complex) when compared with persons suffering from PTB. For induced sputum and bronchoalveolar

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lavage specimens, the specificity of smear examination may be lower, as well as in sputum samples from HIV-positive PTB patients (7,8). The ‘‘sensitivity’’ of sputum smear examination, when related to culture results of the same specimen, is acceptable provided good laboratory practice is in use, i.e., it could range between 60% and 80% (9). Furthermore, sputum smear microscopy may yield results rapidly and at a relatively low cost. Culture facilities, when available, may be of help in some diagnostic situations such as in sputum smear-negative HIV-positive PTB suspects and in cases of suspected extrapulmonary disease. Apart from its cost, the greatest drawback of culture is its turnover time: even using fast modern techniques for culture, it may easily exceed one week, as opposed to conventional techniques that may frequently take four weeks. TB bacteriology services must maintain close coordination with the administrative, epidemiological, and clinical components of the NTP. Those in charge of these services must observe and apply the following principles and guidelines:  National standards for methods, procedures, and laboratory techniques  Executive decentralization down to the least complex diagnostic level  Effective supervision and external quality assurance (EQA) from the immediately superior level  Full integration of TB diagnostic services within the NTP with continuous interaction between members and the various levels of the network for the sharing of expertise Implicit in these general principles and guidelines is the concept of the ‘‘laboratory network’’ as a tool for delivering TB bacteriology services. The interaction mentioned above manifests itself principally through a common set of standards, recording, reporting, information systems, reagents and other laboratory supplies used, and services offered, and through a quality assurance (QA) program built into the system. The network concept is necessary because sputum smear microscopy, the essential diagnostic tool of the NTP, must be carried out according to standards and with assured quality as near as possible to the TB suspect’s/patient’s place of residence. The laboratory network will provide information required for monitoring, evaluating, and planning of the NTP activities at all levels. This information refers to  TB suspects or individuals who present with symptoms or signs suggestive of TB, in particular cough of long duration (usually of more than three weeks, in some settings more than two weeks), which are present in 95% of all cases of sputum smear-positive PTB. To identify TB suspects, adults 15 years of age or older (in some countries 12 years or older), presenting with respiratory symptoms, should be asked whether they have a cough and for

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how long they are coughing. Periodic and continuing information on the number of TB suspects registered by the NTP per time unit can be related to the number of TB suspects examined by the laboratory network. It is then possible to evaluate case-finding activities, thus detecting possible problems in need of remedial action. New smear-positive PTB cases detected over the number of TB suspects investigated and monitored per time unit is an excellent indicator of the performance of the laboratory and of the NTP. This data also offer a good basis for the calculation of necessary resources for the next planning period. Information provided by the laboratory on case diagnosis compared to that provided by the District TB Register, the TB Suspects Registry, and the Treatment Card makes it possible to determine the percentage of diagnosed patients who start treatment. This percentage is clearly a very important performance indicator for the NTP. The increase in bacteriologic confirmation of PTB cases as a function of time is one of the best operative indicators of the NTP’s efficiency. Laboratory data will allow the NTP to chart a trend curve of PTB cases confirmed by bacteriology (mostly sputum smear-positive microscopy) and that of PTB cases not confirmed (mostly sputum smear microscopy, or smear ‘‘not performed’’). Increasing separation of these two curves, also known as the ‘‘open scissor phenomenon,’’ could indicate that case-finding in the concerned NTP may be deteriorating. Monitoring the sputum conversion rate during the course of chemotherapy or the smear rate at the end of treatment are the best indicators for treatment’s efficacy and efficiency.

II. Diagnosis as a Strategy of the NTP For the NTP, a TB patient is a person whose diagnosis has been bacteriologically ‘‘confirmed.’’ Persons for whom the TB diagnosis was ‘‘presumed’’ on the basis of indirect testsa are cases of TB without bacteriological confirmation.

a Direct diagnostic tests confirm the presence of the etiological agent, of AFB, by sputum smear microscopy or M. tuberculosis complex by culture. Indirect diagnostic tests indicate the host’s response to the etiologic agent: clinical symptoms, X-ray images, general laboratory tests such as erythrocyte sedimentation rate (ESR) or immunological assays, etc. They are not specific for TB; e.g., the symptoms and the X-ray abnormalities observed in PTB may also be observed in other pulmonary diseases. For instance, in a setting in Nairobi, Kenya (10), among 340 smear-positive TB subjects, 98% were also positive on culture for tubercle bacilli whereas among 320 TB suspects examined by X-ray only, the culture was positive for tubercle bacilli in only 55%.

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The case-finding in an NTP, particularly in DECs, is very often based on sputum smear microscopy only. In some high- and medium-income countries, it is supplemented by culture examination of the specimens. Consequently, when the magnitude of the disease is to be characterized epidemiologically, the data shown often refer to the ‘‘total number of TB cases.’’ This number actually indicates the total number of TB cases ‘‘notified’’ by the NTP. This concept includes  Persons assumed to have TB (clinical symptoms compatible with TB)  And/or TB suspects with chest X-ray abnormality  Plus bacteriologically confirmed TB cases detected mostly by sputum smear microscopy, sometimes supplemented by culture. The use of such a broad concept has several consequences: The ‘‘clinical’’ one is that among persons notified as TB patients, some may not really have the disease. Such persons receive unnecessary anti-TB therapy and may suffer side effects from drugs they do not require. The ‘‘administrative’’ one results in the waste of scarce resources. Finally, the ‘‘epidemiologic’’ one obscures the magnitude of the TB problem by producing a heterogeneous group containing an unknown proportion of nonexistent TB cases. A correct recording and reporting system with standardized registers for casesb is indispensable for the evaluation of the problem’s evolution over time, such as the proportion of new smear-positive cases, of failures, and of relapses. The most important tools are the ‘‘TB Laboratory Register’’ and the ‘‘District TB Register’’; the cross-checking of these registers is always very informative. The bacteriologic definition of a case of PTB results in the need for ‘‘diagnostic certainty.’’ If the laboratory is responsible for confirming the disease, then this confirmation must be ‘‘reliable,’’ ‘‘timely,’’ and ‘‘accessible.’’  ‘‘Reliability’’ means that all laboratories involved should use the same technical, recording, and reporting procedures and implies that each patient has the right to receive the highest possible standard of care.  ‘‘Accessibility’’ and ‘‘timeliness’’ mean that each person requiring diagnostic examination must receive it as soon as possible. This implies that: the laboratory should be located as close as possible

b

Recently the World Health Organization (WHO) (11) suggested the use of the ‘‘Register of TB Suspects’’ to record all persons identified as TB suspects in a given health facility and all sputum samples sent to the laboratory. It is useful for monitoring whether sputum specimens (i) reach the laboratory and (ii) the laboratory results are returned to the health facility for all sputum samples sent. In other words, whether TB suspects identified are also bacteriologically examined.

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to the health facility where the person seeks medical attention. Alternatively, a system must ensure that the sputum specimen collected will reach the laboratory in a timely manner. Considering the working hours of most patients attending health facilities, the laboratory must also accept specimens outside of regular working hours and deliver the results in a timely fashion.c All these characteristics cannot usually be met by a group of isolated laboratories. It is because of this that the concept of a ‘‘laboratory network’’ was developed. III. TB Laboratory Network Technical Profile 

The great majority of services provided by primary care laboratories require technical simplicity, short TaTs for reporting, and results with good specificity and acceptable sensitivity. These characteristics can be achieved by sputum smear microscopy. A proportion of cases may require more complex diagnostic techniques such as culture; alternatively, special laboratory examinations need to be carried out on a sample of patients to characterize some aspects of the disease such as drug resistance prevalence or the evaluation of new diagnostic technologies. It is also necessary to perform continuous monitoring and evaluation of the quality of work in individual laboratories (QA).

IV. TB Laboratory Network Organizational Profile (12) 



c

Usually the TB Laboratory Network has a peripheral or local level, an intermediate level (regional, provincial, and district), and the central level. The latter is the National Reference Laboratory (NRL), which must be established within the NTP. The laboratories of armed forces, private institutions, nongovernmental organizations (NGOs)d, universities, and others may play a relevant role in the network ‘‘provided’’ they work in coordination with the NTP. Technical and operational standards make it possible for components to apply correctly the techniques that are best adapted to the needs of the health services and communities they serve. Given that the activities must be ongoing and should always be carried out with the same high quality, a system of technical and administrative supervision QA must be established.

Data from several WHO regions indicate that this turnaround time (TaT) may vary from a few hours to a week or more for sputum smear microscopy results. d The size of the NGO cooperation may be considerable: e.g., in India, 514 different NGOs provide services for the Revised NTP, including sputum smear microscopy (13).

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The NRL coordinates the initial organization and function of the laboratory network. Its head, the NTP Laboratory Manager, must define together with the NTP Manager and other public health authorities the physical location of TB laboratory services at all levels, placing TB in the context of diseases prevalent within the communities being served. The NRL should ideally be concerned with TB bacteriology only. It is absolutely essential that NRL staff have full-time jobs and that they do not ‘‘rotate.’’ The NRL duties must include  Technical standardization: Appropriate methods and techniques must be selected to improve the work quality of the entire network, to provide a cost-effective training of its staff members, and to obtain a uniform and reliable recording/reporting system for the NTP. The preparation and periodical updating of the National TB Laboratory Technical Manual and of the Standard Operating Procedures (SOP) Manual for the laboratory network constitutes an important responsibility of the NRL.  Supervision: Regular and ongoing supervision of all laboratories of the network (which includes the external QA at all levels) is another important task of the NRL. In larger countries, a sequential scheme may be employed: the NRL supervises the intermediate level directly and the peripheral one through the intermediate level laboratories.  Planning: Once the requirements of bacteriological examinations for the NTP have been defined and are in accordance with the NTP’s priorities and the resources available, the NRL must plan the activities and needs of the entire laboratory network.  Training: The NRL must train persons according to the ‘‘train the trainers’’ system on standardized procedures, SOPs, etc., according to the NTP’s needs and priorities. To comply with these tasks, the NRL must maintain its own (limited) routine laboratory examination program. This is necessary in order to: 1.

2.

Maintain its own high proficiency and to be able to perform operational research such as the evaluation of new methods or of new indicators and Perform EQA, be it by rechecking of slides or by preparation of slide panels and train staff members from the intermediate level laboratories.

B. The Intermediate Level

In addition to the basic diagnostic technique (i.e., sputum smear microscopy) for the TB suspects of the health institution in which this level laboratory is usually located and for the monitoring of therapy of TB patients, the intermediate level (regional, district, etc.) laboratories may

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apply techniques of moderate complexity such as culture or sometimes even drug susceptibility testing (DST) of isolated strains. They are ideally laboratories for mycobacteriology only but often their duties also include general bacteriology or even other laboratory procedures. Apart from this, their duties—primarily directed to the peripheral level—are the same as described above for the central level. C. The Peripheral Level

These laboratories are usually located within the primary health-care centers. They perform only sputum smear microscopy of specimens from TB suspects in their catchment area to identify smear-positive PTB cases. However, this activity is in most cases integrated at this level with other diagnostic tasks such as hematology, parasitology, etc. Under the NTP, the peripheral laboratories are expected to receive sputum specimens from TB suspectse to perform smear examinations and to record and report the results. V. Resources of the NTP Laboratory Network Adequate resource management requires 1. 2.

knowledge of the resources available within the system in the country (situation analysis) and appropriate programming of activities to be undertaken at the right time and place.

In order to function, the network needs human resources, equipment, and supplies. Thus, the first step to be taken by the NTP laboratory manager and his staff is to perform a ‘‘situation analysis’’ of the laboratory aspects of TB diagnosis in their country. This should include all laboratories involved in the NTP network as regards their manpower (related to TB laboratory examinations), equipment, and supplies. As mentioned before, NGOs, private laboratories, and other public laboratories should also be considered. Once available resources in the country, region, or area where the NTP is to begin or expand its activities are known, priorities must be established. Financial resources, personnel, equipment, and/or supplies are usually not sufficient to allow initiation or extension of the laboratory activities simultaneously in all the health services of a given area. Therefore, priorities must be defined to balance requirements and resources, with e

In addition to specimens collected in the health center where the peripheral level laboratory is located, sometimes there are ‘‘specimen collection centers’’ (usually within the lowest-level health centers) where sputum specimens are collected and then referred to the nearest laboratory for examination. Even though the best ‘‘containers’’ for the sputum specimens are the TB suspects themselves, specimens should not be collected in the laboratory but should arrive there inside adequate containers. Experience shows that smears prepared and fixed (but not stained) in remote areas prior to transportation to microscopy centers are often of poor quality, and fixed but unstained smears can remain infectious when positive (14).

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the aim of organizing DOTS areas. Such decisions must be taken jointly by the NTP manager, TB laboratory network manager, usually the head of the NRL, and other senior members of the NTP. It should be kept in mind that a relatively easy improvement in the laboratory sector of a given area may not be accompanied by as easy improvements of other DOTS components, or ‘‘vice versa.’’ Human resources: Nowadays, staff are usually scarce and insufficiently trained. It must be recognized that even if a laboratory has a highly specialized technical orientation and its staff are often called upon to deal with complex methodologies, it does not follow that the laboratory is necessarily highly proficient nor does its staff necessarily have a high level of public health awareness of the TB problems in the community. It is therefore very useful for the managers of the different laboratory levels to receive training in NTP issues as seen from a public health standpoint. Hence, an inquiry into the number of available technicians at all levels (by mail, e-mail, or, preferably, personal visit) should be followed by training courses that reveal the actual state of technical knowledge and at the same time allow education of the technicians in NTP public health issues. ‘‘Equipment’’ in a clinical TB laboratory cannot be limited to a microscope, which nevertheless constitutes its most essential piece of equipment. Domestically manufactured microscopes are usually not available in DECs and hence they must be imported.f Before selecting a microscope brand and purchasing it, a few key points should be considered:  ‘‘Availability’’ should mean not only fairly rapid delivery but also continuous supply (of microscopes as well as of spare parts) should the network expand.  ‘‘Quality’’ should not be confused with complexity. There are good-quality, mechanically simple, and reasonably priced microscopes on the market.  ‘‘The number of microscope brands’’ purchased should be as few as possible in order to promote compatibility. The purchase contract for the microscopes should always include a maintenance contract for a determined period of time and a reserve stock of the most frequently replaced spare parts (e.g., objectives, oculars, bulbs, etc.).  In some countries where the ‘‘electricity supply’’ is unavailable to peripheral laboratories or where electricity cuts are frequent, microscopes should have swap-out mirrors to be able to use reflected sunlight.

f

Microscopes are quite popular as donation items among sponsors, which for obvious reasons are never refused. Because the donors frequently look for the cheapest but not necessarily the best brand, the country may end up with a dozen or more different brands, which complicates the procurement of spare parts.

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‘‘The procurement order’’ should ideally include a training course on basic microscope repair and service for NTP laboratory staff members who could then transfer this knowledge to the whole network.

The same criteria are generally valid for the purchase of most other equipment. Complex and/or high technology equipment, which is invariably expensive, may rapidly cease to function due to the lack of resources/ logistics for its maintenance or of necessary supplies and spare parts. ‘‘Chemical reagents’’ should be of good quality, particularly those needed for staining of sputum smears by the Ziehl–Neelsen (ZN) technique (15). All steps in the preparation of staining solutions for the ZN technique, from the purchase, e.g., of fuchsine, to the storage of the solution may influence the quality of final ZN result.g It is preferable to centralize the purchase/procurement of guaranteed quality reagents because the purchase of higher volumes may significantly reduce the cost. A more problematic issue is the preparation of staining solutions: 1.

2.

It is an advantage if the NRL (or the regional laboratories in large countries) prepares all the solutions needed for ZN staining centrally and distributes them to the periphery. Alternatively preweighed amounts, e.g., of fuchsine powder, may be distributed in the same way. There is a recent tendency in many countries, including some of the DECs, to use commercial ZNh staining kits. Although there is hardly an objection to be raised against such kits—provided they are of good quality—it is nevertheless possible that this approach may increase the cost of the ZN sputum examination. Anecdotal evidence from a few countries reveals multiple sources for such kits, both national and international. At any rate, it would be

g The fuchsine powder purchased and used may not contain 100% of the dye. A dye content of 88% or more requires no additional action (15). With lesser dye contents a calculation factor must be applied: e.g., for the indicated dye content of 75% (¼0.75) 1 is divided by 0.75 ¼ 1.33. Thus to obtain 1 g of 100% dye of such a product an amount of 1.33 g must be weighed and used for preparation of the staining solution. It was also postulated (16,17) that the chemical composition of ‘‘basic fuchsine’’ may be of considerable importance for the quality of the ZN staining. Constituents of basic fuchsine are rosanilin, pararosanilin, and Magenta II (18). Another example is phenol in the carbol-fuchsine solution (ZN), which precipitates at temperatures below 18 C. Laboratory technicians must know that when in their settings such a temperature situation occurs the carbolfuchsine solution must be kept in the warmest place available in the laboratory. h Such a kit was recently presented at the 35th World Congress of the International Union Against Tuberculosis and Lung Disease (IUATLD), Paris, 2004, by the Global Drug Facility. This kit was being field tested in the Congo (Brazzaville), Nigeria, and Myanmar.

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3.

the responsibility of the NRL to subject all the available kits to a rigorous QA.i The systematic decentralization of the preparation of ZN staining solutions down to the peripheral laboratories appears to involve the most disadvantages and should be avoided whenever possible.

VI. Management of Laboratory Supplies To ensure the continuous flow of laboratory supplies, NRL’s must budget rationally for requirements. The only quantifiable basis for planning is the number of patients recorded and reported and, among them, the number and percentage of PTB cases positive on sputum smear examination.j Assuming that this smear positivity rate is 12% or 0.12, that each TB suspect requires three sputum examinations, and that each case of smear-positive PTB has three follow-ups with two sputum examinations each, the number of microscopic slides, sputum containers, and wooden applicators (if wire loops are not to be used for smearing) needed per smear-positive case detected is (1/0.12)  3 þ 6 ¼ 31. Laboratory material requirements are relatively modest and, for this reason, are ordered every six months rather that every three months. The reserve requirement may be estimated at one year’s supply (15). However, this may depend on the local situation of a given NTP and be subject to variation. The amounts of reagents for the ZN staining technique are usually estimated assuming that 5 mL of each of the solutions are needed for each slide. It is further assumed that two drops or 0.1 mL of immersion oil are used for each slide. After the smears are examined, all used materials are disinfected by placing in a waste receptacle containing 5% phenol or 0.5% hypochlorite (household bleach) solution. Some 40.0 mL of disinfectant solution are used per specimen. These disinfected materials can be autoclaved or disposed of by burning or earth burial. Planning for culture examinations is of less importance because of the limited use of culture by many NTPs. The usual procedure for culture in DECs is to use the Petroff decontamination/homogenization technique (19) i

A similar situation already exists in many countries as regards the culture media for tubercle bacilli [Lo¨wenstein–Jensen (LJ)] with many different commercial sources, again both national and international. Here the sensitive aspect involves not only the QA (as regards growth support for M. tuberculosis complex) but also the expiry date, which is relatively less important for staining solutions. j It has been observed in several countries in the WHO European and American regions (Urbanczik R, unpublished) that about 5% of the persons 15 years or older attending health centers can be considered TB suspects. By knowing the average smear positivity rate, it may be possible to obtain similar numbers as mentioned above. However, this approach may be subject to considerable regional error, and planning based on ‘‘hard’’ data from the TB Laboratory Register should be preferred.

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and to seed two tubes containing 6.0 to 8.0 mL of LJ medium. The calculation of total amounts needed should follow the above-mentioned scheme. For more detailed information on required unit amounts please refer to WHO and IUATLD technical manuals (19,20). VII. Training and Human Resource Development If a TB laboratory is to function effectively, motivated and dedicated staff is crucial. Laboratory personnel must be fully aware of their important role in TB control and must become full partners in the NTP. Training laboratory technicians in the microscopic diagnosis of TB is, accordingly, an essential activity under DOTS. WHO: Laboratory Services in TB control, Geneva, 1998 (21).

The planning of training should conform to the needs and priorities of the NTP and training must be a continuing effort. The long-term goal for human resource development for TB control is to reach and sustain a situation where staff at different levels of the health system have the skills, knowledge, and attitudes necessary to successfully implement and sustain TB control activities, including the implementation of new and revised strategies and tools in relation to the management of TB/HIV coinfection (22). Properly focused, directed, and managed training is an essential strategy for TB control (23). The relationship between diagnostic services and treatment services is a fundamental one. Consequently, it makes no sense to train the laboratory staff in a region where there are no treatment centers for diagnosed cases, nor would it be prudent to train all the laboratory personnel in a region at the same time, leaving these services temporarily without human resources. The laboratory network manager should prepare, jointly with the NTP manager, an annual plan for training activities. This approach should be used to program training at each level of the NTP and the network. The network manager at each level should identify and determine   

which institutions will be in charge of organizing and delivering training; whether the training should be centralized or decentralized; and how costs will be covered.

A. Planning the Training

From the above, the need for careful planning of training activities in the laboratory network is clear, and so is the fact that this planning must be done with the other components of the NTP, at all levels. To plan a basic training course, a laboratory manual is needed, with precise instructions on smear microscopy, including specimen collection; smear preparation, preparation of staining solutions, staining, handling the microscope reading and recording results, reporting on results, and keeping the laboratory register. It should also contain information on the priorities for use of culture and DST.

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Laszlo et al. The following should be evaluated:  The candidates for training  Training needs The following need to be chosen:  The facilitators  A location for training (e.g., a laboratory with enough microscopes and an adjoining meeting room)

The laboratory network manager should be the first person trained for his/her duties (i.e., in international courses given by WHO, IUATLD, Koninklijke Nederlandse Vereniging tot bestrijding der tuberkulose (KNCV), and other partners). However, within the network, courses on smear microscopy have absolute priority. They should not just be technical, but should include the following topics:      

Principles of epidemiology Information on the TB situation (global and local) NTP organization and standards and strategies for TB control Role of the laboratory in the NTP Coordination between health centers (treatment) and laboratory Reports, registers, and forms

B. The Target Population

Vast amounts of money are wasted on training individuals who do not use the acquired knowledge. One priority for training could be, for example, a DOTS area where smear microscopy does not have the required coverage due to a scarcity of trained personnel and where a considerable number of specimens are being sent on to the closest district laboratory. The priority group for training is composed by technicians (or even nurses or other health workers) who will be recruited for microscopy in areas that are being incorporated into the program under DOTS (i.e., pilot or demonstrative areas). If all the region, province, or country is already under DOTS, training becomes a continuing priority. Individuals most likely to continue working in the area where the training takes place should be given priority. Regular contacts between TB laboratory network managers and NTP managers at all levels will allow definition of future needs for retraining and for continuing education. C. The Type of Training

The content of the training should be based on the skills and knowledge needs of the target population, and not on the preferences of those who plan and coordinate the training. The detailed technical content refers to the methods that trainees can and should use in the workplace. Reference may be made to more complex methods for general information and so that trainees will know where and when to use them, without going into the finer details of the techniques.

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Courses are often devoted to technical aspects only and do not include other aspects of knowledge, which should be included in all laboratory courses of the program: the basics of TB epidemiology, the function of the NTP, and the different aspects of the organization and administration of DOTS. If the levels and functions of the network laboratories have been defined, it is easy to establish the contents of the training for each level. D. The Training Method

Because training will mainly be done on laboratory techniques, an important part of it should consist of laboratory practice, particularly in courses for technicians. It is preferable to train in daily routine tasks, without artificially changing conditions. Individuals to be trained should be those involved in the laboratory’s routine activities. They will learn by processing the specimens received at the training laboratory, supported by a technician from that laboratory and supervised by the person in charge of the course. The conditions and the materials of training should not be very different from those available to students in their usual place of work. Because the training will also include aspects of general knowledge of the disease, the most adequate approach is interactive by way of dialogue between trainees and facilitators who can easily transmit the concepts and who can adapt the program’s concepts to the local reality. On the other hand, organizational aspects are better understood when they are seen in action: a visit to health centers where the NTP’s activities are regularly carried out, where the examination of the register books and handling of the reporting system are in place. E. The Training Location

Ideally, the training should be carried out in the trainee’s own workplace; however, this is generally not cost effective because the instructors would have to travel to the local level and remain there for a relatively long time. It is preferable for the students to be trained close to their workplace, if possible in the laboratories with which they will subsequently have ongoing contacts. The local level should be trained at the intermediate (regional or provincial) level, which in turn should be trained at the NRL. NRL staff should also be trained, within or outside the country, in conditions as close as possible to those they will have in their workplace. It is not recommended for the local levels to be trained at the national central level, except in small countries. F. The Length of Training

This is highly variable, depending on the contents of the training, on the prior knowledge and abilities of the students, and on available resources. In general, courses for microscopists last for five to six days, if the trainees have knowledge and some previous experience in the use of microscopes.

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Without this experience, the course should last at least two weeks or should be replaced by a stay in the laboratory, trained by performing routine tasks under the supervision of local technicians and complemented by lectures or group discussions. G. The Follow-Up After Training

Follow-up after the training activity by means of evaluation of the application of knowledge gained and its transfer to the workplace is part of training and should be included in it. As training is one of the activities of the laboratory network in the NTP and as long as there is a continuing and stable relationship between the levels of the network, this follow-up is feasible. How the students put teachings into practice is measured by evaluating the activities of their laboratories by supervision and by periodic quality controls (QCs) of smear microscopy. VIII. Quality Assurance in the Laboratory Network QA with regard to TB bacteriology is a system designed to continuously improve the reliability, efficiency, and use of TB laboratory services (24). It needs to be established in order to achieve the required technical quality in laboratory diagnosis. Intermediate laboratories should supervise the peripheral network, while the NRL should supervise the intermediate network (24,25). The main components of a QA program are as follows:  ‘‘QC’’ is the internal monitoring of working practices in the TB laboratory, including technical procedures, equipment and materials, quality of specimens collected, containers, transportation, recording and reporting, and biosafety issues.  ‘‘External quality assessment’’ (EQA) involves three main methods developed to assess laboratory performance: ‘‘on-site evaluation, panel testing’’ and ‘‘blinded rechecking.’’  ‘‘On-site evaluation’’ consists of visiting the network laboratories to directly observe working conditions, technical and administrative procedures, and the coordination between the laboratory and other services involved in TB control strategies at that level (NTP, DOTS). A checklist is used to verify that standard operational procedures are in place. Supervisors should verify that a functional microscope and an adequate supply of reagents within expiration dates are available, that a Laboratory Registry and standardized request/report forms are properly used, and that results are promptly reported to the health center and slides are stored for ‘‘EQA rechecking.’’ Data on the number of smear examinations per week/month and positivity rates for diagnostic and follow-up examinations are collected

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during the visit. Cross-checking of laboratory and the NTP registries will determine the level of coordination between the laboratory and the clinic by documenting whether smear-positive PTB cases reported by the laboratory are put on treatment. In all site evaluations, a brief meeting should be held with the laboratory personnel, nurse, health workers, and physicians, to discuss findings and, if necessary, the quality improvement measures to be taken. ‘‘On-site’’ evaluation is the most complete QA of laboratories and yet it is most neglected due to the lack of funding, human resources, and political will. ‘‘Panel testing’’ is a method of EQA (25) in which the NRL or the intermediate level periodically send a batch of stained and/or unstained (formaldehyde treated) prepared or manufactured smears to the corresponding peripheral laboratories for processing, reading, and reporting of results. It provides some basic information on the state of the microscope and quality of examinations. It can be used prior to implementing a rechecking program, to quickly detect problems associated with very poor performance or to evaluate the proficiency of laboratory technicians following training. Also, it could be employed to guarantee that technicians periodically examine some positive slides, in areas and settings where positivity rates are very low. In such a situation, this proficiency testing will complement the assessment made by blinded rechecking, where the sample of slides that is submitted to rereading (see section ‘‘Blinded Rechecking: Lot Quality Assurance System’’) may contain few or no positives. A panel must include at least 10 slides, some of these with different grades of positivity, to evaluate the ability of technicians to properly grade positive results. For that purpose, either specially manufactured or stained smear slides collected from the routine at the reference laboratory (RL) can be used (25). The composition of slide sets sent in different panel testing exercises should vary in terms of the number of slides for each of the positivity grades. The frequency of panel testing may be increased or decreased depending on laboratory performance. Panel testing does not however constitute a permanent solution for EQA of sputum smear microscopy. It has the advantage of being relatively simple to implement but provides little information about routine smear microscopy services because the final report reflects more often than not the consensus of reading results of a group of readers rather than individual performance. A. Blinded Rechecking: Lot Quality Assurance System (25–27)

Blinded rechecking consists of periodically rereading at the NRL a sample of randomly selected, representative slides from a controlled laboratory to determine whether that laboratory has an acceptable level of performance. To prevent bias, the NRL must blind the slides to be rechecked to prevent the controller from knowing the initial results. Discrepant results are resolved by a second controller. These programs are not intended to confirm any individual patient’s diagnosis but to assess overall laboratory performance. In the early 1970s, countries established rechecking programs

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in which the usual sample of slides was composed of 10% of negatives and 100% of positives collected at the laboratory to be assessed during a given period. This sampling method is statistically biased and imposes a heavy burden on smear microscopy rechecking services, especially in situations of heavy workload, simply because the sample is based on a proportion (10%) of the total volume of negatives. An improvement in EQA is the recent application of the lot quality assurance system (LQAS), originally designed for manufacturing processes to test whether a ‘‘lot’’ (in this case the smears examined during a specified period of time in a given laboratory) meets a specific standard. If the number of sampled smears reread does not exceed the threshold or ‘‘critical value (CV)’’ of false-negative (FN) and false-positive (FP) smears previously determined, the lot is accepted. For calculating the sample size, information is required on the ‘‘positivity rate’’ (prevalence), the number of smears examined in the period (‘‘size’’), the maximum number of FN and FP that will be tolerated in the sampled smears (CV, for a ‘‘confidence level’’ of 95%). ‘‘Sensitivity’’ is defined here as the ability of the controlled technician to detect AFB, compared to that of the NRL. An average value of 80% is usually assigned. ‘‘Specificity’’ inherent to the ZN method is very high, and it can be set at 100%, also relative to NRL. By definition, any FP result would trigger action. With a specificity set at 100%, the ‘‘sample size’’ and the CV are based on the total number of negative slides. In practice, the number of slides to be selected (sample size) should be fixed beforehand by the RL using a table LQAS method, with confidence interval of 95%, sensitivity of 80%, and specificity of 100%. It has been demonstrated that the expected percentage of error, mainly due to FN, increases with prevalence (positivity rate). Therefore, according to statistical principles, the sample size decreases with increasing positivity rate. An advantage in relation to the traditional sampling method of examining all positives plus 10% of negatives is the smaller size of the sample for laboratories processing more than 500 specimens per period, with relatively high positivity rates ( >10%), e.g., for a lot size N ¼ 1000, 150 positive and 850 negative slides (positivity rate ¼ 15%). The ‘‘conventional’’ sample size (all positives þ 10% of negatives) ¼ 150 þ 85 (10% of 850) ¼ 235; and LQAS a sample size of only of 66 for a sensitivity of 80% and an acceptance number of 0k, according to the table. However, this method has its limitations because  the sample calculation does not take into consideration positive slides, i.e., is biased for negative slides even though the actual sampling includes a few positive slides;  no conclusions can be reached about specificity if no FPs are found; and

k

Simple sample size table (25).

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it does not distinguish between the probability of finding AFB by microscopy, which is determined by the Poisson distribution (2,5) and the lack of proficiency of the microscopist.

B. Quality Control of Culture Methods

QC of culturing methods in the NRL can be done by calculating the proportion of contaminated tubes and by determining the sensitivity of culture media to support the growth of M. tuberculosis (19–21). Contamination control is a simple way of evaluating the quality of culture by calculating the proportion of contaminated tubes out of the total number of tubes inoculated. This proportion should not exceed 3%; lower values may be due to the use of too strong a decontaminating solution, a too long exposure of the specimen to the decontaminating solution, or a too high concentration of malachite green in the egg-based medium. Higher values may indicate poorly preserved specimens during transport and storage, a lapse of too long a time between specimen collection and processing, a too low concentration of the decontaminating solution, and a short time of contact between the specimen and the decontaminating solution. They can also be caused by problems in preparing culture media: nonsterile saline solutions, an autoclave that does not reach the required temperature and pressure, and the presence of contaminants in the laboratory environment and/or in the laboratory’s culture incubation chamber (especially environmental fungi). Constant monitoring in the laboratory culture contamination percentages should be plotted to allow timely problem identification. C. Sensitivity of Culture Media

Monitoring culture quality through results in the laboratory is simple, because culture normally shows a greater sensitivity than smear microscopy. The person who reads the cultures can detect an inversion to this rule when positive diagnostic smear microscopy is followed by a negative culture, or (þþþ) diagnostic smear microscopy specimens are followed by a culture with too few colonies (10 or 20 colonies). Trends on these events should be systematically monitored: one or two observations of this type have no value per se. IX. Evaluation The NTP sets objectives to control TB: to reduce the spread of infection through case detection and cure of the most potent sources of infection, i.e., PTB patients excreting tubercle bacilli. In addition, TB control aims to cure all forms of TB in order to reduce mortality and human suffering. To achieve this, a policy framework and corresponding strategies have been developed (DOTS). Activities are planned and time-limited measurable targets are set; e.g., among the Millenium Development Goals, the four principal targets for global TB control are as follows: by 2005, to detect 70% of

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new smear positive patients arising each year, and to successfully treat 85% of these patients, by 2015, to have halted and begun to reverse incidence, and between 1990 and 2015, to halve TB prevalence and death rates (28). This process of planning can be applied to different levels: from the global to the local one. Once resources needed are secured, the activities that should lead to the hoped-for improvement are developed. The level of performance must be continuously monitored, because if the strategies are not yielding the expected results they should be adjusted or changed. This monitoring is done using ‘‘operational indicators’’ of process and outcome, which point out trends and achievements. Process indicators measure quality of interventions; for most of them, analysis involves the calculation of the proportion of the numbers actually achieved against the expected numbers. These expected numbers depend on previous estimations. A method used to estimate new smear-positive PTB cases to detect is described below. Further evaluation of case-finding activities, where obviously the laboratory plays a basic role, will depend on the accuracy achieved in these estimates. A. Case-Finding Evaluation

An important clinical/laboratory case-finding indicator is the proportion of TB suspects identified and listed in the TB suspect register, who were examined by sputum smear microscopy. This should be ideally 100%: Lower percentages could indicate either problems in explaining and in enlisting TB suspects’ cooperation, poor coordination between the health center and the laboratory, or a poor laboratory performance (e.g., samples are not examined and/or results not reported). The positivity rate: It [(Number of smear-positive results/total smear examinations) 100] is a laboratory indicator that must show a close correlation with the percentage of smear-positive PTB cases detected among TB suspects examined. The expected rates under DOTS vary between 3% and 15%. These values and trends allow the estimation of prevalence of smear-positive PTB cases among TB suspects, the accessibility of health facilities, and the quality of case detection and its improvement. Relatively high positivity rates (15–18%) may indicate high prevalence, low accessibility, and/or absence of a case detection policy. Adult patients should be selected for sputum smear examination on the basis of their respiratory symptoms, i.e., persistent cough of two or more weeks duration. If sputum smear examination is requested from every adult outpatient who presents with a cough, no matter its duration, the positivity rate will drop and the proportion of saliva specimens will increase. The main consequences for the laboratory include the waste of resources, the loss of interest and confidence of laboratory technicians in their work, and decreasing efficiency of diagnostic services. The number of smear microscope examinations per tuberculosis suspect: Low averages, i.e., below 1.6/TB suspect for countries using two sputum smears for diagnosis or below 2.4/TB suspect for those using three, indicate

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that TB suspects may have received insufficient explanations on how many specimens are needed, restrictive laboratory hours, and reluctance to request smear examination on the part of the clinical staff, whether for lack of interest or shortage of resources. Other important TB laboratory indicators include      

Total number of examinations per time period: This is a good measure of the laboratory output—one full-time microscopist should perform no more than 20 to 25 sputum smears/day. Percentage of positive results in the second and third sample: This may be used to measure the additional diagnostic contribution of second and third sputum samples. Percentage of saliva specimens among sputum samples: This measures the quality of sputum samples. Percentage of new sputum smear-positive cases among TB suspects examined. Percentage of culture contamination: This is a measure of good laboratory practice; it should not exceed 3%, nor should it be 0%. Percentage of smear-positive/culture-positive new cases: This is a measure of the contribution of culture to case finding—in good laboratory programs it should add 25% to 30% to case detection rates.

References 1. Global Tuberculosis Control: Surveillance, Planning, Financing. WHO Report 2006. Geneva, World Health Organization (WHO/HTM/TB/2006.362). 2. Frieden T, ed. Toman’s Tuberculosis. Case Detection, Treatment, and MonitoringQuestions and Answers. 2nd ed. Geneva: World Health Organization, 2004: 11–22. 3. Toman K. Sensitivity, specificity and predictive value of diagnostic test. Bull Int Union Tuberc 1981; 56(1–2):18–27. 4. Kubica GP. Correlation of acid fast staining methods with culture results for Mycobacteria. Bull Int Union Tuberc 1980; 55:117–124. 5. David HL. Bacteriology of the Mycobacterioses. Atlanta, Georgia, U.S.: USDHEW, CDC, DHEW Publication No. (CDC) 76-8316, 1976:153. 6. Urbanczik R. Present position of microscopy and of culture in diagnostic mycobacteriology. Zentralbl Bakteriol Mikrobiol Hyg [A] 1985; 260(1):81–87. 7. Yajko DM, Nassons PS, Madej JJ, Hardley WK. High predictive value of the acid fast smear for Mycobacterium tuberculosis despite the high prevalence of Mycobacterium avium complex. Clin Infect Dis 1994; 19(2):334–336. 8. Conde MB, Figueira CM, Moraes R, Fonseca L, DeRiemer K, Kritski AL. Predictive value of the acid fast smear for detection of Mycobacterium tuberculosis in respiratory specimens in a Reference Center of HIV/Aids in Rio de Janeiro, Brazil. Mem Inst Oswaldo Cruz 1999; 94(6):787–790. 9. Zwolska Z, Augustynowicz-Kopec E, Kostrzewa E, Swiderska A, Klatt M, Jaworski A. Sensitivity of microscopy for detection of Mycobacterium tuberculosis and MOTT (mycobacteria other than tuberculosis) on the basis of analysis of

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16. 17.

18. 19. 20.

21. 22. 23. 24. 25.

26. 27. 28.

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22 218 clinical materials submitted in 1998–2001 to the Department of Microbiology in National Tuberculosis and Lung Diseases Research Institute in Warsaw, Poland. Pneumonol Alergol Pol 2002; 70(7–8):368–377 (In Polish). Van Cleeff MRA, Kivihya-Ndugga L, Githui W, Nganga L, Odhiambo J, Klatser PR. A comprehensive study of the efficiency of the routine pulmonary tuberculosis diagnostic process in Nairobi. Int J Tuberc Lung Dis 2003; 7(2):186–189. World Health Organization. Management of Tuberculosis Training for Health Facility Staff. B: Detect cases of TB (WHO/CDC/TB/2003-314b). Geneva: World Health Organization; 2003. Laszlo A. Tuberculosis bacteriology laboratory services and incremental protocol for developing countries. Clin Lab Med 1996; 16(3):697–715. Tonsing J, Ram T. Involvement of non-governmental organizations in the RNTCP. J Indian Med Assoc 2003; 101(3):167–170. de Kantor I, Isola N. Culture of Mycobacterium tuberculosis from non fixed sputum smears. Tubercle (Lond.) 1985; 66(2):137–139. International Union against Tuberculosis and Lung Disease. Technical Guide: Sputum Examination for Tuberculosis by Direct Microscopy in Low Income Countries. 5th ed. Paris: IUATLD, 2000. Yegian D, Budd V. Ziehl–Neelsen technique. Am Rev Tuberc 1943; 48:34–37. Harada K, Gidoh S, Tsutsumi S. Staining mycobacteria with carbolfuchsin: properties of solutions prepared with different samples of basic fuchsine. Microscopica Acta 1976; 78(1):21–27. Lillie RD, ed. Conn’s Biological Stains. 9th ed. Baltimore, Maryland, U.S.A.: William & Wilkins, 1977. World Health Organization. Laboratory Services in Tuberculosis Control. Part III: Culture. Geneva: WHO, 1998:95. International Union Against Tuberculosis and Lung Disease. The Public Health Service National Tuberculosis Reference Laboratory and the National Laboratory Network. Paris: IUATLD, 1998:62–71; 98–110. World Health Organization. Laboratory Services in Tuberculosis Control. Part I: Organization and Managing. Geneva: WHO, 1998:63. World Health Organization. Strategic Framework to Decrease the Burden of TB/ HIV (WHO/CDS/TB/2002.296 WHO-AIDS/2002/2002.2). Geneva: WHO, 2002. World Health Organization. Training for better TB control. Human Resource Development for TB Control (WHO/CDS/TB/2002.301). Geneva: WHO, 2002. Woods GL, Ridderhof JC. Quality Assurance in the Mycobacteriology Laboratory. Clin Lab Med 1996; 16(3):657–675. WHO, APHL, CDC, IUATLD, KNCV, RIT. External Quality Assessment for AFB Smear Microscopy. Washington, D.C.: Association of Public Health Laboratories, 2002:111. Lwanga SK, Lemeshow S. Sample size determination in health studies. In: A practical manual. Geneva: WHO, 1995:80. van Deun A, Portaels F. Limitations and requirements for quality control of sputum smear microscopy for acid-fast bacilli. Int J Tuberc Lung Dis 1998; 2(9):756–765. Report on the meeting of the Second Ad Hoc Committee on the TB epidemic: recommendations to Stop TB Partners, Montreux, Switzerland, 18–19 September, 2003. Int J Tuberc Lung Dis 2004; 8(11):1279–1284.

19 BCG Vaccines: History, Efficacy, and Policies

ANNE FANNING

MARK FITZGERALD

Faculty of Medicine and Dentistry, Walter McKenzie Health Sciences Center, University of Alberta, Edmonton, Alberta, Canada

Centre for Clinical Epidemiology and Evaluation, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada

I. Introduction Elimination of tuberculosis (TB) will require a safe, affordable vaccine that prevents infection as well as progression to active disease in all settings and all ages, for life. While the search for the perfect vaccine proceeds, there are lessons to be learned from the history of the bacille Calmette Gue´rin (BCG) vaccine and the emerging understanding of its genetic evolution. Until a new vaccine is found and proven effective, the first priority is to assure that the more than 8,000,000 TB cases occurring annually have access to curative treatment under DOTS. II. History of Bacille Calmette Gue´rin Development BCG was first used as a vaccine in July 1921 (1). This represented the culmination of 20 years’ work by Albert Calmette and his veterinarian colleague Camille Gue´rin, at the Pasteur Institute in Lille, France (2). At that time, the mortality rate from TB in Lille was 300/100,000/yr, making the development of an effective vaccine a high priority. Mycobacterium bovis from the udder of a cow with tuberculosis was attenuated on glycerine–potato medium. After only 30 passages on media modified with ox-bile (to improve gut absorption 541

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by reducing bacterial clumping), M. bovis showed evidence of reduced virulence in guinea pigs, but subsequent protective immunity. After 230 passages, which were carried out over 11 years, the attenuated live vaccine was first given orally to cattle and then to humans. Wallgren of Sweden (3) and Heimbeck (4) of Norway led the worldwide crusade for the intradermal use of BCG, which remains the preferred mode of administration today (5). The vaccine had a brief setback in 1930 when contamination with a virulent M. tuberculosis strain resulted in the deaths of 75 infants. Over subsequent decades, BCG proved safe, and in 1974, it was included in the Expanded Program on Immunization (EPI), resulting in the administration of over 100,000,000 vaccine doses annually to more than 80% of all newborns (5). Although BCG appears to have saved millions of children from progressive TB disease, its widespread use has clearly failed to stop the epidemic now accounting for more than 8,000,000 cases and 2,000,000 deaths annually. It has failed to protect against infection or to provide long-term protection against adult disease, but it modifies disease in children (6). The search for a better vaccine is driven not only by BCG’s limited efficacy, but also by the uncertainty about its potential risk in the immune suppressed, especially HIV-infected, persons (5,7). It is timely to review the evidence for BCG efficacy (8) and its past (1) and present use (5) in light of recent evidence of strain mutation during attenuation (9–16). Deciphering the M. tuberculosis genome (17) and subsequently the M. bovis genome (18) has made it possible to explore the phenotypic impact of deletions and has revitalized the search for a new and better vaccine, as well as the view that there is a role for a revised BCG in future vaccine trials (9). III. Vaccine Efficacy Trials A. Prospective, Randomized Trials

Evidence of widely variable protection provided by BCG in eight soundly executed, prospective trials is summarized in Table 1. These trials and numerous case–control studies are discussed in detail elsewhere (5,8,19). The present discussion examines the variance in protection in light of what is now known about BCG vaccine strain mutation (9–18) as well as previous speculation about the impact of environmental mycobacterial exposure and other factors (5,8). Precision about the effect of mutation on phenotypic expression and the impact of that expression on vaccine immunogenicity remains elusive. Aronson et al. (20), studying American-Indian communities reported 83% protection by BCG given during 1935–1938. A recent reexamination, 60 years after immunization, showed a persisting 60% protective effect (21). The Chicago study of 1947 (22) followed infants for an average of 18 years. The background rates of TB in 63% of infants was high (300–1999/100,000), although none had known family contact. There were 16 cases in the 1716 vaccinated group and 59 in the 1665 controls group, a significant

Rosenthal et al. (22) Comstock and Webster (23) Palmer (24)

Chicago (infants)

Georgia, (schoolchildren)

Puerto Rico (children)

Frimodt-Moller et al. (27) Tripathy (28)

South India

Chingleput

1965

1950–1955

1950–1952

1950

1949–1951

1947

1947

1935–1938

Start of study

Undocumented addition of Pasteur vaccine (8). Abbreviations: BCG, bacille Calmette Gue´rin; RR, relative risk. Source: From Ref. 19.

a

D’arcy Hart and Sutherland (26)

Britain (adolescents)

Georgia, Alabama Comstock and population Palmer (25)

Aronson (20,21)

References

North American Indians

Prospective, randomized clinical trials

Danish French

Madras

Danish

Tice

NY state Birhaug

88,391 88,391

5808 5069

12,867 13,598

17,854 16,913

27,338 50,634

2341 2498

1665 1716

Tice þ Pasteura Tice

1457 1551

Phipps

Vaccine source

# Control # BCG

2.5–7 (12)

20

14

5.5–7.5

20

12–23

9–11 (60)

Observation years (late observation)

Table 1 Protective Effect of Eight Prospective, Randomized, Controlled Bacille Calmette Gue´rin Trials

Nil

60 (30%)

77

14

31

Nil

75

83 (60%)

Protective effect (%) (late protection)

1.01

0.80

0.27

1.56

0.71

0.36

0.26

0.41

RR

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reduction of 75%. But studies by Comstock and Webster in Georgia, U.S. showed no protection and contributed to the decision not to use BCG in the United States (23,29). In retrospect, these studies were done at a time when active treatment programs reduced rates of TB, and in a setting where positive TB skin tests were associated with a high prevalence of nontuberculous mycobacteria (NTM). Similarly, a study from Puerto Rico (24) showed a low level of protection, as did a study carried out in Alabama (25). In all three studies (23–25), 70% or more of the cases occurred in those who had a positive skin test at the start of the study. Also, in retrospect, the BCG strains used had significant genetic differences. The British trial in 54,239 adolescents, using Danish BCG and vole bacillus (Mycobacterium microti) vaccine showed 84% protection during the first five years and 77% protection after 20 years, equal for the two vaccines (26). Of the 610 cases over 20 years, 274 occurred in the group having a positive skin test at baseline. The South India trial of 1950 also using Danish vaccine showed 60% protection during the first seven years, with a 30% protective effect after 12 years (27). To try to clarify definitively the impact of vaccine potency and environmental factors, the ‘‘trial to end all trials’’ was started in 1965 in India in Chingleput, 40 km from Madras (28). The entire population of 90,000 aged more than 12 months of age was offered vaccine. Two vaccines (Pasteur and Danish) at two different doses were compared, in a highly endemic region (prevelance 10.7cases/1000 population). The results were disappointing and showed no protection except in children (28). The 50% prevalence of reactivity to Battey antigen (from Mycobacterium intracellulare) was thought to afford some protection and thus lessen apparent vaccine impact. The vaccines used were noted at the time to be of low virulence for guinea pigs (28). There was no difference in protection with different vaccine strains or doses. B. Bacille Calmette Gue´rin Strain Mutation and Trial Outcomes

Many explanations for the lack of a consistent protection by BCG have been postulated (5,8). These include vaccine dose, host genetics, nutritional status, background rates of TB, and prior exposure to NTM. Of all the proposed explanations, evidence is increasing that the most likely reason for the variation in effect is strain mutation, an intended but uncontrolled consequence of 40 years of attenuation. In 1961, with the availability of freeze-drying (at minus 80
C), seed lots were finally stabilized. But until then, differences in daughter strains were noted for their variable survival on culture media, colony characteristics, viability counts, virulence in animals, protection against TB and tumors in animals, and presence of the mpb64 gene, and DNA restriction fragments (9). The elegant genetics studies by Behr (9–18,30) and others have documented the deletion of portions of the BCG genome by examining available daughter strains and have proposed the historical timing of the mutations

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Figure 1 Phylogeny of BCG proposed by Behr. Abbreviations: BCG, bacille Calmette Gue´rin; RD, region of deletion; IS, insertion sequence. Source: From Ref. 9.

(Fig. 1). Although the impact of some deletions in terms of production of antigenic proteins, attenuation, and immunogenic potential is understood, many are of uncertain consequence. Research on the evolution of BCG strains (9,12,14) is complicated by poor historical records. The original BCG is no longer available for study, but between first-generation daughter strains and strains in current use, there has been extensive change (Fig. 1) (9). Table 2 (14) shows the strain by name, in order of release from the Pasteur Institute, the deleted region [region of deletion (RD)], and the number of base pair deletions. Between 1924 and 1926, BCG cultures went to at least 34 countries (12). In the 40-year interval after its first use in 1921 (after 230 passages) and until its stabilization in 1961, there were an estimated 943 more passages. In addition to undergoing a single nucleotide polymorphism resulting in the loss of one of two insertion sequences (IS) 6110, BCG has undergone four deletions and two duplications (9). Common to all BCG strains is the absence of RD1 known to code for secretory antigens ESAT6 and CFP10. The deletion of this region is believed to be the reason for the loss of virulence of BCG (13,15). RD1 is also missing in the avirulent M. microti, and its deletion from M. tuberculosis renders it avirulent. Similarly, RD1 is deleted in the Dassie bacillus, a unique member of the M. tuberculosis complex that is also attenuated in animal models (16). This attenuation may have

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Table 2 What Is Deleted from Bacille Calmette Gue´rin (BCG)? Strains of BCG Listed in Order of Their Sourcing from the Pasteur Institute, with Associated Deleted Regions, the Open Reading Frames, and Base Pairs Affected by the Deletion Event BCG strain Russia Moreau Japan Sweden Birkhaug Prague Glaxo Denmark Tice Connaught Frappier Phipps Pasteur BCG family Mean

Deleted regions RD1, RDRussia RD1, RD16 RD1 RD1 RD1 RD1, RD2 RD1, RD2, RDDenmark/ Glaxo RD1, RD2, RDDenmark/ Glaxo RD1, RD2, nRD18 RD1, RD2, nRD18, RD8 RD1, RD2, nRD18, RD8, RDFrappier RD1, RD2, nRD18 RD1, RD2, nRD18, RD14

Number of DR

ORFs affected

Base pairs deleted

2 2 1 1 1 2 3

11 15 9 9 9 20 22

11061 17066 9458 9458 9458 20246 20972

3

22

20972

3 4 5

23 27 30

21793 25221 27192

23 31 48.0 19.3

21793 30866 46202.0 18888.9

3 4 11.0 2.6

Abbreviations: DR, deleted regions; ORF, open reading frames; RD, region of deletion. Source: From Ref. 14.

been the result of the growth on bile-containing media. Putting RD1 back into M. tuberculosis from which it has been deleted restores virulence (15). Early daughter BCG strains, Russia, Brazil/Moreau, and Japan (Fig. 1), still contain RD2 with the mpb64 gene, which codes for the antigenic protein MPB64. But in most derivations after 1931, represented by Pasteur 1173, Danish (Copenhagen) 1331, and Glaxo 1077, RD2 and MPB64 antigenic protein are missing (Table 2) (5,10). Another change noted by Behr when comparing the 1927 Pasteur strain with the 1931 strain was a missing mma3, which encodes for mycolic acid (30). This may have occurred when a switch was made in the BCG production to growth on potato media without bile (30). Altered mycolic acid production is predicted to diminish survival of the organism in the host and in the case of BCG vaccine, where protection depends on persistence, reduced survival is predicted to reduce its effectiveness. Between 1927 and 1931, at about the same time as the loss of one copy of IS6110, mpb64 from the RD2 region, there was reduced expression of MPB70 and MPB83 antigenic proteins and a change in the lipid

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content, methoxymycolates, of the outer cell wall. The reduced expression of antigenic proteins MPB70 and MPB83 has been linked to a point mutation (sigK) in all low producing strains of BCG, e.g., Pasteur and Birkhaug, compared with the high producing strains of Tokyo and Russia (31). This is an important finding for new vaccine development in view of the immunogenic potential of these antigens and their coding genes mpb70 and mpb83 (32). Some mixing of strains may have occurred, causing further confusion, as with Phipps, which started as an early Pasteur 317 and later became Pasteur 575, possibly explaining the variable outcomes with Phipps. Name confusion between Danish and Copenhagen also occurred. One strain of Copenhagen, which was freeze-dried in 1961, may have been an early Moreau via Brazil. Keeping these historical uncertainties in mind and referring to the Tables 1 and 2 and Figure 1, one can speculate why results were so discrepant, and either unexpectedly poor or good. The findings in both the Georgia (22,29) studies using Tice BCG, a strain with uncertain potency, not surprisingly showed a poor protective effect. The Chicago study (19), which demonstrated protection, may have done so because there was some undocumented mixing of Tice BCG with early Pasteur vaccine (10). In the Aronson et al. study (20), which showed protection, strain Phipps, obtained from Pasteur in 1926 before the loss of mpb64, was used initially, but in later years, a different strain was used. The Puerto Rico study using Birhaug/New York (perhaps using a later strain without mpb64) was not protective. The failure to show protection in the Chingleput study with Pasteur and Danish vaccines, which at the time was disappointing, may be related to the reduced expression of MPB64, -70, and -83 (31) after 1931 and now common to the freeze-dried source, Pasteur 1331. In the British study, using both Danish BCG which failed to show protection in India and vaccine from the vole bacillus (M. microti) which is missing MPB64, there was 77% protection. The South India study with Danish BCG showed initial protection, but this faded in later follow-up. A small Canadian study showed impressive protection among children in highly endemic regions, which had an annual case rate of 9%. This study used Montreal (Frappier), derived from Pasteur, starting in 1933, at which time (Fig. 1) it had lost MPB64, but provided a surprising 81% protection (11,32). A BCG similar to BCG Copenhagen with mpb64 was found stored at Frappier. Because records of vaccine source in the early studies were not detailed, certainty about the genetic composition remains speculative. These new insights provide some better understanding of variance, but also identify some confusion. Much remains to be explained in order to fully understand variable protection and to apply that understanding to a designer vaccine. Because prospective randomized controlled trials are very expensive and time consuming, case–control studies were recommended as a more cost-effective way to show efficacy (33). Smith summarized studies in which

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1500 cases were compared to 8500 controls. Overall, these studies showed rates of protection of 2% to 80% against pulmonary TB but greater (52–100%) and more consistent protection against more severe forms of TB such as meningitis. The fact that past studies were done with varying strains of BCG makes uncertain the interpretation of a meta-analysis of case–control as well as randomized prospective studies. However, the authors concluded that BCG reduced the risk of active TB and death from TB, by 51% (34). BCG also showed a 78% protective effect against disseminated disease and 64% protection against meningitis (35). Overall, the outcome evidence suggests that BCG has saved lives of infected children who are 80% less likely to progress to severe, life-threatening forms of childhood disease including miliary and meningeal TB (5,34,35). Despite its failures, Fine (36) estimates that BCG, despite its limitations as discussed earlier, currently prevents 25,000 to 40,000 cases of TB meningitis annually at the cost of US $0.1 to $0.2 per dose. Because BCG has no effect on the reactivation of latent TB infection in adults, which is the major source of transmission, one would expect little impact on the natural history of the epidemic. Attempts (1) to attribute the falling rates of TB to the increased use of BCG neglect the fact that during the 1950s and 1960s when these observational studies were carried out, aggressive case finding and use of treatment were becoming increasingly common, thereby diminishing the likelihood of transmission. Recent molecular epidemiologic evidence of reinfection especially in high-incidence regions reinforces the fact that TB infection is not a single event in early life and gives further reason to doubt the ability of BCG to prevent infection lifelong (37). Any new vaccine must aim for lasting protection. With a growing understanding of why some strains protect and others show no protection, before the vaccine is discarded, it may be possible to fashion a designer vaccine that can deliver the outcomes that would be expected from an ideal vaccine. Much remains to be learnt about what confers an optimal protective effect. Once the ideal candidate vaccine is chosen, the challenge will remain to evaluate it using the most cost-effective study design (38). IV. Global Immunization Practices A. Historical

In 1971, Grzybowski (1) reviewed the use of BCG, which had been scaled up after the Second World War. Fifty years after the first BCG vaccine had been administered, <3% of the population of Asia and Africa had received the vaccine. In contrast, it was widely used in Europe and it was reported that 74.5% of Taiwanese 10- to 14-year-olds and 59% of Koreans had BCG scars. In a 1969 International Union Against Tuberculosis (IUAT) survey of 105 countries, Styblo (39) reported that BCG was compulsory in 36% of European countries, voluntary in the rest, and compulsory in 20% of

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so-called developing countries. BCG was more likely to be given at birth in ‘‘developed’’ countries and throughout childhood in developing countries. Vaccine delivery was attached to school start in about 18% of countries. Prevaccination tuberculin skin testing (TST) was done in 100% of developed countries and 36% of developing countries and postvaccination skin testing in 48% and 17% of these countries, respectively. The corresponding respective figures for revaccination were 56% and 27%. The intradermal method was universally preferred. Vaccines were supplied from the national laboratory in 68% of developed nations and 20% of developing nations. This lack of quality control through a central laboratory and distribution system no doubt created further attenuation. B. Current Use

Today, BCG continues to be included in the EPI (40); in 1989, it was in use in 172 countries (41). Within this program, the estimated rates of BCG immunization in 2003 were greater than 95%, except in Africa where coverage was estimated be closer to 66% in 1995 (5), and lower in the Western Pacific region where coverage was estimated to be in the range of 50% to 60% (41). In low-prevalence countries, BCG is generally used on a more limited basis, often targeting particular groups with a high prevalence of disease. The major suppliers, Serum Staten Institute using Danish 1331, Pasteur-Merieux-Connaught, and Evans-Medeva, using Glaxo 1077, with no MPB64, and Japan BCG laboratory provide 85% of all BCG. Quality control was managed by the Danish State Serum Institute, until 1997 (5). V. World Health Organization Bacille Calmette Gue´rin Policy (5,40) 1.

2.

The World Health Organization (WHO) recommendation of BCG only at birth is adhered to in 156 of 195 countries. This policy assures that maximal protective effect is afforded to reduce life-threatening forms of TB in infancy and childhood. The British policy of immunization in adolescence, to protect before graduating from high school, is gradually being phased out in favor of a more targeted approach in high-risk communities (42). If a neonate has a low birth weight, it is recommended to withhold BCG until the gestational age of 40 weeks is reached, but a study from Guinea Bassau showed that low-birth-weight infants were at higher risk of developing active TB if they did not receive BCG (43). WHO recommends BCG should only be withheld in the presence of symptomatic HIV infection. The basis for this recommendation is that the risk of active TB following infection in infancy is already high but is six times higher in the HIV-infected child (7). Because of the risk of disseminated BCG infection, some countries withhold BCG from individuals with impaired immunity

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3.

4.

and if the mother has HIV infection or there are HIV/AIDS cases in the household. New population-based studies in regions of high prevalence of TB and HIV are needed to determine the efficacy and safety of BCG in HIV-positive and -negative children (7,12,43). A positive TST or BCG scar is considered a contraindication to BCG, and revaccination is not recommended. The method of administration recommended is intradermal inoculation with a 25- or 26-gauge needle in the deltoid insertion, using autodisposable syringes available through the United Nations International Children’s Emergency Fund since 2001. A half dose of 0.05 mL is recommended for infants. The percutaneous method is considered to give less consistent results (5). The International Union Against Tuberculosis and Lung Disease (44) has made recommendations for criteria that should be in place for the discontinuation of the routine use of BCG and the move to a more selective use in high-risk groups. These criteria include the presence of an efficient surveillance system, an average annual notification rate of smear-positive pulmonary TB less than 5/1,000,000 (5), average annual notification rate of TB meningitis in children under the age of 5 years (7), over the last five years, or an average annual risk of infection of less than 0.1%. Discontinuation of BCG may, as in Sweden, result in a small increase in miliary disease and TB meningitis in children (45). Many European countries have moved to a policy of offering BCG to selected at-risk newborns, to health workers, and to some TB contacts (42).

In Canada, BCG administration was universal only for aboriginal people. Although Canada meets the criteria for discontinuation, the persistent appearance of cases in selected high-risk communities such as Canadian aboriginal people, who make up 3% of the population and have 15% of the TB, illustrate the dilemma faced by policy makers. Between 1996 and 2002, there were three cases of BCG dissemination among 4622 children given BCG vaccine, higher than the global rate, and during the same period, there were seven cases of miliary disease and one of meningitis in aboriginal children (46). In 1999, U.S. Centres for Disease Control (CDC), in view of the resurgence of TB during the latter part of the 1980s, reviewed their BCG policy and recommended its use only in limited settings. These included a child (not HIV infected) exposed continuously to an infectious patient who could not be removed from the setting. They also recommended BCG on an individual basis for health workers continuously exposed to multidrug-resistant TB (47). A. Adverse Reactions

An abnormal reaction to BCG vaccination, defined as more than 10 mm of induration at the site of intradermal injection, occurs in 0.2% and is usually

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attributed to the injection being too deep (48). Four different types of adverse events are reported: abscess at the site, lymphadenopathy, osteomyelitis, and dissemination. Rates of adverse events in 1971 were for osteomyelitis 35/1,000,000 and for BCG dissemination < 5/1,000,000 (1,48,49). Recent work of Casanova and coworkers defining the selective immunologic defects underlying susceptibility to serious nontuberculous infection and BCG will help to identify those at risk from vaccination (50). B. Impact of Bacille Calmette Gue´rin on Tuberculosis Skin Test

A meta-analysis of the impact of BCG on subsequent TST identified a risk ratio for positive skin test of 2.12 in those with a history of BCG (51). The effect waned after 15 years. Hence, for the purposes of determining the need for treatment of latent infection, remoteness of BCG and a reaction size greater than 15 mm induration correlate with a greater likelihood of the skin test result being due to latent tuberculosis infection (51). Quantiferon Gold, which assesses whole blood lymphocyte response to antigenic proteins ESAT6 and CP10, differentiates those infected by M. tuberculosis from those who have been immunized with BCG (52). VI. Hope for Future Vaccines Although BCG prevents severe disease in children (7), and perhaps in uninfected young adults with heavy exposure to active disease (5), it has only a limited effect especially against smear-positive disease in adults. It is therefore not surprising that it has not had an impact on the global TB epidemic. A new and better vaccine should prevent infection as well as progression to disease, both pulmonary and extrapulmonary disease. The protection should not be age or gender specific. It should be effective in the presence of NTM and irrespective of the background rates of M. tuberculosis. What has at times seemed like a complete repudiation of BCG is being revised, as evidence for the site of immunogenic potential is elucidated. Genetically engineered segments of BCG show great promise for new vaccine development (53). Determinants of immunity are essential to develop markers of vaccine efficacy (54). True markers of TB immunity must be defined and must be associated with real protection. Novel candidate vaccines are discussed in Chapter 49. The new vaccines will be challenged by the need to coordinate efforts in best study design, the question of how to handle vaccine in HIV-endemic regions, the issue of whether to immunize populations with prior BCG, and the determination of optimal timing for vaccination—pre-exposure, postexposure, or as an adjunct to therapy (53). Comstock’s (55) description of an ideal study setting is that of a country with a committed government and a large number of uninfected, i.e., with high birth rate, high TB risk, low HIV, and low emigration loss, and using a prospective randomized controlled trial design. He emphasized ethical considerations and suggested

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the use of a randomized cluster design in similar regions or in alternate years. He and others have proposed that old BCG strains of proven immunogenicity be studied against later strains whose loss of antigenic proteins suggest lesser efficacy (55). The WHO working group on new TB Vaccines (56) raised concerns regarding the cost, duration, essential infrastructure, markers of protection, and efficacy, and whether any new vaccine should be used in special populations, i.e., in those with HIV infection and those who have had prior BCG vaccination. Responding to the 60-year evaluation of BCG trials in AmericanIndians (21), which showed a 60% protective effect, Dye (57) pointed out the need to recognize the time it will take to assess new vaccines. He reminds the global community that in the meantime, the scale-up for wider DOTS coverage assures that those who have not been protected by BCG will not have to wait until new vaccines have been developed and tested. They have a better than 85% chance of cure if access to treatment is assured. References 1. Grzybowski S. BCG in developing versus developed countries. In immunization in tuberculosis. Fogarty Int Center Proc 1971; 14:127–136. 2. Sakula A. BCG: who were Calmette and Guerin? Thorax 1983; 38:806–812. 3. Wallgren A. Value of Calmette vaccination in prevention of tuberculosis in childhood. JAMA 1934; 103:1341–1345. 4. Heimbeck J. Sur la vaccination pre´ventive de la tuberculose par injection souscutane´e de BCG chez les e´le`ves-infirmie`res de l’hopital ulleval, a` oslo. Ann l’Institut Pasteur 1929; 43:1229–1232. 5. Fine PEM, Carneiro IAM, Milstien JB, Clements CJ. Issues Relating to the Use of BCG in Immunization Programmes. Geneva: WHO, Department of vaccines and biologicals, 1999. 6. Bourdin Trunz B, Fine PEM, Dye C. Effect of BCG vaccination on childhood tuberculosis meningitis and miliary tuberculosis world wide a meta analysis and assesment of cost effectiveness. The Lancet 2006; 367:1173–1180. 7. Obaro SK, Pugatch D, Luzuriaga K. Immunogenicity and efficacy of childhood vaccines in HIV-1-infected children. Lancet Infect Dis 2004; 4:510–518. 8. Rieder HL. Interventions for tuberculosis control IUATLD, 2002:98–125. (www.tbrieder.org.). 9. Behr MA. BCG—different strains, different vaccines? Lancet Infect Dis 2002; 2:86–92. 10. Behr MA. Correlation between BCG genomics and protective efficacy. Scand J Infect Dis 2001; 33:249–252. 11. Behr MA, Small PM. A historical and molecular phylogeny of BCG strains. Vaccine 1999; 17:915–922. 12. Oettinger T, Jorgensen M, Ladefoged A, et al. Development of the Mycobacterium bovis BCG vaccine: review of the historical and biochemical evidence for a geneological tree. Tuberc Lung Dis 1999; 79:243–250. 13. Pym AS, Brodin P, Brosch R, et al. Loss of RD1 contributed to the attenuation of the live tuberculosis vaccines Mycobacterium bovis BCG and Mycobacterium microti. Mol Microbiol 2002; 46:709–717. 14. Mostowy S, Tsolaki A, Small PM, Behr MA. In vitro evolution of BCG vaccines. Vaccine 2003; 21:4270–4274.

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15. Lewis KN, Liao R, Guinn KM, et al. Deletion of RD1 from Mycobacterium tuberculosis mimics bacille Calmette-Gue´rin attenuation. J Infect Dis 2003; 187(1): 117–123. 16. Mostowy S, Cousins D, Behr M. Genomic interrogation of the Dassie bacillus reveals it as a unique RD1 mutant within the Mycobacterium tuberculosis complex. J Bacteriol 2004; 186:104–109. 17. Cole ST, Brosch R, Parkhill J, et al. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 1998; 393:537–544. 18. Garnier T, Eiglmeier K, Camus JC, et al. The complete genome sequence of Mycobacterium bovis. Proc Natl Acad Sci USA 2003; 100(13):7877–7882. 19. Clemens J, Chuong J, Feinstein A. The BCG controversy—a methodological and statistical reappraisal. J Amer Med Assoc 1983; 249:2362–2369. 20. Aronson J, Aronson C, Taylor J. A twenty year appraisal of BCG vaccination in the control of tuberculosis. Arch Int Med 1958; 101:881–893. 21. Aronson NE, Santosham M, Comstock GW, et al. Long term efficacy of BCG in American Indians and Alaska natives. JAMA 2004; 291:2127–2128. 22. Rosenthal SR, Loewinsohn E, Graham ML, et al. BCG vaccination against tuberculosis in Chicago: a twenty year study statistically analyzed. Paediatrics 1961; 28: 622–641. 23. Comstock GW, Webster RG. Tuberculosis studies in Muscogee County, Georgia. Amer Rev Resp Dis 1969; 100(6):839–845. 24. Palmer CE, Shaw LW, Comstock GW. Community trials of BCG Vaccination. Am Rev Tuberc 1958; 77:877–907. 25. Comstock GW, Palmer CE. Long term results of BCG vaccination in the southern United States. Amer Rev Resp Dis 1966; 93:171–183. 26. D’arcy Hart P, Sutherland I. BCG and vole bacillus vaccines in the prevention of tuberculosis in adolescence and early adult life. BMJ 1977; 2:293–295. 27. Fridmodt-Moller J, Thomas J, Parasarathy R. Observations on the protective effect of BCG vaccination in a South India rural population. Bull WHO 1964; 30: 545–574. 28. Tripathy SP. The case for BCG. Ann Natl Med Sci (India) 1983; 19:11–21. 29. Bryder L. We shall not find salvation in inoculation: BCG vaccination in Scandinavia, Britain and the USA, 1921–1960. Soc Sci, Med 1999; 49:1157–67. 30. Behr MA, Schroeder BG, Brinkman JN, et al. A point mutation in the mma3 gene is responsible for impaired methoxymycolic acid production in Mycobacterium bovis BCG strains obtained after 1927. J Bacteriol 2000; 182:3394–3399. 31. Charlet D, Mostowy S, Alexander D, Sit L, Wiker HG, Behr MA. Reduced expression of antigenic proteins MPB70 and MPB 83 in Mycobacterium bovis BCG strains due to a start codon mutation in sigK. Mol Microb 2005; 56:1302–1313. 32. Ferguson RG, Simes AB. BCG vaccination of Indian Infants in Saskatchewan. Tubercle 1949; 30:5–11. 33. Smith PG. Case-control studies of the efficacy of BCG against tuberculosis. International Union Against Tuberculosis, World congress 1986, Singapore. 34. 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. 35. Rodrigues LC, Smith PG. Use of the case-control approach in vaccine evaluation: efficacy and adverse effects. Epidemiol Rev 1999; 21(1):56–72. 36. Fine P. BCG—the challenge continues. Scand J Infect Dis 2001; 33:243–235. 37. Van Rie A, Warren R, Richardson M, et al. Exogenous reinfection as a cause of recurrent tuberculosis after curative treatment. N Eng J Med 1999; 341:1174–1179. 38. Comstock GW. Field trials of tuberculosis vaccines: how could we have done them better? Control Clin Trials 1994; 4:247–276.

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39. Questionnaire on National BCG practices. WHO/TB/71.87 IUAT. Geneva: WHO, 1969. 40. WHO statement on BCG. Weekly Epi Record 2004; 79:27–38. 41. Vaccines, Immunization and Biologicals, vaccine assesment team. WHO UNICEF estimates of BCG coverage. WHO.INT#2004 (www.who.int/vaccines/globalsummary/timeseries/tswucoveragebcg.html). 42. Fine PEM. Stopping routine vaccination for tuberculosis in schools. BMJ 2005; 331:647–648. 43. Kristensen I, Aaby P, Jensen H. Routine vaccinations and child survival: follow up study in Guinea-Bissau, West Africa. BMJ 2000; 321:1435. 44. International Union Against Tuberculosis and Lung disease. Criteria for discontinuation of vaccination programmes using Bacille Calmette-Guerrin (BCG) in low prevalence countries. Tuberc Lung Dis 1994; 75:179–181. 45. Romanus V. Tuberculosis in Bacillus Calmette-Guerin immunized children: a ten year evaluation following the cessation of general Bacillus Calmette-Gue´rin immunization of the newborn in 1975. Paed Inf Dis 1987; 6:272–280. 46. Public Health Agency of Canada. National Advisory committee on Immunizations (NACI) statement on BCG vaccine Nov 30, 2004. (http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/04vol30/acs-dcc-5/index.html). 47. CDC, Division of TB Elimination. The role of BCG vaccine in the prevention and control of tuberculosis in the United States. MMWR 1996; 45:1–14. 48. Lotte A, Wasz-Ho¨ckert O, Poisson N, Dumitrescu N, Verron M, Couvet E. BCG complications: estimates of the risks among vaccinated subjects and statistical analysis of their main characteristics. Adv Tuberc Res 1984; 21:107–193. 49. FitzGerald M. Reporting and managing adverse reactions to bacillus Calmette and Guerin (BCG). CDWR 1991; 17:90–100. 50. Feinberg J, Fieschi C, Doffinger R, et al. Bacillus Calmette Gue´rin triggers the IL-12/IFN-gamma axis by an IRAK-4- and NEMO-dependent, non-cognate interaction between monocytes, NK, and T lymphocytes. Eur J Immunol 2004; 34: 3276–3284. 51. Wang L, Turner MT, Elwood RK, FitzGerald JM. The impact of BCG on PPD skin testing: a meta analysis. Thorax 2002; 57:804–809. 52. Mori T, Sakatani M, Yamagishi F, et al. Specific detection of tuberculosis infection: an interferon-gamma-based assay using new antigens. Am J Respir Crit Care Med 2004; 170:59–64. 53. Doherty TM. New vaccines against tuberculosis. Trop Med Int Health 2004; 9: 818–826. 54. Hoft DF, Worku S, Kampmann B, Whalen C, et al. Investigation of the relationships between immune-mediated inhibition of mycobacterial growth and other potential surrogate markers of protective Mycobacterium tuberculosis Immunity. JID 2002; 186:1448–1457. 55. Comstock GW. Simple practical ways to assess the protective efficacy of a new tuberculosis vaccine. Clin Infect Dis 2000; 30:S250–S253. 56. WHO, Department of Vaccines and Biologicals. Report of the working group on clinical trials of new TB vaccines, April 19 1999 (www.who.int/vaccines-document). 57. Dye C. A booster for tuberculosis vaccines. JAMA 2004; 291:2127–2128.

20 The Role of Contact Tracing in Low- and High-Prevalence Countries

SUE C. ETKIND

JAAP VEEN

Division of Tuberculosis Prevention and Control, State Laboratory Institute, Massachusetts Department of Public Health, Boston, Massachusetts, U.S.A.

Head Unit Europe, KNCV Tuberculosis Foundation, The Hague, The Netherlands

I. Introduction Tuberculosis (TB) outbreaks and resulting transmission to contacts have been documented in many diverse locations all over the world. These include institutions (1), doctor’s offices (2), airplanes (3), crack houses (4), HIV respite facilities (5), drug rehabilitation centers (6), navy ships (7), renal transplant units (8), dialysis centers (9), churches (10), homeless shelters (11–13), and other nontraditional settings such as among exotic dancers (14), transgender populations (15), and bar patrons (16–18). The utility and importance of contact tracings in these settings and for high-risk groups such as the foreign born (19), children under 15 years of age (20–22), and multidrug-resistant cases (23) have also been demonstrated. A. Low-Prevalence Countries

In the United States, Canada, Europe, and other countries with low TB prevalence, contact tracing is recommended for all patients with suspected or confirmed infectious TB (24,25). The main goal of these investigations is to identify and treat secondary cases of active TB and latent TB infection (LTBI) among contacts of infectious TB patients. In two multistate evaluations of routine contact investigations in the United States, secondary cases 555

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were detected among 2% and LTBI among 30% to 40% of close contacts to such patients (26,27). The Centers for Disease Control and Prevention (CDC) estimates that an investigation of a smear-positive case of TB results in an average of six close contacts identified for each case (27). The TB disease prevalence rate among close contacts is approximately 700/100,000 (nearly 100-fold higher than in the general population) (28). It should also be noted that there are populations such as immigrants who live in low-prevalence countries, but have TB detection rates that are equal to those in high-prevalence countries. The infection prevalence among children who are close contacts of immigrant TB patients is high. For example, a study in the Netherlands showed that although the rates were lower than in the country of origin, the main risk factor for being infected among young contacts was being born abroad (29). B. High-Prevalence Countries

In high-prevalence countries, most National Tuberculosis Control Programs (NTPs) recommend investigation and management of childhood contacts of index cases with smear-positive sputum, especially if it occurs within the household. Implementation varies by region and overburdened health services may not give this guideline a high priority (30). Although recommendations for conducting contact tracing vary between high- and low-prevalence countries, the first priority for any TB prevention and control program is the early identification and treatment of persons with TB disease (24). In high-prevalence countries contact tracing is a means of identifying such TB cases, while in low-prevalence countries, it is more often a means of identifying persons with LTBI. In either case, TB programs consider completion of treatment to be the ultimate objective (24,31,32). The basic epidemiologic steps for conducting contact tracing are the same in both low- and high-prevalence countries and cover all aspects of TB control—from surveillance, to case containment, to evaluation and finally, to prevention. Successful contact tracing also requires skills in patient assessment, interviewing, counseling, and evaluation, and the quality of contact tracing has been shown to markedly affect the ability to identify potentially infected persons and allow for their integration into the clinical care system (33). This chapter discusses contact tracing in both low- and highprevalence countries. It emphasizes the use of contact tracing as an epidemiologic tool and outlines the step-by-step methodology needed to accomplish the task in countries that have the capacity to do so. It also discusses newer strategies and technologies and their current and potential additive value to contact tracing procedures. II. Definitions For the purposes of this chapter, the following definitions will apply: Case: A particular instance of a disease. A case is detected, documented, and reported. A case cannot have personal attributes such as age, sex,

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country of birth, or race/ethnicity. A case cannot have disease attributes such as suspected or confirmed, severe or mild, new or recurrent, and pulmonary or extrapulmonary. Patient: A patient is a particular person who is receiving medical care. A patient is interviewed, examined, and treated. A patient has personal attributes, and a patient can be a case. A case is managed; a patient receives medical care. Contact: A person who has shared the same airspace with a person who has infectious TB disease. The likelihood of infectiousness is determined by (i) patient characteristics: sputum smear and culture results, the grade of the sputum smear if positive, site of disease, age, and clinical symptoms; (ii) contact characteristics: exposure time, age, and immune competence; and (iii) environmental characteristics: overcrowding, and limited ventilation. Index case or patient: The first instance of TB disease, or the first person in a particular setting with TB disease, diagnosed or identified in a series of epidemiologically linked and/or genotypically matched cases or persons with TB disease. Presenting patient or case: The patient with, or the case of, TB being investigated to identify contacts exposed during the infectious period. Source case or patient: The case, or the person, that was the original source of infection for secondary cases or contacts. The source case can be, but is not necessarily, the index case. Secondary case or patient: A case or patient who develops TB disease as a result of transmission from an identified index case. Contact tracing: The process of conducting an epidemiologic investigation into a case (or suspected case) of TB in order to identify contacts, screen them for LTBI and TB disease, and give treatment as indicated. Concentric circle: A method of screening contacts in order of their risk of being infected. Contacts designated as high priority are screened first. III. Contact-Tracing Objectives There are several basic reasons for conducting contact tracing. How many of these apply: depends on the epidemiological situation and the resources available in a specific setting or country. These include (i) identifying highand medium-risk persons who have been exposed to the presenting case and who, therefore, are at a greater risk of being infected with TB, and of developing TB disease than the general population; (ii) ensuring that these identified individuals have access to medical evaluation and necessary diagnostic measures as indicated [tuberculin skin test (TST), chest X-ray (CXR), sputum smears, etc.]; (iii) ensuring that individuals who are found to have LTBI or active TB, have access to treatment as appropriate; (iv) if possible, identifying the source of Mycobacterium tuberculosis transmission for the presenting case under investigation. This is particularly important for children with active TB. When TB occurs in young children, given their

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age, there is reason to suspect recent transmission; (v) when possible, identifying environmental factors that may be contributing to the transmission of TB; and (vi) identifying and ensuring medical evaluation, treatment, and follow-up of any additional cases of active TB identified in the course of the contact tracing. Contact tracing may also identify a potential TB outbreak when during the investigation, more infected persons or more TB cases are discovered than were anticipated based on the previous epidemiologic data. In this situation, contact tracing may then lead to expanded outbreak investigation activities. IV. Contact Tracing in Low-Prevalence Countries A. First Step: Whether or Not to Do Contact Tracing?

When a case/suspect TB report comes to the attention of the person responsible for infectious disease follow-up (health department, infection control nurse, etc.), the responsible individual must decide whether contact tracing is indicated or not. Factors influencing this decision include the characteristics of the presenting case that are associated with an increased risk for transmission and the resources available. The efficiency of potential TB transmission is dependant on many factors. To determine these factors, the investigator will need to open a case/contact record, conduct a medical record review (hospital, clinic, or other health care records), talk to the health care provider or other reporting source, and review laboratory reports. Information needed includes: (i) clinical characteristics of the type and extent of TB disease, including the site, dates/sources of laboratory (bacteriological and biological) specimen results for acid-fast bacille (AFB) and cultures (including drug susceptibilities if available), the results of nucleic acid amplification (NAA) testing, CXR or other radiographic procedures, date and results including the extent of disease (cavitary/noncavitary), and TST result(s) in millimeters; and (ii) other patient-related characteristics such as signs and symptoms (presence of cough—productive/ nonproductive, severity, and date of onset?), whether an anti-TB drug regimen was prescribed, including dosages, date initiated, and treatment plan, HIV testing results, and history of prior TB diagnosis. At the same time, any medical conditions or other risk factors that may affect the contact tracing (any psychological or mental conditions that may impact the treatment of the patient or the patient’s ability to identify contacts, or any cultural or lifestyle barriers such as homelessness, unemployment, or language) should be identified. With the above information, the following prioritization criteria are suggested: Contact tracing should be done only if the presenting case has suspected or confirmed pulmonary, laryngeal, or pleural TB. Contact tracing should always be initiated if the sputum smear has AFB on microscopy, unless the result from an approved NAA test for M. tuberculosis is negative

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(if conducted according to the guidelines published by the CDC) (34). If AFB are not detected by microscopy of three sputum smears, contact tracing is still recommended if the chest radiograph (i.e., the ‘‘plain’’ view or simple tomograph) shows cavities in the lung. When sputum samples have not been collected either because of oversight or the patient’s inability to expectorate, results from other types of respiratory specimens (e.g., gastric aspirates or broncheoalveolar lavage) may be interpreted the same way as recommended above. Contact tracing can still be considered even though the above conditions are not met, if the chest radiograph is consistent with pulmonary TB. The decision depends on how many resources can be allocated and whether program goals are being met for investigations of presenting cases that have cavitary TB or are AFB sputum-smear positive. Contact tracing generally should not be initiated for persons with suspected TB disease and minimal diagnostic findings in support of pulmonary TB. Contact tracings are not necessary for cases of extrapulmonary TB, except laryngeal or pleural TB, without pulmonary involvement. As with any investigation, additional information may lead to changes in the decision-making process. B. Next Steps: Now What?

Once the decision is made to conduct a specified contact tracing, the investigation proceeds in a stepwise fashion given below. The Presenting Patient Interview

The patient may be interviewed in the hospital, at the patient’s home, or wherever convenient and conducive to establishing trust and rapport between both parties. A face-to-face meeting (when possible in the primary language of the patient) facilitates building a relationship between the client and the health care provider. The ability to conduct an interview in order to obtain patient and contact information is an important determinant of the success or failure of the contact tracing. The presenting patient interview provides an opportunity to (i) obtain additional information relative to the presenting patient’s potential level of infectiousness or other needed clinical data (e.g., how long has he/she been symptomatic?); (ii) obtain place and time information in order to establish duration and location of potential exposures (e.g., where was the patient during the infectious period—living quarters/work/school or leisure activities, and for how long?); (iii) identify potentially exposed contacts during that infectious period; and (iv) obtain relevant environmental information (ventilation, air volume, etc., at the potential exposure sites). Many factors can interfere with both the patient interview and the subsequent contact interviews. These factors can be attitudinal (on the part of the interviewer or interviewee), social or cultural differences, mistrust of the government or health care system, or fear or stigmatization due to TB and/or TB/HIV (35,36). Understanding these hindering and facilitating

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factors can sensitize the interviewer prior to and during the interview. Understanding how the patient perceives the contact tracing process is also a critical factor (37). In some groups, such as the homeless, interview promptness is essential and even the best interviewer may be unable to solicit the names of contacts. For these hard-to-access populations, some authors have proposed an alternative strategy for case/contact identification. They suggest using epidemiologic links and/or molecular typing or location-based screening as a method of identifying geographic pockets of transmission instead of or in addition to contact tracings (38,39). Which Contacts to Test First: Identification and Prioritization of Contacts by Transmission Risk Assessment

Over 20 years ago, Rose et al. (40) established the need to set limits and establish priorities for the contact tracing process. Without this systematic approach, the investigative efforts are diluted and limited resources are spent on delivering services to persons who are not at demonstrated risk of TB infection or disease. The investigator now has to decide which contacts to test first among the contacts identified. The transmission of M. tuberculosis to contacts is related to the characteristics of the presenting case, the nature of the contact, and the shared environments. To focus the contact tracing on those who are most at risk, a risk assessment of transmission from the presenting case to the identified contacts is necessary. Transmission risk assessment requires that the background information be organized into the basic epidemiologic categories of PERSON, TIME, and PLACE. Upon completion of all three categories of this risk assessment, the investigator will be able to establish contact tracing and follow-up priorities. Person Factors: How Potentially Infectious Was this Case/Suspect?

Characteristics that determine the infectiousness of the presenting patient: As noted, the decision to initiate contact tracing for the case/suspect requires data associated with that case/suspect’s ability to transmit TB (Table 1). These are the same characteristics (clinical data and other patient characteristics) that are now used to identify which contacts had the greatest level of potential exposure and are priorities for testing. Characteristics of contacts: Are some contacts more at risk of being infected than others or, if infected, are they more at risk of progressing to TB disease? (Table 2) Although there appear to be differences in genetic susceptibility to acquiring LTBI and, if infected, progressing to TB disease (41,42), there is no practical method to differentiate susceptibility among contacts with a given level of exposure. However, exposure levels affect the likelihood of acquiring infection. These levels will be outlined under the TIME and PLACE factors that follow. There are contacts who, if infected, have a greater probability of developing TB disease and developing more severe, disseminated forms of TB disease. The two most important factors

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Table 1 Person Assessment Factors: Presenting Patient Characteristics Increased risk of transmission factors Clinical characteristics TB disease site

AFB smear status Smear source Chest radiograph Other characteristics Age Anti-TB drugs Coughing, sneezing, singing

High

Pulmonary Laryngeal Pleural Positive Spontaneous

Low

Extrapulmonary

Cavitary

Negative Induced or clinical specimen (bronchoscopy, etc.) Noncavitary

>10 yr of age No or ineffective Yes

<10 yr of age Yes (> 2 wk) No

Abbreviation: AFB, acid-fast bacille.

are the contact’s age (children less than four years of age) and whether the contact is immunosuppressed. Missed opportunities for TB prevention have been noted for both children (20–22) and persons with HIV infection (43,44). Other medical conditions may also affect the probability of an infected contact developing TB disease.

Table 2 Person Assessment Factors: Contact Characteristics Contacts most likely to be infected Contacts exposed to the patient during the period of infectiousness Contacts exposed to the patient in: Small rooms Poorly ventilated or dark areas Areas without HEPA filters or ultraviolet lights Contacts who: Routinely spend a lot of time with the patient Have been physically close to the patient Have never had TB infection

Contacts at high risk of developing TB disease once infected Contacts with any of these conditions: HIV infection Diabetes mellitus Silicosis Certain types of cancer Severe kidney disease Certain intestinal conditions Low body weight (10% or more below ideal) Contacts taking any of the following: Illicit drugs by injection Prolonged corticosteroid therapy TNFa antagonists Immunosuppressive therapy Contacts who are young children (<4 yrs)

Abbreviations: TNFa, tumor necrosis factor a filters; HEPA, high-efficiency particulate air.

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Time Factors: What Is the Duration of Exposure (Starting and End Points)?

After the investigator has made an assessment of the person factors above, a determination of the duration and intensity of exposure must be made (i.e., how long were the identified contacts potentially exposed to the case while he/she was infectious?). This time period sets the limits for the investigation, allows for the prioritization of contacts within the designated time frame, and determines the time frame for follow-up tests. Unfortunately, exactly when a given patient becomes infectious is unknown, and there is no established scientific method of determining the presenting case’s period of infectiousness. Therefore, methods used to determine the date of first exposure vary from place to place. In the United States, some areas use at least three months prior to diagnosis as the starting point, with the caveat that it may be longer, depending on the history of signs and symptoms, particularly cough, and the extent of disease. In other areas, the starting point is calculated as the date that is 12 weeks prior to the onset of symptoms. If the patient denies symptoms or if the patient is unable to provide the information, the beginning of the period of infectiousness is generally derived from the date of the first positive clinical finding of TB disease or from the known exposure date of identified infected contacts. The end of the period of infectiousness is when all of the following criteria related to the presenting case are met: (i) adequate and effective treatment received for at least two weeks (as shown by M. tuberculosis– susceptibility results); (ii) symptoms, such as the frequency and intensity of cough, are improving; and (iii) there is some evidence of a bacteriological response (such as reduction of the grade of the sputum AFB smear). Some programs have more stringent criteria and require three consecutive negative sputum AFB smears to determine the end of the period of infectiousness. Regardless of the time frames selected by a program, an individual contact’s exposure occurs during that defined period of infectiousness. It begins with the first exposure after the beginning of the period of infectiousness and ends when the contact is broken or the presenting case is not considered to be infectious anymore, whichever comes first. The question frequently asked of investigators is ‘‘How many hours of exposure will be needed before a contact becomes infected?’’ Although models and tools to assist in determining potential TB transmission exist (45–49), factors affecting both the transmission and acquisition of disease are variable and difficult to calculate. Nevertheless, TB programs may elect to establish their own guidelines for the minimum duration of exposure in order to facilitate the contact tracing process. Place Factors: Where Has the Patient Been While Infectious and What Are the Characteristics of Those Environments?

Knowing the level of potential infectiousness of the presenting case and the time frame during which possible exposures may have occurred, the

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next step in the contact tracing process is to establish the place (or places) where contacts may have been exposed. In other words, where did the presenting case associate with others during the established time frame? Possible settings may include the home, congregate housing, school/ colleges, worksites, social groups, etc. Identification of other settings may require a sociological knowledge of the local culture and its definition of ‘‘family’’ and of social networking between groups (15,50–53). (Use of social networking analysis for contact tracing is described in Section ‘‘New Technologies.’’) The environment of exposure refers to both the air volume (generally related to the space where exposure occurs) and to the ventilation of the space. Obtaining and understanding technical environmental information in this regard may be a difficult task. At best, the investigator may be able to obtain descriptive information from the presenting patient and/or contacts, and make a visual assessment of the surrounding area during a field visit. Practically speaking, investigators may need to use a simplified, easy to understand system to characterize the exposure environment. For example, in a recent contact analysis, the authors used a simple ordinal scale to express the size of the exposure environment (1 ¼ size of a vehicle or car; 2 ¼ size of a bedroom; 3 ¼ size of a house; and 4 ¼ size larger than a house) (49). The advantage of this scale is that it is easy to use, does not require measurements, and is easily understandable for the presenting patient. Although other factors (such as the physical proximity of the contact to the case, air humidity, and air exchanges per hour) may also affect transmission, it is impractical to routinely measure them. Using all three factors (person, time, and place), it is now possible to classify contacts as high, medium, or low priority. As always, programs will need to constantly evaluate the effectiveness of their approach and make modifications as needed. Low priority contacts should not be included unless resources permit and the program is meeting its performance goals. Developing a Written Contact-Tracing Plan

Efficient contact tracing requires a continuous system of data collection, organization, analysis, dissemination, and evaluation. To begin the process, the investigator should prepare a contact-tracing plan with time frames for conducting the evaluation of the identified high- and medium-priority contacts. The plan is a working document and should include a register, listing all identified contacts by their prioritization status (recognizing that assignment of priority status can change as additional information about the contacts or their exposure to the patient is gathered). It should also include a contact-tracing evaluation plan (54,55). The Field Investigation

Although there are some settings in both high- and low-prevalence countries where distance is a significant issue (56), the contact field investigation

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is an important component of the contact-tracing process. Sites other than the patient’s primary residence should also be considered for field visits. For example, if the exposure took place at the patient’s worksite, school, or another congregate setting, or bars or other social settings, visits to those settings are also necessary. The field visit serves many purposes. It allows the investigator to: (i) interview or reinterview the patient; (ii) interview and apply the TST to the identified contacts; (iii) observe the contacts for any signs or symptoms suggestive of active TB; (iv) collect sputum samples from any contact who is symptomatic; (v) identify sources of health care, schedule medical evaluations, and make appropriate referrals; (vi) identify additional potential contacts who may also need follow-up—often there may be clues in the residence (such as toys, pictures, trophies, etc.) which help identify missed contacts or provide evidence of potential unnamed sites of transmission; (vii) educate the contacts about the purpose of the investigation and the basics of TB pathogenesis and transmission; (viii) observe the contact’s environment for potential transmission factors (crowding, ventilation, etc.); (ix) assess the contact’s psycho/social needs and other risk factors that may influence future compliance with medical evaluation recommendations; and (x) reinforce confidentiality. The same principles apply to the contact interview as were suggested for the presenting patient interview. Timeliness of the field investigation is also an important factor. Medical Evaluation of Contacts

Wherever the contact tracing and resultant skin testing is performed (field visit, TB clinic referral, etc.), arrangements must be made to ensure that the skin test is read 48 to 72 hours after being placed, and that CXR (and sputum as indicated) are obtained for all contacts who need a medical evaluation. Critical elements of the medical evaluation process include the following: (i) obtaining adequate medical histories for the contacts (including: history and treatment of LTBI or disease; documented previous TST results; TB disease symptoms, including productive, prolonged cough, chest pain, hemoptysis, fever, chills, night sweats, appetite loss, weight loss, or easy fatigability; medical conditions that increase the risk of progression to active TB; history of exposure to the presenting patient; and demographic factors such as age, race/ethnicity, and country of birth); (ii) asking risk factor questions for HIV and offering counseling and testing if their HIV status is not known and they are at risk; (iii) determining locating information for each contact; (iv) assessing potential individual and system-related barriers to their participation in the evaluation process (clinic hours or location, work or family obligation, lack of transportation, etc.; and (v) performing TSTs and follow-up medical evaluation. Tuberculin Skin Tests

Persons with prior positive TST results: Contacts who have a documented prior positive PPD or history of previous TB disease, who are not known

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or likely to be immunosuppressed or have other medical risk factors, need no further evaluation unless they have symptoms suggestive of active TB. Persons who have no prior TST results: All other high-and medium-risk contacts selected for further evaluation who do not have documentation of a previous positive TST or history of previous TB disease should have a Mantoux TST. Persons who are TST POSITIVE initially: All contacts who have a TST reaction with an induration greater than or equal to 5 mm at the first screening, and who have no history of positive reaction in the past, or who report any symptoms consistent with TB should be medically evaluated to rule out TB disease and, if disease is not present, evaluated for treatment of LTBI. The medical evaluation should include a medical history, physical examination, and a chest radiograph. If the chest radiograph is abnormal or if the contact is symptomatic, the contact should be fully evaluated for TB disease, including sputum collection for AFB smear and culture. Persons who were TST NEGATIVE initially: All high- and mediumrisk contacts who are skin test negative initially, should be retested in approximately 8 to 10 weeks to allow time for skin test reactivity to occur (unless at the time of the initial skin test, 10 weeks had already elapsed since the last contact with the presenting case). This period of time between the initial skin test and the date that is 8 to 10 weeks postexposure is referred to as the ‘‘window period.’’ Persons found to be TST POSITIVE at the second testing: These contacts are considered to be newly infected and require further medical evaluation. Persons found to be TST NEGATIVE at the second testing: No further follow-up is indicated. Persons who are currently known or likely to be immunosuppressed or who are less than five years of age: These contacts require a medical evaluation (including a chest radiograph) to rule out TB disease, regardless of the result of the TST, history of a prior positive TST, or history of prior TB disease. Ensuring the medical evaluation of contacts may be problematic for a number of reasons. To address adherence to recommendations, some areas have legal mandates requiring medical examination of identified contacts and others have policies where it is not acceptable to report that a case of TB has no contacts (57). Treatment of LTBI

For contacts found to have LTBI, initiation and completion of treatment is the ultimate goal. However, three groups of contacts who have a negative baseline TST less than 8 to 10 weeks after their last exposure to the infectious TB case merit special mention: contacts younger than five years of age, HIV seropositive or otherwise immunosuppressed contacts, and contacts taking anti-tumor necrosis factor (anti-TNFa) agents. After TB disease has been ruled out, these individuals should be considered for treatment of LTBI, despite the negative result of the initial TST. For children, if

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the reaction to the second TST is negative, and the child is immunocompetent and no longer in close contact with an infectious patient, treatment for LTBI should be discontinued and follow-up is not necessary. For HIV seropositive or otherwise severely immunocompromised contacts (regardless of the result of the postexposure TST), a full course of therapy for LTBI should be completed. Whenever possible, Directly Observed Therapy (DOT) is recommended for contacts on treatment for LTBI. Where resources are limited, DOT for contacts should be prioritized according to risk. Interventions to promote adherence for treatment of LTBI are also recommended. Expansion of Contact Tracing

Given that the focus of contact tracing should be on the high- and mediumpriority contacts, consideration of expansion of contact tracing to lower priority contacts should be a carefully thought out process. When expansion is considered, the suggested framework is found in Figure 1 (a modification of the Concentric Circle, or the Stone-in-the-Pond Principle) (58). Although this framework does not address all contact investigation needs and has considerable limitations (59,60), it does change the focus of the tracing to reflect the currently defined prioritization process. The model keeps the presenting case in the inner circle, but redefines the next circles for high-, medium-, and low-priority contacts as the circles widen out. The critical differences in the use of this concentric circle (as opposed to previous versions) are: (i) prioritization categories have been clearly defined for each

Figure 1 The concentric circle approach to contact tracing. See text for detailed description.

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circle, and (ii) the focus has shifted from testing alone (and using that information to evaluate potential transmission), to now also ensuring that evaluation and completion of treatment for LTBI occur before expansion is considered. Therefore, before deciding to expand the testing beyond the first circle of high-priority contacts, the investigator should ask the following questions: 1.

2.

3.

Has the program been successful in fully evaluating the first circle high-priority contacts, and if appropriate, started them on treatment for LTBI? If the answer is yes, and there is evidence of recent transmission [see (3) below] expansion can be considered to the medium-priority group. If the answer is no, then expansion should not be considered until evaluation and treatment can be assured. Similarly, has the program been successful in fully evaluating the medium-priority second circle contacts, and if appropriate, started them on treatment for LTBI? If the answer is yes, and there is evidence of recent transmission [see (3) below], then expansion can be considered to the lower priority group. If the answer is no, then expansion should not be considered until evaluation and treatment can be assured. Is there evidence of recent transmission in either high- or medium-priority contacts?
Is there an unexpectedly large rate of LTBI or TB disease?
Are there positive TSTs in contacts less than five years of age?
Have any contacts had a change in TST status from negative to positive on postexposure tests?
Is there any evidence of second-generation transmission?

If there is evidence of recent transmission based on the answers to these questions, then expansion of the contact tracing to the next priority circle (and possibly beyond) should be considered. When there is no evidence of recent transmission, then the investigation should not be expanded to the next circle of lower priority contacts and consideration of expansion should only occur in exceptional circumstances (such as those involving highly infectious cases with high rates of infection among contacts or evidence for secondary cases and secondary transmission). The total contact-tracing process should be completed by three months, unless concentric circle testing results require further expansion of the testing. Contact tracing may need to be reinitiated if a TB patient becomes a treatment failure or relapses, and the sputum remains smear positive or becomes positive again. In this situation, newly identified contacts must be examined, and exposed, previously uninfected contacts not on treatment for LTBI who have continued to be exposed, should be reexamined. In some high-profile settings such as schools, institutions, work sites, or other congregate locations, there may be additional obstacles to performing

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the contact-tracing prioritization process (61). Problems may include difficulties in narrowing down just who is a high- or medium-priority contact in ‘‘the inner circle’’; a reluctance to identify individuals in certain settings; the desire on the part of employees or administration to overtest individuals in order to ameliorate the ‘‘hysteria’’ often associated with knowledge of a TB case, and pressure exerted by various organizations or groups to protect their members through case isolation and/or universal testing. To reduce these concerns, some authors have proposed performing TSTs in large congregate settings based on a risk assessment where identified lower risk contacts would only be tested once in eight weeks after the end of the exposure (61,62). The best method for approaching any high-profile situation is to promptly identify and understand the sources of concern. Once this is known, officials/administrators at the setting can be enlisted as collaborators and an educational effort conducted to alleviate potential problems (63). Controlled management of public relations is an essential strategy and all program protocols should include a communication plan for the news media (64). V. Contact Tracing in High-Prevalence Countries A. First Step: Whether or Not to Do Contact Tracing?

As in low-prevalence countries, the first TB control goal for high-prevalence countries is to assure a full course of adequate treatment for all detected active TB patients. Once that is attained, contact tracing becomes the next priority. However, the emphasis and focus of contact tracing in highprevalence areas may differ. In low-prevalence countries, the focus of contact tracing is to identify persons who have been exposed to a case of infectious TB and who may have LTBI, and to assure completion of treatment. Secondary active TB cases may also be identified, but are less likely. In contrast, the contact-tracing focus, as an initiative of the health services, in high-prevalence countries may be directed toward active TB case finding (where the yield is greater than would be expected in low-prevalence areas). Lack of resources may also alter the focus. Although the methods may vary for high-prevalence areas, a decision about whether or not to do contact tracing uses the same principles that have been described for low-prevalence countries. It depends primarily on the characteristics of the presenting case that are associated with an increased risk for transmission. B. Next Steps: Now What?

In low-prevalence countries, availability of resources and the focus on LTBI allow the contact tracing to proceed in a stepwise fashion. In highprevalence countries, other factors influence the direction, extent, and type of contact tracing possible in these settings. These factors may be epidemiologic, methodological, diagnostic or treatment-related, and/or programmatic. All of these are influenced by the affluence of the country and the presence of a concurrent HIV epidemic.

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Epidemiologic Factors

Prevalence of infection (household vs. community transmission): In the past, in Europe, the United States, and in temperate climates in general, TB was seen, at least to some extent, essentially as a household infection. In some high-prevalence countries, those same household conditions (overcrowded, and usually poorly lit and ill-ventilated) that contributed to early TB transmission still exist. Furthermore, current data suggest that in a low-incidence country like the Netherlands, the prevalence of LTBI at the age of 20 is less than 0.5% (58), whereas in high-incidence countries, the prevalence of LTBI at the age of only 10 may be as high as 10% (65). The prevalence of infection among household contacts is also high. In one study, up to 40% of household contacts were infected, while 6% already had developed active disease at the time of diagnosis of the index case (66). A case–control study in Malawi showed that 7% of TB patients had household members who developed TB compared to 1% of control patients (67). In Cameroon, the rate of disease among household contacts was 14.6% (68). In such high-incidence countries, the priority to trace contacts must be limited to the household of the index case. However, other studies suggest that if the risk of infection in the community is high, transmission in the household may be less important. In South Africa, restriction fragment length polymorphism (RFLP) analysis among 832 adults and 35 children showed that 19 (54%) children had household members identified with TB, of which 12 (34%) with an identical strain. Twenty nine (83%) strains from children formed part of the community clusters, but definite contact with source cases was established in only 15 children (43%) (69). Another RFLP study in South Africa among secondary cases in 129 households showed that, although household contacts had a greater risk of being infected with the same strain as community contacts, only 19% of the community transmission took place in the household (70). The presence of an adult with infectious TB and a child with TB therefore does not necessarily imply adult-to-child transmission in that household. This is a confirmation of an early study that collected data from eight different sub-Saharan countries. The authors concluded that, although statistically significant transmission does occur in certain households, its extent was so moderate that it gives some ground for skepticism with regard to the usefulness of contact examinations in some settings (71). Although household transmission remains a significant factor, these findings may have implications for contact tracing and treatment strategies in high-prevalence areas. Establishing contact definitions: Although the definition of household contact would seem obvious at first sight, it is noteworthy that several definitions have been used to describe both proximity of contact (household) and duration of contact within a household. A household has been defined as ‘‘a group of individuals that resided in the same house and shared the same kitchen’’ (72). In an Ugandan study, it was defined as ‘‘a group of people living within one residence who share meals together and have an

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identified head of family that makes the decisions for the household’’ (73). Regarding duration of possible household exposure, in a study in Pakistan, a ‘‘contact’’ was defined as ‘‘any person over three months of age who had lived in the same house as the index case for at least three months and had slept in the same house for on average at least four nights per week, throughout this three-month period’’ (74); or in another study, it was ‘‘those individuals that resided in the same house and shared the same kitchen as the index case for at least three months before the commencement of TB treatment of the index case’’ (72); or in Uganda ‘‘an individual who had resided in the household for at least seven consecutive days during the three months prior to the diagnosis of TB in the index case’’ (73). What all these definitions have in common is that proximity of contact is expressed in sharing a roof for sleeping and eating, while duration of contact is expressed as being in that household for at least three months. In most studies, no specific definitions for household contacts are given. Yet it makes a difference for active screening if only members of the immediate household are targeted, or if the extended family should be regarded as the priority target group. Determining the contact target population: Risk of infection—Age, gender, and HIV status of contacts. Not all exposure results in infection. Early studies of transmission showed that only about 30% of young children in close contact with a smear-positive index case were infected (75). An investigation among household contacts in Kenya showed that children aged 0 to 5, 6 to 9, and 10 to 19 years had 10, 5, and 2 times higher TST reaction rates compared to the general population (76). The gender of the index case in this study made a difference for transmission. Among 56 contacts of a male index case, 32% of the children reacted, while 53% of 114 contacts of a female index case showed a positive skin test (76). A study in Sudan showed that 34% of bacille Calmette–Gue´rin (BCG) unvaccinated children younger than 15 years, who were contacts of an index case in the household, tested TST positive (77). In a prospective cohort study of 1206 household contacts of 30 index cases between 1995 and 1999 in Uganda, 76 (6%) secondary cases were identified (73). The risk among young children was 10% versus adults 1.9%, and among HIV positive 23% versus HIV negative 3.3%. Thus, these data suggest that in general, one-third of those exposed in the household do get infected, and the risk of infection is greater at a young age. Although there are contact tracing questions related to the epidemiologic factors thus described, most TB control programs in high-prevalence countries limit contact tracing to household contacts; in many instances even to household contacts up to the age of six years. Methodologic Factors: Active Screening or Passive Case Finding?

In most high-prevalence countries TB patients are asked if there are any relatives in the household who have symptoms of TB, and if so, the patient is asked to request that they come in for investigation. The initiative is left to

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the index case (passive case finding). In overburdened or poorly organized programs this is probably the maximum effort that can contribute to additional case detection. But if the health services initiate the request that all household members come in for examination and then actively monitor whether this request is being met (active case finding), more cases can be detected. An investigation among household contacts in Kenya showed that screening produced an additional 15% of sputum smear-positive cases (76). In Malawi a cross-sectional study compared the yield of TB case detection for passive (0.19%) and active (1.74%) case finding among household contacts of smear-positive pulmonary TB patients (78). Where the majority of TB patients are HIV positive, active case finding among household contacts yielded nine times more TB cases. A similar finding of TB prevalence in household contacts is reported from Hong Kong (79), where in a random selection of 970 index cases, the rate of active disease among contacts was 1.72% for all ages. Thus, it seems worthwhile for TB control programs to actively followup household contacts for the presence of active TB disease. Cost-effectiveness of active case finding—low- versus high-prevalence countries: Active case finding among contacts is cost effective. Among Canada immigrants, close contact investigation (as compared with passive case detection) resulted in a net savings of $815 for each prevalent case detected and treated and of $2186 for each future case prevented. The authors concluded that close contact investigation was highly cost effective and resulted in net savings (29). But Verver et al. (70) from their study in South Africa warned that, although active case finding among household contacts may be cost effective (as it detected 25% of cases), it has a limited impact at population level because it misses more than three quarters of transmission leading to TB. Diagnosis-Related Factors: Accessibility and Availability of Diagnostic Procedures

The TST: Infection without overt disease can only be diagnosed by a TST. But this test has a number of drawbacks. These include the following: (i) tuberculin is expensive; (ii) the supply chain in many high-prevalence countries is incapable of providing sufficient vials and specific syringes; (iii) the staff is often not well trained in performing the test and reading it correctly; (iv) a high annual risk of infection makes it difficult to determine if a positive test result at increasing age reflects a recent or a remote infection; (v) in areas with high HIV infection prevalence the test often will be false negative (under-diagnosis); (vi) if the test is restricted to young children, the BCG vaccination given at birth, may interfere with the test result (overdiagnosis); and (vii) persons have to return after two to three days for TST reading. In Malawi, the outcome of screening among young children aged five years or less in households of adults diagnosed with smear-positive pulmonary TB was evaluated. The need for childhood screening had been informed

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to 74% of 67 adult hospitalized patients, and in 46% some of their children were screened. But, out of all the 365 young children who belonged to the households of these 67 adults, only 33 (9%) were screened for TB (80). Sputum examination: In symptomatic cases, a sputum smear examination can confirm active TB, but this test is only useful in cases where the patient has overt TB and is capable of producing sputum. Small children generally cannot produce sputum. Another barrier may be the insufficient capacity and proficiency in many laboratories to perform sputum microscopy. CXR: If no sputum can be produced, a CXR is needed. Again, in high-prevalence countries, the cost of a CXR is often prohibitive, and if not, the ability to use CXRs may be affected by the same poor supply chain for providing films and chemicals. X-ray machines in many countries are not widely available and the quality of the CXR and/or proficiency of persons reading CXR’s, especially in small children, is poor. Diagnosis of TB infection and disease in household contacts and particularly young household contacts in high-prevalence countries thus has its difficulties. Yet young childhood contacts of smear-positive TB cases are at high risk for progression of latent infection to active and severe forms of disease (81). Steps are needed to improve childhood screening procedures. New serologic screening tests may overcome some of the problems, but cost and weak supply chains will remain a major obstacle for contact screening in many of these countries. Treatment-Related Factors

As has been noted in low-prevalence countries, no testing should be undertaken if no remedy will be offered. For contacts with active disease, proper treatment according to the national guidelines will be available. But what to do for contacts with LTBI? An accepted treatment regimen for LTBI is isoniazid (INH) chemotherapy for six to nine months. But in high-prevalence countries, use of this therapy has its specific problems. Obstacles include the cost of INH (despite being low), maintaining the supply chain, the long duration of treatment, and the need for supervision of intake. In Malawi, only 17% of a passively detected cohort and 22% of an actively screened cohort of child contacts aged less than six with LTBI were placed on INH treatment (78). Reasons for this low proportion were that (i) most household members could not afford to travel to the hospital several times for CXRs, or were not convinced that screening an apparently healthy child was worthwhile. Clearly better information needed to be provided; (ii) after completion of screening, 40% of children dropped out due to delays in reading the CXRs. Either the child and/or the caretaker had to wait too long or had to return another day. In this case, the links between the TB program and the general services were weak; and (iii) CXR was not performed in 61% because of limited resources. The long duration of treatment for LTBI has been addressed by giving drugs in various combinations for a shorter period of time. Shortening the duration of treatment may overcome some of the operational barriers, but it

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will probably not overcome the problems as cited above, and the overall program cost remains an important aspect to consider. Treatment delivery: The long duration of treatment and the need for supervision of intake are an obstacle for proper adherence with treatment for LTBI. In Malawi, it was found that 71% of care providers could not afford to return their children to the hospital for LTBI treatment (78). Given this obstacle, a strategy of monthly supplies given to the adult caretaker and guardian supervision led to successful TB treatment (82). Multidrug-resistant tuberculosis (MDR-TB): In many high-prevalence countries in the former Soviet Union and in some Asian countries, there are regions with an extremely high incidence of MDR-TB. If a child is infected by an MDR-TB strain, treatment for LTBI with INH may not be effective. It has been suggested that drug-resistant strains are less pathogenic than sensitive strains, but even if this is so, its effect is probably counteracted by a possible longer exposure to chronic MDR-TB cases. This was shown by Texeira et al. (72) who found the prevalence of TB infection and progression to active TB among household contacts exposed to drug-sensitive TB and MDR-TB cases to be comparable, despite the longer duration of exposure of contacts to the index case in patients with MDR-TB. Programmatic Factors: Differing Program Guidelines

High-prevalence affluent countries: In high-prevalence countries that are more affluent, active screening of contacts may be useful. In Taipei, Taiwan only 38.7% of 11,873 contacts responded for X-ray screening. Of these 284 (6.7%) had newly diagnosed active pulmonary TB. In contrast, the yield of mass miniature radiography (MMR, or population-based untargeted radiography) in Taipei is 0.42%, thus contact screening is much more effective using this strategy. The authors suggest that among the nonresponsive group, an additional 426 cases were missed (83). In this setting, a more vigorous approach should be possible. High-prevalence poor countries: NTPs in most high-prevalence poor countries affected by the dual infection of TB and HIV focus on passive case finding and do not regard children as an important factor in the TB epidemic, probably because children do not contribute greatly to the transmission of TB. However, as some data suggest that transmission of TB in high-prevalence countries may occur more often outside the household, the time has come to look at childhood TB globally, from a child survival point of view (84). Alternative community and household case-detection strategies need to be developed, piloted, and evaluated. Diagnosis of both active TB and LTBI in children (with currently available tools) may pose difficulties in any setting, but these are clearly exaggerated in high-prevalence countries. As noted, the TST may be difficult to interpret (if the test is available at all) and a CXR is often not obtainable. If a CXR is available, however, its use can be an important tool when used selectively. In a Malawi study, a CXR revealed less than 1% of active TB cases among asymptomatic contacts, while the yield in contact children

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presenting with cough was 27% (78). Therefore, although an improved diagnostic TB test is needed for children in all settings, these findings suggest that there is potentially a better yield if TB programs concentrate their resources on CXRs for symptomatic children rather than performing them on all young contacts. An alternative broader control strategy may be more active casedetection methods in the community (e.g., at school entry). This is in contrast to the general view that less affluent country TB control programs have to limit themselves to household contacts under the age of six years (29). But protecting the next generation against TB is a task that responsible TB control programs should not ignore (85). A proposed guideline for high-prevalence countries could be as follows: Household contacts: Children under the age of six, who are household contacts with symptoms suggestive of TB or with a skin test of 15 mm or more, irrespective of symptoms, should be treated as active TB, with a full course of anti-TB drugs. All other children under six years of age who are household contacts and who are asymptomatic should be given treatment for LTBI with INH in a dose of 5 mg/kg bodyweight. If the index case is proven to be MDR-TB, no treatment for LTBI should be given, but the child will need to come for clinical follow-up every three months during the first year. Community strategy: Targeted tuberculin skin testing, where logistically and economically feasible, could be introduced at school entry, if this group of children is clearly a risk group. For example, with an annual rate of infection of 1.5% or more in most sub-Saharan African countries, the group of entering six-year olds will have an infection prevalence of over 10%. A cutoff point of 10 mm with symptoms and of 15 mm without symptoms would indicate the need for clinical evaluation. In case no active TB is present, the child with a TST of 15 mm or more should be treated for LTBI, irrespective of a previous BCG vaccination. VI. New Technologies A. Social Network Analysis

In other health fields, social network techniques have been used to show linkages between social networks and health-related behaviors (86–89). Although the effectiveness of using social network analysis in TB control has been seen during outbreak investigations, applying social network techniques successfully to the TB contact tracing activities has been much more limited (50–53). Where attempted, results have generally been positive, but a considerable amount of time and effort were required to identify these networks. At this point in time, the practicality of utilizing this technique has not been demonstrated in either low- or high-prevalence countries and well-designed epidemiologic studies are needed to better determine when and if social network analysis methods can be applied in contact tracing settings.

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B. DNA Fingerprinting (Genotyping)

The primary use of universal genotyping (that is genotyping a strain from all culture positive TB cases) is detecting unsuspected transmission. There are now several published studies from the CDC National Tuberculosis Genotyping and Surveillance Network (NTGSN) where 10,883 patients had isolates analyzed over a five-year period (90). The cluster investigation part of the study protocol demonstrated the significant role of casual transmission and transmission in nontraditional settings which may be overlooked in traditional contact tracings (91). Universal genotyping provides useful information as to trends and chains of transmission over time. However, the use of DNA fingerprinting is limited in real time contact tracings. Because this test is used only for TB cases that have culture positive isolates, genotyping cannot be used for contacts with LTBI, or persons with culture-negative disease. In addition, although genotyping can define the relatedness of M. tuberculosis isolates, it cannot define the relationship between the cases from which the isolate was derived. Isolates with the same genotype do not always represent recent transmission and, even if transmission is occurring, isolates with the same genotype do not necessarily imply a direct linkage between the patients in question (92). In low-prevalence countries where the technology and resources exist to perform genotyping, its use in combination with epidemiologic follow up, can strengthen transmission hypotheses. Targeted genotyping (that is selecting only culture-positive TB cases where there is an identified need—possible epidemiologic connection, cross contamination suspicion, etc.) and sending their isolates for genotyping, has been a useful adjunct to traditional contact tracings. When more than two TB cases have been identified during an investigation, this type of testing may either confirm or disprove transmission between cases that may or may not have been epidemiologically linked. Studies have shown that presumed epidemiologic links may not be supported with genotyping data (93). This knowledge is important, as it may influence decisions about expanding the contact tracing. Although genotyping is an adjunct to contact tracing and an evaluation tool (94–99) it is not a replacement for epidemiologic follow up. As real-time, amplification-based genotyping methods become available, the ability to rapidly identify persons who need a second interview will increase and thus, the ability to more quickly detect secondary cases, preventable cases and sites of transmission. For now, a thorough and properly conducted contact tracing remains the primary technique for identifying relationships between cases. C. Use of Blood Tests for Detection of LTBI

The TST is currently the only test used in the United States for the detection of LTBI during contact tracing. There are two blood tests, however, that have potential use for LTBI detection in this setting. The first, the QuantiFERON-TB1 test (QFT), is a whole blood assay that measures interferon-c release in response to purified protein derivative (PPD). This

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test has been shown to have good agreement with the TST in immunocompetent adults being screened for LTBI, and its use in this group has been approved by the U.S. Food and Drug Administration (FDA) (100,101). As there are insufficient data to demonstrate the QFT’s accuracy in the setting of contact tracing, CDC guidelines do not recommend its use in this situation (101). A second-generation test (QFT-Gold), using specific antigens (ESAT6, CFP10) instead of whole blood, has been developed and its utility in contact tracing is being studied. This test measures release of interferon-y in response to individual TB antigens rather than PPD. This test might differentiate between BCG vaccination and M. tuberculosis infection (102), and it is being studied for its utilization in contact tracing (103). The second blood test for the detection of LTBI, the ELISPOT test (marketed as T_SPOT_TB), is based on principles similar to those of the QFT, although there are some technical differences. ELISPOT results correlate with TB exposure risk better than skin test results for contacts of pulmonary TB patients (104,105), and like QFT-Gold, it appears able to differentiate between BCG vaccination and M. tuberculosis infection. At the time of this writing, ELISPOT has not been approved by the FDA for use in the United States. VII. Summary Clearly there are challenges in conducting contact tracing in both high- and low-prevalence countries, and there are numerous examples in the literature of both highly productive and less-than-adequate investigations (106,107). In high-prevalence countries, the challenges are much more basic and include questions relating to active versus passive follow-up, accessibility and availability of diagnostic procedures, and decisions about the feasibility of treatment for LTBI. In addition, there are differences in programs and guidelines between high-prevalence affluent and high-prevalence poor countries. Thus, there are significant variations in the approach to contact tracing between low- and high-prevalence settings. However, in both types of settings, challenges may be classified as either patient-related or systemrelated. Some of the patient-related challenges for both settings include a reluctance to name contacts initially, misconceptions about the receipt and presumed protectiveness of BCG, cultural health beliefs (e.g., the use of home remedies), competing life style priorities (drug use or the need for food and shelter, and fears related to immigration issues or HIV). System-related challenges in high-prevalence countries may include: lack of funding for infrastructure support, cold chain failures or interruptions, poor supply chain in general, laboratory proficiency and capacity problems, poor training of staff, etc. In low-prevalence countries, these system-related challenges may include failure to prioritize contact activities programmatically and individually; for physicians (particularly those in the private sector)—a lack of education about the need for contact tracing, as well as the importance of treatment for LTBI; lack of after-business hours clinic

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time; public health infrastructure problems such as lack of funding, downsizing, staff turnover, and inexperience; the influence of managed care and other aspects of the changing health care delivery system, which affect access to care and follow-up; and avoiding unnecessary screenings. In spite of these challenges, as resources allow, TB elimination efforts in both low- and high-prevalence countries target groups at highest risk for progression from LTBI to TB disease. This chapter has illustrated that contacts to infectious cases of TB are such a high-risk group and, after case containment and management, are the second priority for TB control programs. Finally, the ultimate goal of contact tracing is to detect overt cases of TB and contacts that have LTBI and to ensure that those individuals start and complete treatment. As every case of TB began as a contact, the ability to rapidly identify TB cases, to effectively conduct the subsequent contact tracing and to ensure completion of treatment for LTBI in high risk contacts is one of the cornerstones of TB control public health efforts. References 1. Centers for Disease Control. Tuberculosis outbreak in a community hospital— District of Columbia. Morb Mort Wkly Rep 2004; 53(10):214–216. 2. Askew Gl, Finelli L, Hutton M, et al. Mycobacterium tuberculosis transmission from a pediatrician to patients. Pediatrics 1997; 100(1):19–23. 3. Kenyon TA, Valway SE, Ihle WW, et al. Transmission of multidrug-resistant Mycobacterium tuberculosis during a long airplane flight. N Engl J Med 1996; 334:933–938. 4. Centers for Disease Control. Crack cocaine use among persons with tuberculosis— Contra Costa County, California, 1987–1990. Morb Mort Wkly Rep 1991; 40(29): 485–489. 5. Daley CL, Small PM, Schecter GF, et al. An outbreak of tuberculosis with accelerated progression among persons infected with the human immunodeficiency virus. N Engl J Med 1992; 326:231–235. 6. Centers for Disease Control. Tuberculosis in a drug rehabilitation center—Colorado. Morb Mort Wkly Rep 1980; 29(45):543–544. 7. LaMar JE, Malakooti MC. Tuberculosis outbreak investigation of a U.S. Navy amphibious ship crew and the Marine Expeditionary Unit aboard, 1998. Military Med 2003; 168(7):523–527. 8. Jereb JA, Burwen DR, Dooley SW, et al. Nosocomial outbreak of tuberculosis in a renal transplant unit: application of a new technique for restriction fragment length polymorphism analysis of Mycobacterium tuberculosis isolates. J Infect Dis 1993; 168(5):1219–1224. 9. Centers for Disease Control. Tuberculosis transmission in a renal dialysis center— Nevada, 2003. Morb Mort Wkly Rep 2004; 53(37):873–875. 10. Cook SA, Blair I, Tyers M. Outbreak of tuberculosis associated with a church. Commun Dis Public Health 2000; 3:180–183. 11. Curtis AB, Ridzon R, Novick LF, et al. Analysis of Mycobacterium tuberculosis transmission patterns in a homeless shelter outbreak. Int J Tuberc Lung Dis 2000; 4(4):308–313. 12. Centers for Disease Control. Public Health Dispatch: Tuberculosis outbreak in a homeless population—Portland, Maine 2002–2003. Morb Mort Wkly Rep 2003; 52(48):1184–1185.

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13. McElroy PD, Southwick KL, Fortenberry ER, et al. Outbreak of tuberculosis among homeless persons coinfected with Human Immunodeficiency Virus. Clin Infect Dis 2003; 36:1305–1312. 14. Centers for Disease Control. Cluster of tuberculosis cases among exotic dancers and their close contacts—Kansas, 1994–2000. Morb Mort Wkly Rep 2001; 50(15):291–293. 15. Sterling TR, Thompson D, Stanley RL, et al. A multi-state outbreak of tuberculosis among members of a highly mobile social network: Implications for TB elimination. Int J Tuber Lung Dis 2000; 4(11):1066–1073. 16. Pettit S, Black A, Stenton C, et al. Outbreak of tuberculosis at a Newcastle public house: the role and effectiveness of contact tracing. Commun Dis and Public Health 2002; 5(1):48–53. 17. Ijaz K, Yang Z, Matthews S, et al. Mycobacterium tuberculosis transmission between cluster members with similar fingerprint patterns. Emerg Infect Dis 2002; 8(11):1257–1259. 18. Kline SE, Hedemark LL, Davies SF. Outbreak of tuberculosis among the regular patrons of a neighborhood bar. N Engl J Med 1995; 333:222–227. 19. Wells CD, Zuber PLF, Nolan CM, et al. Tuberculosis prevention among foreignborn persons in Seattle-King County, Washington. Am J Respir Crit Care Med 1997; 156:573–577. 20. Walia R, Hoskyns W. Tuberculosis meningitis in children: problem to be addressed effectively with thorough contact tracing. Eur J Pediatr 2000; 159:535–538. 21. Curtis AB, Ridzon R, Vogel R, et al. Extensive transmission of Mycobacterium tuberculosis from a child. N Engl J Med 1999; 341:1491–1495. 22. Lobato MN, Royce SE, Mohle-Boetani JC. Yield of source case and contact investigations in identifying previously undiagnosed childhood tuberculosis. Int J Tuberc Lung Dis 2003; 7(12):S391–S396. 23. Snider DE, Kelly GD, Cauthen GM, et al. Infection and disease among contacts of tuberculosis cases with drug resistant and drug susceptible bacilli. Am Rev Respir Dis 1985; 132:125–132. 24. Centers for Disease Control and Prevention. Essential components of a tuberculosis prevention and control program. Morb Mort Wkly Rep 1995; 44(RR-11):1–17. 25. Broekmans JF, Migliori GB, Rieder HI, et al. European framework for tuberculosis control an elimination in countries with a low incidence. Eur Respir 2002; 19:765–775. 26. Reichler MR, Reves R, Bur S, et al. Evaluation of investigations conducted to detect and prevent transmission of tuberculosis. JAMA 2002; 287:991–995. 27. Marks SM, Taylor Z, Qualls NL, et al. Outcomes of contact investigations of infectious tuberculosis patients. Am J Respir Crit Care Med 2000; 162:2033–2038. 28. Binkin NJ, Vernon AA, Simone PM, et al. Tuberculosis prevention and control activities in the United States: an overview of the organization of tuberculosis services. Int J Tuberc Lung Dis 1999; 3:663–674. 29. Verver S, van Loenhout-Rooyackers JH, Bwire R, et al. Tuberculosis infection in children who are contacts of immigrant tuberculosis patients. Eur Respir J 2005; 26:126–132. 30. Enarson DA, Rieder HL, Arnadottit T, et al. Management of tuberculosis. A guide for low-income countries. Int Union Tuberc Lung Dis 2000; 162:2079–2086. 31. Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis infection. Morb Mort Wkly Rep 2000; 49(RR-6):1–51. 32. 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. Morb Mort Wkly Rep 2003; 52:735–739.

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33. Hsu KHK. Contact investigation: a practical approach to tuberculosis eradication. Am J Pub Hlth 1963; 53:1761–1769. 34. Centers for Disease Control and Prevention. Update: nucleic acid amplification tests for tuberculosis. Morb Mort Wkly Rep 2000; 49:593–594. 35. Bock N, Mallory JP, Mobley N, et al. Outbreak of tuberculosis associated with a floating card game in the rural south. Clin Infect Dis 1998; 27:1221–1226. 36. Wallace CE, Cruise P, Tyree AB, et al. Approaches to contact investigation in Texas. Int J Tuberc Lung Dis 2003; 7(12):S558–S562. 37. Shrestha-Kuwahara R, Wilce M, DeLuca N, et al. Factors associated with identifying tuberculosis contacts. Int J Tuberc Lung Dis 2003; 7(12):S510–S516. 38. Li J, Driver CR, Munsiff SS, et al. Finding contacts of homeless tuberculosis patients in New York City. Int J Tuberc Lung Dis 2003; 7(12):S397–S404. 39. Barnes PF, Yang Z, Pogoda JM, et al. Foci of tuberculosis transmission in central Los Angeles. Am J Respir Crit Care Med 1999; 159:1081–1086. 40. Rose DE, Zerbe GO, Lantz SO, et al. Establishing priority during investigation of tuberculosis contacts. Am Rev Respir Dis 1979; 119:603–609. 41. Stead W, Senner J, Reddick W, et al. Racial differences in susceptibility to infection by Mycobacterium tuberculosis. N Engl J Med 1990; 322:422–427. 42. Comstock GW. Tuberculosis in twins: a re-analysis of the Prophit Survey. Am Rev Respir Dis 1978; 117:621–624. 43. Centers for Disease Control. Missed opportunities for prevention of tuberculosis among persons with HIV infection—selected locations, United States, 1996–997. Morb Mort Wkly Rep 2000; 49(30):685–687. 44. Reichler MR, Bur S, Reves R, et al. Results of testing for human immunodeficiency virus infection among recent contacts of infectious tuberculosis cases in the United States. Int J Tuberc Lung Dis 2003; 7(12):S4. 45. Nardell EA, Keegan J, Cheney SA, et al. Airborne infection: theoretical limits of protection achievable by building ventilation. Am Rev Respir Dis 1991; 144: 302–306. 46. Gammaitoni L, Nucci MC. Using a mathematical model to evaluate the efficacy of TB control measures. Emerg Infect Dis 1997; 3:335–342. 47. Fennelly KP, Martyny JW, Fulton KE, et al. Cough-generated aerosols of Mycobacterium tuberculosis: a new method to study infectious. Am J Resp Crit Care Med 2004; 169:604–609. 48. Nolan CM, Goldberg SV. Analysis of the frequency distribution of tuberculin skin test readings: a tool for the assessment of group contact investigations. Int J Tuberc Lung Dis 2003; 7(12):S439–S445. 49. Bailey WC, Gerald LB, Kimerling ME, et al. Predictive model to identify positive tuberculosis skin test results during contact investigations. JAMA 2002; 287: 996–1002. 50. Fitzpatrick LK, Hardacker JA, Heirendt W, et al. A preventable outbreak of tuberculosis investigated through an intricate social network. Clin Infect Dis 2001; 33:1801–1806. 51. McElroy PD, Rothenberg RB, Varghese R, et al. A network-informed approach to investigating a tuberculosis outbreak: implications for enhanced contact investigations. Int J Tuberc Dis 2003; 7(12):S486–S493. 52. Klovdahl AS, Graviss EA, Yaganehdoost A, et al. Networks and tuberculosis: an undetected community outbreak involving public places. Soc Science Med 2001; 52:681–694. 53. Classen CN, Warren R, Richardson M, et al. Impact of social interactions in the community on the transmission of tuberculosis in a high incidence area. Thorax 1999; 54:136–141.

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54. Logan S, Boutotte J, Wilce M, et al. Using the CDC framework for program evaluation in public health to assess tuberculosis contact investigation programs. Int J Tuberc Lung Dis 2003; 7(12):S375–S383. 55. Sprinson JE, Flood J, Fan CS, et al. Evaluation of tuberculosis contact investigations in California. Int J Tuberc Lung Dis 2003; 7(12):S363–S383. 56. Funk EA. Tuberculosis contact investigations in rural Alaska. Int J Tuberc Lung Dis 2003; 7(12):S549–S552. 57. Webb RM, Holcombe M, Pearson MM. Tuberculosis contact investigation in a rural state. Int J Tuberc Lung Dis 2003; 7(12):S353–S357. 58. Veen J. Microepidemics of tuberculosis: the stone-in-the-pond principle. Tuberc Lung Dis 1992; 73(2):73–76. 59. Daley CL, Kawamura LM. The use of molecular epidemiology in contact investigations: a US perspective. Int J Tuberc Lung Dis 2003; 7(12):S458–S462. 60. Institute of Medicine. Advancing toward elimination. In: Geiter L, ed. Ending Neglect: The Elimination of Tuberculosis in the United States. Washington, D.C.: National Press, 2000:86–121. 61. Driver CR, Balcewicz-Sablinska MK, Kim Z, et al. Contact investigations in congregate settings, New York City. Int J Tuberc Lung Dis 2003; 7(12):S432–S438. 62. Greenaway C, Palayew M, Menzies D. Yield of casual contact investigation by the hour. Int J Tuberc Lung Dis 2003; 7(12):S479–S485. 63. Upshur REG, Deadman L, Howorth P, et al. The effect of tuberculosis and tuberculosis contact tracing on school function: As exploratory study. Can J Public Health 1999; 90(6):389–391. 64. Holdsworth GMC, Breathnach A, Asboe D, et al. Controlled management of public relations following a public health incident. J Public Health Med 1999; 21(3): 251–254. 65. Salaniponi FM, Kwanjane J, Veen J, et al. Risk of infection with M. tuberculosis in Malawi. National Tuberculin Survey 1994. Int J Tuberc Lung Dis 2004; 8(16):718–723. 66. Vidal R, Miravittles M, Cayla JA, et al. Increased risk of tuberculosis transmission in families with microepidemics. Eur Respir J 1997; 10:1327–1331. 67. Claessen NJ, Gausi FF, Meijnen S, et al. High Frequency of tuberculosis in households of index TB patients. Int J Tuberc Lung Dis 2002; 6:266–269. 68. Kuaban C, Koulla-Shiro S, Lekama Assiene T, et al. Tuberculosis screening of patient contacts in 1993 and 1994 in Yaounde, Cameroon. Med Trop 1996; 56:156–158. 69. Schaaf HS, Michaelis IA, Richardson M, et al. Adult-to-child transmission of tuberculosis: household or community contact? Int J Tuberc Lung Dis 2003; 7:426–431. 70. Verver S, Warren RM, Munch Z, et al. Proportion of tuberculosis transmission that takes place in households in a high-incidence area. Lancet 2004; 363:212–214. 71. Andersen S, Geser A. The distribution of tuberculosis among households in African communities. Bull WHO 1960; 22:39–60. 72. Teixera L, Perkins MD, Johnson JL, et al. Infection and disease among household contacts of patients with multidrug-resistant tuberculosis. Int J Tuberc Lung Dis 2001; 5:321–328. 73. Guwatudde D, Nakakeeto M, Jones-Lopez EC, et al. Tuberculosis in household contacts of infectious cases in Kampala, Uganda. Am J Epidemiol 2003; 158:887–898. 74. Rathi SK, Akhtar S, Rahbar MH, et al. Prevalence and risk factors associated with tuberculin skin test positivity among household contacts of smear-positive pulmonary tuberculosis cases in Umerkot, Pakistan. Int J Tuberc Lung Dis 2002; 6: 851–857.

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75. Grzybowski S, Barnett GD, Styblo K. Contacts of cases of active tuberculosis. Bull Int Union Tuberc 1975; 50:90–106. 76. WHO Tuberculosis Chemotherapy Centre N. An investigation of household contacts of open cases of pulmonary tuberculosis amongst the Kikuyu in Kiambu, Kenya. Bull WHO 1961; 25:831–850. 77. El Sony A, Khamis AH, Salih AM. Incorporating active case finding in the household into the TB control program in Sudan. Int J Tuberc Lung Dis 2004; 8:S37. 78. Zachariah R, Spielmann MP, Harries A, et al. Passive versus active case finding and isoniazid preventive therapy among household contacts in a rural district of Malawi. Int J Tuberc Lung Dis 2003; 7:1033–1039. 79. Noertjojo K, Tam CM, Chan SL, et al. Contact examination for tuberculosis in Hong Kong is useful. Int J Tuberc Lung Dis 2002; 6:19–24. 80. Claessen NJ, Gausi FF, Meijnen S, et al. Screening childhood contacts of patients with smear-positive pulmonary tuberculosis in Malawi. Int J Tuberc Lung Dis 2002; 6:362–364. 81. Comstock GW, Livesay VT, Woolpert SF. The prognosis of a positive tuberculin reaction in childhood and adolescence. Am J Epidemiol 1974; 99:131–138. 82. Manders AJE, Banerjee A, Borne HW, et al. Can guardians supervise TB treatment as well as health workers? A study on adherence during the intensive phase. Int J Tuberc Lung Dis 2001; 5:838–842. 83. Wang PD, Lin RS. Tuberculosis transmission in the family. J Infect 2000; 41:149–251. 84. Beyers N. Case finding in children in contact with adults in the house with TB Editorial. Int J Tuberc Lung Dis 2003; 7:1013–1014. 85. Donald PR. Children and tuberculosis: protecting the next generation? Lancet 1999; 353:1001–1002. 86. Israel B. Social networks and health status: linking theory, research, and practices. Pat Counsel Health Educ 1982; 4:50–64. 87. Morris M, Kretzchmar M. Concurrent partnerships and transmission dynamics in networks. Social Networks 1995; 17:299–318. 88. Bell DC, Montoya ID, Atkinson JS, et al. Social networks and forecasting the spread of HIV infection. J AIDS 2002; 31:218–229. 89. Rothenberg RB, Long DM, Sterk CE, et al. The Atlanta Urban Networks Study: a blueprint for endemic transmission. AIDS 2000; 14:2191–2200. 90. Tuberculosis Genotyping Network section. Emerg Infect Dis 2002; 8(11):1187– 1319 (Reemerging Tuberculosis issue). 91. Bennett DE, Onorato IM, Ellis BA, et al. DNA fingerprinting of Mycobacterium tuberculosis isolates from epidemiologically linked pairs. Emerg Infect Dis 2002; 8(11):1224–1229. 92. Crawford JT. Genotyping in contact investigations: A CDC perspective. Int J Tuberc Lung Dis 2003; 7(12):S453–S457. 93. Behr M, Hopewell P, Paz A, et al. Predictive value of contact investigation for identifying recent transmission of Mycobacterium tuberculosis. Am J Respir Crit Care Med 1998; 158:465–469. 94. Dunlap NE. The use of RFLP as a tool for tuberculosis control: utility or futility? Int J Tuberc Lung Dis 2000; 4(12):S1134–S1138. 95. Kimerling ME, Benjamin WH, Lok KH, et al. Restriction fragment length polymorphism screening of Mycobacterium tuberculosis isolates: population surveillance for targeting disease transmission in a community. Int J Tuberc Lung Dis 1998; 2(8):655–662. 96. Jasmer RM, Hahn JA, Small PM, et al. A molecular epidemiologic analysis of tuberculosis trends in San Francisco, 1991–1997. Ann Intern Med 1999; 130:971–978.

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97. Bishai W, Graham NMH, Harrington S, et al. Molecular and geographic patterns of tuberculosis transmission after 15 years of directly observed therapy. JAMA 1998; 280(19):1679–1684. 98. van Loenhout-Rooyackers JH, Sebek MMGG, Verbeek ALM. Contact tracing using DNA fingerprinting in an asylum seeker with tuberculosis. Neth J Med 2002; 60(7):281–284. 99. Lambregts-van Weezenbeek CSB, Sebek MMGG, van Gerven PJHJ, et al. Tuberculosis contact investigation and DNA fingerprint surveillance in The Netherlands: 6 years’ experience with nation-wide cluster feedback and cluster monitoring. Int J Tuberc Lung Dis 2003; 7(12):S463–S470. 100. 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; 286:1740. 101. Mazurek GH, Villarino ME. Guidelines for using the QuantiFERON-TB test for diagnosing latent Mycobacterium tuberculosis infection. Morb Mort Wkly Rep 2003; 52(RR-2):15. 102. Mori T, Sakatani M, Yamagishi F, et al. Specific detection of tuberculosis infection with interferon-gamma based assay using new antigens. Am J Respir Crit Care Med 2004; 170:59–64. 103. Brock I, Weldingh K, Lillebaek T, et al. Comparison of tuberculin skin test and new specific blood test in tuberculosis contacts. Am J Respir Crit Care Med 2004; 170:655–669. 104. Lalvani A, Pathan AA, Durkan H, et al. Enhanced contact tracing and spatial tracking of Mycobacterium tuberculosis infection by enumeration of antigenspecific T cells. Lancet 2001; 357:2017–2021. 105. Ewer K, Deeks J, Alvarez L, et al. Comparison of T-cell-based assay with tuberculin skin test for diagnosis of Mycobacterium tuberculosis outbreak. Lancet 2003; 361:1168–1173. 106. Jereb J, Etkind SC, Joglar OT, et al. Tuberculosis contact investigations: Outcomes in selected areas of the United States, 1999. Int J Tuberc Lung Dis 2003; 7(12):S384–S390. 107. Reichler MR, Reves R, Bur S, et al. Treatment of latent tuberculosis infection in contacts of new tuberculosis cases in the United States. South Med J 2002; 95:414–420.

21 Managing Tuberculosis Patients: The Centrality of Nurses

VIRGINIA G. WILLIAMS

CHANTELLE ALLEN

International Union Against Tuberculosis and Lung Disease, Paris, France

ADRA Nepal, Kathmandu, Kingdom of Nepal

SIRINAPHA JITTIMANEE TB Cluster (NTP), Bureau of AIDS, TB, and STIs, Ministry of Public Health, Bangkok, Thailand,

I. Introduction Nurses all over the world make a unique and invaluable contribution to the successful running of health care programs aimed at controlling diseases such as tuberculosis (TB). One of the significant challenges faced by nurses on a daily basis is how to organize effective patient care within the framework of DOTS (1), the strategy recommended by the World Health Organization and widely accepted as the gold standard for tuberculosis control. This chapter will explore the role nurses play in managing patients and patient care in line with the five components of the DOTS strategy (Table 1). The wide variety of roles played by nurses will be covered with the acknowledgment that their activities may differ across different settings. It is important to note that everything described in this chapter is current practice in many parts of the world, not least where resources are severely limited. The concept of management in relation to patient care is particularly relevant in the context of tuberculosis because patients themselves play an essential role in controlling the disease. Patients needing treatment for 583

Standardized treatment with directly observed therapy (DOT)

Case detection by sputum smear microscopy

Political commitment

DOTS element

Educator

Researcher

Coordinator

Administrator

Educator

Practitioner

Researcher

Administrator

Nurse role

Related activities

Offering reassurance to patients if nervous about the diagnosis Community level: how to recognize symptoms; available treatment; where to go for help Individual level: how to produce a good specimen; where and when to deliver the specimen(s) Recording and processing of the specimen Accurate and prompt completion of request forms, laboratory register, and patient register Documentation of dates and results Ensuring accessibility for delivery of samples Establishing a mechanism to ensure appropriate referral for the relevant tests Ensuring patients receive care as close as possible to their home Analysis of laboratory register (at least frequencies or percentage of positive results) Operational research Clinical audit Individual patient level (plus family and/or friends as appropriate) Assessment of attitude to diagnosis and need for information at different stages of the treatment Ongoing education for the patient based on assessments in relation to the disease in general, the type and length of treatment, potential side effects, and available support

Advocacy and leadership Informing policy and strategic decision making Lobbying for funds Collation and analysis of local performance using quarterly cohort reports Operational research to inform service developments Identification of suspect cases Referral to the relevant facility for appropriate tests

Table 1 The DOTS Strategy and the Nursing Role

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Administrator Researcher Coordinator Coordinator Administrator

Practitioner

Abbreviation: DOT, directly observed therapy.

Regular uninterrupted drug supply

Standardized reporting and recording

Researcher

Administrator

Coordinator

Practitioner

Provision of education for DOTS supporters, volunteers, and anyone else involved in caring for the patient Needs assessment, care planning, implementation, and evaluation with regard to social, psychological, and physical factors Supervision, support, and monitoring with regard to ability to adhere to treatment, clinical progress, side effects relating to the medication, and social as well as psychological factors affecting the patient’s progress, e.g., lack of food, social isolation, and lack of work Clear documentation of medication, progress, any problems, and action taken Communication with all members of the health care team (doctor, social workers, community health workers, DOT supporters, etc.) Facilitation of links with other services Establishing an effective default-tracing system Utilization of all existing resources to meet the patients’ needs according to the needs assessment Ensuring services are as convenient as possible within the local setting Monitoring recording and reporting Management of drug supply and clinic services Analysis of treatment progress (sputum conversion) and treatment outcome Evaluation of care provided Clear, accurate, and prompt record keeping Communication with relevant colleagues regarding individual and collective progress Collation and submission of quarterly reports Analysis of the data: what the findings mean at a facility, district, regional, and central level Work with other TB staff to discuss the data Work with other TB staff members to make sure that drugs are available for the patients Ensuring there is a sufficient supply for patients, seen according to level of responsibility (manager of a TB unit to DOTS supervisor) Communication with relevant colleagues to restock drug (individual and facility requirements)

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tuberculosis are not the passive recipients of care. It takes time, effort, and personal resources on the part of the patient to recognize symptoms, seek treatment from the appropriate facility, produce and deliver samples at specified times, and adhere to a lengthy course of powerful medication. Like any other member of the team involved in controlling tuberculosis, good management will enable patients to fulfil their role successfully. Much of the information presented in this chapter originated from regional workshops involving nurses and allied professionals in Europe, the Middle East, Africa, Latin America, and South and Southeast Asia (2). There are also references to a number of relevant presentations made at The Union’s Global Conference in Paris 2004.

II. Role of Nurses in Tuberculosis Control Nurses have four fundamental responsibilities: to promote health, to prevent illness, to restore health and to alleviate suffering. The need for nursing is universal (3). In relation to TB, nurses promote health in order to prevent people becoming vulnerable to the disease in the first place; they prevent illness by reducing transmission of TB in the community by finding and treating active cases; they restore health by ensuring that patients receive the treatment they need; and alleviate suffering by organizing support for patients according to their individual needs. Although little is documented specifically about the role of nurses in TB control, a survey carried out by the author Virginia G. Williams confirmed the breadth of their activities in the African, Eastern, Middle Eastern, and Latin American regions. These activities are as diverse as patient support, health education, and sputum collection and service management. The varied work carried out by nurses is also evident in papers describing specific settings such as the community-based treatment of multidrug-resistant tuberculosis in Peru (4) and the care of patients in prison in Thailand (5). Nurses take on a variety of roles at different stages of the patient’s ‘‘journey’’ according to the setting, the required activity, and the individual needs of the patient. These roles include practitioner, educator, coordinator, researcher, and administrator. They are not attributable to any particular person but rather make up different elements, to a greater or lesser extent, of the work carried out by different nurses. It is not just nurses employed or identified as working with the specialist services, but all nurses working with individuals, families, communities, and other services who need to be aware of, and acknowledged for, the part they play in controlling TB. Each of the roles is discussed in detail below in relation to how they coincide with the key elements of the DOTS strategy (Table 1) (1) and a summary of the nursing role is provided in Table 2.

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Table 2 The Five Key Components of the DOTS Strategy (as Stated by WHO, 1a) Sustained political commitment to increase human and financial resources and make TB control a nationwide priority integral to the national health system Access to quality-assured TB sputum microscopy for case detection among persons presenting with, or found through screening to have, symptoms of TB (most importantly, prolonged cough) Standardized short-course chemotherapy for all cases of TB under proper case management conditions including direct observation of treatment Uninterrupted supply of quality-assured drugs Recording and reporting system enabling outcome assessment of all patients and assessment of overall program performance

A. Practitioner

Most nurses who work with TB patients will be recognizable in their role as practitioners. As practitioners, they are involved in activities associated with the clinical aspects of TB control such as finding cases and managing patients on treatment. Case Finding Detection of Tuberculosis Using Sputum Smear Microscopy

When a patient attends a health facility, the health worker they see, frequently a nurse, should be able to recognize the symptoms and make an appropriate referral for tests and diagnosis. Sputum smear microscopy is the test recommended to diagnose the most infectious cases of TB (6), and in some remote areas, nurses carry out the test itself. Where there is no doctor immediately available, nurses may be required to interpret the results of the test and make the diagnosis, referring any patients with inconclusive results to the nearest unit having a qualified medical practitioner. As a rule, the collection of the three sputum specimens required to diagnose TB is a task carried out by most nurses. Much depends on the information given to the patient about how to produce a good sample, where to take it, and when and what to do next. At this stage, the sick person is likely to be feeling anxious on top of feeling unwell, and so they need very clear information. The nurse can address their concerns about the condition itself, especially with regard to the availability of effective treatment should it turn out that they have TB. Managing Patients During the Diagnostic Process

The term ‘‘case management’’ or ‘‘patient management’’ can lead to the assumption that the diagnosis has been made before the patient receives support. This places an emphasis on treatment, but is often detrimental to case finding that deserves equal attention. The way the patient is managed before they are diagnosed will affect the way they view the service if they are

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found to have TB and require treatment. The patient’s trust and confidence in the service is essential at every stage of their ‘‘journey.’’ Detailed records need to be kept wherever the patient is seen, so that they can be traced if their results are positive and they do not attend follow-up appointments. Accessibility of Diagnostic Services

The way patients find their way into the TB service may well affect their attitude toward it in the future. A patient-centered approach to TB care and control (Fig. 1) acknowledges the variety of ways people with TB come to be diagnosed. Good organization, collaboration, and communication are needed so that services are flexible enough to ensure good access to diagnosis, care, and treatment. Nurses working in a variety of settings (e.g., primary health care facilities, community clinics, and hospital in- and out-patient departments) and playing a variety of roles, including generalists and specialists, are key to this flexibility and therefore essential to ensure that people diagnosed with TB successfully start and go on to complete treatment. Managing Patients on Treatment

Managing patients on treatment for TB is arguably the most significant contribution made by a nurse’s role to TB control. Once a patient has been diagnosed with TB, the care they need is likely to be far more complex than simply convincing them to take the pills. Each patient is an individual with a personal combination of needs and concerns, which may not be of any lesser significance to them than their disease (7). Clinical nursing practice uses a systematic approach to providing individualized, patient-centered care referred to as the nursing process (8): a cycle of assessment, planning, implementation, and evaluation. The nursing process offers a scientific basis for decision-making and improves the quality of planning. Actions made explicit during the planning phase allow for evaluation of the effectiveness of the intervention.

Figure 1

A patient-centered model for tuberculosis care and control.

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The model represented in Figure 1 was developed by nurses and combines the nursing process with the DOTS strategy (7). It aims to maintain the necessary standardized approach to treatment and monitoring, while offering individualized patient-centered care. Case finding and patient holding are identified as the two key elements of TB control and are represented in a cyclical format. Firstly, cases are constantly being found, prompting further investigations with further cases being discovered and so on. Secondly, patients’ needs may change during the six months they are on treatment and so constant evaluation and reassessment are needed in order to ensure that appropriate care is given at every stage of the patient’s treatment. Assessment

One of the most important steps of patient management is needs assessment, because this will form the basis of the care given to each patient and enable the patient to adhere to the treatment regimen. Even in resource-poor settings, it is possible to assess patients at least in terms of the information they might need and concerns they may have with regard to the disease and its treatment. An initial needs assessment offers the opportunity to learn about each patient by addressing the patient’s problems, prioritizing them, and identifying goals with the patient to minimize their problems and prevent complications during treatment. If their needs are ignored, their ability to adhere to treatment may be compromised. Nurses will assess the patient on an ongoing basis to monitor their progress and keep up-to-date with any changes, which may effect treatment and care (4). A variety of factors should be assessed including those set out in Table 3.

Table 3 Factors Requiring Initial and Ongoing Assessment Initial needs assessment Knowledge about tuberculosis Attitude to diagnosis Social support available: family; friends; community History of TB treatment: previous treatment problems; potential for repeated default Risk of nonadherence; alcohol abuse; drug abuse; unemployment; homelessness Possible barriers to care: cost; distance between health facility and home; service hours

Ongoing needs assessment Adherence Clinical progress at key milestones: 2 mo sputum; 5 mo sputum; completion of treatment Accuracy of medication prescribed Availability of drugs Ability to attend doctor’s appointments, and clarify any confusion and/or questions Anything that could disrupt treatment: side effects; pregnancy; bereavement; conflicting information

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Planning

The main focus of care planning will be on where and when the patient will take the treatment, where and when they need to go for their follow-up appointments, and what to do if they have a problem, e.g., side effects, loss of tablets, and change in location. Actions are discussed and planned with the patient, and their consent obtained, according to actual and potential problems. Planning must above all be realistic, achievable for both the patient and the nurse. There may be different services to which the patient can be referred to meet their particular needs. It is essential to be honest about what is available and not raise expectations about what the service has to offer. Sometimes all that is required is the agreement of the frequency and timing of follow-up and the giving of appropriate information including the exchange of accurate contact details. Good communication and access to the service is essential. Even if nothing can be ‘‘done’’ about a particular problem, the simple act of listening, taking an interest, and offering support demonstrates the fact that the service cares and this alone can be motivating for patients. Implementation

Having assessed and planned the care to be provided with the patient, it is essential to do what was agreed. A range of skills is required to provide care for TB patients, only few of which are clinical such as tuberculin testing, Bacille Calmette-Gue´rin administration, injections, wound care, and so on. Core skills include counselling, communication, and teaching. As discussed below, good organizational skills are also required to ensure, for instance, that the correct medication is available and provided as prescribed. The nurse should record the patient’s progress promptly, clearly, and accurately, and any changes or problems should be referred as appropriate. Obviously, the availability of support services will vary from place to place and necessitates to make the best use of local resources. Evaluation

Good record keeping in the implementation phase will allow for effective evaluation. As well as the factors that need to be assessed on an ongoing basis, there are key points at which the service will evaluate progress (Table 3), most often after two months of treatment, to ensure that the patient is making progress to the point that they are no longer infectious (i.e., sputum conversion has occurred) and at the end of treatment to evaluate and record the treatment outcome. Evaluation is based on more than just clinical or physical signs and should also be associated with how the patient looks, what the patient does, and what the patient says (8). B. Educator Health Education

Health education aimed at patients, families, and communities is an essential part of TB control before, during, and after treatment and a key element

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of the nursing role. It is much more likely that someone will present with symptoms if they recognize them, know where to go to get help, and have confidence that effective treatment is available. Health education is essential for patients being tested as well as for patients known to have TB. From the moment patients begin being investigated for TB, they need clear information, for instance, on how to produce a good sputum sample, where they should take it, and when. It is widely acknowledged that a lack of information can compromise compliance, but simply providing the same information to everyone is not necessarily the solution. It cannot be assumed that all patients will want the same information, because their circumstances often vary a great deal as do their priorities. The same can be said for communities, where health beliefs and previous experiences of the disease vary and health education has to be delivered in a manner, which is locally acceptable and understandable. It is essential to make sure that the patients are getting the information they want and need at the time and in a way that they can understand and digest it. The simplest way of achieving this is by listening carefully to the questions they ask. Patients would often like more information than they are given, with clearer explanations to ensure they understand and regular reiteration because many often forget what is said during a consultation (9,10). Once on treatment, the patient’s need for information is likely to change over time, especially because they start to feel better and may not understand why they should continue to take medication. Although explained at the outset, the need to continue medication needs to be regularly reiterated to take account of the patient’s changing condition and circumstances. Good information throughout treatment, based on what the patient wants to know, is essential. As already mentioned, the patient’s need for information should be one of the factors reassessed during routine follow-up (Table 3). Staff Training and Supervision

Experienced nurses specializing in TB are a valuable source of information for new staff members and health workers in general, particularly in primary and community care settings where patients most often present with symptoms. For instance in Mexico, where it is acknowledged that well-informed nurses can strengthen the National Tuberculosis Programme, a network of nurses and allied professionals has been established to ensure that nurses involved in caring for patients with known or suspected tuberculosis are identified and trained appropriately. This was achieved by training the 60 nurses who formed an existing network across the 32 Mexican states. These nurses then went on to identify and train nurses and allied professionals within their local states, and almost 3000 nurses have participated so far. As well as training, the network offers peer support through regular communication and the interchange of experiences via e-mail, telephone, and fax (11). As well as providing information to staff who may identify suspect cases, nurses also educate a wide variety of people involved in treatment

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support. Macq et al. documented the different approaches to the implementation of directly observed treatment and highlighted the fact that, while nurses may themselves observe the intake of medication, they also play a key role in the educating and supervising directly observed therapy (DOT) supporters in general (12). According to the local setting, these DOT supporters may be community health workers, villagers, family members, or others who are willing, trained, responsible, and acceptable to the patient. In Peru, where community health workers are involved in caring for multidrug resistant cases, supervision by a team of nurses is seen as essential to ensure that a high quality of care is delivered (13). C. Coordinator Ensuring Effective Case Finding and Treatment Support

Good coordination is necessary if the patient is to receive the care they need at diagnosis and during treatment. As well as providing patient care directly and educating others to assist in finding and treating active cases of TB, nurses coordinate a variety of services to meet patients’ physical, social, and psychological needs (4). Treatment outcomes are likely to be better where health care professionals (most often nurses) coordinate care for patients on DOT, through the education and support they give to treatment observers, and on collaboration with other services to meet the patient’s broader needs (4,12,14). It is evident that cure rates remain low when a purely technical approach is used (i.e., focusing on a patient’s drug intake) and that they improve when more complex patient-centered strategies are in place (12). Reducing the Risk of Losing the Patient

The length of treatment and the patient’s changing condition requires a well-coordinated service to maintain contact while the patient is moving through different parts of the service. There are a number of potential ‘‘weak spots’’ that present challenges to tuberculosis control in any setting. These ‘‘weak spots’’ occur when the patient needs to move physically (from the hospital into the community, moving home, and so on) or is asked to use a different service (e.g., referral to a specialist service, delivering sputum specimens to a laboratory service, attending for X-ray, and collecting medication from a pharmacist). However services are organized, it is essential that good communication and close links are maintained between all parts of the service. These factors alone highlight the need for good patient management. Nurses often become a trusted contact person or focal point within the service, who is accountable for guiding the patient through the different stages of diagnosis and treatment, monitoring their progress, and offering support where necessary. This is particularly important when unforeseen events threaten to disrupt the patient’s treatment. Efficient Use of Resources

As a rule, best use needs to be made of invariably limited resources. A wellcoordinated service can have a variety of qualified and nonqualified staff

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involved in patient care according to the individual needs and complexity of each case. For instance, if a physician’s time is taken up with routine, uncomplicated cases, care will be delayed for patients with complex clinical problems (15). In general, a complex clinical case may need regular medical follow-up with nursing support; someone suffering mild side effects may need frequent nursing support, and a patient who was diagnosed early on in their disease may need minimal clinical care, could take their treatment with the support of a local volunteer, and see a nurse for routine follow-up. In this way, patients will receive the most appropriate care for their needs. D. Administrator

Depending on the nurse’s position, their role as administrator could involve anything from maintaining individual patient records to managing services (16) to lobbying for additional funds. Recording and Reporting

Accurate, clear, and prompt completion of patient records and registers are essential for the monitoring of patient progress as well as program performance. Having assessed the program performance at a local level, practical solutions can be sought to address any problems, which have been identified. Good management is required in order to support staff, recognize their contribution, and ensure that their workloads are manageable. In Cape Town, South Africa, there have been some innovative management approaches, which have improved both staff morale and patient outcomes. The City Health Department analyses data down to a facility level and gives regular and prompt feedback. It also uses peer review and assists in problem-solving efforts to achieve quick gains in areas of underachievement, and has a system of incentives so that achievements are recognized (17,18). Recording and reporting often feels remote from the job in hand, especially when the data is simply taken off and analyzed centrally. Analysing the data locally in order to monitor the quality and progress of local TB control activities can highlight local achievements as well as areas needing improvement. Not only does the documentation become more relevant, but also the staff members become more motivated to achieve good results and address local problems. Nurses often have valuable practical suggestions to make as to how services can be improved due to the insight they gain from working closely with patients and the local community. Organization of Services

Apart from personal challenges that may present obstacles to treatment completion, the service itself may create barriers simply by the way that it is organized or because it is facing problems such as a lack of qualified staff. The way a service is managed and organized will ultimately affect the ability of staff to develop the necessary relationships with their patients (16). Nurses are often involved in the management of health services including TB units and, as such, can have an impact on the way services are organized in

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order to ensure good access to patients, good collaboration with a variety of services, and the maintenance of drug stocks and other supplies. An example of the wider administrative role played by nurses was presented during the 35th Union World Conference on Lung Health in October 2004. Jittimanee gave an account of how nurses are involved in a wide variety of activities when involved in providing care for tuberculosis patients in Thai prisons (5). To ensure that they can carry out effective case finding and offer appropriate care, the nurses had to gain commitment from the prison authorities to provide separate accommodation for those suffering with TB and allow for liaison with local health services. They have to collaborate with physicians in health units outside of the prisons, who offer additional clinical expertise and negotiate for medication and other supplies from the relevant authorities. Leadership and Advocacy

An experienced nurse with leadership skills can usefully inform policy and has an important role to play in strategic decision-making, especially in regard to service organization. Advocacy is an important part of this role, including lobbying for extra funds, to ensure that the needs of both the patients and the staff are addressed. In this way, the patients will be able to access appropriate services that the staff will be competent and equipped to provide. E. Researcher Cohort Analysis

Nurses involved in coordinating TB control activities often have to register patients and carry out cohort analysis (5). The compilation and analysis of local quarterly reports can lead to useful insights into local performance and identify where improvements could be made (17). The comparison of local results with regional and national data can provide a useful measure of local performance in general. More specifically, comparing laboratory and patient registers can show what proportion of those diagnosed with smearpositive disease are actually starting treatment, and rates of sputum conversion and treatment rates can demonstrate the effectiveness of patient care. Clinical Audit

Case management addressed from the patient perspective helps us to identify and predict potential risks, plan accordingly, and therefore implement stronger programs. One way of measuring the quality of care is to agree a level of performance for a defined population, i.e., to set standards appropriate to the local setting. It is essential that ‘‘levels of excellence’’ are defined locally in order to foster a sense of ownership and promote professional credibility (19). Standards must be achievable, observable, desirable, and measurable and therefore developed by the members of the staff who will be implementing them (20). The International Council of Nurses has recently published a set of standards for TB care and control, based on

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existing best practice, which can be adapted for local use (21). Once standards are set, it is possible to carry out clinical audit by evaluating practice in line with expected outcomes. Clinical audit can demonstrate the quality of care being delivered, highlight where improvements could be made, and test viability of the standards in a particular setting. Research Projects

Problems identified, as well as providing information about where services need to be strengthened, can form a useful basis for operational research projects. Due to their day-to-day contact with patients and their duty of implementing TB control policies, nurses often have good ideas regarding useful topics for research. Due to the pressure of their workloads, it is rare that nurses can undertake research themselves but support from nursing faculties and other research organizations can make nursing-related research a possibility (4,22). III. Conclusion Nurses play a range of diverse roles in their contribution to TB control, and the aim of each of these roles is to ensure that the patient is successfully diagnosed, actively participates in the treatment process, and is ultimately cured of TB. The technical aspects of the DOTS strategy, although they may be logistically challenging, are straightforward in comparison with delivering care to a wide variety of people of different sexes, ages, and states of health, from different places and with different backgrounds, beliefs, and attitudes. Patient care and management are essential aspects of TB control, and nurses have the experience and expertise to make a vital contribution to TB programs at local, national, and international levels. It cannot be denied that the quality of nursing care varies across different settings, but at the same it can be argued that TB programs themselves could be strengthened by investing in the nursing workforce. This could be achieved by sharing examples of good practice to strengthen overall capacity; ensuring that training is consistent, available, and appropriate to truly reflect the role of nurses in TB control; and supporting research to illuminate the key aspects of patient care, which are essential to the success of any DOTS program. References 1. World Health Organisation. Management of Tuberculosis Training for Health Facility Staff: A Introduction. Geneva: WHO, WHO/CDS/TB/2003.314a, 2003. 2. Williams VG. Developing regional networks of nurses and allied professionals to strengthen DOTS expansion. Int J Tuberc Lung Dis 2003; 7(11 suppl 2):S122. 3. International Council of Nurses. The ICN Code of Ethics for Nurses, 2000. 4. Palacios E, Guerra D, Llaro K, et al. The role of the nurse in the community-based treatment of multidrug-resistant tuberculosis (MDR-TB). Int J Tuberc Lung Dis 2003; 7(4):343–346. 5. Jittimanee S. Nursing care for tuberculosis patients in Thai prisons: challenges and limitations. Int J Tuberc Lung Dis 2004; 8(11 suppl 1):S3.

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6. IUATLD. Management of Tuberculosis: A Guide for Low Income Countries. 5th ed. Paris: IUATLD, 2000. 7. Williams G. Patient Holding in Ed P.D.O. Davies Clinical Tuberculosis. 3rd ed. London: Arnold, 2003. 8. McFarlane of Llandaff Baroness J, Castledine G. A Guide to the Practice of Nursing Using the Nursing Process. London: The CV Mosby Company, 1982. 9. Ley P, Llewelyn S. Improving patients’ understanding, recall, satisfaction, and compliance. In: Broome A, Llewelyn C, eds. Health Psychology Processes and Applications. 2nd ed. London: Chapman and Hall, 1995. 10. Boyle SJ, Power JJ, Ibrahim MY, Watson JP. Factors affecting patient compliance with anti-tuberculosis chemotherapy using the directly observed treatment, shortcourse strategy (DOTS). Int J Tuberc Lung Dis 2002; 6(4):307–312. 11. Avena A, Ferreira E, Castellanos M. Organization of the Mexican Tuberculosis Nursing Net. Int J Tuberc Lung Dis 2004; 8(11 suppl 1):S225. 12. Macq JCM, Theobald S, Dick J, Dembele M. An exploration of the concept of directly observed treatment (DOT) for tuberculosis patients: from a uniform to a customised approach. Int J Tuberc Lung Dis 2003; 7(2):103–109. 13. Munoz M, Palacios E, Guerra D, et al. Integral role of community health workers in DOTS-Plus care. Int J Tuberc Lung Dis 2004; 8(11 suppl 1):S116. 14. Munoz M, Palacios E, Guerra D, et al. Creating a social program: formation of an integrated DOTS-plus team. Int J Tuberc Lung Dis 2004; 8(11 suppl 1):S94. 15. Roberts R, Arnold G, Naidoo O. et al. Introducing nurse led TB follow up clinics to streamline services and enhance patient care. Int J Tuberc Lung Dis 2004; 8(11 suppl 1):S228. 16. Dick J, Lewin S, Rose E. et al. Changing professional practice in tuberculosis care: an educational intervention. J Adv Nurs 2004; 48(5):434–442. 17. Azevedo V. Encouraging best practices in TB control. Int J Tuberc Lung Dis 2004; 8(11 suppl 1):S31. 18. Tuberculosis Control Program, City of Cape Town—Metropole Region TB Control Programme: Progress Report 1997–2002. 19. Luthbert JM, Robinson L. The Royal Marsden Hospital Manual of Standards of Care. Oxford: Blackwell Scientific Publications, 1993. 20. Royal College of Nursing. Quality patient care: the dynamic standard setting system. London: RCN, 1990. 21. International Council of Nurses. TB Guidelines for Nurses in the Care and Control of Tuberculosis and Multi-drug Resistant Tuberculosis. Geneva: ICN, 2004. 22. Williams G, Valencia MC, Arrescue AE, Villa STC. Nurses collaborate internationally, regionally and locally to improve tuberculosis control. Nursing and Midwifery Links, March 2004.

22 Involving Community Members in Tuberculosis Care and Control

DERMOT MAHER

JEROEN VAN GORKOM

Stop TB Department, World Health Organization, Geneva, Switzerland

KNCV Tuberculosis Foundation, The Hague, The Netherlands

FRANCIS ADATU-ENGWAU National Tuberculosis and Leprosy Programme, Wandegeya, Kampala, Uganda

I. Introduction Recognition of the principle of community involvement in national tuberculosis programme (NTP) activities is not new. The Ninth Report of the WHO Expert Committee on Tuberculosis in 1974 noted ‘‘it is important that the community should be involved in the program, including its leaders, such as village elders, tribal chieftains, or other influential persons, and the welfare organizations, including the voluntary agencies and laity’’ (1). However, in many countries, tuberculosis control was based mainly on hospitals, to some extent on health centers, and little on community involvement. Community participation was promoted as an essential part of the Primary Health Care (PHC) movement promoted after the Alma Ata Declaration in 1978. Unfortunately, this did not bring about effective tuberculosis control at that time (probably because of the lack of an effective management approach). The potential contribution of communities is now increasingly recognized because of growing awareness, among those directly engaged, of the interdependence of the NTPs and community contribution to tuberculosis control: NTPs need communities to contribute to overcome the limitations of reliance on health facilities in providing 597

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accessible tuberculosis care; and effective community contribution requires a well-organized tuberculosis program. There is also a swing of the pendulum toward again placing communities at the center of public health. The contribution of communities to tuberculosis control represents a particular aspect of the more general issue of community participation in PHC (2). Some commentators have suggested that successful public health in developing countries depends on a recrafted framework, which ‘‘locates organized and active communities at the centre as initiators and managers of their own health’’ (3), and that ‘‘community participation in health extends the reach of health care to the maximum number of people, particularly the poorest and most vulnerable’’ (4). This chapter reviews the main developments over the past decade in community contribution to tuberculosis control, with a focus on the delivery of tuberculosis care as part of NTP activities in high-burden countries. After defining terms, we first provide the historical background to community involvement in tuberculosis care. Secondly, we review the published experience in this area. Thirdly, we set out the principles derived from this experience of community contribution to tuberculosis care as part of NTP activities, and finally, we consider future directions. II. Definition of Terms Tuberculosis control refers to the population perspective, comprising a range of activities under the stewardship of the NTP. Tuberculosis care refers to the individual patient perspective, comprising identification and referral of tuberculosis suspects, diagnosis of tuberculosis, and supporting patients during treatment. Involving community members in tuberculosis care and control includes various activities, such as raising awareness of tuberculosis, advocacy for adequate resources and proper care, identification and referral of tuberculosis suspects for examination, diagnosis of tuberculosis, and supporting patients during their treatment. Where NTPs have formally assessed the role of community members in tuberculosis care and control, the terminology ‘‘community contribution to tuberculosis care’’ has often been used to stress that community activities are a contribution to, and not a substitute for, the activities of the NTP, which retains overall responsibility for tuberculosis control. The term ‘‘community health worker’’ (CHW) or ‘‘community volunteer’’ refers to community members involved in health activities in the community who may or may not receive an incentive but do not receive formal health sector remuneration. A tuberculosis treatment supporter shares the responsibility for the successful completion of treatment with the tuberculosis patient. The support provided to the patient includes psychological and social support, as well as the verification of treatment through directly observed treatment (DOT). This is sometimes referred to as ‘‘communitybased DOT.’’ People who may be a treatment supporter include a relative, friend, employer, CHW, traditional healer, and home-based care provider.

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The systematic contribution of community members to tuberculosis care as part of NTP activities is sometimes referred to as ‘‘community-based TB care’’ or ‘‘community-based DOTS’’ (DOTS being the ‘‘brand name’’ of the internationally recommended tuberculosis control strategy). III. Background In this section, we briefly review the historical background regarding the role of community members in tuberculosis control and review the factors that, from the 1990s onwards, have favored a policy shift toward promoting community involvement. Community involvement in tuberculosis control was very common in many industrialized countries in the first half of the 20th century, at a time of limited state commitment to the organization of tuberculosis control services (mainly based on isolation of infectious patients in sanatoria). The introduction of antituberculosis chemotherapy from the 1950s onwards transformed tuberculosis treatment, which initially remained largely hospital based and in the public sector. Following the demonstration in the 1960s that ambulatory chemotherapy is just as safe and effective as hospital-based chemotherapy, the extent of the shift from hospital-based to ambulatory treatment has very much varied between and within countries. The emergence of resistance to anti-TB drugs highlighted the importance of adherence to treatment, an issue that was not adequately addressed in the era of integration of tuberculosis control measures with the PHC and community participation approach of the 1970s. The development during the 1980s of what became known as the DOTS strategy often relied on a ‘‘vertical’’ approach to program management to support tuberculosis control activities in the PHC system. An essentially ‘‘vertical’’ tuberculosis program is characterized by a specialized organizational structure reaching from national to district and clinic level providing technical and financial support for tuberculosis care in specialized clinics. However, in many countries implementing the DOTS strategy, tuberculosis care delivery is fully integrated in the general health system, and the national program supports tuberculosis control activities through a ‘‘vertical’’ managerial approach that has separate, protected funding mechanisms for safeguarding the essential inputs for tuberculosis control (human resources, antituberculosis drugs, training, monitoring and evaluation, and supervision). This approach in the 1980s gave good treatment results in countries that were mainly exsocialist, had a strong public sector health system, adequate human resources, and a largely accessible network of PHC facilities. A number of trends from the 1990s onwards have favored a policy shift toward promoting community involvement in tuberculosis control: a political trend away from reliance on public sector health service provision in general; increased awareness of the problems associated with reliance on public sector provision of tuberculosis care in particular; and increased awareness of the positive externalities of community involvement in tuberculosis control.

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From the early 1990s onwards, a changing political climate has favored the encouragement of health service provision through a wide range of governmental, nongovernmental, and private sector stakeholders, rather than reliance on the public sector. Worldwide implementation of the DOTS strategy has, therefore, required policy adaptations in different settings, e.g., where the public sector PHC network is poorly developed (particularly in countries in Asia, where the private sector may be more important) or has collapsed under the weight of increasing demand in the face of declining resources, often as a consequence of economic reform programs (particularly in sub-Saharan Africa). Reliance of tuberculosis program service delivery mainly on government health service providers has had to give way to a broader approach to engage the full range of health service providers, including nongovernmental organizations (NGOs), employers, private practitioners, religious organizations, and the community. Until the mid-1990s, tuberculosis program policy in many countries was for inpatient rather than ambulatory treatment during the initial phase. However, this policy proved unsatisfactory for several reasons. Achieving high treatment success rates depends on making treatment available as close and as convenient to the patient as possible (e.g., the home or workplace) and at low cost. A long period of hospitalization is disruptive and costly to patients and their families (e.g., travel costs and opportunity costs), even if the tuberculosis treatment itself is free of charge (5,6). Hospitalization is also expensive for the health care provider. The increasing numbers of tuberculosis cases in countries with high HIV prevalence have resulted in tuberculosis wards filled to overflowing (7). Hospitalization has posed risks of nosocomial transmission of tuberculosis in settings where other patients and staff are often HIV positive and at risk of accelerated development of tuberculosis following infection (8). These problems resulting from hospitalization have forced many tuberculosis programs to explore a policy shift toward decentralized ambulatory tuberculosis care. Before the early 1990s, when tuberculosis control was considered to be primarily the responsibility of governments, WHO and the International Union Against Tuberculosis and Lung Disease (IUATLD) initially promoted implementation of the DOTS strategy through government general health services (9,10). However, the limitations of government health service provision and NTP policy may hinder the achievement of this aim: (i) the access to government health services is inadequate in many countries; (ii) decentralization is insufficient to ensure adequate access to health care; and (iii) human and financial resource requirements often exceed locally available resources. In particular, in sub-Saharan Africa, the dramatic increase in tuberculosis caseload burden in the 1990s (driven by the HIV epidemic) has greatly increased the pressure on existing government health service providers. The need is thus particularly urgent in this region to promote the decentralization of tuberculosis care from hospitals to primary care facilities and beyond, and their integration in the general health services at district level.

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Community involvement in tuberculosis care has the potential to overcome some of the limitations of providing effective tuberculosis care through government health service provision alone, even in the highly decentralized approach using ambulatory treatment (11). The positive externalities of community involvement in tuberculosis control include improved access to tuberculosis treatment at lower cost to the patient and provider. Better access may contribute to improved treatment success and case detection, thus sustaining or improving NTP performance. It may also improve equity through extending access, mobilizing additional resources against tuberculosis, which is a disease of poverty, and improving community oversight and governance of government health facilities. In addition, community involvement can support a patient-centered approach to tuberculosis control, with increased community awareness of the responsibility people have for their own health, which they can exercise in participatory health interventions. IV. Review of Published Experience A. Review of Lessons for Community Involvement in Tuberculosis Control from Other Health Programs

It is useful to review briefly the lessons for community involvement in tuberculosis control from other health programs, drawing on the published literature on community-based health care initiatives (12). Key lessons from the evaluation and review of CHW programs in the 1970s and 1980s concerning recruitment and motivation of community members and the determinants of success are of value to those planning tuberculosis control programs. Concerning recruitment of CHWs, some community-based programs failed to recognize and use existing networks, leaving behind inactive community-based committees and organizations. CHWs and their programs show higher levels of acceptance and lower attrition rates if they come from the community, are identified and selected by the community, and are resident in the community. Selection processes need to be as inclusive as possible, so that as many community members and groups as possible subsequently make use of the CHWs. Gender is an important criterion. Female CHWs may be more diligent and less likely to be motivated by ambition or the hope of material reward, than men. In many settings, CHWs should generally come from the same ethnic or religious group as the community itself. It is important to remain alert to the fact that strict geographical coverage (such as a local government area) may be less important than more functional areas (such as villages served by a particular trading center), and that these networks may change over time. Factors that play a vital role in the motivation of CHWs are support from health service staff and the community, supervision and training, adequate supplies, and a reasonable activity level. Financial incentives may come from three sources: the government, NGOs, and the community itself, and

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local preferences must be considered if sustainability is to be assured. It may also be important for local community-based organizations to be formed by volunteers, in order to create peer-support mechanisms. Determinants of success have included the following: good collaboration between the general health services and the community group; good education of the CHWs and patients (and their families) targeted by particular health activities; training of CHWs and the health services staff; and a system of regular supervision of community members. Substantial challenges include the following: identification of the leadership responsible for managing the change process and of the appropriate community group; maintaining community motivation; and ensuring good communication links between the different elements of service provision. B. Review of Published Experience of Community Contribution to Tuberculosis Care as Part of NTP Activities

In the late 1990s, review of community contribution to tuberculosis program service delivery at district level in high-burden countries found a limited range of published experience, with a particular dearth in subSaharan Africa (13). This was largely because until then the focus of activities aimed at the creation and strengthening of NTPs in introducing and expanding the DOTS strategy, through the government public health sector, particularly in sub-Saharan Africa. Table 1 shows the important features of these studies of community contribution to tuberculosis care that emphasized the community role in supporting tuberculosis patients to promote adherence to treatment (14–26). Due to declining government resources for health in Africa, together with increased tuberculosis incidence due to HIV, overcrowding of hospital wards, and concerns over limited access to tuberculosis care, WHO coordinated the ‘‘Community Tuberculosis Care in Africa’’ project from 1998 to 2000, which evaluated a policy change, from hospitalizing patients for DOT to offering the option of community DOT (27). The project comprised seven district-based studies in six countries, which evaluated feasibility, effectiveness, cost, and cost-effectiveness of providing community DOT. Table 2 shows the important features of the district-based operational research studies to evaluate community contribution to tuberculosis program service delivery. Providing community DOT required community sensitization, identification of the appropriate community group, training of health staff and community members, referral by the district tuberculosis officer for community DOT, and organization of a reliable drug supply and accurate record keeping. For new sputum smear–positive pulmonary tuberculosis patients, treatment success was significantly higher (p < 0.05) under the new policy of community DOT than under the previous policy of hospitalization in Lilongwe, Malawi, (68% vs. 58%) (28) and Kiboga, Uganda (74% vs. 56%) (29). There was no significant difference (p < 0.05) in the cases of Machakos, Kenya (88% vs. 85%) (30), Cape Town, South Africa

Philippines (14)

Philippines (15) Bangladesh (16)

1978

1990

South Africa KwaZulu (19) Natal

Nepal (20)

Indonesia (21)

1997

1997

1997

Four national demonstration centers North and capital provinces of Sulawesi

South Africa Western (18) Cape

1996

Artibonite Valley

Haiti (17)

Thanas

Two rural slums, one urban slum Manila

Location

1997

1997

Country

Year

Rural

Rural

Rural

Rural

Rural

Rural

TB treatment supervisor

All forms

87% treatment success rate

80% treatment success rate Cure rate more than 85%

90% cure rate

Health-care workers (40–50%), women organization volunteers (50–60%)

(Continued )

88% cure rate

High rates of adherence to treatment (no results of treatment outcome given) More than 85% Community health treatment success workers, lay people, rate in survivors volunteers Community workers, 85% cure rate social workers

Smear-positive Lay volunteers PTB, new and retested Smear-positive Church group PTB volunteers New smearMembers of rural positive PTB advancement committee with financial incentive New smearLay persons and positive PTB former patients, financial incentive All forms Farm workers and volunteers

Form of TB

270 new smear- All forms positive cases, 310 other forms 1797 New smearpositive PTB

535

105

138

1525

144

175

Rural, urban Urban

Number of patients

Setting

Results (standard WHO/IUATLD treatment outcome definitions)

Table 1 Summary of Important Features of Published Studies Describing Schemes of Community Contribution to Tuberculosis Care

Involving Community Members in TB Care and Control 603

Nepal (23)

1996

Eastern and central Nepal

12 provinces

Location

Number of patients Form of TB

TB treatment supervisor

Rural

Rural and urban

928

All forms

Various community volunteers

Village doctor New and 55,213 new previously smear-positive treated cases, 57,629 smearpreviously positive PTB treated smearpositive cases Urban and All forms Health center, periurban family/community, none Rural/ remote 12,000 All forms Health center, family/community

Setting

Treatment completion rate increased from 61% to 85%

90% cure rate among new sm þ PTB cases, 81% cure rate among previously treated sm þ PTB cases 91%, 57%, 34% cure rate, respectively 93%, 87% treatment completion rate for smear-positive and smear-negative cases

Abbreviations: IUATLD, International Union Against Tuberculosis and Lung Disease; PTB, pulmonary tuberculosis. Source: As an updated version of a table of which previous versions have been published in the following papers, Table 1 is reproduced from Elsevier and the Int J Tuberculosis Lung Dis, respectively: 1) Maher D. The role of the community in the control of tuberculosis. Tuberculosis 2003; 83:177–182, and 2) Maher D, van Gorkom J, Gordrie P, Raviglione M. Community contribution to tuberculosis care in countries with high tuberculosis prevalence: past, present and future. Int J Tuberculosis Lung Dis 1999; 3(9):762–768.

Four rural districts in central Sulawesi including 224 villages and 362,000 people 1992– South Africa One district in 1995 (26) northern province

China (22)

1996

1993– Sulawesi 1998 (24,25)

Country

Year

Results (standard WHO/IUATLD treatment outcome definitions)

Table 1 Summary of Important Features of Published Studies Describing Schemes of Community Contribution to Tuberculosis Care (Continued )

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Table 2 Important Features of the District-Based Operational Research Studies to Evaluate Community Contribution to Tuberculosis Program Service Delivery

Country

Study site

Setting

Community organization involved

Kenya Malawi

Machakos Lilongwe

Rural Urban

PHC volunteers ‘‘Guardians’’

Uganda

Kiboga

Rural

South Africa

Rural

Zambia

Hlabisa, KwaZulu/ Natal Guguletu, Cape Town Ndola

Parish development committee Traditional healers

Botswana

Francistown

Urban

South Africa

Treatment regimen for new patients with sputum smear–positive pulmonary tuberculosis 2RHZE/6HE 2R3H3Z3E3/ 6HE 2RHZE/6HE

2R2H2Z2/ 4R2H2

Urban

Tuberculosis NGO

2R5H5Z5E5/ 4R5H5

Urban

Catholic diocese HIV/ AIDS home care program HIV/AIDS home care program

2RHZE/6HE

2RHZE/4HR

Abbreviation: PHC, primary health care.

(67% vs. 65%) (31), Hlabisa, South Africa (77% vs. 75%) (32), and Ndola, Zambia (61% vs. 49%) (33). The reduction in the average cost per patient treated ranged from 36% (Cape Town, South Africa) to 58% (Machakos, Kenya) (34–38). Thus the main benefit of community involvement in tuberculosis control in these pilot projects was cost reduction, rather than improved treatment outcome. In Latin America, there are examples of substantial community involvement in tuberculosis care based upon a variety of well-established community development and community health organizations. Activities include case-finding, community-based DOT, defaulter tracing, support groups, and lobbying local governments. There are, however, very few objective data on the impact of community involvement on treatment outcomes (39). In Asia, there are examples of extensive community involvement in tuberculosis care based on a network of community-based NGOs ranging from very large to the much smaller organizations. In some settings, these NGOs act

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on behalf of the NTP for extensive geographical areas. In others, they act in a much more limited capacity, for example, focusing on community-based DOT in a small area. Treatment outcome data usually show satisfactory cure rates of 80% to 90%, where NTPs work with these NGOs (40). V. Principles of Community Contribution to Tuberculosis Care as Part of NTP Activities The experience of community contribution to tuberculosis program service delivery documented by WHO in several regions has yielded clear policy recommendations for integrating the community contribution to tuberculosis care as part of routine NTP operations (27). The policy recommendations address the following issues: the settings in which community contribution to tuberculosis care is relevant; the necessary steps in planning to increase community contribution to tuberculosis care; the integration of community tuberculosis care with local NTP activities; identifying suitable community groups or organizations; financing; selection, training, and motivation of community tuberculosis treatment supporters; auditing and reporting of results; antituberculosis drug regimens and logistics; and sustainability and expansion of the community tuberculosis care approach. 1. NTPs, health services, HIV/AIDS care and support NGOs, and communities should take steps toward increasing the community contribution to tuberculosis care in their settings.



This is especially so for settings where the tuberculosis caseload is overwhelming currently available resources. Even in those settings not currently experiencing an overwhelming caseload, increasing community contribution, including community-based DOT, may expand access to treatment for underserved patient groups, and may further improve treatment outcomes.

NTPs should extend tuberculosis care to the community in settings where health services are providing the basic elements of the internationally recommended tuberculosis control strategy. Extension to the community improves the scope for increasing access to services that are currently of acceptable quality, but are under some strain (e.g., services are costly or tuberculosis wards are congested). Extension to the community also offers the potential to increase access to tuberculosis services under difficult circumstances (e.g., community poverty, long distances to health facilities, civil disruption, and insecurity). Steps to be taken when planning to increase the community contribution to tuberculosis care include:


Obtain political commitment from local leaders (endorsement of support for approach) and Ministry of Health

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(responsibility for financing to provide start-up and recurrent costs, either directly or by brokering funding from partners). Conduct a situation analysis that includes all tuberculosis services and community contributions to tuberculosis care. Identify all relevant partners who might play a role in enabling community contribution to tuberculosis care. Specify the roles and functions of each partner. Establish the relationship between the partner and functions in the context of the existing health delivery system, in order to build upon and develop current strengths before seeking to develop new systems. Develop a training plan to cater for all the relevant partners and functions. Design and produce training tools (e.g., technical and operational manuals/guidelines and training manuals) tailored to the roles and tasks of the partners. Prepare for training (identify funds, identify relevant facilitators, conduct ‘‘training the trainer’’ sessions, and schedule training). Conduct the training. Monitor and evaluate to identify new needs for training and retraining.

2. Community contribution to tuberculosis care should be closely linked to, or integrated with, local NTP activity.






Community contribution to tuberculosis care should be seen as complementing and extending NTP capacity, not replacing NTP activities. Effective community contributions to tuberculosis care, especially community-based DOT, require a strong reporting system, access to laboratory facilities, and a secure drug supply, through the NTP. Roles of community volunteers need clear and careful definition.

The community and the government should identify tuberculosis as a priority public health problem and agree to take shared responsibility. The NTP should be strong, with all the necessary components in place, particularly an effective recording and reporting system. Tasks of the community tuberculosis treatment supporter may vary but could include the following: support to tuberculosis patients to ensure adherence to treatment (including DOT); promotion of information and education about tuberculosis; referral of tuberculosis suspects for sputum examination; referral of tuberculosis patients on treatment for sputum checks; recording necessary information in DOT cards; referral of patients who have adverse drug reactions; feedback of

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Maher et al. information about treatment outcomes to the tuberculosis team; and involvement in early planning about community contribution to tuberculosis care. They may also provide counseling and support, and help destigmatize the disease. 3. Existing community groups and organizations should be approached to determine how they might be able to make a contribution to community tuberculosis care, rather than setting up new systems, groups, and organizations. For example, home-based care services (whether HIV/AIDS specific or providing a wide range of chronic disease care) represent an opportunity for collaboration with NTPs to include tuberculosis case detection and care. 4. Although community-based DOT is cheaper and more costeffective than hospital-based care, new resources are needed for training and supervising community tuberculosis treatment supporters. Ministries of Health need to ensure adequate financing for the community contribution to tuberculosis care to cover the new costs involved in harnessing this resource, while recognizing that this is a cost-effective approach. Key financing issues include:





Community contribution to tuberculosis care is associated with cost savings but also with new costs, which require new investment. Community contribution to tuberculosis care should not replace government commitment or funding, but should be regarded as complementary and supplementary. Budgets should not be cut because of perceived cost savings—on the contrary, there is a need to manage more patients and to finance new costs. There are urban and rural differences in programs, which may need different approaches to financing and budget levels.

New costs for community contribution to tuberculosis care include one-time start-up costs, e.g., situational analysis, community mobilization, and supervision. Ongoing recurrent costs include training, incentives, supervision, and management at district, regional, and central levels. Potential sources of funds include government, NGOs, and donor agencies. However, government has the primary responsibility for financing and it needs to identify the new costs, put them in a national budget, and seek partners for help with financing. As a general principle, patients should not be asked to fund their own care. 5. The selection of community volunteers and the way in which they contribute to tuberculosis care should involve collaboration between the NTP, tuberculosis patients, community representatives, and community group leaders.

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Identification of suitable community tuberculosis treatment supporters requires consultation with the community and consideration of the benefits for sustainability of using a well-established, rather than a recently established, community group. It is necessary to ensure the selection of volunteers who can be trained to develop good practices, who can maintain confidentiality and who will fit into the relevant team structure specific to the local situation. 6. Training requirements may vary depending on the setting, ranging from short, repeated ‘‘on the job instruction’’ by NTP staff to more formal short courses of instruction supported by regular updates. Training of different categories of health workers at the various levels of the health system as well as training of community members as tuberculosis treatment supporters has been important components in each of the pilot projects. Requirements include definition of the tasks and roles of the community tuberculosis treatment supporters (to ensure an effective working relationship with health workers), identification of relevant groups and categories to carry out the identified tasks, and steps to be taken in management. Booklets to support the community tuberculosis treatment supporter have been developed together with more comprehensive training materials (41). Systematic training of CHWs usually takes place prior to delivery of the relevant community-based health care activity, e.g., provision of oral rehydration solution for childhood diarrhoea. However, in the case of tuberculosis, an alternative to training community members in advance is to train someone at the time of identification of the tuberculosis patient. The advantage of this system is that a trained supporter chosen in discussion with the patient becomes available for each tuberculosis patient at the time of need, thus avoiding potential problems in training a cadre of supporters who wait for the eventuality to arise. This may help to build motivation because the community immediately perceives the problem and thus feels more ownership of the program. 7. Community volunteers need regular support, motivation, instruction, and supervision by NTP staff to ensure that quality outcomes are maintained. Health service support to community tuberculosis treatment supporters, including supervision, requires a system of regular contact between the community tuberculosis treatment supporters and general health service and NTP staff. Regular review meetings and a link person between the peripheral health unit and the community tuberculosis treatment supporters help to foster effective communication. 8. NTPs should consider the motivation of community volunteers, including what incentives, if any, are needed or appropriate.

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Maher et al. Preventing ‘‘dropout’’ of community tuberculosis treatment supporters requires ensuring that they continue to receive whatever is the perceived benefit in a specific setting. Some community tuberculosis supporters may require direct incentives, others may receive incentives ‘‘in kind,’’ whereas others act in a purely voluntary capacity motivated by the perceived benefit to their community. Local communities and programs will decide cooperatively what is most appropriate and effective. Good coordination between these community organizations is important to avoid high turnover of volunteers because of competition based on differences in remuneration or provision of incentives. 9. Conducting regular audit and reporting of results are important to monitor and evaluate the community contribution to tuberculosis care in each program. NTPs should ensure that an effective recording and reporting system is extended into the community, with registers active beyond the peripheral health units. Records need to identify the treatment supporter responsible for each tuberculosis patient for DOT and for recording antituberculosis drug administration on the patient treatment card. The patient needs to keep an identity card with information including type of treatment, type of DOT supervision, sputum results, and other clinical details. NTPs should actively monitor community contribution to tuberculosis care using the standard NTP performance indicators (case-finding and treatment outcomes), information on the numbers of patients choosing different DOT options, and, as they are developed, quality of care indicators. 10. NTPs should ensure an effective, secure, and safe system of supply of antituberculosis drugs to tuberculosis patients and their treatment supporters. The regimens used should be consistent with national guidelines. Drugs should be provided and packaged in ways to promote adherence, e.g., as fixed-dose combinations and in calendar blister packs. Drug regimens: NTPs should choose drug regimens that are consistent with international policy and facilitate community-based DOT. For example, all the ‘‘Community tuberculosis care in Africa’’ projects used oral regimens, with ethambutol instead of streptomycin in the initial phase. Drug formulation and packaging: Drugs should preferably be provided in fixed-dose combinations and in calendar blister packs. Community support to tuberculosis patients can facilitate the use of rifampicin in the continuation phase under the recommended proper case management conditions. Drug stock keeping: There should be an established system of recording drug stocks at all levels. When drugs are provided to health units or sub–health units, a designated person should

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record the amounts received. Standardized forms may be needed for this purpose. Similarly DOT forms will be needed for community-based workers to record drugs given to patients. Drug supplies: The central level NTP should procure anti-TB drugs. Proper and secure storage needs to be assured for all antituberculosis drugs. Security of drugs is important. All attempts must be made to ensure that drugs are not stolen from health units and do not appear in the ‘‘black market.’’ Problems with drug security are likely to contribute to the generation of drug resistance. Drug distribution: There must be a regular supply of anti-TB drugs. This should be quarterly from central level and regional level to the districts. It should be monthly from districts to health units, and possibly twice weekly from health units to CHWs. However, there needs to be flexibility in this approach, and the system adapted to the local situation. The important principle is that the patient has an uninterrupted supply of drugs and that drugs do not leak out of the system. 11. NTPs need to consider the key issues of sustainability and expansion of the community contribution to tuberculosis care, and collaboration with HIV/AIDS programs (leading to integration where demonstrably beneficial). Because loading community members with successive additional responsibilities is generally not sustainable, it is necessary to provide additional support that commensurate with the new responsibilities. Obtaining the commitment of Ministries of Health, NTPs, donor agencies, and NGOs to ensure the sustainability of the community approach requires advocacy and policy development based on results. NTPs should develop costed plans for expansion of the community approach. NTPs should develop clear criteria for choosing the districts targeted for expansion (e.g., NTP performance and problems of access). Ministries of Health should consider opportunities for collaboration between NTPs and HIV/AIDS programs (leading to integration where demonstrably beneficial), e.g., CHW provision of integrated HIV/AIDS and tuberculosis care (provided that the stigma commonly attached to HIV/AIDS does not deter tuberculosis patients from obtaining care from HIV/AIDS groups). VI. The Future Applying the lessons learnt from assessment of community contribution to tuberculosis service delivery in a wide variety of settings is a crucial part of the internationally recommended strategy to expand the control of tuberculosis worldwide. Expansion requires rigorous evaluation. It is also important to encourage further relevant operational research. The main

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focus of the community contribution to tuberculosis control has so far been on community support for tuberculosis patients to promote adherence to treatment, including through DOT. This section describes the development of policies to integrate community contribution to tuberculosis control as part of routine NTP activities, indicates the priority operational research questions, and explores the potential for expanding the scope of community contribution to tuberculosis program service delivery. It is useful to examine first how community contribution to tuberculosis program service delivery relates to the broad trends in international health policy development, notably influenced by the movement for health sector reform, and by the report on the Commission on Macroeconomics and Health (42). Many health sector reform agendas include broadening equitable access to health services and improving health outcomes for poor and vulnerable population groups (43). Measures recommended to improve equity include improved distribution of health services and community oversight (44). Tuberculosis is a disease that overwhelmingly affects poor and vulnerable population groups. Community contribution to tuberculosis program service delivery has the potential to improve equity through improved access to health services and better community oversight, which may also be a means of improving quality (45). In exploring the linkages between health and development, the Commission on Macroeconomics and Health has highlighted the need for increased health coverage of the poor, which requires greater financial investments in specific health sector interventions and a properly structured health delivery system that can reach the poor (42). The Commission identifies as the highest priority the creation of a service delivery system at the local (‘‘close-to-client’’) level, complemented by nationwide programs for Table 3 Operational Research Questions Regarding Community Contribution to Tuberculosis Program Service Delivery
How and why does the community contribution to tuberculosis program service delivery work better in some settings than others?
How can an anthropological perspective contribute to successful implementation and sustainability?
How can community-based tuberculosis programs integrate effectively with local HIV/AIDS care efforts?
In settings where NTPs achieve high rates of treatment success, how can community groups contribute to improved case-finding?
What is the acceptability of community contribution to tuberculosis program service delivery to patients, their families, the community, and health workers?
Which tuberculosis treatment regimens and antituberculosis drug formulations are most practical and effective for use when community members support patients and observe their treatment?
What other research is necessary to improve NTP performance as measured by standard treatment outcome measures?

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major diseases, such as tuberculosis. The changes in international health policy resulting from the report of the Commission on Macroeconomics and Health are likely to favor the international uptake of the policy recommendations on community contribution to NTP service delivery. Global policy guidelines reflect the recommendations arising from the experience of community tuberculosis care documented by WHO. For example, the WHO document ‘‘Treatment of Tuberculosis: Guidelines for National Programs (Third Edition)’’ includes guidance on harnessing the community contribution to supporting tuberculosis patients during their treatment and ensuring treatment success. WHO coordinates a global network of technical assistance to support national level implementation of the internationally recommended strategy to control tuberculosis. Integrating community contribution as part of routine NTP operations requires incorporation of community tuberculosis care policy recommendations at national level, and implementation with the assistance of the technical support agencies. National plans for improving coverage by the internationally recommended strategy should include budgeted plans for community tuberculosis care activities. Community contribution to tuberculosis program service delivery raises several specific operational research questions (Table 3). The future of tuberculosis control depends not only on successfully overcoming technical challenges, but also to a great extent on generating and sustaining political will. Lobbying, advocacy, and social mobilization, led by community organizations, can contribute to pushing tuberculosis control high in the local and national public health agenda. The scope for community involvement in tuberculosis control, therefore, goes beyond the involvement of community members in supporting tuberculosis patients to ensure treatment adherence and contributing to case-finding in the community. Although the organization of health services in many countries with high tuberculosis incidence has not generally allowed communities the opportunity to guide the delivery of health services, ongoing health-care reforms may provide opportunities for this form of community participation. For example, decentralization (one of the most important components of health-care reforms) entails devolution of some power and resources to local level and the creation of mechanisms that allow the participation of the community in the allocation of these resources and in local decisionmaking. Health-care reforms may, therefore, facilitate community involvement in guiding tuberculosis program service delivery within the overall package of health care. References 1. World Health Organization Expert Committee on tuberculosis, 9th report. World Health Organization Technical Report Series No. 552. Geneva, Switzerland: WHO, 1974. 2. Wood CH, de Glanville H, Vaughan JP, eds. Community Health. 2nd ed. Nairobi, Kenya: African Medical and Research Foundation, 1997.

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3. Macfarlane S, Racelis M, Muli-Musiime F. Public health in developing countries. Lancet 2000; 356:841. 4. Rohde J, Chatterjee M, Morley D. Community health and development. In: Rohde J, Chatterjee M, Morley D, eds. Reaching Health for All. Delhi: Oxford University Press, 1993:7–9. 5. Foster SD. Affordable clinical care for HIV-related illness in developing countries. Trop Dis Bull 1990; 87:R1–R9. 6. Saunderson P. An economic evaluation of alternative programme designs for tuberculosis control in rural Uganda. Soc Sci Med 1995; 40(9):1203–1212. 7. Okot-Nwang M, Wabwire-Mangen F, Kagezi VBA. Increasing prevalence of tuberculosis among Mulago Hospital admissions, Kampala, Uganda (1985–1989). Tuberc Lung Dis 1993; 74:121–125. 8. Harries AD, Maher D, Nunn P. Practical and affordable measures for the protection of health workers from tuberculosis in low-income countries. Bulletin of the World Health Organization 1997; 75:477–489. 9. World Health Organization. Treatment of tuberculosis. Guidelines for national programmes. WHO/CDS/TB/2003.313. 3d ed. Geneva, Switzerland: WHO, 2003. 10. Enarson DA. Principles of International Union against Tuberculosis and Lung Disease collaborative tuberculosis programmes. Bull Int Union Lung Dis 1991; 66:195–200. 11. Maher D, Hausler HP, Raviglione MR, et al. Tuberculosis care in community care organisations in sub-Saharan Africa: practice and potential. Int J Tuberc Lung Dis 1997; 1:276–283. 12. Hadley M, Maher D. Community involvement in tuberculosis control: lessons from other programmes. Int J Tuberc Lung Dis 2000; 4(5):401–408. 13. Maher D, van Gorkom JLC, Gondrie PCFM, Raviglione M. Community contribution to TB care in countries with high TB prevalence: past, present, and future. Int J Tuberc Lung Dis 1999; 3:762–768. 14. Pardo de Tavera M, Saturay GV, Marfil L, et al. A model of supervised community participation in the prevention and short-term therapy of TB among the poor in Asia. 24th Conference of the International Union Against TB and Lung Disease, Brussels, 1978. 15. Manalo F, Tan F, Sbarbaro JA, Iseman MD. Community-based short-course treatment of pulmonary TB in a developing nation: initial report of an eight-month largely intermittent regimen in a population with a high prevalence of drug resistance. Ame Rev Res Dis 1990; 142:1301–1305. 16. Mushtaque A, Chowdhury R, Chowdhury S, et al. Control of TB by community health workers in Bangladesh. Lancet 1997; 350:169–172. 17. Olle-Goig JE, Alvarez J. Control of TB in a district of Haiti: directly observed versus non-observed therapy. Int J Tuberc Lung Dis 1997; 1:S68. 18. Dick J, Clarke M, Tibbs J, Schoeman H, Combating TB: lessons learned from a rural community project in the Klein Drakenstein area of the Western Cape. South African Med J 1997; 87:1042–1047. 19. Wilkinson D. Managing TB case-loads in African countries (letter). Lancet 1997; 349:882. 20. Malla P, Bam D, Sharma N. Preliminary report of four demonstration DOTS treatment centres in Nepal. Int J Tuberc Lung Dis 1997; 1:S69. 21. NSL and KNCV. Report of a visit to Sulawesi, Indonesia, Indonesia. Progress report number 7, October 1997. 22. China TB Control Collaboration. Results of directly observed short-course chemotherapy in 112842 Chinese patients with smear positive tuberculosis. Lancet 1996; 10:358–362.

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23. Mathema B, Pande SB, Jochem K, et al. Tuberculosis treatment in Nepal: a rapid assessment of government centers using different types of patient supervision. Int J Tuberc Lung Dis 2001; 5:912–919. 24. Becx-Bleumink M, Wibowo H, Apriani W, Vrakking H. High TB notification and treatment success rates through community participation in central Sulawesi, Republic of Indonesia. Int J Tuberc Lung Dis 2001; 5:920–925. 25. Becx-Bleumink M, Djamaluddin S, Loprang ZF, de Soldenhoff R, Wibowo H, Aryono M. High cure rates in smear positive TB patients using ambulatory treatment with once-weekly supervision during the intensive phase in Sulawesi, Republic of Indonesia. Int J Tuberc Lung Dis 1999; 3:1066–1072. 26. Edginton ME. TB patient care decentralised to district clinics with community-based directly observed treatment in a rural district of South Africa. Int J Tuberc Lung Dis 1999; 3:445–450. 27. Maher D, Floyd K, Sharma B, et al. Community contribution to TB care: practice and policy. Review of experience of community contribution to TB care and recommendations to National TB Programmes. (WHO/CDS/TB/2003.312). 28. Nyirenda T, Harries A, Gausi F, et al. Decentralisation of tuberculosis services in an urban setting, Lilongwe, Malawi. Int J Tuberc Lung Dis 2003; 7(9):S21-S28. 29. Adatu F, Odeke R, Mugenyi M, et al. Implementation of the DOTS strategy for tuberculosis control in rural Kiboga District, Uganda, offering patients the option of treatment supervision in the community, 1998–1999. Int J Tuberc Lung Dis 2003; 7(9):S63–S71. 30. Kangangi J, Kibuga D, Muli J, et al. Decentralization of tuberculosis treatment from the main hospitals to the peripheral health units and the community in Machakos district, Kenya. Int J Tuberc Lung Dis 2003; 7(9):S5–S13. 31. Dudley L, Azevedo V, Grant R, Schoeman J, Dikweni L, Maher D. Evaluation of community contribution to tuberculosis care in Cape Town, South Africa. Int J Tuberc Lung Dis 2003; 7(9):S48–S55. 32. Colvin M, Gumede L, Grimwade K, Maher D, Wilkinson D. Contribution of traditional healers to a rural tuberculosis control programme in Hlabisa, South Africa. Int J Tuberc Lung Dis 2003; 7(9):S86–S91. 33. Miti S, Mfungwe V, Reijer P, Maher D. Integration of tuberculosis treatment in a community-based home care programme for persons with HIV/AIDS in Ndola, Zambia. Int J Tuberc Lung Dis 2003; 7(9):S92–S98. 34. Sinanovic E, Floyd K, Dudley L, Azevedo V, Grant R, Maher D. Cost and cost-effectiveness of community-based care for tuberculosis in Cape Town, South Africa. Int J Tuberc Lung Dis 2003; 7(9):S56–S62. 35. Floyd K, Skeva J, Nyirenda T, Gausi F, Salaniponi F. Cost and cost-effectiveness of increased community and primary care facility involvement in tuberculosis care in Lilongwe District, Malawi. Int J Tuberc Lung Dis 2003; 7(9):S29–S37. 36. Moalosi G, Floyd K, Phatshwane J, Moeti T, Binkin N, Kenyon T. Cost-effectiveness of home-based care versus hospital care for chronically ill tuberculosis patients, Francistown, Botswana. Int J Tuberc Lung Dis 2003; 7(9):S80–S85. 37. Nganda B, Wang’ombe J, Floyd K. Cost and cost-effectiveness of increased community and primary care facility involvement in tuberculosis care in Machakos District, Kenya. Int J Tuberc Lung Dis 2003; 7(9):S14–S20. 38. Okello D, Floyd K, Adatu F, Odeke R, Gargioni G. Cost and cost-effectiveness of community-based care for tuberculosis patients in rural Uganda. Int J Tuberc Lung Dis 2003; 7(9):S72–S79. 39. Jaramillo E. Community contribution to tuberculosis care: a Latin American perspective. (WHO/CDS/TB/2002.304) (Spanish).

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40. Sharma BV. Community contribution to tuberculosis care: an Asian perspective. (WHO/CDS/TB/2002.302). 41. World Health Organization. A guide for tuberculosis treatment supporters. (WHO/ CDS/TB/2002.300). 42. World Health Organization. Report of the Commission on Macroeconomics and Health. Macroeconomics and Health: Investing in Health for Economic Development. Geneva, Switzerland: WHO, 2001. 43. World Bank. World Development Report 1993: Investing in Health. Oxford, United Kingdom: Oxford University Press, 1993. 44. World Bank. Sector strategy: health, nutrition and population. Washington, USA: World Bank, Human Development Network, 1997. 45. Cassels A. Health sector reform: key issues in less-developed countries. WHO/SHS/ NHP/95.4. Geneva, World Health Organization, 1995.

23 Molecular Epidemiology: Its Role in the Control of Tuberculosis

MARCEL A. BEHR

KEVIN SCHWARTZMAN

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

Respiratory Division and Respiratory Epidemiology Unit, Montreal Chest Institute, McGill University, Montreal, Quebec, Canada

I. Introduction In the early 1990s, researchers in microbiology, epidemiology, and public health began to apply recent advances in molecular biology to the study of tuberculosis (TB) transmission. A key step was the development and distribution of a standardized and specific genotyping technique for Mycobacterium tuberculosis, which exploits bacterial polymorphisms in the number and chromosomal location of the insertion sequence IS6110: IS6110-based restriction fragment length polymorphism (RFLP) analysis (1). Since then, researchers and public health authorities have used RFLP analysis (and related techniques) to address a number of epidemiologic questions relevant to TB control, a discipline now known as molecular epidemiology. Careful attention to both elements of the term ‘‘molecular epidemiology’’ is essential to informative molecular epidemiologic analyses. The molecular validity hinges on standardized, reproducible genotyping conducted by trained personnel with suitable quality-control procedures, including appropriate laboratory standards. However, to be meaningful, the genotyping must address specific research and/or clinical questions in 617

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a well-defined epidemiologic context. In this chapter, we briefly describe key molecular techniques, and illustrate their use in outbreak and populationbased studies. We then review important insights from the application of M. tuberculosis genotyping to TB epidemiology and control. Finally, we address methodologic challenges faced by efforts to incorporate ‘‘realtime’’ genotyping toward improved TB control. The genotyping of M. tuberculosis isolates has contributed to major advances in the understanding of the history, global spread and worldwide distribution, and evolution of this pathogen. However, in this chapter we focus on applications most immediately relevant to public health. We highlight and summarize a range of applications of M. tuberculosis genotyping to molecular epidemiology in Table 1. II. IS6110-Based RFLP The standard method for obtaining RFLP patterns from M. tuberculosis DNA is illustrated in Figure 1; technical details are available in a number of publications (1,20,21). Briefly, this method exploits the variable number and chromosomal location of repetitive insertion elements, called IS6110, between different bacterial clones. In order to generate RFLP patterns, whole genomic DNA is extracted and cut with the restriction enzyme PvuII, to generate a large number of fragments of DNA. These fragments are separated on an agarose gel by size, with smaller fragments migrating fastest and therefore traveling the furthest from the wells. Once separated, these DNA fragments are transferred onto a membrane for Southern hybridization. By blotting this membrane for labeled IS6110, it is then possible to determine which genomic fragments contain the IS6110 element, and thereby generate a pattern for each isolate based on the number of IS6110-containing fragments (Fig. 2). Because molecular weight ladders are run in parallel by interpolation across lanes, it is also possible to estimate a size for each of these IS6110containing fragments. The determination of the number and size of these bands is generally done by computer-aided visualization: a computer algorithm assigns putative bands, which are then read by consensus—usually by three members of the laboratory team, who must agree as to the presence of each band, as opposed to a potential artifact of hybridization. Once banding patterns have been generated, the next step involves matching the patterns just obtained to one another, and to any already stored in the relevant database. A perfect match occurs when both the number of IS6110 bands and their molecular weights are the same for two isolates. However, determining ‘‘sameness’’ is not trivial: A key issue in pattern comparison is to first know the type and magnitude of error obtained when repeated analyses of the same DNA are performed. To account for this error, control organisms should be run with each gel in order to permit the laboratory to determine the degree of measurement error for that laboratory. Two sources of error bear consideration: (i) all bands in a (Text continues on page 625.)

IS6110 RFLP

IS6110 RFLP

(4)

Detection of outbreaks in marginalized groups

IS6110 RFLP

Primary technique

(3)

(2)

Reference

Transmission during brief contacts

Outbreak investigations Identification/extent of outbreaks

Issue

East Coast cities, U.S.A.; 1998–2000

Rural counties, Tennessee and Kentucky, U.S.A.; 1994–1996

Comments

(Continued )

Transmission from first patient inferred; documentation of rapid spread and progression to active disease among HIVinfected persons. Many outbreaks subsequently described, using similar approach Demonstrated that not only Outbreak involved 21 transmission, but also rapid persons with active TB; progression to active disease, 18 infected by a single can occur with brief contacts source case; involving HIV-negative transmission persons. Questions raised documented in about virulence of infecting physician’s waiting strain room Results used to inform Outbreak included 20 expanded contact persons with active TB, investigation in relevant among members of an milieu extended network of young gay, bisexual, or transvestite AfricanAmerican males

Main finding

Isolates from 11 patients San Francisco, had similar patterns; U.S.A.; housing those from 2 earlier facility for HIVresidents did not infected persons; 1990–1991

Setting

Table 1 Examples of Applications of Molecular Epidemiology to Tuberculosis Control

Molecular Epidemiology: Its Role in the Control of Tuberculosis 619

Reference

Primary technique

(6)

IS6110 RFLP

Main finding

Denver, U.S.A.; 1988–1994

Indicates that empiric treatment to cover suspected drug resistance can be initiated based on rapid typing, before final culture and drug susceptibility results become available Recognized the frequency of laboratory crosscontamination. Identification of cultures as false-positive can allow clinicians to stop unneccessary treatment if genotyping is conducted promptly

Comments

Community-based design 191 (40%) of 473 cases allowed identification of risk found in RFLP-defined factors (e.g., nonwhite clusters; only 19 had groups, U.S. birth, HIV) and epidemiologic links by settings, and hence targeted conventional contact interventions tracing

False-positive cultures for M. tuberculosis identified in 4% of 199 patients whose isolates were typed

Hospital outbreak, Three patients from a London, U.K. renal unit shared an isoniazid-resistant strain; two others had distinct organisms

Setting

Tuberculosis transmission and control in the community (7) IS6110 RFLP San Francisco, Contribution of U.S.A.; recent transmission 1991–1992 to burden of tuberculosis in the community

Detection of laboratory crosscontamination as cause of falsepositive cultures

Management of individual patients (5) Spoligotyping Rapid identification of drug-resistant disease, in suspected outbreaks

Issue

Table 1 Examples of Applications of Molecular Epidemiology to Tuberculosis Control (Continued )

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IS6110 RFLP

IS6110 RFLP

IS6110 RFLP

(11)

(12)

Impact of tuberculosis control strategies on community transmission

Assessment of public health contact investigation for detection of transmission

IS6110 RFLP

(9)

(10)

IS6110 RFLP

(8)

Transmission within vs. outside the household

Transmission by persons with smear-negative pulmonary tuberculosis Transmission between population subgroups

North Holland province, Netherlands; 1998–2000

Cape Town suburbs, South Africa; 1993–1998 San Francisco, U.S.A.; 1991–1997

Netherlands (nationwide); 1993–1995

San Francisco, U.S.A.; 1991–1996

(Continued )

At least 32 of 183 (17%) Highlighted contribution of smear-negative cases to secondary cases in tuberculosis transmission clusters attributed to and morbidity infection by smearnegative source patients Among 623 Dutch-born Studies have shown variable evidence of transmission cases, 17% attributed to from foreign- to local-born transmission by populations, depending on foreign-born source setting and population cases structure/mixing patterns Stressed the importance of Only 81 (19%) of 433 nonhousehold transmission secondary cases in high-incidence settings reflected household transmission Longitudinal comparisons Incidence rate of detected reduction in shared clustered cases declined isolates among U.S.-born from 10.4 to 3.8 cases patients, as the result of per 100,000 enhanced interventions to reduce transmission in this population Many studies show limits of Although 134 (86%) of contact investigation for 155 clustered patients detection of community were found to have transmission, because of epidemiologic links, 85 casual contacts. Conversely, (63%) of these were contacts who are successfully impossible to detect targeted do not appear in through prospective ‘‘clusters,’’ because of contact investigation treatment of latent infection

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Molecular ‘‘clock’’ of genotypic markers

Methodologic findings Changes in genotype during transmission

Recurrent tuberculosis: relapse vs. reinfection?

Issue

(15)

(14)

(13)

Reference

IS6110 RFLP

IS6110 RFLP

IS6110 RFLP

Primary technique

Main finding

Comments

Netherlands; 1986–1996

New York City, U.S.A.; 1991–1995

Of 253 New York isolates Demonstrated that requirement for strict with characteristic identity of IS6110 banding drug-resistance patterns may lead to phenotype (4 drugs), underestimates of clustering 206 had exactly and of recent transmission matching IS6110 RFLP pattern (17 bands; strain W), while 40 others were identical save for one additional matching band (strain W1) Subsequent investigation Differences in banding suggested that rapidity of pattern found in 27 of changes in banding patterns 546 paired isolates from may differ according to patients with two or disease setting (16) more isolates; suggested half-life of banding patterns was 3.2 years

Not all recurrences reflect Miners in Gauteng 14 of 65 recurrences treatment failure or (22%) involved isolates province, South nonadherence; impact of different from the Africa; 1995 exogenous reinfection varies initial infecting strains with setting and patient factors, e.g., HIV

Setting

Table 1 Examples of Applications of Molecular Epidemiology to Tuberculosis Control (Continued )

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IS6110 RFLP, Spoligotyping, MIRU–VNTR

Spoligotyping

(18)

(19)

Comparison of genotyping techniques for population-based studies

Global distribution and spread of strain families

In locations where genetic Unusual pyrazinamide diversity is limited, shared resistance phenotype in genotypes may reflect history 77 Quebec-born rather than recent patients led to transmission. Interpretation discovery of conserved of typing results should take RFLP patterns and this into account characteristic pncA gene deletion, in the absence of transmission Montreal, Canada; Using IS6110 matches as PCR-based techniques may discriminate too poorly 1996–1998 gold standard for between unrelated isolates, clustering, estimated for population-based sensitivity of research spoligotyping was 83% with 40% specificity; for MIRU–VNTR estimated sensitivity was 52%, with 56% specificity Some strain families are Worldwide; Among 11,708 isolates, ubiquitous, while others are 1995–2002 there were 813 shared restricted to one or only a spoligotypes and 1300 few locations unique spoligotypes. Four strain families accounted for 35% of all isolates

Quebec province, Canada; 1990–2000

Abbreviations: RFLP, restriction fragment length polymorphism; PCR, polymerase chain reaction.

IS6110 RFLP, PCR-RFLP

(17)

Background genetic diversity of M. tuberculosis isolates in geographic areas

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Figure 1 Restriction fragment length polymorphism typing of Mycobacterium tuberculosis, using insertion sequence IS6110. Source: Courtesy of Ms. Allison Scott, Department of Epidemiology and Biostatistics, McGill University, Montreal, Quebec, Canada.

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Figure 2 IS6110 restriction fragment length polymorphism autoradiograph. Lanes 1, 8, 15, and 22 are DNA ladders. H37Ra (the positive control) is in Lane 2. Source: Courtesy of Ms. Allison Scott, Department of Epidemiology and Biostatistics, McGill University, Montreal, Quebec, Canada.

particular lane may give higher estimated molecular weights than is normally observed for those same bands on other gels (lane error), (ii) individual bands within each lane may give slightly different molecular weight estimates, in particular when the thickness of the band makes it difficult to assign an exact weight with confidence. The software used for pattern comparison (e.g., Gelcompar, Applied Math, Kortrijk, Belgium) must therefore be programmed to accept certain degrees of error (typically around 2–5%), so as to account for this variability. Understanding its true extent is a prerequisite to setting the appropriate error threshold, in order to permit valid comparisons of patterns within a database (22). In judging whether two isolates should be considered matched or unmatched, simple matching rules for isolates run on the same membrane no longer suffice when databases exceed 100, or even 1000 genotypes. Permitting too much variation may translate into false-positive matching, whereas not accepting sufficient variability may result in matched genotypes being reported as different.

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Another issue is determining the degree of genotypic matching sufficient to consider the bacteria epidemiologically related. In some studies, authors have considered highly similar RFLP patterns to indicate matching isolates (23), whereas others have considered isolates to be matched only if they share patterns identical by IS6110 and other genotyping modalities (24). Although no firm rules have been established to define genotypic matching, it stands to reason that the criterion should not be fixed, but instead vary according to the context and the question. Just as different thresholds are used to define a positive Mantoux test, it appears reasonable to apply a stricter criterion when comparing isolates from two persons without any known epidemiologic link than would be suitable when comparing serial isolates from the same patient over time. This issue is exemplified in Figure 3 (A), where a clonally related family of bacteria was described in Quebec, Canada, in a setting where the incidence rate is less than 2 per 100,000. Applying loose matching criteria in this setting would clearly suggest a considerable burden of ongoing transmission, when there is no epidemiologic evidence to support epidemic TB.

Figure 3 Illustration of IS6110 restriction fragment length polymorphism patterns for persons from the province of Quebec, Canada. Panel (A) shows pattern similarity among clonally related organisms. Panel (B) shows the diversity of patterns observed among unrelated organisms. Source: From Ref. 17.

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While comparing studies from different settings, it is therefore important to determine the matching criterion employed. The concern about matching criteria is greater in the case of isolates with low numbers of IS6110 elements, typically defined as five copies or fewer, as low-copy isolates are observed to have limited pattern resolution. For certain questions this is not an issue: one can often rule out transmission between two individuals if their patterns are clearly different, and one can often demonstrate exogenous reinfection if a patient’s new strain is clearly different from the one previously isolated. However, in population-level studies, the likelihood of finding matching between two persons by chance alone increases, so these low-copy isolates are generally subjected to secondary typing, to address community-level questions. The other important limitation of RFLP is the need to grow large quantities of bacteria in order to generate sufficient DNA for genetic typing. Because of the slow doubling time of M. tuberculosis, one can expect at least six to eight weeks between obtaining a sputum sample and generating an RFLP pattern. Additionally, it is a normal practice to collect a set of isolates for typing and run them together on a membrane, as a ‘‘batchedanalysis’’; therefore, only the busiest laboratories will normally produce RFLP patterns within three months of the patient diagnosis. It is for this reason that polymerase chain reaction (PCR)-based techniques, which require much smaller amounts of template DNA, have emerged as potential alternative modalities for TB molecular epidemiology. These PCR-based techniques may potentially be better suited to outbreak investigations, because they can greatly reduce delays associated with IS6110-based RFLP. III. Spoligotyping This modality was developed to exploit the variable presence of spacers in the direct repeat locus. Its inventors used oligonucleotide probes to identify which spacers were present; they coined the term ‘‘spacer-oligo typing,’’ foreshortened to spoligotyping (Fig. 4) (5). Because this is a PCR-based test, the major advantage over RFLP is the need for minimal amounts of DNA. Additionally, because the results appear simply as spot present/ absent, there are generally fewer challenges to interpretation than those detailed above for RFLP, as illustrated by the results obtained in the same rural Quebec example (Fig. 5). However, spoligotyping generally appears to have lower molecular resolution than IS6110-based RFLP, as measured by the number of different patterns generated by each modality in a cross section of isolates (25,26). In an epidemiologic analysis, isolates with unique high-copy RFLP results were subjected to spoligotyping in order to determine the specificity of spoligotype matches; over half of these RFLP unique isolates had a spoligotype match, indicating a specificity of less than 50% (18). While newer spoligotype membranes with more spacers have been developed (27), the specificity of spoligotyping appears insufficient to supplant RFLP.

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Figure 4 Spoligotyping uses 43 unique spacers: for illustrative purposes only a few spacer sequences are drawn above. Up to 43 samples can be applied to the membrane at one time—41 clinical isolates, a negative control (water) and a positive control (H37Ra). A square (&) denotes the presence of a spacer and a dot () denotes the absence of a spacer. Source: Courtesy of Ms. Allison Scott, Department of Epidemiology and Biostatistics, McGill University, Montreal, Quebec, Canada.

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Figure 5 Illustration of spoligotype patterns generated for the same isolates depicted in Figure 2. Compared to IS6110 restriction fragment length polymorphism, the greater ease of interpretation of patterns is evident; however, there are fewer distinct patterns. In panel (A), the shared deletion of two spacers is seen for all members of the clonally related group of isolates. Source: From Ref. 17.

Therefore, for community-based transmission studies, this modality will likely remain a secondary typing method, to support other techniques. However, because of its ease and interlaboratory reliability, spoligotyping has been extremely useful for characterizing larger strain groupings, and for describing the worldwide distribution of M. tuberculosis strains, as discussed later in this chapter. Another specific application has addressed the control of bovine TB (28). IV. Mycobacterial Interspersed Repetitive Units—Variable Number of Tandem Repeats A newer PCR-based typing modality involves testing for different copy number of repetitive units throughout the M. tuberculosis genome. Originally

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demonstrated with five tandem repeats (29), subsequent iterations have been developed with 12 repeats (30) and the potential for automation. With this modality, all isolates provide an amplicon with each primer pair, but the size of the amplicon varies in a quantum fashion, based on differences in amplicon length that are multiples of the repeat size (Fig. 6). These results are therefore less subject to varying interpretation, because one can readily determine if a tandem repeat is present in three, four, or five copies. As with spoligotyping, this method employs PCR, so it requires minimal quantities of bacterial DNA. It therefore lends itself to direct testing in the reference lab. However, the discriminatory capacity of mycobacterial interspersed repetitive units–variable number of tandem repeats (MIRU–VNTR) has

Figure 6 Example of polymerase chain reaction (PCR) amplification of a mycobacterial interspersed repetitive units–variable number of tandem repeats locus (MIRU 24) and the resulting gel. The length of the PCR product is estimated using the four DNA ladders loaded on each gel. Source: Courtesy of Ms. Allison Scott, Department of Epidemiology and Biostatistics, McGill University, Montreal, Quebec, Canada.

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not been well characterized until recently. Small studies of outbreak strains demonstrated a comparable molecular clock to IS6110-RFLP (31,32), and highlighted nosocomial transmission (33), but did not address the epidemiologic specificity of matching MIRU–VNTR patterns. In the same study that investigated spoligotype specificity, MIRU–VNTR patterns were also generated, and somewhat surprisingly, the specificity of MIRU–VNTR was little better than spoligotyping. Specifically, 40% of isolates with unique RFLP patterns had matching MIRU–VNTR patterns, translating into a specificity of 60% and a positive predictive value of just 10% (18). The addition of different repeats has recently been reported to provide increased resolution in certain ‘‘ancient’’ strains of M. tuberculosis (34); the potential therefore exists to improve the specificity of this typing method. Whether an improved MIRU–VNTR can return sufficiently specific results for molecular epidemiologic investigations remains to be determined. Ideally, the introduction of this modality, like any other, should be preceded by a head-to-head comparison with IS6110-RFLP results, in order to understand its operating parameters in a defined epidemiologic setting. Table 2 compares attributes of the three major genotyping techniques. V. Molecular Epidemiology in Suspected Outbreaks Prior to the development of IS6110-RFLP, M. tuberculosis organisms could be characterized by phage-typing or phenotypic characterization. Unfortunately, phage-typing is technically cumbersome and many strains cannot be successfully typed. Phenotypic characterization requires the observation of a remarkable and fixed characteristic of the strain under study. For instance, during the Lubeck disaster—in which infants were inadvertently immunized with virulent M. tuberculosis instead of bacille Calmette–Gue´rin—the laboratory substitution was deduced because of the green fluorescence of the Kiel strain of M. tuberculosis (35). The most common phenotype available for tracking organisms is antibiotic susceptibility patterns, but this has two important limitations. First, outbreaks of pan-susceptible organisms will be difficult to characterize. Second, if organisms acquire drug-resistance mutations during person-to-person transmission, the extent of the outbreak will likely be underestimated. Thus, while resistance-based typing led to the suspicion of TB transmission (36), the extent of the problem was difficult to appreciate prior to the advent of IS6110-based RFLP analysis. The application of novel genotyping techniques to outbreak settings served to simultaneously validate the methodology and to address an important epidemiologic question. Because the probability of active disease soon after acquiring M. tuberculosis infection increases dramatically with underlying HIV infection, early outbreak reports emphasized HIV-related health-care settings—notably hospices and inner city hospitals. In a first step, isolates from individuals between whom transmission was highly unlikely were shown to have different IS6110 patterns, demonstrating that sufficient background diversity existed in the community under study (2). Of

Interpretation not usually problematic Yes (identical patterns) No

Use of standard control strains Interpretation not usually problematic Yes (identical patterns) No

Yes (1) Use of standard control strains for intergel variability Variable band assignment by readers: consensus reading No (vary between studies) Relatively frequent: low number of IS6110 copies Yes Yes

Yes No Good

Modest

Yes No High

Poor

Abbreviations: PCR, polymerase chain rection; RFLP, restricted fragment length polymorphism; MIRU–VNTR, mycobacterial interspersed repetitive units–variable number of tendem repeats.

Use in outbreak investigations Use in population-based transmission studies Sensitivity for population-based Unknown, as this was the first studies typing system; usually considered gold standard Specificity for population-based Unknown, as this was the first studies typing system; usually considered gold standard

Universal matching criteria Nontypeable strains

Pattern interpretation

Use of standard control strains

Yes (5)

> 2 mg Southern blot

Amount of DNA required Technique for detection of target element Standardized method for obtaining genotype Measurement of variability Yes (30)

Spacers between repeated DNA Scattered repeated loci in the sequences in the direct repeat genome found in variable locus numbers Nanograms Nanograms PCR PCR

MIRU–VNTR

Insertion sequence IS6110

Spoligotyping

Target DNA element

IS6110 RFLP

Table 2 Comparison of Genotyping Techniques for Tuberculosis Molecular Epidemiology

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note, although this background diversity in RFLP patterns has been amply demonstrated in a large number of studies, this does not guarantee that such RFLP diversity will be found in all epidemiologic settings. The demonstration of a ‘‘founder strain’’ of M. tuberculosis in Quebec, Canada (17), and reports of limited strain diversity in other isolated settings (37,38) highlight the importance of establishing background RFLP diversity before using genotyping to infer TB transmission. Faced with sufficient background RFLP diversity, genetic analysis of isolates from possible outbreak cases then allowed investigators to determine that individuals belonged to ‘‘clusters’’ defined by shared M. tuberculosis genotypes. These reports served to confirm that cases were indeed bacteriologically linked, but provided additional important information. While one might suspect that all cases in the same residence might be part of an outbreak, the demonstration that certain cases had unrelated RFLP patterns, and were therefore not part of the outbreak, served to better define the extent of the transmission chain. In doing so, it was possible to refine estimates of the temporal sequence from transmission events to subsequent active TB cases; in the case of the San Francisco outbreak, the investigators demonstrated the minimal incubation period between exposure and active TB to be less than four weeks (2). Other reports extended these observations to characterize hospitalbased outbreaks of multidrug-resistant tuberculosis (MDR-TB). These again demonstrated the extreme susceptibility of HIV-infected persons to M. tuberculosis and highlighted the need for extensive contact investigation, active case detection, and treatment of latent infection in the context of HIV/AIDS (39–41). Genotyping of these isolates was triggered by the clinical observation of an excess of MDR-TB cases. The genotyping results— coupled with traditional contact investigation—highlighted the extensive spread of TB within hospitals, and underlying deficiencies in infectioncontrol practices. In New York City, these observations led to the recognition of a highly prevalent strain, termed strain W, that spanned a number of defined outbreaks. By characterizing all isolates with the distinctive multidrug-resistance phenotype, Frieden et al. described an outbreak involving 267 patients within 11 hospitals over a four-year span (42). VI. Community-Level Studies Because the utility of genotyping for outbreak studies became evident, researchers began to investigate the extent of outbreaks using communitybased studies. Because outbreak studies demonstrated that certain individuals suspected of being in an outbreak might have different RFLP patterns, it followed that the converse may also apply, i.e., that chains of transmission might be larger than first suspected. Therefore, communitylevel studies differed conceptually, in that all isolates available for study from the community of interest over a given time period were first subjected to genotyping; after that, the RFLP results were employed to define clusters

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within the community. Unlike outbreak studies, community-level investigations identify multiple, distinct RFLP-defined clusters, which may vary tremendously in size. Investigators have generally reported 1.

the proportion of TB patients within the community whose isolates are shared with at least one other patient, estimated by: Number of clustered isolates Total number of isolates genotyped

2.

the proportion of TB patients within the community believed to have developed active TB attributable to transmission which occurred in that community during the time period of interest, estimated by: Number of clustered isolates Number of clusters Total number of isolates genotyped This is often called the ‘‘n-1’’ method: it assumes that for each cluster of n members, one developed reactivation TB and then transmitted the infecting organism to the others. Hence one case is subtracted from each cluster of n members, leaving the remainder as secondary cases (‘‘n-1’’) (43). Note that the specific source case for each cluster need not be determined; the method simply assumes that one (unidentified) cluster member transmitted the infection to the others.

In Switzerland, genotyping of 165 M. tuberculosis isolates from patients diagnosed in Berne (61% of culture-positive cases during 1991– 1992) identified nine clusters of 2 to 22 patients sharing a distinct genotype. The largest cluster (22 patients) resulted primarily from transmission among homeless persons and/or drug or alcohol users, but also involved staff and patrons of a restaurant, and two individuals without identifiable links to the others (44). Although this study did not include all eligible cases in the community, it did suggest that (i) an unexpectedly high proportion of cases reflected recent transmission (as opposed to reactivation); and (ii) standard public health interventions had not identified these links or permitted ‘‘preventive’’ treatment of high-risk contacts. Key studies further highlighted the burden of unexpected transmission in the early 1990s (7,45). In San Francisco (1991–1992), 40% of patients had isolates belonging to RFLP-defined clusters, but only 10% of these (i.e., 4% of all cases) had been linked by conventional contact tracing. Assuming that one (initial) case per cluster resulted from reactivation, it was estimated that 31% of San Francisco cases reflected recent transmission within the city (7). In London, public health authorities similarly documented a higher than anticipated proportion of cases from recent transmission (19% in 1993), coincident with a doubling of case rates in many areas (46).

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Beyond demonstrating the burden of ongoing transmission, these community-level studies also identified epidemiologic risk factors for cluster membership, and hence for ongoing transmission. In the U.S. studies, cluster members were disproportionately nonwhite, U.S. born, and HIV infected—highlighting spread among poor inner-city residents. These findings were central to the redevelopment of TB control strategies—by documenting the extent of the problem, and by guiding public health providers as to key groups or areas to target (47). Community-based molecular epidemiologic studies demonstrated two very different phenomena underlying the increasing incidence (and concentration) of TB within cities: extensive transmission among poor, mainly U.S.-born residents, and reactivation of remotely acquired infection among foreign-born residents, whose numbers were increasing (48,49). Interventions undertaken to reduce community and hospital transmission included: improved contact investigation; broadened use of directly observed therapy for active disease; proactive screening and management of latent TB infection—targeting persons and settings at particularly high risk (HIVinfected persons; hospices, prisons, and rooming houses); and intensified hospital infection-control precautions (11). In San Francisco, a marked drop in TB incidence among U.S.-born residents from 1992 to 1997 reflected the successful adoption of these measures. There was a dramatic reduction in the incidence of clustered cases in the U.S.born, from 13 to 3 per 100,000. Incidence among the foreign-born remained unchanged. Hence the molecular analyses confirmed that intensified control measures successfully reached the targeted groups and settings (11). Similar findings in New York City also suggested the importance of targeted screening and treatment for latent TB, to reduce incidence among the foreign-born (49). Although American investigators found little evidence of transmission between foreign- and U.S.-born TB patients, Dutch researchers estimated that 17% (95% confidence interval, 9–25%) of 623 cases among Dutchborn persons during 1993 and 1995 reflected transmission from foreignborn persons (9). Yet during 1992 and 1999, RFLP typing suggested that only 0.9% of Danish-born TB patients had been infected by Somali-born immigrants to Denmark (the immigrant group with the largest number of TB cases), while 1.8% of the Somali-born TB patients had likely been infected by Danish-born source cases (50). Clearly, the variable estimates for transmission between immigrants and persons born in low-incidence countries reflect important differences in epidemiology—notably differences in risk factors for TB exposure within these countries, and in opportunities for contact between population subgroups. A. Laboratory Cross-Contamination

A practical, but sobering, lesson from molecular typing was the extent of laboratory cross-contamination as the cause of false-positive cultures (51). Because patient samples are batched for decontamination, and certain instruments are used to read sequential culture vials, it is now known that

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different steps in the laboratory detection of M. tuberculosis are prone to false-positive results. Estimates of the extent of this problem have varied between studies, but certain settings have suggested that 3% to 4% or more of cases were misdiagnoses (6,52). Genotyping has thus confirmed crosscontamination when isolates from simultaneously processed specimens were found to share matching DNA, while patients determined to be wrongly diagnosed had only a single positive culture for M. tuberculosis— most often when the diagnosis was judged unlikely from a clinical and epidemiologic standpoint. As a result of these reports, laboratories have instituted measures to minimize the risk of false-positive cultures, and also to ensure that they are promptly detected, before inappropriate treatment is offered. However, these findings emphasize that all laboratories undertaking M. tuberculosis cultures, whether for clinical care or research, need to be mindful about quality control and the risk of falsely positive cultures. B. Further Insights from Tuberculosis Molecular Epidemiology

Molecular epidemiologic studies have afforded other important insights into the development and spread of TB. Case reports and small series showed that some persons with recurrent or persistent active TB had in fact become infected with new mycobacterial strains, which were distinct from the original infection. Genotyping of the original and subsequent isolates clearly demonstrated them to be distinct. Not surprisingly, active TB resulting from reinfection was observed primarily (though not exclusively) in HIV-infected individuals (53,54). The frequency of active disease from reinfection reflects not only individual immune function, but also the probability of encountering M. tuberculosis in the surrounding community. Genotyping has indicated that reinfection is seldom responsible for recurrent TB in low-incidence settings (the United States and Canada) (55). However, in a South African setting with very high TB incidence and HIV seroprevalence, 14 (36%) of 39 cases of recurrent disease among gold miners resulted from exogenous reinfection, based on IS6110 RFLP typing (13). Similar results were observed in the absence of HIV infection in a study from a Cape Town suburb, in which 12 of 16 patients with recurrent TB had reinfection rather than relapse (56). Because of the observed pattern of reinfection causing disease, it was also possible to revisit the definitions of primary versus acquired drugresistance—a classification that previously reflected each patient’s history of prior diagnosis and treatment. Using molecular typing, van Rie et al. demonstrated significant misclassification error, as patients exogenously reinfected with resistant strains would otherwise be classified as having acquired drug resistance during treatment (57). It is now possible to provide a molecular definition of acquired drug resistance: this entails serial isolates with the same RFLP patterns, but different antibiotic susceptibilities. This definition can inform the clinician about the cause of clinical relapse, and also guide researchers seeking to understand risk factors for development of resistance (58).

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Many countries with limited resources limit laboratory diagnosis to acid-fast staining. The use of smear-based diagnosis has been supported by the knowledge that smear-positive cases are clearly more infectious than smear-negative cases; however, the differences in contagion from these groups has previously been difficult to quantify. Using clusters defined by RFLP analysis, investigators estimated the proportion of TB in San Francisco associated with transmission from smear-negative cases, using several different measures. For methodologic reasons, it was not possible to provide a definitive estimate, but rather to determine the minimum proportion of active TB attributable to smear-negative source cases. Whether measured by how many clusters were initiated by a smear-negative source, how many clusters included only smear-negative cases, or how many clustered cases followed only smear-negative cases, the results indicated that at least onesixth of TB in San Francisco was attributable to smear-negative sources (8). Although these results have been used to reconsider hospital infection-control priorities in resource-rich settings, the important lesson may be that smear-negative patients in developing countries are infectious at a time when standard TB workup returns negative results. As long as global TB control relies on a low-sensitivity diagnostic test, significant transmission can occur before the initiation of therapy. C. Limitations

Common to all genotyping methods is the need for sufficient M. tuberculosis genomic DNA for genetic analysis. Consequently, molecular epidemiology of TB has to date been restricted to the study of organisms from persons with active TB. Although sampling organisms from persons with latent infection is presently not feasible, the ability to generate spoligotype patterns from Egyptian mummies attests to recent technical developments in genotyping (59). Therefore, should methods become available for sampling minute quantities of mycobacterial DNA from persons with latent TB infection, it may theoretically be possible to explore bacterial diversity in hosts without clinical active TB. A second issue relevant to latent infection is the fact that the period between acquisition of tuberculous infection and the development of active disease varies from weeks to decades. It therefore follows that the longer the study period, the more likely that investigators will detect secondary cases of active disease, and hence the higher the observed frequency of clustering. However, the transmission so detected will become increasingly remote, limiting potential interventions by health authorities. Therefore, the ideal study duration is probably governed less by considerations about what can be detected, but instead by consideration of what information lends itself to action. In shorter studies (e.g., two to three years), the contribution of recent transmission to TB occurrence will generally be underestimated, as cases observed at the beginning of the accrual period may reflect transmission from unstudied source cases, while cases observed toward the end may give

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rise to secondary cases after accrual is complete. Gaps related to these ‘‘edges’’ can be minimized with longer accrual periods, but then investigators often restrict analysis to rolling ‘‘windows’’ (e.g., two years), in order to exclude clusters of patients whose disease is separated by too many years to be considered recently transmitted (11). Another reason for underestimating the degree of recent transmission is incomplete sampling, for a number of potential reasons. Reasons include incomplete case ascertainment, the inability to recover culture material and/or mycobacterial DNA, and out-migration of secondary cases from the study catchment area before diagnosis (60). When secondary cases are not subject to RFLP analysis, the source case will be misclassified as having a unique RFLP result. As the proportion of cases attributable to recent transmission is usually estimated by the ‘‘n-1’’ method, missed cases that would have belonged to clusters decrease both the numbers of clustered isolates and the number of clusters, and falsely lower estimates of transmission (61). In settings where most clusters are small, missed cases will lead to greater underestimation of transmission than where clusters tend to be large (61). The accuracy of RFLP-defined clustering as an estimate of recent transmission is also influenced by long-term changes in TB incidence, and by the age structure of the population. Clustering studies tend to underestimate transmission in settings where the annual risk of infection has been constant over time (62). Where the infection risk has been decreasing—as in most industrialized countries—they will tend to underestimate transmission in younger age groups, while overestimating transmission among older patients (62,63). However, these biases should not affect comparisons of similar settings (e.g., the same city several years apart, or different cities with similar epidemiologic and demographic parameters) because these parameters are unlikely to change much over short periods. D. The Utility of Molecular Epidemiology in Tuberculosis Control

The application of genotyping techniques to community-based TB epidemiology has provided important insights to public health authorities, as outlined above. TB control staff were able to target intensified interventions to subgroups and settings at particularly high risk for transmission, and to demonstrate the impact of these interventions at a community level. However, the context of these observations must also be emphasized: molecular analyses allowed investigators and health authorities to detect and manage ‘‘pockets’’ of intense transmission in areas of overall low incidence, which had not previously been fully recognized. In high-incidence regions, molecular epidemiologic studies are generally not required to suspect a high burden of community transmission. The relationship between TB incidence and community infection risk was established well before the widespread use of genotyping (64) and evidence of pediatric TB is usually sufficient to indicate significant ongoing TB

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transmission. The study of TB molecular epidemiology in selected high incidence communities is useful in providing a refined picture of TB transmission in such settings, and many of the lessons learned from these few studies are likely applicable to a number of high incidence settings. For instance, a study in two Cape Town suburbs experiencing annual notification rates exceeding 300 per 100,000 provides an insight into transmission patterns in a very high-risk setting. The estimated proportion of cases resulting from ongoing community transmission during 1993 and 1998 was 57% (433 of 765 genotyped cases)—probably an underestimate because of incomplete sampling (10). In this community, the risks of exposure in the surrounding community were so high that of the 433 cases deemed secondary to recent community transmission, only 81 (19%) reflected household spread. Conversely, only 46% of households with two cases or more showed concordance of genotypes between cases; over half of putative household secondary cases stemmed from contagion elsewhere in the community (10). Whether these results indicate that spread occurs outside of the household, or rather that the Western concept of household is artificial in this context, is less important than the practical implications: householdbased public health interventions will likely have only minor impact on this ongoing TB epidemic. These findings are highly relevant to TB control activities in high-incidence areas, where it has often been assumed that infection occurred within households, despite the great potential for exposure elsewhere (65). In low-incidence areas, the proportion of recently transmitted active disease resulting from nonhousehold transmission is variable, and reflects the social and epidemiologic context. When transmission involves transient contacts within marginalized groups, the yield of standard contact investigation is predictably limited. Conversely, in settings where named contacts are successfully targeted for treatment of latent TB—thereby interrupting progression to active disease—RFLP clustering studies must necessarily highlight persons who were missed, because source cases could not or would not name them. For this reason, it should not be surprising that a small proportion of individuals in RFLP clusters had been named in contact investigations. In fact, a higher proportion of named individuals in these clusters raises a different concern: this would imply that individuals were named as contacts, but not successfully reached by interventions to prevent the development of active disease. By this reasoning, in San Francisco and Amsterdam, where only 10% and 6% of clustered patients had connections identified by conventional contact investigation, it can be argued that few identified contacts subsequently developed active TB (7,66). In these settings, a high proportion of clustered TB therefore points to difficulties in identifying contacts, rather than problems in their management. In contrast, studies where standard contact investigation identified the index exposure for more of the clustered TB cases point to individuals for whom preventive interventions were unfortunately unsuccessful (67).

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Using RFLP, it has now been possible to contrast linkages identified prospectively by traditional contact investigations with those suggested retrospectively by ‘‘cluster investigations.’’ A study involving four U.S. jurisdictions found that such retrospective cluster investigations led to the identification of 38% of all epidemiologic linkages found as a result of genotyping, with the remaining 62% identified by conventional contact tracing (68). These data therefore suggest avenues to improved TB control, involving better use of traditional contact data and directions where the scope of investigations might be extended. Retrospective cluster investigations have also led to formal social network analyses, highlighting the importance of shared places, in situations where standard contact questioning based on ‘‘named individuals’’ is poorly informative (69,70). In principle, cluster investigations resulting from population-based genotyping studies can point public health providers toward previously unrecognized contacts, allowing them to target for screening and treatment those previously unidentified persons at highest risk for latent or secondary active TB. However, there is little published evidence thus far to support this premise. Most cluster investigations were reported long after diagnosis of the cases involved. This reflects: (i) the retrospective nature of most genotyping studies; and (ii) the earliest date any cluster can be detected is when at least two cases have been genotyped, by which time transmission has already occurred, and other exposed persons may no longer be identified or found. For instance, in the Netherlands, health authorities have submitted all M. tuberculosis isolates to the national reference laboratory for genotyping since 1993 and in turn, the national laboratory has provided ongoing feedback about newly identified clusters and cluster members to local health authorities since 1995. During the period 1995–2000, 3954 (45%) of 8726 cases reported nationwide belonged to RFLP-defined clusters. ‘‘Cluster feedback’’ to local public health nurses led them to document more than twice the number of epidemiologic links between cases found by contact investigation alone. As in other jurisdictions, specific genotyping results highlighted opportunities for improvement in contact management and infection-control practices. However, contact investigations were reopened or broadened for only 34 cases (0.9% of those clustered)—leading to diagnosis of 71 additional contacts with latent TB, and 12 with smear-negative active disease (71). An important finding from the Dutch national study was that 55% of clustered cases could not be linked epidemiologically at all—even through post hoc cluster investigation. Another study from the Netherlands suggested that meticulous, prospective contact investigation could not be expected to identify even half the cases linked by genotyping with post hoc cluster investigation, because possible contacts were defined by shared, high-traffic places, such that individual contacts could not possibly be named and targeted (12). Although these studies clearly demonstrate the limits of conventional contact investigation, they do not suggest a clear alternative. It has become

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increasingly clear that in the urban setting, public health authorities need to consider places for transmission—as well as individuals at risk. What is less clear is how to focus interventions on the relatively small groups of persons who have shared those environments with contagious TB patients, without having to screen vast numbers of others who may have been to the same stores or used the same buses at different times, for example. E. Genotyping Databases

As in the Netherlands, public health authorities in the United States and the United Kingdom have also implemented large-scale genotyping databases, incorporating all available M. tuberculosis isolates from multiple jurisdictions. However, the Dutch database covers a compact geographic area, while the United States and the United Kingdom databases cover much larger areas, with considerable variation in social and epidemiologic features. Such databases may be useful for documenting the broader spread of unusual strains, such as a multidrug-resistant strain from New York City (14). In principle, broader surveillance of M. tuberculosis genotypes could also alert authorities as to the introduction of distinctive strains with respect to other phenotypes, most notably virulence. To date, a major contribution of these projects has been the availability of high quality reference laboratories to address epidemiologic and public health questions of local interest. For example, most of the work reported by the British laboratory related to outbreak investigations (72). The U.S. National Tuberculosis Genotyping and Surveillance Network has provided useful information about the limits of contact investigation at four of its seven sentinel sites, but much of the data addresses local outbreaks and investigations (68). The need to broaden the network to include all isolates across the country is much less well defined, as genotyping data are only truly meaningful when accompanied by high-quality, consistent epidemiologic and contact information. As molecular typing is most useful for addressing specific scientific or public health questions, the benefits of linking isolates from California to those from Maryland are likely to be limited to situations of suspected transmission events involving patients from these two states. While efforts to compile national and international databases of M. tuberculosis genotypes have initially addressed technical issues of genotype comparison, the epidemiologic questions best answered by these databases remain to be further defined. On the other hand, they have provided valuable information about the extent to which strain ‘‘families’’ are spread around the globe. For example, the ‘‘Beijing strain’’ family was initially found to predominate within a group of 69 isolates obtained from Beijing, other Chinese sites, and Mongolia; 52/69 isolates shared at least two-thirds of their IS6110 bands (ranging in number from 15 to 20) (73); furthermore, these strains were also discovered to be genetically similar to the W strain associated with MDR-TB in New York City and other U.S. cities (14). Although

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the number of IS6110 bands varies, DNA obtained from Beijing/W strains share a characteristic spoligotype pattern, known as S00034 (74). The W strain first attracted attention as the result of outbreak studies involving MDR-TB. Interestingly, while the Beijing/W strain was strongly associated with multidrug resistance in New York, in other contexts, it has had either no such association or occasionally an inverse association with drug resistance (75). Although small case series and outbreak characterization in various locations highlighted the broad distribution of this strain family, its true prevalence cannot be established from studies of outbreaks or selected isolates. Only population-based sampling, or comprehensive databases including all available isolates for a given place and time period, can estimate its true prevalence, which has varied from zero in French Guiana and Martinique, to 50% or greater in several Asian locations, e.g., 67% in a random sample of 500 isolates from Hong Kong (75,76). Similarly, the relative prevalence of various strain families in ‘‘global’’ databases will reflect the sampling strategy used, so that results will be driven by countries or areas most heavily represented in the library of isolates under study. However, this limitation is less important when the geographic spread of distinctive strains is evaluated—by documentation of spoligotypes seen in only a few locations (77), or by serial analyses suggesting the importation of new strains into a given location (78). While spoligotyping serves as a convenient marker system to generate such databases, the same spoligotype pattern can arise independently in different bacterial lineages (16). Consequently, the deletion of certain spacer oligonucleotides, although providing a molecular signature for epidemiologic purposes, cannot be relied upon to serve as a unique evolutionary signature, undermining their utility in generating phylogenies. In contrast, large genomic deletions have been shown to behave as unique evolutionary polymorphisms, both in the classification of M. tuberculosis complex species (79,80), and in samples of M. tuberculosis sensu stricto organisms (81,82). Consequently, a modified form of spoligotyping has been developed, named deligotyping, which uses the same platform as spoligotyping but detects the presence/absence of large genomic deletions instead of spacer oligonucleotides (83). The use of deletionbased markers should provide a simpler and more robust definition of M. tuberculosis strain families (e.g., Beijing strain, Manila strain); in combination with more rapidly evolving markers used for epidemiologic purposes, it permits an enhanced understanding of the emergence and dissemination of these organisms across space and time. VII. Concluding Thoughts and Future Directions Molecular epidemiology has proved a valuable tool in providing a refined picture of the TB epidemic. At this point, an important question is whether more molecular epidemiology is needed, or whether the lessons from

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well-described high- and low-incidence settings can be applied elsewhere. The most appropriate answer may be a bit of both. In most high-incidence countries, the degree of ongoing transmission has been firmly established by a small number of studies. These data indicate that the risk of infection in the community is so substantial that patients can have dual infection, and that cured patients can develop TB again from reinfection. While alarming, these results still point to the fundamentals of TB control, including efficient case finding and appropriate and complete treatment of TB disease. In low-incidence countries, the risk of outbreaks among HIV-infected persons and others in congregate living settings has now been well established; the genotyping of cases arising in these contexts is unlikely to change public health management. However, there remain situations where confirming or excluding transmission is valuable, for example, when two cases of TB arise within a workplace: an event which might simply reflect independent reactivation of latent infection, or alternatively an unfolding outbreak (3). The latter scenario clearly requires extensive public health intervention, while the former may not. Genotyping the relevant isolates can guide public health providers accordingly. The future of molecular epidemiology may be realized by moving from descriptive research toward real-time genotyping. As noted above, IS6110-based RFLP generally takes months after diagnosis, so that most RFLP-based studies involve batching the isolates for typing, followed by a formal analysis incorporating epidemiologic information after some arbitrary interval, e.g., two years. Although these results have been of great value in describing the epidemiology of TB, results have generally been post hoc. It seems unlikely that many novel insights into TB transmission will result from a second decade of M. tuberculosis genotyping. However, efforts are now under way to employ PCR-based modalities to generate genotype results within the same time frame as other bacteriologic studies, such as classification and antibiotic susceptibility testing. This will clearly demand extra laboratory effort, and the capacity of PCR-based typing methods to provide epidemiologically valid information remains to be demonstrated. But in theory, the integration of ‘‘real-time’’ genotyping results with public health investigations may be the next frontier of TB molecular epidemiology. Rapid typing can flag strains that have already been implicated in clusters, providing an earlier opportunity to mobilize public health efforts. It is also possible that the greatest value of real-time typing will not be the detection of matches, but simply the rapid identification of particular bacterial strains. The capacity of different strains to produce phenotypically distinct disease remains to be demonstrated in human populations. However, recent advances in M. tuberculosis bacteriology have for the first time shown a direct link between a genetic variant, its biochemical impact and a resultant change in host immune response (84). Together with advances in human genetics that increasingly implicate host factors in the pathogenesis of TB (85), an improved understanding of bacterial factors may provide a novel opportunity to intervene. The past

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decade of TB molecular epidemiology has shed light on people who transmit and places where transmission occurs, yielding pragmatic improvements in TB control activities. A refined understanding of why certain host-pathogen combinations result in disease or infection may enable control efforts tailored to an improved biologic understanding of the host-pathogen interaction. Acknowledgments Dr. Behr is the recipient of a New Investigator career award from the Canadian Institutes of Health Research. Dr. Schwartzman is the recipient of a Chercheur-Boursier Clinicien career award from the Fonds de Recherche en sante´ du Que´bec. The authors gratefully acknowledge the assistance of Esther TomKee with the preparation of this chapter, and of Allison Scott with preparation of figures. References 1. van Embden JD, Cave MD, Crawford JT, et al. Strain identification of Mycobacterium tuberculosis by DNA fingerprinting: recommendations for a standardized methodology. J Clin Microbiol 1993; 31(2):406–409. 2. 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. 3. Valway SE, Sanchez MPC, 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. 4. Sterling TR, Thompson D, Stanley RL, et al. A multi-state outbreak of tuberculosis among members of a highly mobile social network: implications for tuberculosis elimination. Int J Tuberc Lung Dis 2000; 4(11):1066–1073. 5. Kamerbeek J, Schouls L, Kolk A, et al. Simultaneous detection and strain differentiation of Mycobacterium tuberculosis for diagnosis and epidemiology. J Clin Microbiol 1997; 35(4):907–914. 6. Burman WJ, Stone BL, Reves RR, et al. The incidence of false-positive cultures for Mycobacterium tuberculosis. Am J Respir Crit Care Med 1997; 155(1):321–326. 7. 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(24):1703–1709. 8. Behr MA, Warren SA, Salamon H, et al. Transmission of Mycobacterium tuberculosis from patients smear-negative for acid-fast bacilli. Lancet 1999; 353(9151):444–449. 9. Borgdorff MW, Nagelkerke N, van Soolingen D, et al. Analysis of tuberculosis transmission between nationalities in the Netherlands in the period 1993–1995 using DNA fingerprinting. Am J Epidemiol 1998; 147(2):187–195. 10. Verver S, Warren RM, Munch Z, et al. Proportion of tuberculosis transmission that takes place in households in a high-incidence area. Lancet 2004; 363(9404):212–214. 11. Jasmer RM, Hahn JA, Small PM, et al. A molecular epidemiologic analysis of tuberculosis trends in San Francisco, 1991–1997. Ann Intern Med 1999; 130(12):971–978. 12. van Deutekom H, Hoijng SP, de Haas PEW, et al. Clustered tuberculosis cases. Do they represent recent transmission and can they be detected earlier? Am J Respir Crit Care Med 2004; 169(7):806–810.

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24 Economic and Financial Aspects of Global Tuberculosis Control

KATHERINE FLOYD Stop TB Department, World Health Organization, Geneva, Switzerland

I. Introduction Tuberculosis (TB) control requires resources, whether they are resources that must be paid for with money or resources that are provided free of any monetary cost. This basic fact means that both financial and economic analyses are highly relevant to TB control. Economics is the study of how goods and services are produced, distributed, traded, and consumed. It has two major components: macroeconomics, which studies the economy as a whole and therefore considers aggregate measures such as national income, economic growth, unemployment, and inflation; and microeconomics, which focuses on the economic behavior of individual actors such as consumers (e.g., patients), firms (e.g., hospitals), or specific sectors (e.g., the health sector), under conditions of resource scarcity. The concept of resource scarcity is important, because it means that economics, including health economics, is concerned with both efficiency and equity—efficiency because the more efficient the use of resources, the greater the amount of goods and services that can be produced with those resources that are available—and equity because when resources are not infinite, access (whether based on willingness and ability 649

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to pay or some nonmarket-based method of resource allocation) is variable. Compared to most other parts of the economy, societies often place relatively high priority on equity in the social sectors, including health care. In the context of TB control, examples of topics addressed by economic studies include whether investment in TB control interventions is an efficient way to use scarce health sector resources, how to improve the efficiency of TB control interventions, analyses of the supply and demand for existing and future TB services or products, how TB affects the socioeconomic status of patients and whether it can cause poverty, the total costs that TB imposes on the national or global economy, and the relationship between TB and economic growth. Topics that are more general but have relevance to TB control include what financial mechanisms to use for raising, allocating, and spending health sector resources in an efficient and equitable manner—for example, whether services should be provided free at the point of access and paid for by a collective financing mechanism such as taxes or social insurance, whether services should be paid for by patients themselves, or whether there should be some combination of both approaches to financing. Economic and financial analyses are closely related. Economists often work on financial analyses; one subdiscipline of economics is financial economics, and financial analysis often draws on the microeconomic theory. Financial analyses are defined as studies of how individuals, businesses, and organizations raise, allocate, and use (spend) monetary resources. In the context of TB control, they can include assessments of what funding is needed for TB control, what funding is available for TB control and what the major sources of financing are, what funding gaps exist, what financial mechanisms are used to distribute funds, and how funds are spent. Analyses of funding and expenditures can cover all sources of funding and expenditures or may focus on a particular subset of these sources—such as national TB control programs operating in the public sector, or patients and their households. An important distinction between economic and financial analyses is that financial analyses focus on resources that are paid for, i.e., monetary resources. In economic studies, both resources that are paid for (‘‘financial costs’’) and resources that are used but not paid for (e.g., voluntary labor) are considered. Examples of topics covered by economic and financial analyses and the reasons why they are important are provided in Table 1. This chapter is structured in four main parts. The first provides an overview of the economic and financial studies of TB control that have been undertaken in recent years and their major findings, according to the topic areas identified in Table 1. The subsection on cost and cost-effectiveness studies is the longest, because the majority of economic studies of TB control fall into one of these two categories. Building on this overview, the next two sections provide details from studies that are both very recent and of particular relevance to TB control efforts in the next decade. The first of these sections covers two cost-effectiveness studies that were completed in 2005. While building on previous work in this area, both studies have (Text continues on page 654.)

Market analysis, i.e., analysis of supply and demand for TB diagnosis and treatment services

Link between TB and poverty

Economic impact of TB at national or household level

Topic

Example

(Continued )

No study has convincingly If TB can be shown to have an important impact demonstrated that TB has an impact on the national economy, this can help to justify on economic growth. There are increased investment in TB control. Even if a several studies that demonstrate the macro-economic impact cannot be demonstrated, economic impact of TB at household micro-economic studies that show a substantial level. In 2006, the World Bank impact at the household level can help to make a commissioned a study of the case for investment in TB control and for public economic impact of TB in Africa. subsidy of diagnosis and treatment. Study of the relationship between TB Evidence for a link between TB and poverty, and and four indicators of poverty in especially evidence on how TB control may help to Liverpool, United Kingdom. This alleviate poverty, can help to justify increased found that TB rates were correlated investment in TB control. This is particularly the with all four indicators (1). case at present, given the importance of poverty in the international development agenda. Study on market supply and demand Understanding consumer and provider behavior in for TB drugs (2001) (2). relation to provision and consumption of TB diagnosis and treatment services can help to identify how to improve equity and efficiency in production and consumption of services (e.g., whether there is a role for regulation of the private sector, use of financial and other incentives); identification of a large market can help make a case for investment in new product development (e.g., new drugs).

Why the topic is relevant to TB control

Table 1 Examples of Economic and Financial Analyses Relevant to Tuberculosis Control

Economic and Financial Aspects of Global Tuberculosis Control 651

Cost-benefit of TB control interventionsa

Cost-effectiveness of TB control interventionsa

Cost of TB control interventionsa

Topic

Example

Financial cost analysis undertaken for Data on the cost of interventions are needed when the Global Plan to Stop TB, developing budgets for TB control. Questions are 2006–2015 (3). frequently asked about what it costs to implement different aspects of TB control. The cost of interventions is needed to assess their affordability in the context of available or potential financing for TB control. Series of cost-effectiveness studies of To assess the relative efficiency of investment in community-based care in Africa TB control compared to other health sector (4–8). interventions (if a generic measure of effectiveness such as DALYs or QALYs is used) and/or to assess the most efficient way to deliver a given TB control intervention. To assess the relative efficiency of investment in TB Analysis of the returns to the United States of America that could arise control compared to any other intervention within from investment in TB control in and outside the health sector. other countries (9).

Why the topic is relevant to TB control

Table 1 Examples of Economic and Financial Analyses Relevant to Tuberculosis Control (Continued )

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Since 2002, WHO has reported on TB control, like health care generally, needs to be financing for TB control in its annual financed. Economic analyses can help to identify global TB control report, with a the most efficient and equitable mechanisms for particular focus on high-burden raising and distributing funds. Data on financing countries (10). Many studies have and expenditures are required to answer frequently been done for health care generally asked questions about how TB control is funded e.g., of social and private insurance and what funding gaps exist, at both global schemes, user fees, contracting, and country level. Identifying where important use of global budgets, different funding gaps exist can help to channel funding reimbursement mechanisms in (from national or international sources) to where it insurance schemes. is needed. Comparisons among countries can help identify possibilities for improving financing of TB control and where there is scope to improve the efficiency with which available financing is used. Access to and use of DOTS services The need for and access to TB control services is in Bangladesh (unpublished). likely to vary according to socio-economic status. Studies of this variation can help to identify problems in existing patterns of service delivery (e.g., if the poor are not using services in proportion to their need for these services), and potential solutions.

a ‘‘Economic evaluation’’ comprises cost, cost-minimization, cost-effectiveness, and cost-benefit studies. Abbreviations: DALY, disability adjusted life year; QALY, quality adjusted life year.

Equity in access to and use of services (especially those that are publicly funded)

Financing of TB control

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a broader geographic scope and cover a wider and more comprehensive range of interventions, while also using a consistent approach to costing, a consistent approach to assessment of how interventions affect transmission, and a generic measure of effectiveness that allows comparisons with other health sector interventions. The next section of the chapter concerns the financial analyses included in the World Health Organization’s (WHO) annual TB control report for 2005 and the Global Plan to Stop TB, 2006– 2015 (3,10). These illustrate recent trends in the financing of TB control and the financial investments that will be needed in the next 10 years. The financial analyses for the Global Plan were undertaken jointly with the epidemiological analyses that underpin the Global Plan, and therefore the results included in this chapter are complementary to those provided in Chapter 1. The fourth and final part of the chapter draws overall conclusions about the existing body of work on economic and financial aspects of TB control and what new work is needed in the next 5 to 10 years. II. Overview of Economic and Financial Analyses Related to TB Control Undertaken in Recent Years A. The Economic Impact of TB at National Level

TB can have an economic impact at the national level in three main ways. First, spending on TB control interventions by governments, the private sector, and individuals uses up national resources. Second, time may be lost from productive work during illness, which in turn may result in productivity losses, i.e., lost economic output. Third, premature mortality causes many years of potentially productive years of life to be lost, which may also result in productivity losses. In practice, quantifying these impacts is difficult, as has been well documented with reference to HIV/AIDS and malaria (11,12). Of the three types of impact, spending on TB control interventions is directly measurable and, therefore, is the easiest to quantify. Even so, while work on National Health Accounts (NHA) is improving information on health sector expenditures from all sources, NHA data for TB specifically are lacking. The most comprehensive data about spending on TB control are those included in the WHO annual TB control reports since 2002, but these are restricted to spending channeled through the public sector and do not include spending in the private or corporate sectors or out-of-pocket expenditures by patients and their households (10). Quantifying productivity losses from morbidity and premature mortality is difficult for a variety of reasons. A simplistic approach to quantifying losses would be to assume that for a given unit of time lost to morbidity or mortality (e.g., one day, one month, or one year), the economic output equivalent to the average productivity of labor is lost. It is well recognized that average productivity can be misleading; therefore, an improvement would be to use estimates of the marginal productivity of labor. Even then, people with TB may not be representative of the working population as a whole, so that using average and marginal productivity figures for the working population

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can produce misleading results. For example, if unemployment rates among TB patients are relatively high or TB patients are disproportionately poor, economic losses may be overestimated using this approach. A further problem with estimating economic losses in this way is that both households and firms can use various coping mechanisms to mitigate the loss of work time by one member or employee—such as making better use of underemployed labor, relying on existing staff to work harder, and substituting ‘‘leisure’’ time for work time. It is also hard to account for the long-term consequences of these coping mechanisms, for example, via their effect on educational enrolment and attainment. These difficulties mean that estimating the economic impact of TB-related morbidity and mortality by aggregating costs estimated at the microeconomic (firm or household) level is problematic, and few attempts have been made. The main relatively recent study is for India, which estimated that the present value (in 1993–1994) of all current and future benefits due to DOTS implementation was US $8.3 billion, equivalent to 4% of the gross domestic product (GDP) at that time. It was argued that the current and future costs of DOTS implementation were likely to be less than US $8 billion, and therefore that TB control using the DOTS strategy would contribute to economic growth (13). An alternative approach that has been used for other major global health problems including malaria and HIV/AIDS is to assess the economic consequences of TB using macroeconomic data. In this case, national economic growth is treated as a dependent variable, and the burden of TB is treated as one of several independent variables. Only one such analysis has been done, the results of which were inconclusive (14). The World Bank commissioned a new study of the economic impact of TB in Africa in 2006. To produce credible results, this study will need to overcome the methodological challenges described above. B. The Economic Impact of TB at Household Level

Although one of the most important causes of death due to infectious disease, TB is a relatively rare disease on a population basis, with about nine million new cases each year among a global population of over six billion people (Chapter 1). Any economic impact from TB at national level is therefore diluted when assessed on average across whole national populations. However, among households directly affected by TB, the impact can be large and is easier to document reliably. (Table 2 summarizes results from studies undertaken during the period 1996–2005). Several studies have reported on the financial expenditures that TB patients and their households incur and/or have made assessments of the cost of time lost from work due to illness, often in the context of cost-effectiveness studies. In developing countries—where the impact is likely to be greatest in relation to household income—these include studies of costs up to diagnosis in Bangladesh (15), Kenya (16), and Zambia (17), costs prior to diagnosis and during treatment in Thailand (18), India (19), and Tanzania (20), and costs during treatment in Bangladesh (21), Botswana (4), Egypt (22), Kenya (5),

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Table 2 Summary of Evidence About the Economic Impact of Tuberculosis at Household Level, 1996–2005 Place and year of study publication

Average costs incurred by patients and their households (year 2001 US$)

Costs up to diagnosis Bangladesh, 1998 (15)

Cost per patient US $267, of which US $125 was lost income and US $122 was medicines. Kenya, 1998 (16) Cost per patient for diagnostic process with smear microscopy and PCR around US $10. Zambia, 1998 (17) Cost incurred by patients US $65, cost incurred by carers US $27. Costs prior to diagnosis and during treatment Thailand, 1999 (18) Mean expenditure pre-diagnosis US $247 for patients with below average income, US $71 for those with above average income, and US $61 for those with income below the poverty line. Mean expenditure after diagnosis US $55 for those with below average income, US $61 for those with above average income, and US $63 for those with income below the poverty line. India, 1999 (19) Total cost US $186 per patient. Expenditures US $64. Wage losses zero for around 50% of patients. Average work days lost 83, with 48 days before treatment and 35 days during treatment. Among employed patients, mean wage losses US $122. Average debt incurred US $44 in rural areas, US $86 in urban areas. Majority of patients took out loans to cover costs associated with TB. Expenditures represented 13% of family income, wage losses 26%, debts 14%. Eleven percent of children discontinued school. Tanzania, 2001 (20) Cost per patient estimated as between US $202 and US $1585. Most of the cost was for productivity losses, ranging from US $168–1506. Expenditures on e.g., examinations, tests, consultations, drugs and transport varied from US $35–79. Costs during treatment Bangladesh, 2002 (21) Patient cost US $11 for community-based care, US $20 for clinic based care. Botswana, 2003 (4) Caregiver cost US $577 for home-based care and US $754 for hospital-based care. Egypt, 2002 (22) Patient cost US $22–77 for outpatient care and US $238–251 for hospital-based care. (Continued )

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Table 2 Summary of Evidence About the Economic Impact of Tuberculosis at Household Level, 1996–2005 (Continued ) Place and year of study publication Kenya, 2003 (5)

Malawi, 2003 (6)

Pakistan, 2002 (23)

South Africa, 1997 (24)

South Africa, 2003 (7) Syria, 2002 (22) Tanzania, 2005 (25)

Uganda, 2003 (8)

Average costs incurred by patients and their households (year 2001 US$) For new smear-positive patients, cost estimated as US $123 with conventional hospital care, US $53 with decentralized treatment including community based care. Cost to family members US $123 and US $53, respectively. For new smear-negative cases, patients incurred costs of US $64 with both treatment strategies; family costs were US $94 with conventional approach and US $40 with decentralized treatment. For new smear-positive patients, patient costs were US $239 with the conventional hospital-based care and US $111 after care was decentralized to include outpatient treatment at local health centers. Patient costs US $24 for unsupervised treatment, US $58 for health facility based DOT and US $32 for community-based DOT. Patient cost US $100 with community-based care and US $296 with conventional treatment including a two-month hospital stay. Patient cost US $119 for clinic care, US $76 where clinic and community options available. Patient cost US $42–43 for outpatient care. Cost per patient around US $100 when communitybased care used, around US $150 when health facility based care relied upon. Patient cost US $95 with conventional hospital-based treatment and US $56 with community-based care.

Abbreviations: PCR, polymerase chain reaction; DOT, directly observed therapy.

Malawi (6), Pakistan (23), South Africa (7,24), Syria (22), Tanzania (25), Thailand (26), and Uganda (8,27). The results suggest that patient costs generally range from around US $50 to US $300 during treatment. Although studies of costs prior to diagnosis are scarce, the data suggest that these costs can be higher than costs incurred during treatment. One study in Bangladesh reported costs of around US $250 prior to diagnosis compared to less than US $50 during treatment (15), and a study in Thailand reported costs prior to diagnosis that were similar or higher than those during treatment (18). C. TB and Poverty

Poverty alleviation is central to the current international development agenda. In this context, demonstrating a link between TB and poverty

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and showing how TB control contributes to poverty alleviation can help to sustain and increase investment in TB control efforts. Poverty has conventionally been defined in terms of monetary income using either an absolute or relative standard. The World Bank’s definition of absolute poverty is living on US $1 or less per day. Many countries use relative measures of poverty, such as falling in the lowest quintile of the income distribution. Recently, the World Bank has used a broader definition of poverty, which considers not only the lack of income but also deprivation in terms of food, housing, knowledge, power, or access to infrastructure and social services. The relationship between TB and poverty is covered in detail in Chapter 45 and for this reason is considered only briefly here. The evidence suggests that variations in income and other proxy indicators of poverty (e.g., poor housing) within and among countries are associated with variations in the burden of TB, with lower rates of TB in higher-income countries, regions, or population groups. There are very limited data about whether TB control efforts reach those living in poverty to the same extent as those who do not or what measures could help to improve their access and treatment outcomes relative to the population of TB cases as a whole. A better understanding of both these issues requires socioeconomic data on patients being treated in TB control programs and similar data for the population of TB cases as a whole; neither kind of data is routinely collected. It also requires more information on existing barriers to accessing and completing treatment, especially among the poorest. Several suggestions for future work on these topics within the context of a ‘‘propoor’’ agenda are included in Table 1 of Chapter 45. The available data clearly show that TB can worsen the socioeconomic status of individuals and households by causing expenditures and wage losses that can be large in relation to income (as described in the previous sub-section of this chapter). However, they do not demonstrate whether or to what extent TB causes poverty, i.e., the extent to which people who were above the poverty line prior to developing TB fall below that line as a consequence of developing TB. Data on socioeconomic status before and after completion of treatment is needed for this purpose, as are currently being collected as part of an evaluation of public–private mix (PPM)-DOTS in Bangalore, India. D. Market Analysis

Market analyses in the context of TB control involve assessing the actual or potential supply of and demand for diagnosis and treatment services, or particular products, e.g., new drugs. This can include analysis of what factors affect demand (e.g., price, quality, and distance to a health facility), and, on the supply side, the quantity and type of providers offering services, how they set prices, and their profit levels. Market analyses can be used to better understand provider and consumer behavior, which in turn can help to design interventions, regulatory schemes, incentives, or other measures to improve the efficiency, quality, and equity of services. They can also be

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Figure 1 Estimated market size for new drugs compared to the cost of new product development, U.S. dollars (millions).

used to assess the potential size and value of the market for a new product, which when compared with development costs may provide a case for investment in new product development. The main recent example of a market analysis related to TB control was undertaken by the Global Alliance for TB Drug Development. This assessed the potential size and value of the market for new drugs (2). The main result was that the market for a new drug was large enough to justify private sector investment in new product development, as long as part of the development costs (those associated with discovery and failure) were funded by the public sector (Fig. 1). E. Cost and Cost-Effectiveness of TB Control Interventions

There have been two recent reviews of studies about the cost and cost-effectiveness of TB control (28,29), which cover the periods 1980–2003 and 1980–2004. The first of these reviews included studies in all countries, whereas the second focused on low- and middle-income countries where the burden of TB is highest. Of the 31 cost studies published in the period 1980–2003, about half were done in the 22 high-burden countries that have been the focus of global TB control efforts in recent years, and about half in high-income countries, principally the United States (Table 3) (29). The major topics covered include costs prior to diagnosis from a health systems or provider perspective, costs during treatment from a health systems or provider perspective, and costs incurred by patients and their households prior to diagnosis and during treatment in developing countries (Table 2). Of the 66 cost-effectiveness studies published in the period 1980– 2003, about one-third were done in the 22 high-burden countries (29). As

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Table 3 Summary of Cost Studies of Tuberculosis Control by Topic and Location, 1980–2004

Topic Diagnosis and treatmentb Patient/household costs Infection control Screening Standard vs. shortcourse chemotherapy Other All

North America

Western Europe/ Japan

22 highburden countriesa

Other

Total

6

2

6

1

15

0

0

5

1

6

5 2 0

0 1 0

0 0 2

0 0 0

5 3 2

0 13

1 4

0 13

0 2

1 32c

a

The 22 high-burden countries are defined as the countries that ranked 1st to 22nd in terms of total estimated cases in 1998, and which account for around 80% of the total estimated number of global cases. They are India, China, Indonesia, Bangladesh, Pakistan, Nigeria, the Philippines, South Africa, Ethiopia, Vietnam, the Russian Federation, DR Congo, Brazil, Tanzania, Kenya, Thailand, Myanmar, Afghanistan, Uganda, Peru, Zimbabwe, and Cambodia. b One study is entered twice—once in the ‘‘22 high-burden countries’’ category and once in the ‘‘Other’’ category. c The total is 32 studies, rather than the 31 studies reported in the text, because one study is entered twice (see noteb). Source: From Ref. 29.

with cost studies, more than half of all cost-effectiveness studies were undertaken in high-income countries, mainly the United States (Table 4). In high-income countries, studies are dominated by analyses of screening for TB infection or disease, and treatment of latent TB infection (TLTI, also called preventive therapy). In contrast, almost all (28 out of 32, or 88%) of the cost-effectiveness studies that have been done in developing countries have focused on treatment for active TB disease, with 18 out of 32 (56%) studies done in Africa (Tables 4 and 5) (28). Only three studies (all in sub-Saharan Africa) have investigated TLTI, and one study in Indonesia has examined bacille Calmette–Gue´rin (BCG) vaccination. The vast majority of analyses related to treatment in low- and middle-income countries compare short-course chemotherapy with longer ‘‘standard’’ treatment regimens (mainly in the 1980s and early 1990s) or assess alternative approaches to the delivery of short-course chemotherapy (mainly since the late 1990s, with comparisons largely either outpatient treatment at health facilities compared with inpatient care, or health facility–based treatment compared with community-based care) (28). More recently, studies concerning the treatment of multidrug-resistant TB (MDR-TB) and public– private partnerships in TB control have begun to emerge.

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Table 4 Number of Studies on the Cost-Effectiveness Studies of Tuberculosis Control by Topic and Location, 1980–2004

Topic BCG vaccination Screening TLTI (preventive therapy) Diagnostic methods Standard vs. short-course chemotherapy DOTS vs. non-DOTS DOT vs. SAT Short-course chemotherapy strategies (excluding community-based care) Community-based care MDR-TB treatment Other All

North America

Western Europe/ Japan

22 highburden countries

Other

Total

0 11 10 2 0

1 2 1 0 0

0 0 2 1 2

2 3 2 2 2

3 16 15 5 4

0 5 0

0 0 0

2 0 3

0 0 0

2 5 3

0 1 3 32

0 0 0 4

6 2 2 20

2 0 2 15

8 3 7 71a

a

The total is 71 rather than 66 because where studies were done in more than one of the four locations defined, or covered more than one topic, they were counted twice. Abbreviations: DOT, directly observed therapy; SAT, self-administered treatment; TLTI, treatment of latent TB infection; BCG, bacille Calmette-Gue´rin. Source: From Ref. 29.

The principal findings from the cost and cost-effectiveness studies that have been done in low- and middle-income countries are as follows:





Short-course chemotherapy is more cost-effective than the longer standard course chemotherapy regimens that were used to treat TB until the late 1980s. It enables higher cure rates to be achieved, and although drug costs are higher, overall costs are either similar or lower. For example, a study in Malawi, Mozambique, and Tanzania reported a cost per patient cured of around US $300 to $450 (in year 2001 prices) for short-course chemotherapy compared to US $450 to $600 for standard chemotherapy, assuming treatment included a two-month period of hospitalization at the start of treatment (the norm in these countries at the time the study was done in 1989) (30). With outpatient care, it was estimated that these costs would be approximately halved; Short-course chemotherapy for active TB is one of the most costeffective health interventions available. In the World Bank’s World Development Report of 1993, the study from Malawi, Mozambique,

0 0 1 2

0

0 0 3

0

0 0 5

ECA

1 0 0 4

EAP

1 2

0

0

0 0 1 0

LAC

0 1

0

0

0 0 0 1

MNE

0 2

0

2

0 0 0 0

SA

1 18

1

7

0 3 4 2

SSA

0 1

0

0

0 0 1 0

All regions

2 32

1

9

1 3 7 9

Total

1 9

0

0

0 3 1 4

Consider transmission

Abbreviations: EAP, East Asia and Pacific; ECA, Europe and Central Asia; LAC, Latin America and the Caribbean; MNA, Middle East and North Africa; SA, South Asia; SSA, Sub-Saharan Africa; TLTI, treatment of latent TB infection; MDR-TB, multidrug-resistant TB; BCG, bacille Calmette-Gue´rin. Source: From Ref. 28.

BCG vaccination TLTI (preventive therapy) Active case finding and diagnosis Short-course vs. standard chemotherapy, or DOTS vs. non-DOTS Short-course chemotherapy using outpatient or community-based care Treatment of HIV-positive TB patients Treatment of MDR-TB All interventions

Topic

Table 5 Number of Studies on the Cost-Effectiveness of Tuberculosis Control by Topic and World Bank Region in Low- and Middle-Income Countries, 1980–2004

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a

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and Tanzania described above was used to estimate that short-course chemotherapy cost around US $1 to $3 per year of life saved [or disability adjusted life year (DALY) gained] in low-income countries; Outpatient and community-based care strategies are lower-cost and more cost-effective ways to deliver short-course chemotherapy than the conventional hospital-based approaches to treatment, which were widely used (especially in Africa) until the late 1990s. For new drug-susceptible cases treated in DOTS programs, the health system cost per patient treated is generally in the range of US $100 to $200 (in year 2001 prices) in low-income countries when outpatient and community-based approaches to care are used, compared with around US $200 to $350 when treatment includes hospitalization for the first two months. Higher figures of around US $500 to $700 (in year 2001 prices) per patient treated apply to outpatient and community-based care approaches in middle-income countries such as South Africa, with costs of around US $1500 to $2000 when treatment includes a two-month period of hospitalization. Outpatient and community-based care strategies reduce patient costs substantially, with costs incurred by patients ranging from around US $100 to $300 with hospital-based care and from around US $50 to $100 with outpatient or community-based treatment. The societala cost per patient successfully treated, the most commonly used measure of cost-effectiveness in these studies, ranges from around US $200 to $500 for outpatient and community-based care and from around US $700 to $900 for hospital-based strategies in low-income countries, with higher figures of around US $800 to $1300 and US $1500 to $2300, respectively, in middle-income countries; Treatment of MDR-TB using both first- and second-line drugs is much higher cost than treatment for drug-susceptible cases using short-course first-line regimens. In the one published study for low- or middle-income countries, undertaken in Peru and published in 2002, the cost per patient treated was around US $2500. Three recent (as yet unpublished) studies of individualized treatment (i.e., a drug regimen tailored to each patient’s drug susceptibility test results) using first- and second-line drugs found a cost per patient treated of around US $10,000 in Estonia and the Russian Federation and US $3500 in the Philippines. Drug costs were similar in these three settings, with the much higher costs in Estonia and the Russian Federation due to lengthy hospitalization of patients during treatment. The cost per DALY gained was around US $150 to $250 in Peru and the Philippines, and around US $500 in Estonia and the Russian Federation. Compared with widely used benchmarks for assessing the cost-effectiveness of health-care

Includes both health system (provider) and patient costs.

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Floyd interventions (such as a cost per DALY gained of less than per capita income or multiples of per capita income), these results suggest that treatment for MDR-TB can be cost-effective in a range of settings.

The cost and cost-effectiveness studies that were undertaken in low- and middle-income countries between 1980 and 2004 are listed as References 4–8, 15–24, 26, 27, and 30–56. F. Cost-Benefit of TB Control Interventions

Most economic evaluations of health sector interventions in recent years have been cost or cost-effectiveness analyses, and analyses related to TB control interventions are no exception. Cost-benefit analyses, in which health effects (as estimated in cost-effectiveness analyses) are converted into a monetary value, have been rare. This reflects difficulties with putting a monetary value on a year of life, including equity concerns that this favors interventions that benefit wealthier population groups (because one way to value a year of human life is to use the value of the annual income of the population group benefiting from an intervention). A notable recent example is a study of the domestic returns to the United States of investment in TB control in countries that are the source of large numbers of immigrants—Haiti, Mexico, and the Dominican Republic. This suggested that the costs of investment in improving TB control in these three countries were lower than the value of the benefits that would be produced by (a) lower screening and treatment costs in the United States and (b) lower economic productivity losses associated with TB-related morbidity and mortality among immigrants in the United States (9). G. Financing of TB Control

Work on financing of TB control in recent years falls into one of four categories: the theoretical justification for full or partial public financing of TB control; analysis of National Tuberculosis Program (NTP) budgets and expenditures and total TB control costs during the period 2002–2005, with a focus on the 22 high-burden countries; assessments of donor funding for TB control from the mid-1990s to 2004; and projections of the total global funding requirements for TB control over the period 2001–2005 and the decade 2006–2015. The standard economic arguments for public sector intervention in TB control, including public financing of control programs, are based on the existence of market failures. Market failures occur when market-based outcomes are inefficient or inequitable, or both. One reason why market-based resource allocation is inefficient in the context of TB control is the existence of ‘‘externalities’’. These occur when societal costs and/or benefits diverge from individual costs and/or benefits, such that individual decision-making in a free market will produce outcomes that are suboptimal for society as a whole. In TB control, positive externalities exist because the benefits associated with curing patients extend beyond the individual treated, due to the effect of successful treatment on preventing transmission to others. Negative externalities exist because poor treatment can slow transmission to other individuals and can also generate drug resistance, which causes the overall costs of

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effective treatment to rise. Other market failures include problems with protecting individuals from catastrophic financial risks through insurance schemes, with market-based outcomes leaving large numbers of people uninsured. A useful review of market failures in TB control and their implications for public intervention including public financing is provided in Jack 2001 (57). Two studies of donor funding for TB control, the first conducted in the late 1990s and the second in 2005, show that total funding increased from US $16 million per year in 1991 to over US $400 million per year by 2004 (58,59). Studies of donor funding provide only a partial picture of funding for TB control, however, and analyses of TB control financing need to be set in the context of contributions from high-burden countries themselves. Financial analyses of TB control begun by WHO in 2002 as part of its routine assessment of global TB control include assessment of financing of NTP budgets and total TB control costs from all sources, and further details are provided in section IV. Assessments of total funding needs for global TB control have been conducted by the Stop TB partnership as part of the development of the first and second Global Plans to Stop TB, which cover the periods 2001–2005 and 2006–2015, respectively. Further details about the second Global Plan are provided in section IV. H. Equity in Access to and Use of Services

Equity in access to and use of resources that have been made available for TB diagnosis and treatment does not mean that everyone is expected to have equal access and equal utilization, but rather that access and use be ‘‘fair.’’ Exactly what is fair is not easy to define, but could include equal access for equal need, as well as greater priority for individuals with more serious disease compared to those with less severe forms of TB. Equal access and use for equal need are difficult to achieve, because the objectives of equity and efficiency are often in conflict. For example, ensuring that everyone has equal access to services is likely to mean much higher costs per person in remote rural areas compared to urban areas. This means that in practice, societies make trade-offs between equity and efficiency. Along with other forms of analysis, economic analyses can be used to quantify who is accessing and using services, and how this is related to variables such as need, financing of services, and socioeconomic status. For health care in general, various studies have shown that the most disadvantaged groups often use health services less in absolute terms and that they do not use collectively financed services in proportion to their financial contribution. Studies for TB specifically are scarce, however, and better evidence is needed to support policy development in this area. Equity in the context of TB control is a topic covered in Chapter 45, and readers should refer to this chapter for a more thorough discussion. III. Major Results from Two Recent Cost-Effectiveness Studies As the previous overview section of this chapter has shown, among the economic and financial studies of TB control undertaken up to 2004, a large

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number have been cost-effectiveness studies. However, what was missing from this set of studies was an up-to-date and comprehensive overview of the value for money provided by current and potential interventions against TB in all major regions of the world, expressed using a common measure of effectiveness and based on a consistent approach to the evaluation of transmission. Even in 2004, there were few data for China, India, and other large countries in Asia, even though Asia carries the largest burden of TB, and only limited information for Latin America and the Caribbean, the Middle East and North Africa, and Europe and Central Asia. Of the 32 studies documented for the period 1980–2004 in low- and middle-income countries, only nine attempted to include an estimate of the benefits gained from reduced transmission (Table 5) and only 10 used a measure of effectiveness that allowed comparison with other diseases (Table 6). Furthermore, when transmission was considered, the benefits were typically assessed through mathematical modeling (using computer simulations) for a particular epidemiological situation, an approach that produces specific solutions for each setting rather than results that are generally applicable. Finally, although the benefits from prevented transmission are much lower when TB is endemic, none of the studies included in Table 4 made a clear distinction between the cost-effectiveness of interventions in epidemic and endemic situations. Two recent studies have helped to address these limitations and provide an updated assessment of the cost-effectiveness of TB control interventions in all major regions of the world where TB accounts for a major share of the burden of disease (28,60). A. Disease Control Priorities in Developing Countries Project

The first of these studies was undertaken as part of the Disease Control Priorities in Developing Countries Project (DCPP) (28). In common with other studies conducted for this project, the cost-effectiveness analyses for TB control were conducted for each of the six World Bank regions, using a standardized methodological framework. This methodological framework included a standardized set of costs valued in year 2001 US$ prices and the use of DALYs gained as a generic measure of effectiveness to allow comparisons to be made among a wide variety of health-care interventions. The major results from this study (Figs. 2 and 3) are as follows:
The cost-effectiveness of TB control depends not only on local costs but also on the local characteristics of TB epidemiology, such as whether TB is epidemic or endemic, whether rates of HIV infection are low or high, and the extent to which drug resistance exists. It also depends on the rate of application of any chosen intervention.
Short-course chemotherapy for the treatment of infectious and noninfectious TB patients within the framework of the DOTS strategy is highly cost-effective for the control of either epidemic or endemic TB (US $5 to US $50 per DALY gained, for regions excluding Eastern and Central Europe). When a new treatment

1 3 0 1

0

0 0 5

0 0 5 0

0

0 0 5

Case averted

2 18

0

10

6

0

0 0

Case cured or successfully treated

2 5

1

0

1

0

1 0

Death averted

0 4

0

0

3

1

0 0

Year of life saved

0 2

0

1

0

0

0 1

QALY gained

1 4

0

0

1

2

0 0

DALY gained

Note: The total for all interventions is greater than the number of studies because some studies use more than one measure. Abbreviations: MDR-TB, multidrug-resistant TB; QALY, quality-adjusted life year; DALY, disability-adjusted life year; BCG, bacille Calmette-Gue´rin; TLTI, treatment latent TB infection. Source: From Ref. 28.

BCG vaccination TLTI (preventive therapy) Active case finding and diagnosis Comparison of shortcourse with standard chemotherapy or the DOTS strategy with non-DOTS treatment Outpatient and/or community-based care using short-course chemotherapy and DOTS Treatment for HIVpositive patients Treatment of MDR-TB All interventions

Topic

Case detected or diagnosed

Table 6 Number of Studies on the Cost-Effectiveness of Tuberculosis Control by Effectiveness Measure and Intervention in Low- and Middle-Income Countries, 1980–2004

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Figure 2 Cost-effectiveness of interventions against endemic tuberculosis. Note: Column 7 is for ambulatory (outpatient) treatment in sub-Saharan Africa. Cost-effectiveness of vaccination and TLTI is calculated for an initial incidence rate of 100 per 100,000 population per year. Abbreviations: EAP, East Asia and Pacific; ECA, Europe and Central Asia; LAC, Latin America and the Caribbean; MNA, Middle East and North Africa; SA, South Asia; SSA, sub-Saharan Africa; TLTI, treatment of latent tuberculosis infection. Source: From Ref. 28.

program is compared with a previous program, implementation of DOTS can save money, as well as prevent cases and deaths.
Some additions to DOTS are less cost-effective, but still represent good value for money. These include treatment of patients with MDR-TB (using either standardized or individualized drug regimens) and treatment of TB patients with HIV infection (with or without supporting antiretroviral therapy). For these additional interventions, the cost per DALY gained is less than the annual average value of per capita economic productivity, even for least-developed countries.
The least cost-effective TB control intervention is TLTI. Where TB is endemic and the population is unaffected by HIV, this costs about US $5500 to US $26,000 per DALY gained. TLTI is more cost-effective during outbreak situations (US $150 to US $500 per DALY gained) and when it is targeted at people who are coinfected with TB and HIV (US $15 to US $300 per DALY gained).
BCG vaccination to prevent severe forms of childhood TB is much less effective than short-course chemotherapy, but nearly as costeffective (US $40 to US $170 per DALY gained).

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Figure 3 Cost-effectiveness of managing epidemic tuberculosis (TB). Note: Five interventions used in the management of TB epidemics that are linked with HIV and MDR-TB (TLTI for people coinfected with TB and HIV; treatment of infectious MDR-TB with a standardized or individualized regimen; treatment of HIV-infected TB patients with TB drugs; treatment of HIV-infected TB patients with TB and antiretroviral drugs) are compared with two standard methods (TLTI, with active disease excluded by X-ray screen; treatment of active infectious disease, allowing for transmission). Cost-effectiveness ratios (plotted on a logarithmic scale) vary with the treatment rate; for illustration here, 20% of eligible people are treated annually with each intervention. Abbreviations: EAP, East Asia and Pacific; ECA, Europe and Central Asia; LAC, Latin America and the Caribbean; MNA, Middle East and North Africa; SA, South Asia; SSA, sub-Saharan Africa; MDR-TB, multidrug-resistant TB; TLTI, treatment of latent TB infection. Source: From Ref. 28.




For any intervention with the potential to cut transmission (that is, excluding BCG vaccination), control of epidemic disease produces more favorable cost-effectiveness ratios than control of endemic disease. This is because the benefits gained from reduced transmission are greater during outbreaks.

B. Cost-Effectiveness of TB Control in the Context of the Millennium Development Goals

The second study that provides a recent assessment of the costeffectiveness of TB control interventions in a range of geographical regions, using a generic measure of effectiveness (DALYs gained) and including analysis of the impact of interventions on transmission, was undertaken as part of a series of cost-effectiveness analyses focused on the five health priorities

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identified in the Millennium Development Goals (60–66). These five priorities are malaria, HIV/AIDS, TB, child health, and maternal and neonatal health. While the analyses in each case covered 14 geographical regions (defined based on epidemiological criteria), the published papers focus on Southeast Asia and Africa. The study on TB considered three interventions: treatment of new smear-positive cases in DOTS programs, treatment of new smear-negative and extrapulmonary cases in DOTS programs, and treatment for MDRTB cases in DOTS-Plus programs (60). All results were expressed in terms of international dollarsb (I$) in year 2000 prices. Costs in I$ are approximately four to five times higher than costs in US$. The main results were that in both regions, treatment of new drugsusceptible cases in DOTS programs was easily the most cost-effective intervention. The average cost per DALY gained was less than I$8 at all geographic coverage levels considered (50%, 80%, 95%), equivalent to about US $2. The next most cost-effective intervention in both regions was combined treatment for both smear-positive and smear-negative cases at a geographic coverage level of 95%. Adding treatment for new smear-negative cases at a 95% coverage level cost I $52 per DALY gained in Southeast Asia and I $95 per DALY gained in Africa. The further addition of treatment for MDR-TB cases in DOTS-Plus programs (i.e., implementation of the full combination of interventions) cost I $123 per DALY gained in Africa and I $226 per DALY gained in Southeast Asia. These results are broadly similar to the DCPP results for epidemic TB (28). The order in which interventions should be introduced according to the cost-effectiveness results (i.e., the ‘‘expansion path’’) was the same for both regions. Treatment for smear-positive cases at a coverage level of 50% would be introduced first. With more resources, geographic coverage would be expanded to 80% and then to 95%. With further funding, treatment of smear-negative cases would be introduced, followed by the addition of treatment for patients with MDR-TB. The order is consistent with the results from the DCPP, whether the comparison is with epidemic or endemic TB. Three main policy implications were identified based on the results. The first was that treatment of smear-positive cases in DOTS programs

b

International dollars are used to account for differences in price levels across countries. Costs in international dollars are calculated by dividing domestic currency amounts by the purchasing power parity exchange rate (as opposed to the official exchange rate which is used for costs in US$). The PPP rate is the amount of domestic currency required to purchase the same quantity of goods and services as US $1 could purchase in the US. As an example, the official exchange rate for Indian rupees to the US$ was US $1 ¼ Rs. 44.9 in 2000, while the international dollar exchange rate was US $1 ¼ Rs. 14.6 (i.e., Rs. 14.6 could buy the same in India as US $1 could purchase in the United States). A cost of Rs. 44.9 in India is equivalent to US $1 and I$3.1. As this example illustrates, costs in international dollars are usually higher than in US$.

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should be the basis of any TB control strategy, as has become standard practice in almost all TB control programs. The second was that there is a strong economic case for treating smear-negative and extrapulmonary cases in DOTS programs and for treating MDR-TB cases in DOTS-Plus programs. This supports the range of interventions included in the WHO’s new Stop TB strategy as well as the Global Plan to Stop TB, 2006–2015 (see section IV). The third was that substantial scaling up of all three interventions is needed in the next 10 years if the Millennium development goals (MDGs) and related targets for TB control are to be reached and that this would require particular attention to improving the case detection rate so that many more TB cases are diagnosed and successfully treated.

IV. Recent Trends in Financing of TB Control and Projected Needs for the Decade 2006–2015 The main recent analyses related to the financing of TB control are included in WHO’s annual report on global tuberculosis control and in the Global Plan to Stop TB, 2006–2015 (3,10). Data from the annual WHO TB control report, which has included financial data since 2002, show that NTP budgets in the 22 high-burden countries increased substantially between 2002 and 2005 (Fig. 4), almost doubling from US $413 million in 2002 (excluding South Africa, because no data were available for this country in any year) to US $741 million in 2005 (also excluding South Africa). Most of the increase was for spending

Figure 4 National TB program budgets by line item 2002–2005, 21 high-burden countries (excluding South Africa).

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on initiatives to increase case detection and cure rates once 100% geographic coverage of DOTS has been achieved (e.g., community-based care, PPM-DOTS, and social mobilization) and investment in capital equipment (typically microscopes and vehicles for supervision). Financing has also increased, notably from high-burden country governments themselves and from the Global Fund for AIDS, TB, and Malaria (GFATM) (Fig. 5). NTP budgets represent the funds that are for activities or inputs specific to TB control, and which are managed by NTP staff. However, these are only part of the financial resources needed to implement TB control services. Health system staff and infrastructure that are shared among many kinds of disease programs and services are also needed for TB control, for example, when TB patients are hospitalized at the beginning of treatment or when they visit general outpatient facilities for DOT or for monitoring of treatment progress. This utilization of general health services accounts for an important share of the costs of TB control (Fig. 6) and increases the share funding for TB control that is provided by high-burden country governments (Fig. 7). Total TB control costs were almost double the total value of NTP budgets in the 22 high-burden countries in 2005 and amounted to about US $1.3 billion in 2005. Overall, about 80% of this total cost was funded by highburden country governments (Fig. 7), but there was large variation among countries, with some—especially in Africa—relying heavily on donor financing (Fig. 8). Projections of financial needs for TB control during the next decade have been made as part of the development of the Global Plan to Stop TB, 2006–2015. The total cost of the Global Plan for the 10-year period

Figure 5 National TB program budgets by funding source 2002–2005, 21 highburden countries (excluding South Africa).

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Figure 6 Total TB control costs by line item 2002–2005, 22-high burden countries. Note: Total TB control costs for Thailand and South Africa could not be broken down as for other countries, so the total is presented as ‘‘Unknown.’’ ‘‘Other’’ includes costs for hospitalization and fluorography in the Russian Federation, not reflected in the national tuberculosis program budget.

Figure 7 Total TB control costs by funding source 2002–2005, 22 high-burden countries.

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Figure 8 2005.

Floyd

Sources of funding for total TB control costs, 22 high-burden countries,

is US $56 billion, of which US $25 billion is currently estimated as available and US $31 billion is a funding gap (Table 7). Most of the costs identified in the plan are for investment in DOTS programs (US $29 billion), followed by DOTS-Plus and collaborative TB/HIV activities (both around US $6 billion). The cost of research and development is US $9 billion, most of which is for drugs and vaccines. Over 40% of country-level investments are needed in Africa (US $19.4 billion), followed by Eastern Europe with a total need of US $9.2 billion, while other regions each need between US $2 billion and US $6 billion (Fig. 9). The total costs per year increase steadily over time, from US $4.2 billion in 2006 to US $6.5 billion in 2015 (Fig. 10). Of the US $44.3 billion needed for investment at country level, the biggest regional cost increases

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Table 7 Total Costs and Funding Gaps According to the Global Plan to Stop TB, 2006–2015 (US$ billions)

Global Plan component

Costs

Available funding

Funding gap



Implementation of existing interventions DOTS expansion—country 28.9 needs DOTS-Plus—country needs 5.8 TB/HIV—country needs 6.7 Advocacy, communication 2.9 and social mobilization Technical cooperation— 2.9 international agency needs Research and development Vaccines 3.6 Drugs 4.8 Diagnostics 0.5 Total (all components) 56.1

Costs in first Global Plan to Stop TB, 2001–2005 6.0

21.8

22.5

1.1 0.6 0.0

0.7

2.2

0.3

2.1 0.6 0.1 25.3

1.5 4.2 0.4 30.8

0.4 0.3 0.2 9.1

Figure 9 Total cost of TB control by region according to the Global Plan to Stop TB, 2006–2015 (US$ billions). Note: AFRhigh and AFRlow are African countries with high and low HIV prevalence, respectively. Abbreviations: EEUR, Eastern Europe; EMR, Eastern Mediterranean region; LAC, Latin America and the Caribbean; SEAR, South-East Asian region; WPR, Western Pacific Region.

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Figure 10 Trends in the cost of TB control according to the Global Plan to Stop TB, 2006–2015 (US$ billions).

over the plan period are in Africa and Eastern Europe, with costs in other regions remaining fairly stable (Fig. 11). In all regions, DOTS expansion accounts for the largest share of costs, although TB/HIV is important in Africa and DOTS-Plus is important in Eastern Europe (Fig. 12). There are large projected funding gaps (Table 1, Fig. 13), which, in the case of implementation (as opposed to R&D), are mostly explained by the planned introduction and scaling up of DOTS-Plus, TB/HIV

Figure 11 Total resource requirements at country level according to the Global Plan to Stop TB, 2006–2015 (US$ billions).

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Figure 12 Distribution of country funding needs by region and activity according to the Global Plan to Stop TB, 2006–2015 (US$ billions).

collaborative activities and advocacy, communication, and social mobilization (as illustrated by comparing Figs. 13 and 14). Funding will need to increase from both high-burden countries and donors if these gaps are to be filled—but particularly from high-burden countries. Filling the estimated funding gaps at country level requires a doubling in existing domestic investment, whereas it would require a 10-fold increase in donor funding. V. What New Work Is Needed in the Next 5 to 10 Years? This chapter has shown that most of the economic and financial analyses of TB control in recent years have been cost or cost-effectiveness studies, with increased attention paid to financing of TB control in high-burden countries in the last five years. Several of the cost studies have also provided evidence about the economic impact of TB on individuals and households. The main findings are that TB treatment using the DOTS strategy is highly cost-effective in developing countries, especially when outpatient and community-based approaches to care are used; additions to DOTS such as treatment of patients with MDR-TB using first- and second-line drugs and use of preventive therapy for HIV-positive individuals also appear costeffective in the context of widely used benchmarks, although the empirical data on costs and effectiveness remain limited; expenditures and other costs associated with diagnosis and treatment can be high in relation to individual and household income; investment in TB control in high-burden countries has increased considerably in the last five years, notably from high-burden country governments themselves and from the Global Fund for AIDS, TB, and malaria; and resource mobilization will need to improve dramatically if the second Global Plan to Stop TB, 2006–2015 is to be fully implemented.

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Figure 13 Projected funding and funding gaps for implementation of existing TB control interventions according to the Global Plan to Stop TB, 2006–2015 (US$ billions).

Building on this body of work, there are several topics where further work is merited over the next 5 to 10 years. These include the following:
The economic impact of TB on national economies, and the extent to which available or potential control strategies could reduce this impact: Existing studies are scarce, while it has been argued that an up-to-date and credible assessment is needed to help convince Ministries of Finance to support greater investment in TB control.

Figure 14 Projected funding needs for implementation of existing interventions according to the Global Plan to Stop TB, 2006–2015 (US$ billions).

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Such a study could build on available evidence about the impact of TB at household level, which has been reasonably well documented for several countries. The World Bank commissioned such a study for Africa in 2005, with the results due in mid–late 2006. This study could later be expanded to consider other parts of the world; TB and poverty/equity: Poverty alleviation is central to the international development agenda, yet existing data about how TB affects poverty (as opposed to how poverty affects TB) are limited. The extent to which existing diagnostic and treatment services reach different population groups or how access to services could be improved for disadvantaged groups are also not well documented; Cost and cost-effectiveness studies for major components of the new Stop TB strategy and the related Global Plan to Stop TB, 2006–2015 for which the evidence base is still limited or lacking: This should include more work on DOTS-Plus, especially when implemented at a large scale in high-burden countries (as is planned in China); PPM-DOTS, especially for scaling up in large countries such as India and for other countries where PPM-DOTS is likely to be essential for reaching international TB control targets (studies are now being done in, e.g., India, Indonesia, and the Philippines); and collaborative TB/HIV activities, especially in the context of widespread provision of antiretroviral therapy to HIV-positive TB patients; The cost of general health system strengthening needed to scale up TB control alongside interventions for other health priorities: Improving TB control in many countries is likely to depend on strengthening health systems as a whole, as well as investment in TB programs specifically. However, a major problem in producing estimates of the costs of improving existing TB control efforts, such as the estimates of financial needs set out in the Global Plan to Stop TB, 2006–2015 has been the difficulty in defining and then costing the general health system strengthening that is needed to support improvements in TB control efforts. Major issues include the fact that some health system–strengthening needs cannot be assessed for TB control in isolation but should consider, at least, the other major priority programs or services that need to be expanded; and limited information about existing health system capacity and constraints (and what is needed to overcome these constraints). Much more country-based work is needed to define what health systems strengthening is needed, and how much this will cost; Financing of TB control: Existing work on the financing for TB control needs to be sustained, and strengthened so that data are available for a wider range of countries. Among the high-burden countries, an assessment of TB control costs and sources of funding in South Africa would be particularly useful, because it is the one high-burden country for which data have not been reported to WHO since annual monitoring efforts began in 2002 (and has

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The author would like to thank Chris Dye, Andrea Pantoja, and Pam Baillie for help with preparing the figures for this chapter. References 1. Spence DPS, Hotchkiss J, Williams CSD, Davies PDO. Tuberculosis and poverty. Br Med J 1993; 307:759–761. 2. Global Alliance for TB Drug Development. The economics of TB drug development, 2001. www.tballiance.org [see publication section]. 3. Stop TB Partnership. The Global Plan to Stop TB, 2006–2015. Geneva: World Health Organization, 2006. 4. Moalosi G, Floyd K, Phatshwane J, et al. Cost-effectiveness of home-based care versus hospital care for chronically ill tuberculosis patients, Francistown, Botswana. Int J Tuberc Lung Dis 2003; 7:S72–S79. 5. Nganda B, Wang’ombe J, Floyd K, Kangangi J. Cost and cost-effectiveness of increased community and primary care facility involvement in tuberculosis care in Machakos District, Kenya. Int J Tuberc Lung Dis 2003; 7(9 suppl 1):S14–S20. 6. Floyd K, Skeva J, Nyirenda T, et al. Cost and cost-effectiveness of increased community and primary care facility involvement in tuberculosis care in Lilongwe District, Malawi. Int J Tuberc Lung Dis 2003; 7:S29–S37. 7. Sinanovic E, Floyd K, Dudley L, et al. Cost and cost-effectiveness of communitybased care for tuberculosis in Cape Town, South Africa. Int J Tuberc Lung Dis 2003; 7:S56–S62. 8. Okello D, Floyd K, Adatu F, et al. Cost and cost-effectiveness of community-based care in rural Uganda. Int J Tuberc Lung Dis 2003; 9:S72–S79. 9. Schwartzman K, Oxlade O, Barr RG, et al. Domestic returns from investment in the control of tuberculosis in other countries. N Engl J Med 2005; 353(10):1008–1020. 10. WHO. Global Tuberculosis Control: Surveillance, Planning, Financing. HTM/TB/ 2005.349. Geneva: World Health Organization, 2005. 11. Mills A, Shillcutt S. Communicable diseases. Available at: www.copenhagenconsensus. com, 2004. 12. Chima R, Goodman C, Mills A. The economic impact of malaria in Africa: a critical review of the evidence. Health Policy 2003; 63:17–36. 13. Dholakia R. The potential economic benefits of the DOTS strategy against TB in India. Geneva: World Health Organization, 1996. 14. Grimard F, Harling G. The impact of tuberculosis on economic growth (available at www.hec.ca/neudc2004/fp/grimard_franque_aout_27.pdf), 2005:53. 15. Croft RA, Croft RP. Expenditure and loss of income incurred by tuberculosis patients before reaching effective treatment in Bangladesh. Int J Tuberc Lung Dis 1998; 2:252–254.

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16. Roos BR, van Cleef MRA, Githui WA, et al. Cost-effectiveness of the polymerase chain reaction versus smear examination for the diagnosis of tuberculosis in Kenya: a theoretical model. Int J Tuberculosis Lung Dis 1998; 2:235–241. 17. Needham DM, Godfrey-Faussett P, Foster SD. Barriers to tuberculosis control in urban Zambia: the economic impact and burden on patients prior to diagnosis. Int J Tuberc Lung Dis 1998; 2:811–817. 18. Kamolratanakul P, Sawert H, Kongsin S, et al. Economic impact of tuberculosis at the household level. Int J Tuberc Lung Dis 1999; 3:596–602. 19. Rajeswari R, Balasubramanian R, Muniyandi M, et al. Socio-economic impact of tuberculosis on patients and family in India. Int J Tuberc Lung Dis 1999; 3:869–877. 20. Wyss K, Kilima P, Lorenz N. Costs of tuberculosis for households and health care providers in Dar es Salaam, Tanzania. Trop Med Int Health 2001; 6:60–68. 21. Islam MA, Wakai S, Ishikawa N, et al. Cost-effectiveness of community health workers in tuberculosis control in Bangladesh. Bull World Health Organ 2002; 80:445–450. 22. Vassall A, Bagdadi S, Bashour H, et al. Cost-effectiveness of different treatment strategies for tuberculosis in Egypt and Syria. Int J Tuberc Lung Dis 2002; 6:1083–1090. 23. Khan MA, Walley JD, Witter SN, et al. Costs and cost-effectiveness of different DOT strategies for the treatment of tuberculosis in Pakistan. Health Policy Plan 2002; 17:178–186. 24. Floyd K, Wilkinson D, Gilks C. Comparison of cost effectiveness of directly observed treatment (DOT) and conventionally delivered treatment for tuberculosis: experience from rural South Africa. Br Med J 1997; 15(7):1407–1411. 25. Wandwalo E, Robberstad B, Morkve O. Cost and cost-effectiveness of community based and health facility based directly observed treatment of tuberculosis in Dar es Salaam, Tanzania. Cost Eff Resour Alloc 2005; 3:6. 26. Kamolratanakul P, Chunhaswasdikul B, Jittinandana A, et al. Cost-effectiveness analysis of three short-course anti-tuberculosis programmes compared with a standard regimen in Thailand. Int J Health Plann Manage 1993; 46(7):631–636. 27. Saunderson PR. An economic evaluation of alternative programme designs for tuberculosis control in rural Uganda. Social Sci Med 1995; 40(9):1203–1212. 28. Dye C, Floyd K. Tuberculosis. In: Jamison DT, Alleyne GAO, Breman JG, et al., eds. Disease Control Priorities in Developing Countries. 2nd ed. Washington D.C.: Oxford University Press, 2006. 29. Floyd K. Costs and effectiveness—the impact of economic studies on TB control. Tuberculosis (Edinb) 2003; 83:187–200. 30. Murray CJL, De Jonghe E, Chum HJ, et al. Cost effectiveness of chemotherapy for pulmonary tuberculosis in three sub-Saharan African countries. Lancet 1991; 338:1305–1308. 31. Barnum HN, Tarantola D, Setiady IF. Cost-effectiveness of an immunization programme in Indonesia. Bull World Health Organ 1980; 58:499–503. 32. Masobe P, Lee T, Price M. Isoniazid prophylactic therapy for tuberculosis in HIV-seropositive patients—a least-cost analysis. S Afr Med J 1995; 85:75–81. 33. Foster S, Godfrey-Faussett P, Porter J. Modelling the economic benefits of tuberculosis preventive therapy for people with HIV: the example of Zambia. AIDS 1997; 11(7):919–925. 34. Bell JC, Rose DN, Sacks HS. Tuberculosis preventive therapy for HIV-infected people in sub-Saharan Africa is cost-effective. AIDS 1999; 3(12):1549–1556. 35. Barnum HN. Cost savings from alternative treatments for tuberculosis. Soc Sci Med 1986; 23:847–850. 36. Joesoef MR, Remington PL, Jiptoherijanto PT. Epidemiological model and costeffectiveness analysis of tuberculosis treatment programmes in Indonesia. Int J Epidemiol 1989; 18:174–179.

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37. Sawert H, Kongsin S, Payanandana V, et al. Costs and benefits of improving tuberculosis control: the case of Thailand. Soc Sci Med 1997; 44(12):1805–1816. 38. Migliori GB, Khomenko AG, Punga VV, et al. Cost-effectiveness analysis of tuberculosis control policies in Ivanovo Oblast, Russian Federation. Bull World Health Organ 1998; 76(5):475–483. 39. Xu Q, Jin SG, Zhang LX. Cost effectiveness of DOTS and non-DOTS strategies for smear-positive pulmonary tuberculosis in Beijing. Biomed Environ Sci 2000; 13(4):307–313. 40. Jacobs B, Clowes C, Wares F, et al. Cost-effectiveness analysis of the Russian treatment scheme for tuberculosis versus short-course chemotherapy: results from Tomsk, Siberia. Int J Tuberc Lung Dis 2002; 6:396–405. 41. Wilton P, Smith RD, Coast J, et al. Directly observed treatment for multidrugresistant tuberculosis: an economic evaluation in the United States of America and South Africa. Int J Tuberc Lung Dis 2001; 5(12):1137–1142. 42. Suarez PG, Floyd K, Portocarrero J, et al. Feasibility and cost-effectiveness of standardised second-line drug treatment for chronic tuberculosis patients: a national cohort study in Peru. Lancet 2002; 359:1980–1989. 43. van Gorkom J, Kibuga DK. Cost-effectiveness and total costs of three alternative strategies for the prevention and management of severe skin reactions attributable to thiacetazone in the treatment of human immunodeficiency virus positive patients with tuberculosis in Kenya. Int J Tuberc Lung Dis 1996; 77:30–36. 44. Murray CJL, Salomon JA. Expanding the WHO tuberculosis control strategy: rethinking the role of active case-finding. Int J Tuberc Lung Dis 1998; 2(suppl 1):S9–S15. 45. Khomenko AG, Punga VV, Rybka LN, et al. Cost benefit of detection and treatment patients with tuberculosis in Ivanovo region, Russian Federation. Problemy tuberkuleza 1998; 3:9–13. 46. Walker D, McNerney R, Mwembo MK, et al. An incremental cost-effectiveness analysis of the first, second and third sputum examination in the diagnosis of pulmonary tuberculosis. Int J Tuberc Lung Dis 2000; 4(3):246–251. 47. Sebro K, Rolle S, Gray S, et al. Are routine chest X-rays for students entering university worthwhile? J Qual Clin Pract 2001; 21:154–156. 48. Kivihya-Ndugga L, van Cleeff MRA, Githui WA, et al. A comprehensive comparison of Ziehl-Neelsen and fluorescence microscopy for the diagnosis of tuberculosis in a resource-poor setting. Int J Tuberc Lung Dis 2003; 7(12):1163–1171. 49. Albert H. Economic analysis of the diagnosis of smear-negative pulmonary tuberculosis in South Africa: incorporation of a new rapid test, FASTPlaqueTB, into the diagnostic algorithm. Int J Tuberc Lung Dis 2004; 8(2):240–247. 50. Hudson CP, Wood R, Maartens G. Diagnosing HIV-associated tuberculosis: reducing costs and diagnostic delay. Int J Tuberc Lung Dis 2000; 4(3):240–245. 51. Tibbit LR. The economics of short-course therapy for tuberculosis in the Cape Divisional Council area. S Afr Med J 1982; Spec No:31–33. 52. Chunhaswadikul B, Kamolratanakul P, Jittinandana A, et al. Anti-tuberculosis programs in Thailand: a cost analysis. Southeast Asian J Trop Med Public Health 1992; 23(2):195–199. 53. Nunn P, Gathua S, Kibuga D, et al. The impact of HIV on resource utilization by patients with tuberculosis in a tertiary referral hospital, Nairobi, Kenya. Tubercle Lung Dis 1993; 74(4):273–279. 54. Anand K, Pandav CS, Kapoor SK, et al. Cost of health services provided at a primary health centre. Natl Med J India 1995; 8(4):156–161. 55. Dick J, Henchie S. A cost analysis of the tuberculosis control programme in Elsies River, Cape Town. S Afr Med J 1998; 88(3 suppl):380–383. 56. Floyd K, Blanc L, Raviglione M, Lee JW. Resources required for global tuberculosis control. Science 2002; 295:2040–2041.

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57. Jack W. The public economics of tuberculosis control. Health Policy 2001; 57(2): 79–96. 58. Stop TB Annual Report 2000. Geneva: World Health Organization. WHO/CDS/ STB/2001, 12, 2001. 59. Trends in donor financing for TB control. Geneva: Stop TB Partnership, 2005. 60. Baltussen R, Floyd K, Dye C. Achieving the millennium development goals for health: cost effectiveness of strategies for tuberculosis control in developing countries. Br Med J 2005; 331(7529):1364. 61. Evans DB, Adam T, Tan-Torres Edejer T, et al. Achieving the millennium development goals for health: time to reassess strategies? Br Med J 2005; 331(7525): 1133–1136. 62. Tan-Torres Edejer T, Aikins M, Black R, et al. Achieving the millennium development goals for health: cost effectiveness of strategies for child health in developing countries. Br Med J 2005; 331(7526):1177. 63. Adam T, Lim SS, Mehta S, et al. Achieving the millennium development goals for health: cost effectiveness of strategies for maternal and neonatal health in developing countries. Br Med J 2005; 331(7528):1299. 64. Morel C, Lauer J, Evans DB, et al. Achieving the millennium development goals for health: cost effectiveness of strategies for malaria control in developing countries. Br Med J 2005; 331(7525):1107. 65. Hogan D, Baltussen R, Hayashi C, et al. Achieving the millennium development goals for health: cost effectiveness of strategies to combat HIV/AIDS in developing countries. Br Med J 2005; 331(7530):1431–1437. 66. Evans D, Lim S, Adam T, et al. Achieving the millennium development goals for health: evaluation of current strategies and future priorities for improving health in developing countries. Br Med J 2005; 331(7530):1457–1461.

25 Advancing and Advocating Tuberculosis Control Globally Through the Stop Tuberculosis Partnership

PETRA I. HEITKAMP

MARCOS A. ESPINAL FUENTES

World Health Organization, Jakarta, Indonesia

Stop Tuberculosis Partnership Secretariat, World Health Organization, Geneva, Switzerland

I. Introduction The World Health Organization (WHO) declared tuberculosis (TB) to be a global emergency in 1993. However, political commitment to control the growing pandemic was lacking and TB continued to exact its remorseless toll. This chapter outlines the development over the last decade of growing international consensus, political will and powerful forms of international organization against TB. It highlights the Stop TB Partnership established in 2000, including its goals, achievements, and how it catalyzes and advocates for TB control, functioning through various organizations and institutions. Advocacy is a key role of the Partnership, both as a specific function and as an intrinsic element in all of its catalytic activities. Advocacy is important at global, national, and local levels. The Stop TB Partnership focuses on global advocacy, as described in this chapter. National and local advocacy is addressed in Chapter 41. II. Role of Partnerships and Advocacy In spite of all previous activities to date, the majority of the world’s TB patients continue to live in areas where sound TB control services have 685

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yet to be provided, and only about half of symptomatic TB patients are detected. Much more advocacy is required to ensure policy and implementation beyond the traditional health-care provider perspective, and society needs to be mobilized at large in partnership efforts to control TB. Advocacy is aimed at ‘‘policy change through social influence and action.’’ In health promotion literature (1,2), advocacy is being described as ‘‘action taken on behalf of individuals and/or communities to overcome structural barriers to health’’ with key outcomes related to healthy public policy and organizational practice. Continuous advocacy efforts are needed to ensure that TB policies become reality with political commitment and resources. Without sufficient social pressure, the political commitment will not be achieved, and the best laid plans and most effective strategies are usually not carried out. At a global and national policy level, communities have to further advocate for integration of TB into the international and national development agendas, highlighting issues such as poverty, inequity, health system strengthening, access, and the interrelationship between individuals and communities with health structures. TB control policies need to be further linked in the sustainable development agenda through poverty-reduction strategies, sector-wide approaches, basket-funding, etc. This will require better advocacy, communication, and collaboration between those working within and beyond the government health sector. So, why do we need partnerships to advocate for TB control? Different explanations apply at different levels. First of all, the magnitude of the burden of TB is itself a strong justification for a partnership. TB is present in almost every country of the world and no single government or organization can defeat this deadly scourge, thus, joint efforts are essential. The TB burden is part of the ‘‘globalization’’ of public health (3–5). For example, increasing international travel also increases the risk of transmission of TB in areas where it is no longer prevalent. In addition, the TB control agenda toward the Millenium Development Goals (MDGs) is not only a biomedical issue but part of a much broader development approach. The drive to produce results to meet the MDGs has led many stakeholders to focus on their priority diseases first, with an implicit assumption that through specific interventions the system will be strengthened more generally. This involves a risk, however, that constraints are tackled independently and in parallel for every disease or MDG goal, thereby creating parallel approaches, which are likely to result in duplications, distortions, disruptions, or distractions (6). Under such circumstances, partnerships are needed to coordinate activities and avoid chaos and ineffectiveness. Partnerships provide opportunities for increased speed, impact, and effectiveness through important linkages in various areas: geopolitical between developing and developed countries; experimental between e.g., analytical and applied research; professional/disciplinary between health and nonhealth social systems in disciplines such as medical anthropology (7),

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epidemiology (8), political economy (9), and the law (10,11); ideological between e.g., trade and sustainable development; scale between international, national, and local. This explains the rising number of global partnerships—several dozen now in public health alone (12,13). At a practical level the linkage between the public and private sector is of crucial importance to TB control on all fronts: in R&D the collaboration with the pharmaceutical industry, in implementing the current tools available the involvement of private health-care services, not only medical practitioners but also the business occupational health services, and in global advocacy and governance the involvement of private sector including industry. The changing political context shows a shift toward networked governance (14,15) and global public policy networks (16) for negotiating and promoting global standards, facilitating joint action strategies (optimizing resource use, tackle coordination failures) and facilitating implementation of intergovernmental agreements. The aim is to create consensus across different viewpoints and contexts, through defining problems to be tackled and agreeing on joint solutions. The creation of the Stop TB Partnership is an appropriate development in the context of this changing society. III. Advocacy, Communication, and Social Mobilization These interrelated functions are of critical importance in advancing TB control. The Stop TB Partnership has defined them as follows: Advocacy is an act of supporting community efforts to obtain resources or change policies. In the global context, advocacy for TB is to be understood as a broad set of coordinated interventions, directed at placing TB high on the political and development agenda, for securing international and national commitment and mobilizing the requisite resources. In country contexts, advocacy efforts broadly seek to ensure that national governments remain strongly committed to implementing national TB control/ elimination policies. Communication is a two-way process with participation and dialogue as the key elements. In the context of TB control, communication may be viewed as being directed at creating an overall enabling environment, through tailored strategies and empowering discourses. All communication activities make use of some form of media and channels for communicating ideas. Social mobilization in the national and subnational contexts is a process of generating public will, by actively securing broad consensus and social commitment among stakeholders for the elimination of TB, for the public benefit. Community mobilization is a particular grassroots-level process in the context of wider social mobilization. Advocacy has been a key element in drawing worldwide attention to TB and in promoting its global control over the past 15 years (Fig. 1). Following the increasing neglect of the epidemic from the 1970s and the subsequent integration of many national TB control services, attention focused on documenting the severity of the global crisis and the effectiveness

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Figure 1 Development of global tuberculosis control: adoption of DOTS and increase in funding. Source: From Refs. 17–19.

of specific control measures (20). During the 1980s until mid-1990s, debate among individual TB control officials and public health opinion leaders served to establish a credible base of consensus among experts concerning most central issues for controlling TB (21). Increasingly, to create a broader and more sustainable base of social and political support, a much wider array of media were deployed, with messages segmented to appeal to a diversity of institutional audiences, particularly governments, foundations, and public health professionals. Although WHO at its inauguration in 1948 identified TB as one of the areas of work in need of international support, it was not until the 1990s that TB control became part of the global health agenda. Fundamental to this advocacy and agenda setting was the realization that the main challenges facing control of TB had become more political and managerial rather than scientific. When WHO declared TB to be a ‘‘global emergency’’ in 1993, a significant share of the TB resources was invested in advocacy. Following a major media event in April 1993 (22) the DOTS strategy was launched in 1995 (23) through an active and highly effective ‘‘branding’’ campaign (21) with sustained TB advocacy benefits. The DOTS Observer was introduced as an advocacy tool in 1996, and from 1997, World TB Day became the annual event to commemorate the discovery of the Koch bacille (1882),

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after the first such event in 1982. A peak in the number of TB news items was noted in the international media during this campaign to disseminate TB messages. The period of 1993 to 1998 witnessed a rapid expansion of institutional commitment and capacity to address TB, as well as the active involvement of new governments, donors, and implementing organizations in support of the DOTS strategy. Political commitment among governments has been one of the elements of the DOTS strategy from the outset. With the involvement of new stakeholders through the Stop TB Initiative in 1998, political commitment grew beyond government commitment to the DOTS strategy. It became a principal consideration to engage the highest levels of authority in different stakeholders; the Director-General of WHO and the President of the World Bank together hosted the Ministerial Conference in Amsterdam, as well as the first and second Partners Forum, respectively in 2001 and 2004. Furthermore, the Forum in 2004 featured statements from the Indian Prime Minister Atal Behari Vajpayee, UN Secretary-General Kofi Annan, President Bill Clinton, and others, all committing personal and institutional support to fight TB. These prominent individuals have been effective spokespersons in drawing the world’s attention to special TB agendas. At the AIDS International Conference in 2004, Nelson Mandela reminded the HIV community and large sections of international society of the importance of TB linked to HIV. International public attention has an immediate trickle-down effect on the political commitment of politicians in developing countries. Around the Amsterdam Ministerial Conference, countries such as China, India, and Indonesia clearly announced strong commitment and national policy shifts in favor of TB program implementation. The comparative institutional advantages of various partners strengthen the development and implementation of declarations and plans, including the Global Plan to Stop TB, 2006–2015 (GPSTB). These joint global advocacy efforts have been recognized as successful in raising and maintaining a high TB profile not only on the international agendas, but also in support of national political commitment (24). Over the last five years a growing set of coordinated advocacy and communication activities was carried out at global level. The Stop TB Partnership established an Advocacy and Communications Taskforce at the end of 2001 to support the implementation of the Global Plan to Stop TB, 2006–2015 and ensure actions to support all its commitments. The Taskforce met on an ad-hoc basis between 2002 and 2004 to coordinate advocacy activities, especially TB/HIV advocacy (25), while building stronger mechanisms in response to the growing TB communication requests and gaps not only at global level, but increasingly from countries and the Stop TB Partnership working groups (26). The gaps in 22 high TB burden countries were recognized, where almost no country communication capacity exists (27). As part of the development of the GPSTB 2006–2015, comprehensive communication plans have been prepared (28,29), while countries are assisted in the preparation of Global Fund to fight AIDS, Tuberculosis and Malaria (GFATM) proposals on TB communication. Country communication strategies are

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needed to focus on the community and patient needs, accountability, and support for the control of TB. This will require the involvement of a far greater diversity of audiences, through targeted campaigns, and creating opportunities for individuals and communities to improve their TB and health knowledge and thereby their capacity to improve and protect their health. It calls for specific and measurable steps for mobilizing society to affect the health-seeking behavior of TB risk groups, addressing stigma and access barriers, and convincing decision makers who can take actions to assist. Country-specific experiences show the positive impact and potential of specific community interventions. Grassroots participation in TB control addresses people’s concerns, provides a support to overstretched public health services, and often increases the social status of individuals (30–33). For the TB control community to reach the MDG for TB, it will require better and scaled up communication and collaboration between those working within and beyond the traditional health sector, and most crucially, between professionals and the communities themselves (34) through intensive social mobilization and community participation. Advocacy and communication have contributed significantly to the shift in TB control toward a specialized, well-defined management system with fully integrated service delivery. The Partnership confirmed the importance of advocacy, communication, and social mobilization and in March 2004 (35) established a full Advocacy, Communication, and Social Mobilization working group. In a planned and coordinated manner, strategic Stop TB communication combines: (i) advocacy to raise and sustain political and financial commitment; (ii) communication to stimulate dialogue about behavioral and social change, and (iii) social mobilization to build a multisectoral response. IV. The Stop Tuberculosis Partnership The Stop TB Partnership as a movement is essentially an advocacy network (36) to raise the public profile of the disease and advocate for increased international and/or national response, and resource mobilization. It is also a movement to coordinate and build consensus among the partners, which may be an even more important role. This section outlines the development (Table 1), various bodies and functions of the Stop TB Partnership showing its role as a platform for collaborative implementation, research and development, and technical assistance and service support. A. Background

High-burden countries called in March 2000 for common action to guide TB control efforts in ‘‘the Amsterdam Declaration’’ (37) based on groundwork in previous years (38–40). WHO’s World Health Assembly endorsed the Partnership in a Resolution in May 2000, calling upon organizations of all types ‘‘to support and to participate in the global partnership to stop TB by which all parties coordinate activities and are united by common goals, technical strategies, and agreed-upon principles of action . . . ’’ (41).

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Table 1 Steps Toward the Development of the Stop TB Partnership Year

Milestone

1991

WHA resolution sets targets for case detection and cure for year 2000 TB is declared a global health emergency New framework for TB control (1994) is launched as the ‘‘DOTS’’ strategy (1995) London Committee calls for a partnership and World Health Organization launches Stop TB Initiative Amsterdam Ministerial Conference. Delegations from 20 high-TB burden countries, together with members of Stop TB Initiative pledge in Amsterdam Declaration to develop and implement a global partnership against TB WHA resolution endorses concept of a GPSTB and postpones targets to 2005 Stop TB (Interim) Coordinating Board meets in Bellagio to devise governance and structure for the Partnership Global TB Drug Facility is launched and Stop TB working groups are established Stop TB First Partners’ Forum is hosted by the World Bank (Washington) endorses Framework for the Partnership and launches GPSTB 2001–2005 Independent Partnership Evaluation confirms added value Second Ad-hoc Committee outlines constraints to TB control progress and calls for partnership commitment and intensified action in countries, taking account of the needs for health system strengthening Stop TB Second Partners’ Forum in Delhi pledges accelerated action with Intensified Support of Action in Countries Initiative and endorses TB/MDG targets WHA resolution adopts TB/MDG targets and calls for improved TB/ HIV collaboration and national Stop TB partnerships to ensure sustainable financing

1993 1994–1995 1998 2000

2000 2001 2001 2001

2003 2003

2004

2005

Abbreviations: MDG, millennium development goal; GPSTB, Global Plan to Stop TB, 2006–2015; WHA, World Health Assembly.

In response to this call, the first Partners’ Forum (42) committed to a Partnership Framework (Fig. 2) and unveiled the GPSTB 2001–2005 (43), a budgeted, consensus-based, five-year business plan with four main strategic areas: expansion of the currently available anti-TB strategy—DOTS—so that all people with TB have access to effective diagnosis and treatment; adaptation of the DOTS strategy to meet evolving challenges of HIV and drug resistance; improvement of available tools by developing new diagnostics, new drugs, and new vaccines; and strengthening of the Stop TB

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Figure 2

Stop TB partnership framework. Source: From Ref. 43.

Partnership so that the actions of each partner make the most mutually supportive, efficient contribution to the actions of all. The years following this launch have been marked by joint implementation through the Stop TB Working Groups to implement activities according to these strategies. In progress toward the 2005 targets, partners pledged their accelerated action (44), while acknowledging constraints and outlining immediate support mechanisms for countries (45). Such partnership efforts are now done in concert with the GFATM, which has substantially increased the available funding for TB control directly to the most burdened countries. Today the GFATM is the number-one donor for TB control worldwide. Parallel to the developments leading to a partnership, there has been a strong historical societal movement to Stop TB, which has contributed to a collaborative and broader scope and vision of TB control (46). B. Values

In the long term, the Stop TB Partnership aims for the elimination of TB as a public health problem by 2050. Its mission is to ensure that every TB patient has access to effective diagnosis, treatment, and cure; to stop the transmission of TB worldwide; to reduce the inequitable social and economic burden of the disease; and to develop and implement new preventive, diagnostic, and therapeutic tools and strategies to eliminate TB. The Stop TB Partnership is committed to certain values in the pursuit of its goals, believing that rapid and enduring progress will result if they are observed. These are Urgency—Almost two million people continue to die each year from a disease that has long been curable at low cost. This situation is unjust and demands urgent action.

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Equity—Inequities that increase the most vulnerable groups’ susceptibility to infection and disease, and reduce their access to quality treatment, must be reduced. Shared responsibility—TB recognizes no borders:—control and eventual elimination of TB is a global public good and a shared responsibility of the global community. Inclusiveness—The Partnership welcomes as members all individuals and organizations that share its vision and values. Consensus—The Partnership strives to achieve consensus on priorities and best practice, and to act in a coordinated way based on the comparative strengths of individual Partners. Sustainability—Elimination of TB as a public health problem will take many years. The Partnership is committed to sustained action, and to strengthening national capacity. Dynamism—The TB epidemic is constantly evolving and requires flexibility and continuous innovation in pursuit of its aims. C. Structure and Achievements

The Stop TB Partnership has a structure that enables it to observe its values and meet its goals. It has three core organs: (i) The Partners’ Forum, a biennial plenary meeting of the Partners, is the Partnership’s foundation; (ii) The Coordinating Board and its Executive Committee whose members represent its diverse constituencies, and the guide the work of (iii) a small Secretariat based in WHO’s Stop TB Department at headquarters in Geneva. The Secretariat implements the decisions of the Coordinating Board and carries on the day-to-day activities. The Partnership has seven working groups, where the partners discuss and move forward on the agenda and implementation in vital technical areas. The Working Group on DOTS Expansion, led by WHO, published a Global DOTS Expansion Plan in 2001 (47), and guided all 22 high-burden countries in developing detailed national plans for DOTS expansion, some of them within the aegis of a national health plan. This group supports countries technically as they implement these plans, and coordinates several subgroups on public–private mix, laboratory services, and childhood TB. It actively assists countries in the establishment and functioning of Interagency Coordinating Committees/Country Coordinating Mechanisms in all high burden countries, specifically to secure international funding through the GFATM. Several countries are now showing a rapid establishment of national TB movements, such as in Brazil, Mexico, Indonesia, Pakistan, Philippines, and Uganda. Some of these are well advanced; others are in early phases of establishment. The Working Group on DOTS-Plus for Multidrug-resistant Tuberculosis (MDR-TB) aims to develop an affordable, effective, and evidence-based response to MDR-TB in resource-poor settings. It has succeeded in reducing the price of second-line TB drugs by 95% through the use of competitive, pooled procurement under its Green Light Committee (GLC) also housed at WHO (48).

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The Working Group on TB HIV aims to reduce the burden of TB in populations with high prevalence of HIV. Since its establishment in April 2001, it has worked quickly to develop a new strategic framework to decrease the burden of TB/HIV (49). Working Group members are now putting this framework into practice, promoting collaborative activities between TB and HIV/AIDS programs in key countries. They are also developing field guidelines for phased introduction of collaborative TB and HIV program activities. The three research and development working groups are making substantial progress. The Working Group on new Drug Development led by the Global Alliance on TB Drug Development (GATB), has prepared an important portfolio of more than 25 potential compounds. The working group aims to accelerate the discovery and development of new TB drugs that shorten and improve treatment, and are affordable by low-income countries. The Working Group on New TB Diagnostics, led by the Foundation of Innovative New Diagnostics has more than 20 tests in the development pipeline and it is expected that a new diagnostic test will be introduced in the field by 2010. The Working Group on New TB Vaccines has accomplished its main objective for the Global Plan to Stop TB, 2006–2015, which was to have five new vaccines entering clinical trials by 2005. The Working Group on Advocacy and Communications, recently created by the Stop TB Coordinating Board in 2004, is working to increase the power of Stop TB’s ‘‘brand’’ and is supporting regional and country work in community mobilization and political advocacy. Strategic communication is now recognized as an essential integrated ingredient of TB control strategy (50). The Global TB Drug Facility (GDF) is another vital component of the Partnership (see Chapter 26). Launched in 2001, and managed by Partnership Secretariat, it is housed at WHO. It aims to supply through grants and direct procurement the TB drugs needed to rapidly expand DOTS coverage in many high burden countries, which still lack the resources to procure high-quality drugs. Within five years of its launch, the GDF has successfully placed more than seven million patient treatments in 58 countries. Drug costs have been reduced by approximately one-third, and the average drug cost per patient for a complete six-month regimen is less than US $20. An independent evaluation (51) concluded that the combined approach of pooled financing and commodity purchase has been the key to the success of the GDF. V. Characteristics of a Successful Partnership Global health partnerships are seen overall as having a positive impact in terms both of achieving their own objectives and of being welcomed by countries (52,53). Inputs of an effective partnership include goals, a simple and compelling one, structure, and process. The outputs and challenges of the Stop TB Partnership can be structured according to six points shown in Table 2. (Text continues on page 698.)

. . . pool risks and resources to innovate . . . share knowledge across the partnership . . . build a common brand with the legitimacy and momentum to attract funds . . . quantify the costs of working in partnership . . . avoid cost controls impairing effectiveness

Output results Clear understanding of the benefits and costs of partnership Partners . . . . . . avoid duplication of investments or activities . . . extract economies of scale

Input results Clear overall goals and scope

Characteristics of successful global health partnerships Characteristics of the Stop TB Partnership

(Continued )

Coordination through the Partners’ Forum and Coordinating Board, GPSTB, the Global DOTS Expansion Plan, the Partnership’s Working Groups GDF is already the largest single purchaser of TB drugs; GLC has reduced second-line drug prices dramatically through pooled procurement; secretariat and task forces centralize common aspects of advocacy and resource mobilization GDF, GLC, and GATB constitute innovative approaches to market failure in infectious disease control Secretariat is building state-of-the-art, Web-enabled information management and communication products ‘‘DOTS,’’ ‘‘STOP TB,’’ and ‘‘GDF’’ enjoy increasingly universal brand recognition, through World TB Day and other advocacy activities; Partnership is attracting increasing funding External evaluation of GDF and Partnership in 2003; preparation of GPSTB 2006–2015 Adequate investment in meetings and information infrastructure

By 2005, 70% case detection and 85% cure By 2015, burden of disease and death reduced to half 1990 levels

Table 2 The Stop TB Partnership as a Successful Partnership

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Partnership evaluates performance against goals in three areas: outcomes, activities, and ‘‘relationships’’ Governance model that balances responsiveness and participation

Partners agree early on roles, resource commitments, and milestones

Sufficient planning and monitoring capabilities Partnership develops a detailed operating plan shortly after launch

Structure appropriate to the task: Simple affiliation; lead partner; general contractor; secretariat; or joint venture company

Characteristics of successful global health partnerships

GPSTB released in October 2001, at the Partnership’s formal launch in Washington and 8 months after the first meeting of Stop TB (Interim) Coordinating Board Partners agree on roles, responsibilities, and milestones in the Washington Committment/Keeping the Pledge and planning/budgeting toward millenium development goals ongoing in GPSTB 2006–2015 Ongoing self-evaluation against goals by individual Partnership organs; Annual review of progress by Coordinating Board; Global Plan progress report; Complete external evaluation executed in 2003

Modified secretariat model (secretariat housed by a leading partner) as is appropriate when partners seek profound gains from combination, partners are many and diverse, and a modicum of independence from partner organizations is important

Characteristics of the Stop TB Partnership

Table 2 The Stop TB Partnership as a Successful Partnership (Continued )

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Abbreviations: GATB, global alliance for TB drug development; GDF, global TB drug facility; GLC, green light committee; GPSTB, Global Plan to Stop TB, 2006–2015. Source: Adapted from Refs. 12, 13.

Sufficient human resources Partners assign high-level liaisons who fully support the partnership Partnership has a full-time, accountable leader Partnership has a sufficient operating staff

Coordinating Board members are strong advocates for the Partnership; All Partners have named a Stop TB liaison; Stop TB Ambassador appointed Full-time Executive Secretary and appointed Chair of Coordinating Board Full-time Secretariat staff of approximately 20 in Partnership building, Advocacy and Communications, Information Management, Finance/ Resource Mobilization, and the GDF

Relatively large Coordinating Board balanced by the Board’s Executive Committee; Working Groups have subgroups and many members Partnership’s Basic Framework document, Operating Procedures and memorandum of understanding agreement with World Health Organization spell out governance procedures

Main governance organs have few members

Partnership establishes in advance decision procedures for major, recurrent decisions

Policy direction set by the Coordinating Board, but Partnership has many specialized organs and channels for electronic communication, working groups on specific issues

Partnership maintains many channels for communication, but few decision-making organs

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First, the Stop TB Partnership has clear goals as part of internationally recognized frameworks, and a well elaborated structure with which to work toward them. The goals are further defined by measurable, achievable overall targets, and a clearly defined and focused scope: one disease—TB, geographical focus on 22 high TB burden countries, and focus on one stop TB strategy. These targets have been adopted by WHO Member state countries through World Health Assembly (WHA) resolutions, ensuring country ownership over plans and implementation toward target-results. Globally, there is skepticism toward reaching any of the MDGs related to difficultto-tackle policy and systems constraints, including poverty. Although such constraints lie beyond the immediate control of the Stop TB Partnership, it should strive to more actively contribute to the health-systems agenda, poverty reduction, demand-side barriers, and policy neglect. Second, the partners have understood the benefits and costs of partnership, and are working to maximize the former while minimizing the latter. The GDF has shown economies of scale in drug procurement. New information mechanisms are in place to improve partner-to-partner and secretariat-to-partner communication. The Partnership could, however, make better use of individual Partners’ resources and expertise. Ensuring that the partners deliver on agreed commitments represents a challenge due to the horizontal and voluntary nature of partner relationships. The voluntary contributions to partnerships can lead to high transaction costs for autonomous actors. Continuing negotiations are required to find areas of overlap, while respecting the different agendas. Third, a structure has been developed appropriate to the challenge of TB and involving the range of current and potential Partners. This could be called a modified secretariat structure. In a pure secretariat structure, the Secretariat would sit outside of any Partner organization. The partners, however, opted to base the Secretariat within WHO in order to facilitate collaboration with WHO, to benefit from WHO’s robust infrastructure and international legitimacy. Concerns remain about partnership institutional issues at global level, particularly related to nonstandard business practices, complex governance and difficulties in structuring and standardizing management practices (54). Generally these challenges are amenable to relatively straightforward solutions, including for example more appropriate representation on governing bodies, and more business-like approaches (25). The Partnership will require continuous amendments in management mechanisms to ensure it stays a flexible, catalytic network and platform for coordination. Fourth, the partners have developed thorough operating plans, and have agreed to a division of labor and to interim measures of success in endorsing and jointly implementing the GPSTB and the Washington Commitment (2001) Keeping the Pledge (2004) statement. Progress toward achieving these milestones is evaluated periodically in the ‘‘Progress report of the GPSTB.’’ Consolidated work-planning and budgeting for the next 10 years has taken place through the GPSTB 2006–2015. Although

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the Partnership has shown its catalytic role in increasing funding for TB in the last five years, the Partnership must mobilize many more resources at an accelerated pace to increase the human and financial resources needed to stop TB as delineated in the GPSTB 2006–2015. A survey commissioned by the Partnership shows that donor funding has steadily increased from US $135 million in 1999 to US $405 million in 2004, with GFATM being the main donor channelling funding to countries and the Bill and Melinda Gates Foundation to research and development. Likewise, high TB burden countries have also increased their own resources for TB control, fivefold in Pakistan (as compared to 2002), threefold in Uganda, and more than double in Bangladesh, China, Kenya, Indonesia, Myanmar, and Mozambique (55). While all this is very encouraging, it is also certain that these trends need to be seen against a backdrop of strong growth in development assistance for health over the last three decades. Increases in real donor spending on health and population have been of the order of 3% per annum since 1975. There has been little success in attracting a wide range of new funding sources, with the exception of Foundations—especially the Bill & Melinda Gates Foundation, which focuses mostly on research and development of new tools. The aim of global health partnerships to attract more, and more diversified, funding remains a challenge. Fifth, the governance model has successfully balanced the need for consensus with the need for decisive rapid action. The membership of the Coordinating Board has been carefully calibrated to ensure representation of the diverse constituencies. The Stop TB Partnership has adopted a framework document detailing the roles of its respective organs and decision procedures for major recurring events, such as the composition, selection, and terms of service of Board members. The membership of the Partnership can be strengthened in links with private/corporate, community, and patient groups. Active outreach to community groups is required while at the same time accommodating, supporting, and resourcing community-based approaches and perspectives. Social and cultural barriers and values need to be overcome, and new ways of ‘‘communicating’’ need to be found. To increase the effectiveness of global partnerships the governance is likely to require greater formality, clarity, and accountability. Various forms of accountability (56) need to be further explored, including reputationrelated accountability. Loss of credibility is one of the most effective negative sanctioning mechanisms to further accountability in and of partnerships. Peer accountability and financial accountability need to be embedded within the general operating procedures to account for activities and funds. Greater transparency will also be ensured by certification, selfregulation. and codes of conduct to establish benchmarks, including through International Standards of TB Care and the recent ISO certification awarded to the GDF. The Partnership will need to find mechanisms to enhance the accountability vis-a`-vis their beneficiaries, partner organizations, TB patients, communities, and countries but also vis-a`-vis the public at large.

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Finally, the Partners have dedicated sufficient resources to enable the Partnership to function productively. This means supporting a full-time Secretariat, seconding staff to the Secretariat; and designating Stop TB Partnership liaisons in their own organizations. On a larger scale, the mobilizing, pooling, and coordinated allocation of resources (financial, commodity, and human) is clearly shown through the GDF. The success of the Partnership will be measured according to the provision of sustainable support to countries. It must continue to help build up regional and national Stop TB Partnerships to sustain efforts in TB control while also strengthening the country health system. The call for financial sustainability was endorsed by the World Health Assembly in May 2005 (57). The Partnership is welcomed by countries with partnership or donor contribution to providing the necessary drugs (through funding, donation, or discounted price), funding for some operational costs, and technical assistance. Without all three, impact can be limited. Close harmonization between the Partnership and the GFATM is therefore crucial and the Stop TB Partnership signed a memorandum of understanding with the GFATM in 2005. Several areas of cooperation had been agreed to ensure a productive long-term relationship. The availability of substantial amounts of new partnership funding—particularly through GFATM—raises serious concerns about sustainability and perhaps also macroeconomic stability at country level. There is a risk that country spending patterns will not be determined by national priorities, but rather by the need to sustain the activities and services provided by external partners. The Stop TB Partnership, which is mainly an advocacy/technical partner to countries, needs to assist countries in addressing these complicated health systems, financing, and policy challenges. Notwithstanding the positive evaluations from the various external evaluations, the attributable impact of the Stop TB Partnership is difficult to determine at this point. Some indication could be given through the accelerated detection of TB cases since the active takeoff of the Partnership in 2001. Secondly, impact may be inferred by the WHA adoption of norms and standards advocated by the Partnership. In general, it will be important to measure the effects of the Partnership on other parts of the health system, and on the improvements in the life conditions of people for whom it was established. The Partnership recently endorsed the ‘‘Best Practice Principles for Engagement at Country Level’’ as defined by the high-level Forum on Health MDGs in 2005 November. However, further work needs to be done with other global health partnerships to address the many aspects of partnerships’ impact at country level. Finally, to achieve global advocacy for TB control through the Partnership, advocacy needs to be recognized and supported as crucial in addressing the challenges ahead: (i) increased human and financial resources to implement the GPSTB 2006–2015 and sustainability at country level, and strengthen partnerships; (ii) enhanced political commitment, policy changes to integrate TB in development policies and larger accountability; (iii) consistent high profile of TB control and the Partnership’s mission on the world agenda.

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VI. Conclusion The Stop TB Partnership has shown innovation in processes and actions, by creating synergy between new developments and implementation, and by providing continuous leadership as a catalyst, and by effective use of advocacy. As the world has come to resemble a globalized village, several initiatives/partnerships have emerged. However, countries are often unable to cope with so many initiatives, which in many cases subtract instead of adding value. It is essential that the Stop TB Partnership continue to add value by delivering the goods and benefits to countries heavily affected by the deadly TB pandemic. The Partnership also needs to stay ahead and innovative at the global level. It will be judged over next 10 years by how far it is able to influence the TB pandemic by helping countries to reach the MDGs and the Partnership’s own Targets through the implementation of the GPSTB 2006–2015. Reducing by half the incidence, prevalence, and mortality, as well as introducing new diagnostics, drugs, and vaccines in the field, will set the path for the ultimate goal: elimination of TB from the world once and for all. References 1. Nutbeam D. Evaluating health promotion—progress, problems and solutions. Health Promotion Int 1998; 13:27–44. 2. Stead M, Hastings G, Eadie D. The challenge of evaluating complex interventions: a framework for evaluating media advocacy. Health Educ Res 2002; 17(3): 351–364. 3. Walt G. Globalization of international health. Lancet 1998; 351:434–437. 4. Kickbush I, Buse K. Global influences and global responses: international health at the turn of the twenty-first century. In: Merson M, Black R, Mills A, eds. International Public Health: Diseases, Programs, Systems and Policies. Gaithersburg, Maryland: Aspen Publishers, 2001:701–737. 5. Commission on Global Governance. Our Global Neighborhood: The Report of the Commission on Global Governance. Oxford: Oxford University Press, 1995. 6. Travis P, Bennett S, et al. Overcoming health-systems constraints to achieve the Millennium Development Goals. Lancet 2004; 364:900–906. 7. Farmer PE. Infections and Inequalities: The Modern Plagues. Berkeley, CA: University of California Press, 1999. 8. Wilkinson RG. Income distribution and life expectancy. In: Kawachi I, Kennedy BP, Wilkinson RG, eds. The Society and Population Health Reader. Vol. I: Income Inequality and Health. New York: New York Press, 1999:28–35. 9. Kapstein EB. The third way and the international order. In: Giddens A, ed. The Global Third Way Debate. Cambridge: Polity Press, 2001:372–383. 10. Gostin L. Public Health Law: Power, Duty, Restraint. Berkeley: University of California Press, 2000. 11. Fidler D. The future of the World Health Organization: what role for international law? Vand J Transnatl L 1998; 31:1079–1126. 12. Gates Foundation. Developing successful global health alliances. Unpublished document, April 2002. Online at: www.gatesfoundation.org/ 13. Caines K, Buse K, Carlson C, et al. Assessing the Impact of Global Health Partnerships. London: DFID Health Resource Centre, 2004.

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14. Benner T, Reinicke WH, Witte JM. Multisectoral Networks in Global Governance. In: Towards a Pluralistic System of Accountability. Oxford, UK: Government and Opposition Ltd, 2004:191–210. 15. Waddell S. Global Action Networks: a global invention helping business make globalisation work for all. J Corpor Citizen 2003; 12:27–42. 16. Reinicke WH. The other World Wide Web: public policy networks. Foreign Policy 1999–2000; Winter:44–56. 17. Michaud CM, Murray CJL. Aid flows to the health sector in developing countries: a detailed analysis, 1972–1990. In: Health Transition Working Paper Series Number 93.08. Cambridge MA: Harvard Center for Population and Development Studies, 1991. 18. Raviglione MD, Pio A. Evolution of WHO Policies for tuberculosis control, 1948– 2001. Lancet 2002; 359:775–780. 19. Stop TB Partnership. Trends in International Funding for TB Control 1999–2004. Geneva, Switzerland: Stop TB Partnership and HLSP Institute, 2005. 20. Kochi A. The global tuberculosis situation and the new control strategy at the World Health Organization. Tubercle 1991; 72:1–6. 21. Ogden J, et al. The politics of ‘branding’ in policy transfer: the case of DOTS for tuberculosis control. Social Sci Med 2003; 57:179–188. 22. WHO. TB: A Global Emergency – WHO Report on the TB Epidemic, 1994, WHO/ TB/94.177, Tuberculosis Programme. Geneva: WHO, 1994. 23. WHO. Report on the Tuberculosis Epidemic: Use Dots more widely, WHO/TB/ 97.224. Geneva: WHO, 1997. 24. Stop TB Partnership. Draft Summary Strategic Plan of the Stop TB Partnership Working Group for Advocacy, Communication and Social Mobilization: 2006– 2010. Geneva: Stop TB Partnership/WHO, 2005. 25. IHSD. Independent External Evaluation of the Global Partnership to Stop TB. UK: IHSD, 2003. 26. UNAIDS, Stop TB Partnership. Fight AIDS, fight TB, fight now: TB/HIV information pack. Geneva, 2004. 27. Stop TB Partnership Secretariat. Experts’ Consultation on communication and social mobilisation, 29 June–1 July, Cancun: Mexico. Geneva: WHO, 2003. 28. McCoy S, Raftis T. Advocacy and Communication Assessment of the 22 High Burden Countries. Geneva: Stop TB Partnership/WHO, 2002. 29. Stop TB Partnership. Draft Country-level strategic framework for Advocacy, Communication and Social Mobilisation to support TB – Global Plan to Stop TB 2006–2015. Geneva: Stop TB Partnership, 2005. 30. Chowdhury M. Health workforce for TB control by DOTS: the BRAC case. A joint learning initiative: human resources for health and development, JLI Working Paper 5–2, September, 2003. 31. Hossain SM, Bhuiya A, Khan AR, Uhaa I. Community development and its impact on health: South Asian experience. BMJ 2004; 328:830–833. 32. Hadley M, Maher D. Community Involvement in tuberculosis control: lessons from other health care programmes. Int J Tuberculosis Lung Disease 2000; 4(5):401–408. 33. Obara N. The Involvement of Lady Health Workers in TB Control to Strengthen the Primary Health Care System in Pakistan, Powerpoint Presentation and Informal Documentation. Tokyo, Japan: Research Institute Tuberculosis, 2005. 34. How Can Communication And Social Mobilization Help the DOTS Strategy? http://www.stoptb.org/wg/advocacy_communication/assets/documents/Mexico Presentations/September14/ACS%20Outcome%20Map%20for%20TB%20Control %20-%20B.%20Lozare.ppt#256,1 (accessed May 2005).

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35. Stop TB Partnership Secretariat. Summary of decisions and actions, Coordinating Board meeting, New Delhi, 22–23 March 2004, Geneva: Stop TB Partnership/ WHO, March, 2004. 36. WorldBank, Global Health Programs, Millennium Development Goals, and the World Bank’s Role, Operations Evaluation Department (OED), Global Public Policies and Programs Study – Background Paper. Washington, D.C.: World Bank, 2004. 37. Stop TB Initiative. Amsterdam Declaration to Stop TB: ‘‘A Call for Accelerated Action Against Tuberculosis’’. WHO/CDS/STB/2000.6. Geneva, WHO, 2000. 38. WHO. Report of the ad hoc committee on the tuberculosis epidemic, London, 17–19 March 1998. WHO/TB/98.245. Geneva: WHO, 1998. 39. Brundtland GH. Launch of the Stop TB Initiative. IUATLD World Conference, Bangkok, November, 1998. 40. Stop TB Initiative. Amsterdam 22–24 March 2000-‘‘Tuberculosis and Sustainable Development.’’ Report of a conference. WHO/CDS/STB/2000.6. Geneva: WHO, 2000. 41. World Health Organization. Fifty-third World Health Assembly. Resolutions and Decisions. Resolution WHA 53.1. WHA53/2000/REC/. Geneva: WHO, 2000. 42. Global Partnership to Stop TB. Washington Commitment to Stop TB. WHO/CDS/ STB/2001.14a. Geneva: WHO, 2001. 43. Stop TB Partnership. Global Plan to Stop TB, WHO/CDS/STB/2001.16, Geneva: WHO, 2001. 44. Stop TB Partnership. Keeping the Pledge to Stop TB. WHO/HTM/STB/2005.31A. Geneva: WHO, 2004. 45. WHO. Intensified Support and Action Countries (ISAC). A special emergency initiative to accelerate DOTS expansion and reach the 2005 targets and the 2015 MDGs, by the DOTS Expansion Working Group, The Global Fund to Fight AIDS, Tuberculosis and Malaria, Other Financial Partners, and the Stop TB Partnerships. Geneva, Switzerland: WHO, 2003. 46. Kumaresan J, Heitkamp P, Smith I, Billo N. Global Partnership to Stop TB: A Model of an Effective Public Health Partnership. Int J Tuberculosis Lung Diseases 2004; 8(1):120–129. 47. World Health Organization. Global DOTS expansion plan – progress in TB control in high-burden countries 2001, 1 year after the Amsterdam Ministerial Conference. WHO/CDS/STB/2001.11. Geneva: WHO, 2001. 48. Gupta R, Kim JY, Espinal MA, et al. Responding to market failures in tuberculosis control. Science 2001; 293:1049–1051. 49. World Health Organization. Strategic framework to decrease the burden of TB/HIV. WHO/CDS/TB/2002.296 WHO/HIV_AIDS/2002.2. Geneva: WHO, 2001. 50. WHO. Strategic and Technical Advisory Group to WHO, Report of meeting, June 2004. Geneva: WHO. 51. Mckinsey. Evaluation of the Global TB Drug Facility, Final Report, 2003. 52. High-level Forum on the Health MDGs. Best practice principles for global health partnership activities as country level, Paris, November, 2005. 53. High-level Forum on the Health MDGs. Summary of discussions and action points. Third High-level Forum on the Health MDGs, Paris, November 14–15, 2005. 54. Ruggie JG. Marriages of convenience – but marriages nonetheless, an interview. In: Stern S, Seligman E, eds. The Partnership Principle: New Forms of Governance in the 21st Century. London: Archetype, 2004. 55. World Health Organization. Global tuberculosis control – surveillance, planning, financing. WHO Report 2005. Geneva. WHO/HTM/TB/2005.349.

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56. Benner T, Witte JM. Everybody’s Business: Accountability, Partnerships, and the Future of Global Governance, Research project, Exploring and Analyzing the Role of Accountability in Global Governance, 2004:36–47. 57. World Health Organization. Sustainable financing for tuberculosis prevention and control. Fifty-eight World Health Assembly. Agenda item 13.4. Resolutions and Decisions. Resolution WHA 58.14. WHA58.14/2005/REC/. Geneva: WHO, 2005.

26 The Global Drug Facility: A Revolution in Tuberculosis Control

VIRGINIA C. ARNOLD and IAN M. SMITH Office of the Director–General, World Health Organization, Geneva, Switzerland

I. Introduction In October of 2001, a shipment of anti-tuberculosis (TB) drugs arrived in Chisinau, the Republic of Moldova, a country with one of the highest TB rates in Europe, chronic drug shortages, and, until some months earlier, no established DOTS program. The shipment, which had traveled from a manufacturer in Mumbai, India, through a supply chain that had never before been tested, was en route to local health facilities, where it would eventually save 5000 lives. Its successful distribution marked the beginning of a revolution in TB control. Unlike traditional procurement mechanisms, the organization responsible for the shipment had coordinated every component of the supply chain: from quality-assured manufacturing to postdelivery technical assistance. Some six months earlier, the newly created Global Drug Facility (GDF) verified that the drugs to be distributed to the Republic of Moldova met international quality standards. After the same drugs had arrived in newly established DOTS clinics, the GDF sent a team of TB and drug experts to monitor the program and to ensure that patients would reap the most

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benefit from the drugs. By linking demand for anti-TB drugs directly to supply and monitoring, the GDF introduced a new approach to drug supply. Managed by the World Health Organization (WHO), the GDF is an initiative to increase access to high-quality anti-TB drugs for DOTS implementation and offers three services: grants of first-line drugs to support DOTS expansion; a direct procurement service for countries, donors, and other agencies to buy drugs for use in DOTS programs; and a list of quality anti-TB drugs. Adopting an innovative approach to the supply of drugs, the GDF differs from traditional drug procurement mechanisms in four ways: by linking demand for drugs to supply and monitoring; by outsourcing all services to partners on a competitive basis; by using product packaging to simplify drug management; and by linking grants to TB program performance (1). Through its grant and procurement services, the GDF has procured drugs for 4.4 million patients in its first four years of operations (2). II. History of the GDF A continuous supply of drugs is one of the foundations of the DOTS strategy. Although poor drug supply is not unique to TB control, its impact may be especially severe. Erratic supplies severely undermine a TB control program, contributing to the emergence of multidrug-resistant TB (3). In a landmark meeting held in London in April 1998, a group of TB experts identified drug supply as a key impediment to DOTS expansion, highlighting financial constraints, inefficient procurement mechanisms, and poor supply management (4). Their meeting concluded with a call to develop a facility to overcome drug supply problems—the first step toward the creation of the GDF. Recognizing the urgent need to overcome this serious constraint to rapid DOTS expansion, countries attending the Ministerial Conference on TB and Sustainable Development held in Amsterdam in March 2000 adopted a declaration calling on the global community to ‘‘build new international approaches towards ensuring universal access to, and efficient national systems of, procurement and distribution of TB drugs,’’ a declaration that was endorsed by the World Health Assembly that same year (5). The nascent Global Partnership to Stop TB responded to this call and established a core technical group to develop a prospectus for the GDF, which was endorsed at the Stop TB Interim Coordinating Board meeting in February 2001. A month later, the GDF was formally launched on World TB Day, 24 March 2001. The objectives of the GDF, as set out in the prospectus, are to: (i) ensure uninterrupted access to high-quality anti-TB drugs for DOTS implementation; (ii) catalyze rapid DOTS expansion to achieve the WHO global targets for TB control; (iii) stimulate political and public support in countries worldwide for public funding of TB drug supplies; and (iv) secure sustainable global TB control and eventual elimination of TB (6). The GDF fulfills these objectives through (i) grants of drugs to countries that qualify for support; (ii) direct procurement of drugs through bulk purchasing; and (iii) maintenance of a list of ‘‘prequalified’’ drugs that meet international quality standards.

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From the beginning, the architects of the GDF envisioned an organization that would provide drugs via a comprehensive, transparent service line. As a single operating entity, the GDF was established to oversee every component of the drug supply chain: from assuring quality in manufacturing, delivery, and procurement, to providing postdelivery monitoring and evaluation. A small staff in WHO manages the procurement, grant-making, and monitoring functions by outsourcing, on a competitive basis, to collaborative and contractual partners who have demonstrated a technical or financial advantage in a specific area. The GDF has established a full information management system and associated standard operating procedures for the administrative, management, and reporting functions, to ensure transparency and speed of operations, and has been certified as ISO 9001:2000 compliant by the International Organization for Standardization. The GDF demonstrates many key aspects of the essential medicines concept. Anti-TB drugs supplied are carefully selected with a view to improving treatment success. The procurement of the drugs through international mechanisms has reduced the price and increased the reliability of supplies. Distribution of the drugs has been effected through international and national organizations and the provision of patient kits and blister packs and the use of fixed-dose combination (FDC) tablets has facilitated the process. Improved use of the products is facilitated by the supply of these drugs through a DOTS program. III. Operating Mechanisms of the GDF The grant service line of the GDF comprises four elements: application, review, supply, and monitoring. The application mechanism is designed to be simple and to rely on information that should already be available in the country, including a multiyear plan and budget for DOTS expansion, technical guidelines consistent with WHO policies on TB diagnosis and treatment, the most recent report on DOTS performance, and an independent monitoring report. Focusing on countries with limited resources, grants are prioritized for programs in countries with a per capita annual gross national product of less than US $1000. Applications are reviewed by an independent technical review committee (TRC), made up of experts in TB control, TB program management, and drug management. Prior to final approval, an on-site assessment is carried out by a team of experts in TB control and drug management, to ensure conditions for a GDF grant are fulfilled and to assist the recipient program plan for drug distribution and monitoring. Following approval by the TRC and the signing of a grant agreement, which specifies the numbers of additional patients to be treated with GDF support, the GDF places the order of anti-TB drugs with the procurement agent, which has been selected through a process of competitive bidding to manage the supply process. The procurement agent also coordinates the services of other selected agents for preshipment inspection, laboratory

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analysis, freight, and insurance. The drugs, specified and quantified by the GDF, are tendered through limited international competitive bidding of prequalified suppliers and purchased for direct shipment to the recipient country. Grant recipients and the GDF are able to monitor the progress in the supply of drugs through a web-based tracking system (7) that also automatically sends e-mail updates on progress with the shipment. Renewal of GDF grants is on the basis of performance and, as such, regular monitoring is a crucial element of GDF operations. Routine quarterly and annual reports on DOTS coverage, case detection, and treatment outcomes are the basis of this monitoring, supplemented by external monitoring of the program by Stop TB technical partners. These reports are subject to a desk audit by an independent agency (which has also been appointed through a competitive bidding process) and submitted to the TRC for a decision on grant renewal. In the second year of operations, the GDF introduced a direct procurement service line, comprising three elements: application, supply, and monitoring. A list of countries, organizations, and non governmental organizations (NGOs) preapproved to apply to buy drugs through the GDF is available on the GDF website (8). These have all made DOTS their policy for TB control and are therefore able to order anti-TB drugs directly through the procurement agent and receive free technical assistance, in the same fashion as countries receiving GDF grants. The third service provided by the GDF is the published list of ‘‘prequalified’’ products. Quality of anti-TB drugs is of paramount importance for effective TB control, and, therefore, a key principle for the GDF. The list of prequalified drugs was created as a tool to provide national programs with the details of products suitable for use in DOTS programs, which meet international quality standards as determined by WHO. The GDF also uses the list to determine which companies will be invited to tender for the supply of anti-TB drugs through the GDF. The list is developed through the WHO prequalification mechanism for HIV/AIDS, TB, and malaria products (9). The mechanism includes a document review by a WHO-appointed expert committee, followed by an inspection of the manufacturing facility. When a company meets all of the requirements of Good Manufacturing Practices (GMP) and when the individual products from that company meet all of the WHO requirements, the company and the drugs are included on the list. The list is dynamic— companies and products are included as they complete the process. Each company is reevaluated at least every three years. However, if quality problems occur in the interim period, the company would be removed from the list. IV. Achievements Over the past four years, the vision outlined in the 2001 GDF prospectus has steadily become a reality. By the end of December 2004, the GDF

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had provided treatment for several million patients with high-quality antiTB drugs, catalyzed DOTS expansion, significantly reduced the cost of anti-TB drugs, and contributed to several systemwide impacts. A. Patient Treatments

Of the 4.4 million patient treatments ordered by the GDF by the end of 2004, 3.45 million were for grants and 1.03 million for direct procurement using recipient country, multilateral or bilateral donor funds (10). Countries applied for three-year grants for a variety of reasons: financial crises, inefficient or slow procurement, drug quality concerns, increased demand for drugs, and socioeconomic changes. Several countries applied for one-year emergency grants as a stopgap measure to address problems that had suddenly arisen, such as financing gaps, irregular procurement practices, and late deliveries. B. Standardization

One of the aims of the GDF is to promote standardized treatment regimens and products, which will contribute to simplification of drug management in support of effective TB control. The GDF offers a limited catalogue of WHO-approved anti-TB drugs and formulations that promotes the use of FDC tablets in WHO-approved regimens. In particular, the GDF catalogue promotes the use of the fourdrug FDC tablet in blister sheets and patient kits. The emphasis on FDCs is in response to the lack of product standardization in TB programs and the clear benefits of FDCs over single drugs, which include reduced opportunities for monotherapy and therefore risk of drug resistance; fewer tablets for a patient to swallow; simplified drug calculations for practitioners; and reduced use of nonstandard treatment regimens (11–14). In 2004, the GDF promoted further simplification of TB drug treatment by introducing patient kits, based on a model developed by the Revised National TB Control Program in India (15). Each patient kit (one kit for treatment Categories I and III and a second for Category II patients) contains a full course of treatment for one patient in a single box and uses only FDC tablets (Fig. 1). The use of patient kits enhances rational drug treatment because all drugs will be available in the appropriate dosages and quantities, simplifying drug quantification, facilitating drug management, and contributing to more efficient procurement. By 31 December 2004, nine countries had changed to a WHO-recommended regimen as a result of GDF support, while 34 countries had introduced FDC tablets (2). C. Drug Management

The GDF has simplified drug management in several ways. By promoting a limited list of products based on WHO recommendations and focusing on FDCs, the diversity of products used by TB programs is lessened, leading to increased standardization. GDF has also simplified international

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Figure 1 Global drug facility patient kits contain a full course of treatment for an individual patient.

procurement, making its products available through only two mechanisms—via grants or direct procurement. For clients using the direct procurement service, technical assistance from the GDF, Stop TB Partners, and the GDF procurement agent ensures that drug needs are estimated correctly, that only quality suppliers are used, and that the recipient is able to track the progress as the order is shipped. Drug distribution within the country involves a chain of activities that includes clearance through customs, transportation from warehouse to health centers, and maintenance of stock records, adequate stock levels, and appropriate conditions of storage. An optimum distribution system requires good documentation of quantities of products entering and leaving storage areas and of quantities dispensed to patients. Reducing the number of different products moving within the system considerably simplifies this process. With FDCs and patient kits, the number of product items is reduced significantly when compared with single drugs. To promote rational drug use, health providers must prescribe the appropriate anti-TB drugs in the right doses, drugs must be available in treatment centers, and patients must adhere to the drug regimens prescribed. If drug treatment regimens have not been standardized, procured in the appropriate quantities, and distributed in a timely manner, anti-TB drugs will neither be appropriate for patients, nor available when patients

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and providers need them. GDF simplifies rational use of anti-TB drugs through its catalog of user-friendly, quality products based on FDCs and patient kits. D. Cost Reduction

Through standardization of drug products, a bulk-buying procurement system, international competitive bidding, and guaranteed payment to suppliers, the GDF reduced the prices of anti-TB drugs by more than 30% in its first year of operations. From 2001 to 2003, the GDF paid US $10 to $12 for a standard six-month course of treatment. Recent increases in prices of raw materials for anti-TB drugs have led to a rise in overall prices, but the current (2005) price of approximately US $16 for the standard six-month regimen is still one of the most competitive on the international market. E. Health System Impacts

The GDF has had a catalytic impact on DOTS expansion, which goes beyond the provision of drugs. More countries are introducing DOTS expansion plans and drug management plans as part of the application process, and several new partners are now providing technical and financial assistance for DOTS. As a result, the GDF has had a positive system-wide impact. Postdelivery technical assistance has provided countries with concrete, feasible recommendations for improving drug management. In 2004, for example, every GDF-supported country followed more than half of the recommendations for improving drug management. In that same year, more than 70% of countries anticipated no drug stock-out, while the number of countries using outdated drugs decreased sharply (50–14%). These are benefits that are passed on to improved drug management for other diseases. In addition, by reducing the costs of drugs, the GDF has helped generate surplus funds that governments can reallocate to other elements of the health system. By 2004, 88% of GDF grant countries had increased their National Tuberculosis Program (NTP) budget line, amounting to a combined total increase of US $6,000,000 during the period of GDF support (2). V. Future Challenges and Opportunities A. Phasing Out of Grants

One of the biggest concerns related to GDF grants is lack of sustainability. Skeptics initially suggested that countries would discontinue budget lines for anti-TB drugs if they received grants and would therefore remain GDF dependent in the longer term. However, through close monitoring of program financing, the GDF ensures that grants continue to be truly additional. All grant agreements require, as one condition of support, that ‘‘public sector funding for TB control activities will not be reduced as a consequence of, or during the period that GDF grants are received.’’ This statement takes into consideration the fact that many countries do not have a specific budget line item for anti-TB drugs, but a budget for overall TB

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activities. The GDF strongly discourages national programs from deleting the line item for anti-TB drugs within the national health budget. During country visits, prior to signing grant agreements, this issue is discussed with the Ministry of Health. The GDF does not provide 100% of all drug needs for countries in the form of a grant; and support is in addition to government and donor funding. Sustainability in the international development arena is often understood to mean that countries receiving external assistance (in this case grants) should not become dependent on these resources. Projects use a variety of mechanisms to ensure sustainability over the long term, such as cost sharing, capacity building, and phase-out plans. The GDF’s mandate allows it to provide up to three years of support for countries receiving grants. Following this period, countries have three options: (i) reapply for another three-year grant (subject to resource availability), (ii) continue to access GDF products and services through the direct procurement service, or (iii) select a different organization for their drug procurement and management services. The GDF has developed a phase-out strategy, the underlying principle of which is that improvements in TB control should be sustained, i.e., phase-out from grants should not harm the program and any gains in DOTS expansion, product standardization, quality, or cost attributable to the GDF should not be lost in the process of phasing out grants. B. Expanding Direct Procurement

Expansion of the direct procurement service line provides a significant opportunity for the GDF to further support DOTS expansion. However, some countries may find it difficult to secure the funds needed to purchase drugs through direct procurement, particularly if they have budgetary constraints and/or are unable to attract additional donor support. These countries will remain reliant on GDF grants, unless an alternative funding source can be identified. To overcome these challenges and to increase the numbers of patients receiving drugs through direct procurement, the GDF will need to improve marketing of direct procurement by enhancing country-level communication and by improving donor collaboration. As a preliminary step in expanding the direct procurement line, the GDF will first need to gather information on each grant recipient’s capacity for procurement and quality assurance. Currently, such information is scarce and most funding mechanisms do not collect or evaluate such data. Secondly, the direct procurement service line can be expanded through enhanced collaboration with major donors and financing institutions such as bilateral donors, the Global Fund for AIDS, TB, and Malaria (GFATM), the World Bank, and regional development banks. Presently, most donors (multi- and bilateral) do not specifically recommend procurement agents for drug procurement. As a result, the traditional source for direct procurement tends to be either WHO (which has an agreement with the GDF) or through a government budget line. Therefore, potential exists for greater collaboration

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between the GDF and major donors who are providing funds directly to countries to purchase anti-TB drugs. Based on the success with which the GFATM and the GDF collaborated in Indonesia, in which GFATM funded 20% of the total direct procurement order, there is reason to believe that such collaboration is feasible and mutually beneficial. In May 2005, the Stop TB Partnership and the GFATM signed a memorandum of understanding, in which the GFATM encourages recipients to use the GDF for their TB procurement needs, as part of a global fund grant. It is possible that such agreements with other major donors could be initiated. C. Scaling-Up Technical Assistance

Providing grants without monitoring their impact damages TB control. The GDF monitors country performance at every step of the grant and procurement process to ensure that it achieves results. All countries that are approved or placed under consideration for a grant undergo country visits prior to receipt of drugs (one to two drug management consultants). The visits are used to brief the country on the GDF and to provide a rapid assessment of the drug distribution system. Four to six months after the drugs arrive, a monitoring visit (composed of a team of drug management and TB consultants) assesses the financial and drug management aspects of the TB program and verifies that all the GDF terms and conditions of support have been met. In order to be approved for second- and third-year grants, the GDF TRC must be satisfied with the performance and the impact as illustrated in the consultants report on the country. Monitoring missions have increased over the four years of operation, in line with the increase in grant and direct procurement applications. It will become increasingly a challenge for the GDF to find technical agencies that are able to carry out these missions pro bono. The GDF cannot reduce or eliminate its missions to countries without compromising the quality of support it provides and may need to look for separate funding for technical assistance, as well as mechanisms to increase the pool of consultants to carry out such work. Other possibilities could include entering into long-term agreements with specific consulting firms or even creating a separate facility to broker technical assistance for the GDF and to solicit funds for these activities. VI. Conclusion The GDF was established quickly and with a focused mandate—to address a key constraint to reaching the WHO targets for TB. The lessons learnt in terms of strategy, governance, and operations are vital for any new initiatives in the supply arena. The GDF changed rapidly over its first four years, as lessons were learned, the needs of its clients changed and the overall operating environment changed. In the first year, the GDF employed a ‘‘start-up’’ business

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model, with initial seed funding from one donor, in order to quickly provide grants for anti-TB drugs to countries in need. In the second year, these procedures and systems were fine-tuned and the GDF moved from an interim, ad hoc operation to a full-scale procurement and support mechanism as monitoring and TB drug management support were introduced. The direct procurement service line was introduced to cover the needs of those countries interested in procuring high-quality drugs at affordable prices with their own resources, rather than using grants from the GDF. The third year refined the basic business model (development of an information management system, financial reporting mechanisms, and introduction of standard operating procedures) and introduced the list of ‘‘prequalified’’ products. In 2004, the GDF continued to improve the basic business model, as well as to meet the changing needs of its clients for high-quality anti-TB drugs. More donors followed from the two successful evaluations (16,17). This ensured that the grant service line was able to continue. The main concerns for the GDF in 2004 were how to cope with an increased demand for drug management and monitoring support, low detection rates in GDF countries, and establishing relationships with other grant-making agencies, such as the GFATM. The GDF explored a future service line (diagnostic kits) to assist countries with low case detection rates. A new advocacy campaign ‘‘A New Perspective on TB Procurement’’ focused on direct procurement, on the new patient kits, and on promoting the model of drug procurement developed by the GDF (18). With the continued support of key technical partners and the commitment of the GDF, the GDF has proven to be one of the most effective ways to support DOTS and save lives. The mechanism is tried and trusted, and donors remain supportive. As new challenges arise, the GDF is in a strong position to develop and enhance its service lines both to ensure that past achievements are sustained and to offer new opportunities to countries that are engaged in the fight against TB.

References 1. Kumaresan J, Smith I, Arnold V, Evans P. The Global TB Drug Facility: innovative global procurement. Int J Tuberc Lung Dis 2004; 8:130–138. 2. World Health Organization. Progress Report 7 (1 July–31 December 2004). Global TB Drug Facility. Available at http://www.globaldrugfacility.org 3. Raviglione MC, Gupta R, Dye CM, Espinal MA. The burden of drug resistant TB and mechanisms for its control. Ann NY Acad Sci 2001; 953:88–97. 4. World Health Organization. Report of the ad hoc committee on the TB epidemic. WHO/TB/98.245. Geneva, Switzerland: WHO, 1998. 5. World Health Organization. Fifty-third World Health Assembly. Stop Tuberculosis Initiative. WHA53.1. Available at http://ftp.who.int/gb/pdf_files/WHA53/ ResWHA53/1.pdf 6. World Health Organization. Global TB Drug Facility: a global mechanism to ensure uninterrupted access to quality anti-tuberculosis drugs for DOTS implementation. WHO/CDS/STB/2001.10a. Geneva, Switzerland: WHO, 2001.

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http://www.stoptb.unwebbuy.org http://www.globaldrugfacility.org WHO Prequalification Project. http://www.who.int/prequal/. World Health Organization. 4 million treatments in 4 years. WHO/HTM/STB/ 2005:32. Geneva, Switzerland: WHO 2005. World Health Organization. Fixed-dose combination tablets for the treatment of tuberculosis. WHO/CDS/TB/99.267. Geneva, Switzerland: WHO, 1999. Blomberg B, Spinaci S, Fourie B, et al. The rationale for recommending fixed-dose combination tablets for treatment of tuberculosis. Bull World Health Organ 2001; 79:61–68. World Health Organization. Frequently asked questions about the 4-drug fixed-dose combination tablet recommended by the World Health Organization for treating tuberculosis. WHO/CDS/STB/2002.18. Geneva, Switzerland: WHO, 2002. World Health Organization. Operational Guide for National Tuberculosis Control Programmes on the introduction and use of fixed-dose combination drugs. WHO/ CDS/TB/2002.308. Geneva, Switzerland: WHO, 2002. Khatri GR, Frieden TR. Controlling TB in India. N Engl J Med 2002; 347:1420– 1425. Evaluation of the Global TB Drug Facility. Final Report. McKinsey & Company, 2003. Available at http://www.stoptb.org/gdf/documents/GDF_Report-April2003.pdf. Independent External Evaluation of the Global Stop TB Partnership. Institute for Health Sector Development, 2003. Available at http://www.stoptb.org/documents/ STBP%20Evaluation%20Executive%20Summary.pdf. World Health Organization. Sustaining the gains. WHO/HTM/STB/2005.34. Geneva, Switzerland: WHO, 2005.s.

SECTION IV: CONTROL OF TUBERCULOSIS—TAILORING TUBERCULOSIS CONTROL

27 Fundamentals of Tuberculosis Control: The DOTS Strategy

FABIO LUELMO

LEOPOLD BLANC

Tuberculosis Control Programmes Consultant, The Hague, The Netherlands

Stop TB Department, World Health Organization, Geneva, Switzerland

DONALD A. ENARSON International Union Against Tuberculosis and Lung Disease, Paris, France

I. Introduction The objective of tuberculosis (TB) control is to reduce morbidity, mortality, and transmission of TB. In developed, industrialized countries, a substantial reduction was observed early in the 20th century before chemotherapy, thought to be due to improvement of socio-economic conditions (nutrition and housing), with possibly some effect from isolation of TB patients in sanatoria (1). Information on the trend in TB prior to chemotherapy from developing countries is sparse, being restricted virtually to studies reported from Tunisia and cities of Algeria [quoted by Styblo and coworkers (2)], showing a declining trend but at a much lower rate than was reported in the industrialized countries, and data on TB mortality from Latin America. It is likely that substantial reduction of the TB burden would only take place in such countries after implementation of well-organized TB control measures (3), an epidemiological term denoting ‘‘ongoing operations or programs aimed at reducing the incidence and/or prevalence’’ of TB (4). Effective measures have been developed and given the term ‘‘the DOTS’’ (a ‘‘brand’’ name). This is a summary of principles for TB control

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Figure 1 Progress toward the 70% case-detection target 1995–2004. The number of smear-positive cases notified under DOTS 1995–2004 (open circles), expressed as a percentage of estimated new cases in each year. The total number of smear-positive cases notified (DOTS and non-DOTS) (closed circles) as a percentage of estimated cases. Source: From Ref. 5.

that have been sustained for several decades and of strategies that were proven effective in many countries. By the end of 2004, 182 out of 211 countries had adopted the DOTS strategy as their official policy and over 77% of the global population lived in countries or areas in which DOTS had been introduced, a major increase since 1995, when only 35% of the population was covered. In 2004, the DOTS programs reported 3.7 million new and relapse TB cases, of which 1.8 million were smear positive, representing 46% of the estimated global incidence of smear-positive cases (Fig. 1) (5). II. Principles of Tuberculosis Control The basic technical recommendations on case detection, treatment, and program organization were described in a national conference held in the United States in 1960 (6), shortly after the convincing demonstration of the efficacy of chemotherapy for TB. They were established at the global level in the ninth report of the World Health Organisation (WHO) Expert Committee on TB in 1974 (7) and are still valid. They included integration of TB activities into the Primary Health Care program management by a single directing authority with responsibility at a national level, good planning, and operational evaluation. Technical aspects of the 1974

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WHO-recommended strategy included priority to passive case detection, using direct microscopy of sputum samples complemented with active detection in high-risk groups, regular ambulatory treatment with direct observation of drug intake, intermittent treatment, and bacteriological follow-up of treatment. Only a few developing countries (such as Algeria, Chile, Cuba, Libya, Tunisia, and Uruguay) followed those recommendations while maintaining sufficient resources and political support during the process of integration of TB activities into the general health facilities. Those countries achieved substantial and sustained reduction in their TB problem, and some (most notably Cuba) are now at the level where they are embarking on the process of TB elimination as a public health problem. The use of short-course chemotherapy including rifampicin by large national programs since the mid-1970s was key to the changes in the treatment strategy. Starting in 1978, at the invitation of the Government of the United Republic of Tanzania, Annik Rouillon and Karel Styblo [respectively, Executive Director and Director of Scientific Activities of the International Union Against TB and Lung Disease (IUATLD)] applied those concepts and developed a simple model of case registration and reporting, which allowed cohort analysis of patients on treatment as the essential element to monitor TB program quality (8). Along with the development partners, they tested the strategy in various countries in Africa [Tanzania (9), Kenya (10), Benin (11), Senegal, Mali, Malawi (12), and Mozambique (13)], the Americas [Nicaragua (14)] and the Eastern Mediterranean (Yemen). Based on the success in a few districts, the strategy was quickly expanded nationwide in some of these countries (15). III. A Strategy Called DOTS In May 1991, the 44th World Health Assembly (WHA) set out global targets for TB control for the year 2000 and urged member states to control TB through the introduction of an effective TB control strategy (16). Based on a predictive model to evaluate the impact of interventions, the global targets for TB control, which are detecting at least 70% of the infectious cases estimated and curing at least 85% of them, might be expected to lead to a 40% decrease in contacts infected (17), and a decrease in the mortality, prevalence, and incidence of TB. The global efforts toward TB control were further intensified in 1993 when the WHO declared TB a global emergency (18) and the World Bank stated that short-course treatment of TB was ‘‘one of the most cost effective of all health interventions’’ in its 1993 World Development Report (19). In response to the recognition by the 44th WHA (1991) of TB as a major public health problem and the potential for cost-effective control, a ‘‘framework for effective TB control’’ was published by WHO in 1994 (20). This strategy, called DOTS (21), encompassed five elements necessary for basic TB control. To help countries implement the strategy, WHO

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developed training materials (22,23) and technical guidelines for diagnosis and treatment (24), laboratory organization (25), and program evaluation (26), promoted the strategy to national governments, monitored its implementation gaining valuable information for expansion, and reported on progress. These efforts were supplemented by the IUATLD (27–29), which supported national programs and training courses and produced technical materials, and by the Royal Netherlands TB Association. Case definitions, diagnostic categories of patients, and treatment outcomes for monitoring were agreed on and published (30). IV. How the DOTS Strategy Has Been Expanded: From the London Meeting to the Global DOTS Expansion Plan Following the establishment of a global surveillance and monitoring report by WHO in 1997, it became apparent that countries were still far from the year 2000 targets, especially with regard to case detection (31). WHO convened an ad-hoc committee in 1998 to discuss the TB situation in countries with respect to the 2000 targets and to make recommendations for rapid TB control. Lack of political will and commitment was identified as a major single constraint; other impediments to reaching the 2000 targets included lack of financial and human resources, poor organization and management services, unreliable drug supply, and information gaps (32). To overcome these constraints the ad-hoc committee recommended the following actions:
Enhance political commitment in the 22 high-burden countries (HBC), which account for 80% of the disease burden, to increase national human and financial resources
Increase international resources to support low income and least developed countries
Establish a Global Drug Facility (GDF)
Train not only TB program staff but also all health workers in TB control Major achievements have been made since the 1998 ad-hoc committee outlined the major constraints. First, the political commitment has increased, and TB is among the three diseases that have special global attention. The Global Partnership to Stop TB was established in late 1998, with the aim of controlling and eliminating TB as a public health problem. The ministerial Conference on TB and Sustainable Development, which took place in Amsterdam in March 2000, is considered a milestone in TB control. It led to the Amsterdam Declaration to Stop TB calling for accelerated action to expand TB control measures, and mobilization of national and international resources to reach targets by 2005 (33). Second, the financial resources have increased substantially. An analysis of financial resources needs and gaps to control TB for the 22 HBC was carried out in 2001 (34). For basic DOTS implementation, it

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was estimated that the 22 HBC required around US $1 billion per year over the period 2001–2005, while a further US $200 million was necessary for other low- and lower-middle–income countries. Interestingly, endemic country governments pledged about 70% of the global resources needed. Financial resources have further increased recently with the establishment of the Global Fund to Fight AIDS, TB, and Malaria. Third, the Stop TB Partnership launched the GDF in March 2001, with a substantial initial investment by the Canadian International Development Agency, to increase access to high-quality drugs worldwide. The GDF gives grants of anti-TB drugs to lower-income countries and provides a direct procurement mechanism for countries and organizations that wish to buy their own drugs at reduced cost (35). Fourth, extensive training has been undertaken by countries, but due to high turnover and limited number of staff, human resources remain the leading constraint listed in the DOTS Expansion Working Group (DEWG) meeting in 2003, which declared a health workforce crisis to control TB. Although the DOTS strategy was widely accepted by many countries, most of them failed to reach the targets by 2000. It was necessary to turn the accelerated action called by the Amsterdam declaration into activities. In response, the DEWG—one of the six working groups of the Stop TB Partnership—developed in 2000 the Global DOTS Expansion Plan, which is based on two pillars: development of five-year national expansion plan and establishment of Inter-agency Coordination Committees (ICC). In 2003, the 20 HBC had developed a plan and 18 had a national ICC for TB. The National TB Program (NTP) managers monitor these plans and the various partners discuss the progress achieved in external country visits, regional NTP managers’ meetings, and the annual DEWG meeting. Despite the progress made by countries, constraints to DOTS expansion still remain. The main constraints identified at the end of 2002 were inadequate human resources in terms of number of staff and of qualified staff; lack of a strategy to cope with decentralization of the health system; noncompliance of the private sector with the DOTS strategy; inadequate or weak health infrastructures; and the lack of collaborative activities between the HIV and TB programs. In some countries, the high level of multidrug-resistant TB (MDR-TB) poses a challenge to the basic DOTS strategy. To address newly identified constraints, additional strategies need to be included in the basic DOTS framework. V. The Expanded DOTS Framework for Effective Tuberculosis Control The DOTS strategy document was expanded in 2002 to include the accumulated experience, the threat of MDR-TB and HIV, and the need to involve all health-care providers in TB control activities (Table 1) (36). The expanded strategic framework reinforces the five essential elements and includes additional strategies to respond to the TB control challenges identified.

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Table 1 Basic Operations for Implementation of DOTS at the Country Level Establishing a National Tuberculosis Program with a central unit to ensure political and financial support Preparing a program development plan—usually comprising a medium-term strategic plan and one-year operational plans Preparing a program manual, including technical and operational aspects, and a laboratory manual Establishing the recording and reporting system Planning and implementing a training program, with earmarked resources for human capacity development Establishing a microscopy services network, including peripheral microscopy and provincial-level laboratories with responsibility for quality control. When resources are available, developing culture and sensitivity testing to monitor drug resistance Establishing patient-centered treatment services integrated in the primary health infrastructure and expanding access through other health providers (nongovernmental organizations, corporations, private, and community) Securing a regular supply of good-quality drugs and diagnostic materials Designing a plan for supervision Development of information, education, communication, and social mobilization; involvement of private and voluntary health-care providers; economic analysis and financial planning; and operational research are the additional key operations.


Sustained political commitment to increase human and financial resources for TB control, as an integral part of the national health system: Ideally, the respective governments should provide the necessary funding to ensure sustainability (at least for several decades), but countries with insufficient resources can obtain technical and financial international support. Political commitment includes the integration of TB control activities in the health system at all levels with nationwide coverage. DOTS expansion requires fostering partnerships linked to a long-term action plan and social mobilization to sustain political will.
Access to quality-assured sputum-smear microscopy, both for case detection and for monitoring of treatment: A priority is the identification of individuals with cough of long duration (over two weeks) attending general health facilities for any reason, to screen them with sputum microscopy and detect infectious cases of pulmonary TB. Because HIV infection is now the most important factor that increases the risk of developing TB, strategies to prevent, detect, and treat TB in HIV-infected individuals must be implemented (37). Special efforts must be carried out to identify TB cases among institutionalized, captive, and vulnerable

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populations such as prisoners (38). As more resources become available, additional diagnostic tools such as culture and drug susceptibility testing may be added to supplement sputum-smear microscopy in a systematic way, but only when the basic sputum-smear microscopy services are of a high quality. Once public facilities are able to provide TB diagnosis and treatment with satisfactory outcome (over 80% treatment success in new sputum smear–positive pulmonary cases) in a particular area, other health providers should be included in case detection and case registration in a phased manner, and they should follow good diagnostic standards (39). These providers include nonpublic government facilities, nongovernment and corporate organizations, and private practitioners. Standardized short-course chemotherapy to all TB cases under proper case-management conditions, including direct observation of treatment: Proper management conditions imply technically sound services with a patient-centered approach. Treatment of TB cases, and in particular of the most infectious smear-positive pulmonary patients, is the most effective intervention to reduce TB mortality, morbidity, and transmission. Successful treatment depends on access to TB care, both through existing health services (governmental and nongovernmental) and through community participation. Barriers to access include costs (drugs, transport, loss of wages), poor offer of health services at times convenient to the patient, and inadequate personal attention. Integration of TB services in general health care has taken place in most countries, but has often resulted in loss of adequate resources to ensure free treatment and quality of care. Thus planning and management have become the key aspects to achieve successful treatment program outcomes. Substantial progress has been achieved in reducing the cost of essential TB drugs, the use of fixed-dose combinations to reduce monotherapy and facilitate drug management and intake, and presentation as blister packs and patient kits (40). High prevalence of MDR-TB is a man-made problem in some countries due to improper case management, most frequently due to irregular drug supplies, errors in prescription of medications, failing to directly observe the swallowing of medications when recommended, or to the use of medications of poor quality. MDR-TB patients require treatment of long duration with more costly and less-effective drugs. Uninterrupted supply of quality-assured dugs, with reliable drug procurement and distribution systems: Whenever rifampicin is used, it should always be in the form of fixed-dose combinations with other drugs, in preparations only of proven bioavailability (41). Recording and reporting system enabling outcome assessment of treatment outcome and overall program performance: The system

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VI. The Success of the DOTS Strategy Well Applied The first challenge for the routine application of a successful public health strategy in a community where resources are severely limited is the sustainability of the program over the long period required to achieve substantial impact. Among the early partners of the IUATLD, programs have been expanded nationwide and sustained for two and a half decades in Tanzania, Malawi, Mozambique, Kenya, Yemen, Senegal, and Nicaragua. In Nicaragua, despite a progressive deterioration in the economic situation and expansion of war throughout the country, there was an increase of 39% in the rate of successful treatment (43). Accompanying the strengthening and renewal of the program, there has been a steady decline in the proportion of smear-positive patients presenting for treatment who had been previously treated (from 28.4% in 1988 to 16.1% in 1995) with an accompanying decline in the proportion of such patients who failed treatment (from 8.1–2.5%) (44). Similar observations have been made in Benin where the prevalence of multidrug resistance remains exceedingly low after more than a decade of extensive use of the DOTS strategy (45). In Southern and Eastern Africa, progress in the fight against TB has been severely hampered by the spread of the HIV/AIDS epidemic. The dramatic increases in numbers of patients are severely stretching the already meager health service resources. In Malawi, where case-notification rates have been rising steadily over the past decade, an increasing proportion of TB patients die while on treatment and their life expectancy is drastically curtailed for years afterward (46). At the time (1978) that Tanzania was beginning to strengthen its TB services with what became the DOTS strategy, Dr. Kan Guan-Qing and Prof. Zhang Li-Xing introduced the same elements into the TB Control Programme in the Beijing Municipality of China (population 10 million) (47). After pilot testing in one municipality, the strategy was scaled up throughout the whole municipality over the subsequent five years. Over the subsequent two decades, there was a decline in mortality averaging 7% per year and a decline in prevalence and notification rate of 17.2% and 9.1% per year, respectively (48). This was accompanied by a decline in prevalence of TB infection in unvaccinated children from 46% in 1950 to 1.4% in 1995 (49).

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In 1991, after a national survey of TB prevalence, China started the implementation of the DOTS strategy in 13 of the 31 mainland provinces inhabited by 560 million people, almost half the population of the country (50). In 2000, with the support of the World Bank, 1132 of the 1208 counties in the 13 areas had been using DOTS strategy for at least five years. Another survey was done at that time to reevaluate the national TB burden, providing the opportunity to assess the effect of the control project. Between 1991 and 2000, prevalence of TB was reduced by more than 30% in areas implementing the DOTS strategy while it remained almost unchanged in the rest of China. This reduction in prevalence over a median period of implementation of seven years suggests that if the DOTS strategy is implemented countrywide in China by 2005, the prevalence rate could be reduced by 50% before 2015, the target adopted as one of the United Nations’ Millennium Development Goals (51). In 1990, the Government of Peru gave priority to TB and reorganized the TB control program, giving priority to integration of TB in the general health system, bacteriological case detection, directly observed shortcourse treatment, regular supply of good-quality TB drugs, training, and systematic monitoring of results, complemented by operational and epidemiological studies. By 1997, the proportion of health facilities providing TB services had increased from 24% to 99%, the number of smear microscopy laboratories had increased 2.5 times and culture laboratories 5 times, and the annual number of diagnostic smears had increased from 210,000 to 1,400,000. Treatment success in new smear-positive TB cases reached 92.1% and default diminished to 3.7% in 1997. As a result, reported incidence increased until 1993 and then decreased consistently in spite of additional case-detection efforts. The decrease in incidence was estimated at 5.8% per year (Fig. 2) (52). Additional evidence of impact of the program was the reduction in TB mortality, particularly in the under-15 age group, and a low level of annual risk of TB infection of around 1% for 1994– 1995 (53) in relation to the reported incidence, indicating a reduction in transmission. India has the largest TB burden of all countries in the world, with an estimated annual incidence of 1.76 million TB cases. In 1992, the Government of India and WHO carried out a review of the TB program, which resulted in the adoption of the DOTS strategy (India Revised National TB Control Programme) and substantial political and financial commitment including a World Bank loan. After testing in urban and rural pilot areas, the Revised Strategy expanded to cover a population of over 1 billion early in 2005 and should reach full coverage by 2006. The strategy includes coverage with free TB treatment of all patients, intermittent treatment in both the initial and continuation phases, directly observed treatment, and use of patient treatment boxes to ensure regular availability of drugs. A very good monitoring system allows rapid information of the results of case detection and treatment, available in the Web together with the guidelines and training materials (54). The program has achieved over 85% success

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in the treatment of new smear-positive TB cases, and prevented over 200,000 TB deaths in the first eight years (55). VII. Threats to Progress in the Fight Against Tuberculosis and the Way Forward Experience to date shows that the DOTS strategy is feasible, it can achieve important results in reducing disease burden in some locations (for example, China and Peru), it can be safely applied without extending drug resistance, and it is sustainable even in settings where resources are extremely limited. Nevertheless, substantial threats remain to prevent the achievement of targets expected when the strategy was launched. HIV/AIDS is clearly a major challenge. Among all the regions of the WHO, the numbers of reported TB cases are rising the most rapidly in the Africa Region, and particularly in the countries of Southern and Eastern Africa, where the HIV/AIDS epidemic has been the most pronounced. Although the DOTS strategy has not been shown to be able to contain or reverse the increase in TB cases associated with HIV/AIDS, it has been effective in providing high-quality care for TB patients living with HIV and prolonging their life, preventing emergence of drug resistance, and probably reducing the impact on transmission (56) when the strategy has been followed rigorously. The legacy of poor case management and poor program performance has produced a substantial backlog of chronic, multidrug-resistant cases of

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TB, which are very difficult to treat and represent an important risk of transmission (57,58). In spite of recent advances in improving access for the expensive medications required to treat such cases, the results of treatment are still much less encouraging than those for drug-susceptible organisms. Organizing and monitoring the care of such patients is extremely demanding and poses challenges for programs in terms of the additional resources necessary to carry them out and for patients in terms of duration and intensity of treatment. Finally, the national health sector has a weak capacity to absorb and utilize effectively the additional resources that are currently becoming available, particularly in those countries with larger needs and higher TB incidence. This is more evident regarding organization and human resources, and the problem is compounded by the loss of qualified staff and increased health-care demands due to the HIV/AIDS epidemic. DOTS is a general strategy applicable in countries with various local conditions and resources. The technical and operational interventions within the strategy evolve to include advances in technology and new experience, and plans are periodically adjusted to the TB program capacity and the epidemiological situation. However, the present tools have limitations. For example, sputum-smear microscopy is useful to detect the main sources of infection but only helps diagnosis of about half of all TB cases, culture is more sensitive but is slow to produce results, and six to eight months (up to two years in drug-resistant cases) is still a long time to maintain a patient on regular treatment. Efforts to develop more effective tools for TB diagnosis, treatment, and prevention are currently under way, at the same time that governments improve the national capacity to better use current and future technology and face the challenge of providing better access to health care to the whole population.

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54. www.tbcindia.org. 55. Khatri GR, Frieden TR. Controlling tuberculosis in India. N Eng J Med 2002; 347:1420–1425. 56. Royal Netherlands Tuberculosis Association (KNCV) and International Tuberculosis Surveillance Centre, The Hague. Tuberculosis control in the era of the HIV epidemic. Int J Tuberc Lung Dis 2001; 5(2):103–12. 57. Heldal E, Dahle UR, Sandven P, et al. Risk factors for recent transmission of Mycobacterium tuberculosis. Eur Respir J 2003; 33:637–642. 58. Van Rie A, Warren R, Richardson M, et al. Classification of drug-resistant tuberculosis in an epidemic area. Lancet 2000; 356:22–25.

28 Tuberculosis Control in the Countries of Eastern Europe and the Former Soviet Union

MALGORZATA GRZEMSKA

RICHARD ZALESKIS

Stop TB Department, World Health Organization, Geneva, Switzerland

Regional Office for Europe, TB Unit, World Health Organization, Copenhagen, Denmark

I. Introduction Tuberculosis (TB) remains a serious health problem in Eastern Europe, although the total number of notified cases constitutes just 10% of cases recorded worldwide (1). Over the decade 1992 to 2002, the World Health Organization (WHO) European Region (2) experienced a substantial increase of more than 30% in TB case notification. In Eastern Europe, the rate of increase reached nearly 15% annually by 1995, but in 2003, the increase appears to have been halted and incidence started to decline. In 2003, 338,643 new TB cases were reported (1). Among all cases notified in 2003, about 80% were notified in the countries of the former Soviet Union and Romania (1). The group of countries commonly known collectively as Eastern Europe comprises 27 former socialist countriesa. This chapter

a Albania, Armenia, Azerbaijan, Belarus, Bosnia and Herzegovina, Bulgaria, Croatia, Czech Republic, Estonia, Georgia, Hungary, Kazakhstan, Kyrgyzstan, Latvia, Lithuania, Macedonia, Moldova, Poland, Romania, Russian Federation, Serbia and Montenegro, Slovak Republic, Slovenia, Tajikistan, Turkmenistan, Ukraine, and Uzbekistan.

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describes the epidemiology of TB and considers the issues involved in the control of TB in these countries. II. Historical Review of TB Control in the Countries of Eastern Europe and the Former Soviet Union Following the Second World War, the epidemiological situation of TB was very serious throughout Europe, including in the countries of Eastern Europe (3), with the disease mainly affecting young people. To cope with this situation, a centralized (vertical) system for TB control centered on specialized institutions providing treatment and care services, as had been established in the Soviet Union before the war, was adopted in all Eastern European countries. With minor differences between countries, the TB control policies on prevention, diagnosis, and treatment followed the system in use in the Soviet Union. Many countries acquired experience in combating TB through applying this model. Most countries in the region had established a well-managed centralized TB control program by the 1960s. The system consisted of TB research institutes (several in Russia and one per country or Soviet republic), a network of anti-TB dispensaries, TB specialized hospitals, and TB sanatoria (4). All patients with active TB were hospitalized for a period of six to eight months. Several regimens of chemotherapy were applied, although no recognized standards were followed. Chest radiograph examination was extensively used to monitor and evaluate the response to chemotherapy (5,6). Bacteriological investigations (sputum-smear microscopy and culture) were also used, but they were not quality assured, and the results were not used to guide patient management. Radiographic confirmation of cavity closure was the principal definition of cure (7). Surgery was performed when there was a limited or no response to treatment, and patients continued rehabilitation in specialized TB sanatoria (4). Adjunct therapies were widely used in former Soviet countries and included inhalation, intrapleural, or intrabronchial administration of anti-TB drugs, ‘‘galvanization’’ and electromagnetic therapies, and autotransfusion of irradiated blood (5). Dispensary group registers to record and follow-up patients were developed during 1950 to 1960. Patients with active TB disease as well as those who had completed treatment were classified into several groups, and follow-up was carried out, sometimes for several years, before an individual would be discharged from the register (5,8). To prevent a relapse of disease, patients completing treatment received a two-month course of isoniazid chemoprophylaxis (sometimes administered with rifampicin) in the spring and autumn for up to three years. Chemoprophylaxis was also administered to children who had a new positive Mantoux (tuberculin skin test) reaction, as well as to adults who were contacts of a smear-positive TB case (8). Massive active screening with miniature chest radiographs was carried out annually among the majority of the population. Mobile units were

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used to reach rural areas. People applying for jobs and applicants for university had to present the result of a chest radiograph prior to being recruited or admitted. Vaccination with bacille Calmette-Gue´rin (BCG) was administered at birth, and multiple revaccinations were then given throughout childhood and adolescence (9). A survey performed in 1994 to 1996 on BCG vaccination policy in Europe showed that the tradition of repeated vaccinations still persisted in Eastern Europe after the dissolution of the Soviet Union (10). III. Epidemiology The vertical TB control approach, backed by socioeconomic development, was successful in case finding and prevention of further transmission of TB (11,12). The system, supported by legislation, involved all elements of the health-care and welfare services (3,11). Based on general preventive and organizational measures, it was relatively effective and resulted in a steady decline in morbidity and mortality rates (4,11,13,14). For example, morbidity rates decreased to 34.2 to 40.6 cases per 100,000 population in the Russian Federation by the late 1980s, levels comparable at that time to those in other Eastern European countries (4). The same trends were observed in the Baltic States and many other republics of the former Soviet Union (3,13– 15). However, it became clear that a vertical program could not provide services to the entire population through its specialized structure, and without adequate coverage, it could not bring TB fully under control (11). Since the dissolution of the Soviet Union in 1991, the health infrastructure has been deteriorating dramatically in many countries of the former socialist block (3,12–15). The transition from a centralized to a market economy has given rise to, or exacerbated, a number of economic, political, and social problems such as unemployment, malnutrition, poverty, alcoholism, drug abuse, homelessness, overcrowded living conditions, particularly in prisons, migration, and large number of refugees and asylum seekers, which have further worsened the health situation of the population (3,12– 14,16–19). In addition, deep economic recession followed by high levels of inflation has resulted in a disruption of health services and a shortage of funding for basic needs such as anti-TB drugs and other commodities. The TB situation in these countries reflects the abrupt and complex political and social changes, including armed conflicts that have taken place since 1991. The epidemiological situation is now critical in 16 of the 52 countries in Europe (group 1), as evidenced by a resurgence of TB and a significant increase in notification rates between 1992 and 2003 (Fig. 1). TB case notification rates in these countries doubled since 1990. In 2003, all countries of this group except Armenia and Estonia reported more than 50 cases per 100,000 population, whereas Georgia, Kazakhstan, Kyrgyzstan, Moldova, Romania, and the Russian Federation reported more than 80 cases per 100,000 (1).

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Figure 1 TB notification in the World Health Organization European Region, 1980 to 2003. Group 1—former Soviet Union and Romania; group 2—other Eastern European countries; group 3—Western Europe.

A sizeable epidemic of the disease continues in Kazakhstan, Kyrgyzstan, and Romania according to the official statistics, where 175, 120, and 127 TB cases per 100,000 population, respectively, were notified in 2003 (1). The socioeconomic crisis experienced in the region since 1991 is not the only cause of increasing trends in TB burden and notification (4). Paradoxically, improvements in TB case recording and reporting systems have also contributed to the increase (4,16,17). However, the quality of reporting is not always certain. Errors may result in overreporting, for instance, when nonactive TB cases are included. This happens particularly where diagnosis is based on chest radiography without bacteriological confirmation. In the former Soviet Union, TB data were not disclosed publicly. TB morbidity was very high in prisons, particularly in the GULAG system, but precise figures were either unknown or not reported. It finally became possible during the 1990s to publish full statistics on TB, including other sectors (prison, military, railway, etc.) (20). For example, in the Russian Federation, the statistics for 1999, for the first time, included prisoners, homeless people, foreigners, and immigrants from other parts of the former Soviet Union (4). These more complete data reveal that the majority of cases are among persons from 20 to 49 years of age, the most economically productive years of life (1).

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Although expanded reporting has contributed to the higher numbers of recorded cases, the trends do reflect a true increase in the incidence of TB. Indeed, suboptimal rates of TB case detection mean that current case notification rates do not fully reflect the real TB burden (21). The current significant increase in TB case notification in Eastern Europe can be compared to the increase of the epidemic in the African countries most affected by HIV/AIDS. It is projected that by 2005, TB will increase by 8% per year in Eastern Europe and by 10% per year in the African countries affected by HIV/AIDS (1). In addition, multidrug-resistant TB (MDR-TB) or TB resistant to at least isoniazid and rifampicin, which is more difficult and can be up to 100-fold more expensive to treat, is spreading in many countries of Eastern Europe (22,23). The regions of the former Soviet Union face an unprecedented epidemic of MDR-TB. According to the WHO/International Union Against Tuberculosis and Lung Disease (IUATLD), global report on drug resistance surveillance issued in 2004 (23), the highest levels of drug resistance were reported in the countries of the former Soviet Union. More specifically, the prevalence of MDR-TB among new cases was reported as 14.2% in Kazakhstan, 13.7% in the Tomsk oblast in Russia, 13.2% in Karakalpakstan (the autonomous republic of Uzbekistan), 12.2% in Estonia, 9.4% in Lithuania, and 9.3% in Latvia (23). Prevalence of MDR-TB above 30% among previously treated cases was notified in Kazakhstan (56.4%, one of the highest rates in the world), Lithuania, Estonia, the Tomsk and Orel oblasts (Russia), and Karakalpakstan in Uzbekistan (Fig. 2). Estonia has an increasing prevalence of resistance to at least one drug and of MDR-TB among new cases (24). In Latvia, MDR-TB among new cases remains very high (24); however with appropriate TB control measures (DOTS and DOTS-Plus), by 2001, the absolute number of MDR-TB cases had fallen by 28% in Latvia (25). In contrast, less than 0.6% to 1.6% of new patients in the Czech Republic and Poland have MDR-TB, a clear sign of good TB control (23). Countries such as the Czech Republic, Slovakia, and Slovenia

Figure 2 Countries/settings in Eastern Europe with high multidrug-resistant TB among new and previously treated cases (1999–2002).

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with low MDR-TB rates are considered to be among the best TB control programsb in the world. Findings from Eastern Europe demonstrate that the main cause of MDR-TB is poor management of TB patients: inadequate choices of chemotherapy regimens and follow-up treatment, frequent lack of drugs, and poor adherence by patients. It should be stressed that the WHO/IUATLD surveys covered only a small proportion of the total geographical area of Eastern Europe, and the full picture of MDR-TB in the area is still unknown. There is therefore an urgent need to expand drug-resistance surveillance to other countries and areas of Eastern Europe. Recently published anti-TB drug resistance surveys suggest that MDR-TB is a major problem in Moldova, Uzbekistan, Archangelsk, and Samara oblasts of the Russian Federation (8,26–29). In addition, recent studies demonstrated that drug-resistant Beijing/W genotype isolates of Mycobacterium tuberculosis are dominant in the patient population in the Russian Federation, especially among prisoners, posing a serious challenge to treatment programs (28–31). However, the role of the Beijing strain is still disputed, for instance, with regard to its virulence. IV. Adaptation to the International Standards With the transition from a centralized to a market economy, there was considerable disruption of the public health and social services. Health budgets were substantially reduced, which made the maintenance of the previous vertical TB control system much less practicable (15,16). Adaptation of TB programs to internationally recommended standards began in the mid-1990s, with the assistance of WHO and other technical and financial partners. At the first meeting of the managers of national TB programs from Eastern Europe held in 1994, an agreement was reached to adopt the WHO recommended TB control strategy, later termed the DOTS strategy (32). Pilot DOTS projects were first carried out in selected countries in 1995 (Ivanovo and Tomsk oblasts in the Russian Federation, Kyrgyzstan, Georgia, Armenia, and Azerbaijan) (14,15). The DOTS strategy was gradually adapted to the setting in which laboratories performing sputum culture were available as well as the extended network of inpatient facilities (33). The pilot projects introduced diagnosis and registration of cases based on sputumsmear microscopy (and culture where available). Standardized short-course chemotherapy regimens (partially administered in inpatient facilities) and the WHO recommended system for monitoring treatment outcome based on cohort analysis. Efforts to evaluate the impact of the various DOTS pilot projects included a comparison between the effectiveness of the WHOrecommended standardized treatment and the Russian-recommended regimen in Tomsk oblast, where DOTS services were supported by MERLIN b

Stable or decreasing rate of TB notification and deaths, free access to TB diagnosis and treatment, and low rate of drug resistance among indigenous population.

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(a British NGO). Short-course chemotherapy regimens showed 90% smear conversion at six months in smear-positive patients and significantly higher six-month culture conversion rates and lower overall death rates in smearnegative patients (7). The treatment success rate achieved in the pilot DOTS project supported by the U.S. Centers for Disease Control and Prevention (CDC) and WHO in the Orel oblast was 79% in new smear-positive patients and 81% in new culture-positive patients. Although the success rates achieved were slightly lower than the WHO global target of 85% cure, the results were encouraging in the first year of the DOTS implementation (34). Additionally, cost effectiveness analyses of TB control policies comparing the old and new approaches were carried out in the Russian Federation (Ivanovo and Tomsk oblasts), Armenia, and Poland. The results of these studies showed that substantial savings could be made by limiting active screening and prolonged hospitalization and redirecting the resources to essential TB control activities (35–38). Gradually, more countries decided to abandon the previous practices and adopt the new TB control approach of DOTS, which led to further DOTS expansion in Europe. Numerous partners have been instrumental in improving TB control in Eastern Europe, including CDC, the Finnish Lung Health Association, Me´decins sans Frontie`res, MERLIN, the New Jersey Medical School Global TB Institute, the Norwegian Lung and Heart Association, NO-TB Baltic, Open Society Institute, Partners in Health, Project Hope, Public Health Research Institute, and others. V. Applying International Standards There was a substantial increase in the number of countries adopting the DOTS strategy between 1995 and 2003. In 1995, only 5 of the 27 Eastern European countries were following the DOTS strategy, compared with 26 countries in 2003 (1,2). Experience from the pilot areas and countries suggests that DOTS represents a minimum essential package for TB control and that it can be adapted to local circumstances (14,15,31,39,40). The EURO Regional Committee (ministers of health from the WHO European Region member states) at its 52nd session in 2002 recognized that TB is out of control in many countries of Eastern Europe, and the rates of MDR-TB are the highest in the world among surveyed countries and unknown in most of Eastern Europe (41). Addressing this situation, the Committee adopted a resolution ‘‘Scaling up the Response to Tuberculosis in the European Region of WHO’’ (42) and endorsed the ‘‘DOTS Expansion Plan to Stop TB in the WHO European Region 2002–2006’’ (2). The objective of the plan is to achieve the global TB control targets (to detect 70% of infectious TB cases and to successfully treat at least 85% of them) in Europe by 2005. Among the 27 countries of Eastern Europe, 12 have implemented DOTS countrywide, 13 are in the expansion phase, and 2 countries recently started pilot testing the strategy. Many Western European countries have also adopted the DOTS strategy (Fig. 3).

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Figure 3

Progress on DOTS expansion in Europe, 1995 to 2003.

VI. Policy Development with Examples from Countries Since 1990, the representatives of European TB control programs (initially from Western Europe and as of 1996 including also Eastern European participants) have met regularly in Wolfheze, the Netherlands, to discuss the key issues in the European TB control and agree on a common set of recommendations. These meetings organized by the KNCV Tuberculosis Foundation (previously known as The Royal Netherlands Tuberculosis Association), and partially supported by WHO and the European Commission, became the international platform for TB control in Europe. In 1996, a uniform case definition and a minimum set of variables for reporting on each case were determined by consensus (43). Subsequently, consensus-based recommendations were developed on uniform reporting of TB treatment outcome (44) and of anti-TB drug resistance surveillance data (45). These recommendations along with several training initiatives supported by WHO and the partners (training workshops organized in Estonia, Poland, and Italy) resulted in a gradual shift from previous policies to the DOTS strategy. In 2004, when eight previously socialist countriesc joined the European Union, their TB control policies were fully in line with the international standards. The prevailing structures have maintained a strong central unit, usually serving also as a referral inpatient facility as well as an epidemiology and research center. Program delivery has been integrated (to a varying degree in different countries) with the general health services, including private practitioners (33,46). Some countries of the former Soviet Union have been somewhat reluctant to revise their policies in line with the DOTS strategy. To encourage change, WHO and partners initiated a policy dialogue within the Russian Federation in 1999, through the establishment of a High-Level Working

c

Czech Republic, Estonia, Hungary, Latvia, Lithuania, Poland, Slovak Republic, and Slovenia.

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Group (HLWG) (47). The HLWG headed by a Deputy Minister of Health consists of high-ranking Russian representatives from the Ministries of Health and Justice and of scientists from TB research institutes as well as WHO representatives. Thematic working groups have been reviewing all aspects of TB control in Russia and, through consensus building, updating recommended approaches to case detection, diagnosis, treatment, management of MDR-TB and TB/HIV, recording and reporting systems. The recommendations of the HLWG have been submitted to the Ministry of Health for approval. The HLWG platform and the results of analysis from pilot DOTS projects have proved to be the most effective way to modernize TB control policies in the Russian Federation (47–49), and WHO is actively promoting this model in other countries of the former Soviet Union. A similar process including gradual implementation of DOTS in selected counties coupled with the revision of technical and operational recommendations has been under way for several years in Romania (50). Still coping with one of the highest incidence rates of TB in Europe, Romania has successfully shifted to the DOTS strategy, with improvement in case detection and treatment outcomes. Revision of TB control policies requires flexible adaptation of the DOTS strategy according to the priorities and existing infrastructure of each country. Analysis of the TB control programs shows improved performance, with low default rates and high treatment success in DOTS compared to non-DOTS areas (1,31,41,42). VII. Challenges A. Drug Resistance

The extent of drug resistance and MDR-TB in Eastern Europe represents a critical challenge to TB control. Data from several countries [the Czech Republic, Poland, Edinburgh (Scotland), Burkina Faso, Beijing (China), Botswana, and Fort Worth, Texas, U.S.A.] show that good TB control programs are associated with a low burden of MDR-TB (23,51). An important priority for TB control is therefore the implementation of DOTS to prevent the development of MDR-TB. However, it has been shown (Republic of Korea, Peru, and Russian Federation) that standard short-course chemotherapy will not achieve high cure rates, where there is substantial existing MDR-TB (24–30). In addition, the frequency of TB recurrence is high among MDR-TB patients declared ‘‘cured’’ after short-course chemotherapy (52–54). Cure rates for MDR-TB using the standard DOTS regimen were extremely low in a number of countries, in the range of 50% to 55% in the stronger programs like those of Korea and Peru, but as low as 10% in weak programs (52). The management of MDR-TB using second-line drugs becomes essential in such settings to prevent amplification and further transmission of drug-resistant strains. To this end, an international consortium of experts and agencies has been developing and refining a new strategy, ‘‘DOTS-Plus,’’ to add specific treatment of MDR-TB to

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programs that have built a solid foundation of a well-performing DOTS program (53). DOTS-Plus pilot projects are in progress in Estonia, Latvia, the Russian Federation (four oblasts), and Uzbekistan (Karakalpakstan) in collaboration with the WHO’s Green Light Committee (54), with others planned in Kyrgyzstan, Romania, and Georgia. B. Prison Populations

The prisons in the former Soviet Union have been highlighted as a breeding ground for TB and especially MDR-TB (see also Chapter 31 and 36). TB spreads easily in prisons due to overcrowding, poor ventilation, malnutrition, and poor hygienic conditions (20,55–58). Prisoner patients are frequently transferred between pretrial detention centers and prisons, and may be housed with otherwise healthy persons in crowded, poorly ventilated cells. Prisoners are often affected by other diseases, poor nutrition, HIV infection, and alcohol and drug abuse, all of which favor TB transmission and progression. One Siberian prison reported a TB prevalence of 7000 cases per 100,000 prisoners (56). The incidence of TB is approximately 50-fold higher, and the mortality rate is approximately 28-fold higher among prisoners than among the civilian population (59). Drug shortages and weak laboratory services resulting in late diagnosis and inadequate treatment have led to a high burden of MDR-TB in the penal system (28,30,55–58). In 2001, MDR-TB was confirmed in 52.3% of 65 isolates among patients of the Central Penitentiary Hospital of Azerbaijan. The vast majority of isolates belonged to the Beijing genotype (57). MDR-TB was found to be high among prisoners in the Archangelsk prison (Russia): 34% among new cases and 55% among previously treated cases (28). TB control in prisons is poorly integrated with civilian TB control programs. Prisoners with TB are released once their sentences are completed or during mass amnesties without appropriate follow-up in civilian society (56–58). Once outside the prison, this group is highly mobile and tends to avoid health authorities. Serious operational problems hamper the completion of care for released prisoners. Prison staff who share the same air in confined space for prolonged periods are obviously at high risk of TB infection and disease, but there are no published data to quantify this problem. Therefore, an urgent need exists to provide DOTS and DOTSPlus services in the prison sector and to integrate TB control in the penitentiary and civilian sectors, through decentralizing diagnosis and treatment, improving education and training in TB and human rights, prioritizing infectious TB cases, and joint reporting system and shared laboratory facilities for culture and drug susceptibility testing. Coordination also needs to be improved both at the national and at the local (oblast) level (59). C. The HIV Epidemic

The HIV epidemic is not yet widespread in Eastern Europe, but the region has the fastest-growing HIV trend in the world. Growth rates in new infections reported over the last several years in Estonia, Russia, and Ukraine are among the world’s highest, with estimated HIV incidence of 1000/100,000 (60).

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At the end of 2001, WHO estimated that 1.56 million people living with HIV/ AIDS were residing in Europe, compared with 420,000 two years previously (42). According to the report of the United Nations Development Program released in 2004, 1.8 million people infected with HIV have lived in the countries of Eastern Europe (61). Some 280,000 people in Eastern Europe had contracted HIV in 2003 (61). There has been an alarming increase in the number of HIV-infected patients reported in the Russian Federation: from 23 cases, in 1987, to 228,588 cases, in 2002 (62). A similar trend is reported in Ukraine: from a few cases in early 1990s to 52,356 cases in 2002 (63). Latvia has experienced a 58-fold increase in HIV seroprevalence among all persons tested in the country from 1996 to 2001 (from 16 to 906 per 100,000 persons tested) (25). The HIV epidemic in these countries is mainly concentrated among specific risk groups, in particular injecting drug users who are increasing in number due to global trafficking of heroin, unemployment, and poverty (64,65). HIV-testing policies can be expected to have an impact on HIV prevalence data, provided that testing is targeted to the high-risk groups of the population. However, although the Russian Federation tests more people for HIV than any other country in Europe (except Portugal)— 126.3 tests per 100,000 population (66)—anecdotal information indicates that the current testing practice has not been effective in reaching high-risk groups such as injecting drug users, commercial sex workers, and men who have sex with men. The rapidly growing HIV epidemic could, in turn, fuel a TB/HIV coepidemic in the former Soviet Union. Of all new TB cases that occurred in Europe in 2000, 2.6% were attributable to HIV coinfection (67). In the Russian Federation, 1% of all new TB cases were estimated to be HIV positive, and 35% adult AIDS patients died from TB in 2001 (62). In Latvia, from 1998 to 2001, HIV-1 seroprevalence among TB cases increased from 0.1% to 1.4% and among MDR-TB cases from 0% to 5.6% (25). The rapid spread of HIV, the overlap with TB, and the high levels of MDR-TB represent a major public health threat for the future. Despite the clear interrelationship between TB and HIV, national TB and HIV/AIDS control programs in most countries do not cooperate sufficiently because of their traditionally vertical structure. Full collaboration between these programs is critically needed. Thus, measures to combat HIV should take account of TB as a major killer of people living with HIV/AIDS (intensified case finding and treatment of active disease as well as TB preventive treatment). And TB programs should recognize HIV as the most potent force driving the TB epidemic (safe injecting drug use with other preventive methods and provision of antiretroviral drugs) (64,68). D. Political Commitment

There is now strong political commitment to sound TB control based on the DOTS strategy in Eastern Europe (2,42). However, the progress of DOTS expansion is still slow (1), which poses a serious concern in many countries,

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especially in the former Soviet Union. What is meant by political commitment? First the governments in the region need to actively promote and support sound TB control and mobilize adequate resources. Declarations of commitment by some countries have not yet been translated into resource allocation and action. Expenditures need to be increased to finance rational strategies to address TB and the related social conditions. Without well-coordinated external assistance, some countries will continue to face great difficulties in controlling TB. However, overdependence on donor agencies and lack of ownership are serious constraints for the improvement of TB control as well as for the sustainability of successful programs. Therefore, at the beginning of 2005, in a letter to all Members States, the WHO Regional Director declared TB a regional emergency and called on Member States faced with the high burden of TB to increase their national expenditure on rational strategies to address TB and its accompanying social conditions. E. Operations and Infrastructure

Serious challenges for effective TB control are also present at the operational level. The ‘‘iron curtain’’ of the past allowed little access to foreign literature (partially due to poor knowledge of English), which hindered appropriate TB control interventions (4). Lack of qualified staff is a major constraint, and in many countries health-care staff is poorly trained, underpaid, and lacks motivation (4,20,69). National educational programs, which include training of the health care workers as well as education of the population, are a most important aspect of TB control. Basic epidemiology training to enable data analysis and use of data in program management may improve the situation. Poor health infrastructure in some countries, such as poorly performing laboratory systems (lack of standard methods, lack of quality assurance and safety measures, outdated equipment, and irregular supply of reagents), old hospital buildings without proper infection control, large and crowded patient rooms, absence of effective ventilation, etc. are additional constraints to effective TB control (70,71). Services provided by vertical programs for TB control, which have little or no link with primary health-care systems, do not reach the entire population. Health sector reform currently taking place in many countries could be an opportunity for decentralization and integration of TB care with the primary health care systems, noting that appropriate training, education, advocacy, and social mobilization, as well as increased funding from local authorities, are needed to sustain uninterrupted function of TB-control activities (33,69,72). F. Poverty

TB is a disease of poverty. Special efforts need to be undertaken in the countries of Eastern Europe to reach poor and vulnerable sections of the population, such as marginalized ethnic groups, homeless people, immigrants from high TB burden areas, and others. In the socioeconomic

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circumstances, still present in many Eastern European countries, health measures alone will not bring TB under control (4,21,73). Improvements in socioeconomic conditions in individual countries and in Europe as a whole are needed to combat TB effectively. VIII. Conclusions During the past decade, substantial progress has been made in countries recognizing the problems involved in TB control and that solutions may be within their grasp. However, scaling-up the effective and evidence-based strategy for TB control is not only a responsibility for individual countries but must be addressed as an international emergency for Europe, involving the joint efforts of governments and nongovernmental and international organizations. It is gratifying to note that at the time of writing [late 2005], there is increasing evidence, as shown in the flattening of epidemiological indices in Eastern European countries, that the efforts of national governments, WHO, and technical and financial partners and donors are beginning to pay off. References 1. World Health Organization. Global tuberculosis control: surveillance, planning, financing. WHO Report 2005. WHO/HTM/TB/2005.349, ISBN 92 4 156291 9. 2. World Health Organization European Regional Office. DOTS expansion plan to stop TB in the WHO European Region 2002–2006. WHO Regional Office for Europe 2002, ISBN 92 890 1367 2. 3. Raviglione MC, Rieder HL, Khomenko AG, et al. Tuberculosis trends in Eastern Europe and the former USSR. Tuberc Lung Dis 1994; 75:251–259. 4. Perelman MI. Tuberculosis in Russia. Int J Tuberc Lung Dis 2000; 12:1097–1103. 5. Drobniewski F, Tayler E, Ignatenko N, et al. Tuberculosis in Siberia: 2. Diagnosis, chemoprophylaxis and treatment. Tuberc Lung Dis 1996; 77:297–301. 6. Coker R. Control of tuberculosis in Russia. Lancet 2001; 358:434–435. 7. Mawer C, Ignatenko NV, Wares F, et al. Comparison of the effectiveness of WHO short-course chemotherapy and standard Russian antituberculous regimens in Tomsk, Western Siberia. Lancet 2001; 358:445–449. 8. Coker RJ, Dimitrova B, Drobniewski F, et al. Tuberculosis control in Samara Oblast, Russia: institutional and regulatory environment. Int J Tuberc Lung Dis 2003; 7(10):920–932. 9. Global tuberculosis programme and global programme on vaccines. Statement on BCG revaccination for the prevention of tuberculosis. Wkly Epidemiol Rec 1995; 70(32):29–31. 10. Trnka L, Dankova D, Zitova J, et al. Survey of BCG vaccination policy in Europe: 1994–96. Bull WHO 1998; 76(1):85–91. 11. Raviglione MC, Pio A. Evolution of WHO policies for tuberculosis control, 1948– 2001. Lancet 2002; 359:775–780. 12. Migliori GB, Raviglione MC. Central and Eastern Europe. In: Davies PDO, ed. Clinical Tuberculosis. 2nd ed. London: Chapman & Hall, 1998. ISBN 0 412 80340 2. 13. Zaleskis R, Leimans J, Pavlovska I. The epidemiology of tuberculosis in Latvia. Monaldi Arch Chest Dis 1997; 52(2):142–146.

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14. Zalesky R, Abdullajev F, Khechinashvili G, et al. Tuberculosis control in the Caucasus: successes and constraints in DOTS implementation. Int J Tuberc Lung Dis 1999; 3(5):394–401. 15. Raviglione MC, Grzemska M, Alisherov A, et al. Tuberculosis control in Kyrgyzstan—an opportunity. World Health Forum 1996; 17(1):85–90. 16. Zaleskis R. The former Soviet Union: social upheaval and epidemic multidrugresistant tuberculosis. In the chapter ‘‘The global Tuberculosis Situation’’. Infect Dis Clin N Am 2002; 16(1):33–39. 17. Drobniewski FA, Verlander NQ. Tuberculosis and the role of war in the modern era. Int J Tuberc Lung Dis 2000; 12:1120–1125. 18. Pavlovic M, Simic D, Krstic-Buric M, et al. Wartime migration and the incidence of tuberculosis in the Zagreb region, Croatia. Eur Respir J 1998; 12:1380–1383. 19. Aerts A, Habouzit L, Mschiladze M, et al. Pulmonary tuberculosis in prisons of the ex-USSR state Georgia: results of a nation-wide prevalence survey among sentenced inmates. Int J Tuberc Lung Dis 2000; 12:1104–1110. 20. Perelman MI. Tuberculosis in Russia. Consilium Med 2001; 3(12). 01_12/564.shtml (Rus). 21. Shilova MV. Specific features of the spread of tuberculosis in Russia at the end of the 20th century. Ann N Y Acad Sci 2001; 953:124–132. 22. World Health Organization. Drug resistant tuberculosis: levels are ten times higher in Eastern Europe and central Asia. Wkly Epidemiol Rec 2004; 79(12):118–120. 23. Anti-tuberculosis drug resistance in the world. Report No. 3. The WHO/IUATLD Global Project on Anti-tuberculosis Drug Resistance Surveillance. WHO/HTM/ TB/2004.343. 24. Espinal MA. The global situation of MDR-TB. Tuberculosis 2003; 83:44–51. 25. Morozova I, Riekstina V, Sture G, et al. Impact of the growing HIV-1 epidemic on multidrug-resistant tuberculosis control in Latvia. Int J Tuberc Lung Dis 2003; 7(9):903–906. 26. Cox H, Hardreaves S. To treat or not to treat? Implementation of DOTS in Central Asia. Lancet 2003; 361:714–715. 27. Crudu V, Arnadottir T, Laticevschi D. Resistance to anti-tuberculosis drugs and practices in drug susceptibility testing in Moldova, 1995–1999. Int J Tuberc Lung Dis 2003; 7(4):336–342. 28. Toungoussova OS, Mariandyshev A, Bjune G, et al. Molecular epidemiology and drug resistance of Mycobacterium tuberculosis isolates in the Archangel prison in Russia: predominance of the W-Beijing clone family. Clin Infect Dis 2003; 37(5):665–672. 29. Reichman LB, Tanne J. Timebomb: the Global Epidemic of Multidrug Resistant Tuberculosis. New York: McGraw-Hill, 2002. 30. Drobniewski F, Balabanova Y, Ruddy M, et al. Rifampin- and multidrug-resistant tuberculosis in Russian civilians and prison inmates: dominance of the Beijing strain family. Emerg Infect Dis 2002; 8(11):1320–1326. 31. Ruohonen RP, Goloubeva TM, Trnka L, et al. Implementation of the DOTS strategy for tuberculosis in the Leningrad Region, Russian Federation (1998–1999). Int J Tuberc Lung Dis 2002; 6(3):192–197. 32. Leowski J. Report on the First Meeting of National Tuberculosis Programme Managers from Central and Eastern Europe and the Former USSR. Bulletin No. 2, Warsaw: WHO. 33. TB Manual. National Tuberculosis Programme Guidelines. EUR/01/5017620. 34. Kherosheva T, Thorpe LE, Kiryanova E, et al. Encouraging outcomes in the first year of a TB control demonstration program: Orel Oblast, Russia. Int J Tuberc Lung Dis 2003; 7(11):1045–1051.

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35. Migliori GB, Khomenko AG, Punga VV, et al. Cost-effectiveness analysis of tuberculosis control policies in Ivanovo Oblast, Russian Federation. Bull WHO 1998; 76:475–483. 36. Jacobs B, Clowes C, Wares F, et al. Cost-effectiveness analysis of the Russian treatment scheme for tuberculosis versus short-course chemotherapy: results from Tomsk, Siberia. Int J Tuberc Lung Dis 2002; 6(5):396–405. 37. Meerding WJ. Economic evaluation of tuberculosis control in Armenia. WHO Regional Office for Europe. EUR/ICP/CMDS 04 03 02. 38. Snyder DC. Cost savings from new strategies for tuberculosis control in Poland. WHO/TB/98.241. 39. Zaleskis R. DOTS implementation in Europe: successes and challenges. Int J Tuberc Lung Dis 2003; 7(11, suppl 2):160. 40. Zaleskis R. Tuberculosis control in the WHO European Region. Documents of the International Conference on Global Tuberculosis Control in the countries of central Asia, 20–21.09.2004:152–153. 41. Zaleskis R, Magnusson G. Scaling up the response to tuberculosis in the WHO European Region. Eur J Public Health 2003; 13(1):96. 42. World Health Organization European Regional Office. Scaling up the response to tuberculosis in the European Region of WHO (Resolution). Regional Committee for Europe. Report of the Fifty-Second Session, 2002. Copenhagen, Denmark: WHO Regional Office for Europe. EUR/RC52/R8. 43. Rieder HL, Watson JM, Raviglione MC, et al. Surveillance of tuberculosis in Europe. Working group of the World Health Organization (WHO) and the European Region of the International Union Against Tuberculosis and Lung Disease (IUATLD) for uniform reporting on tuberculosis cases. Eur Respir J 1996; 9(5):1097–104. 44. Veen J, Raviglione M, Rieder HL, et al. Standardized tuberculosis treatment outcome monitoring in Europe. Recommendations of a working group of the World Health Organization (WHO) and the European Region of the International Union Against Tuberculosis and Lung Disease (IUATLD) for uniform reporting by cohort analysis of treatment outcome in tuberculosis patients. Eur Respir J 1998; 12(2):505– 510 (Review). 45. Schwoebel V, Lambregts-van Weezenbeek CS, Moro ML, et al. Standardization of antituberculosis drug resistance surveillance in Europe. Recommendations of a World Health Organization (WHO) and International Union Against Tuberculosis and Lung Disease (IUATLD) working group. Eur Respir J 2000; 16(2):364–371 (Review). 46. Ahamed N, Yurasova Y, Zaleskis R, et al. Pocket Guide on Tuberculosis for Primary Health Care Providers for the WHO European Region. World Health Organization, 2004. 47. Heifets L. WHO and Russia: the turning point in joint efforts against TB. Int J Tuberc Lung Dis 2003; 7(2):101–102. 48. Jakubowiak W, Malakhov K, Kluge H, et al. Recent achievements in TB control in the Russian Federation. Int J Tuberc Lung Dis 2003; 7(suppl 2):S166. 49. Kluge H, Jakubowiak W, Pashkevich D, et al. Recommendations of the Russian Ministry of Health to expand the World Health Organization (WHO) TB control strategy in the Russian Federation based on the experience gained from the TB pilot project implementation. Int J Tuberc Lung Dis 2003; 7(suppl 2):S294. 50. Ditiu L. National Tuberculosis Programme in Romania 1997–2000: how it works. Cent Eur J Public Health 1999; 7(4):189–190. 51. Augustynowicz-Kopec E, Zwolska Z, Jaworski A, et al. Drug resistant tuberculosis in Poland in 2000: second national survey and comparison with the 1997 survey. Int J Tuberc Lung Dis 2003; 7(7):645–651.

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52. Centers for Disease Control and Prevention. Primary Multidrug-Resistant Tuberculosis—Ivanovo Oblast, Russia, 1999. MMWR 1999; 48:661–664. 53. Stop TB working group on DOTS-Plus for MDR-TB. A prioritized research agenda for DOTS-Plus for multidrug-resistant tuberculosis (MDR-TB). Int J Tuberc Lung Dis 2003; 7(5):410–414. 54. DOTS Plus and the Green Light Committee. WHO/CDS/TB 2000.283. 55. Portaels F, Rigouts L, Bastian I. Addressing multidrug-resistant tuberculosis in penitentiary hospitals and in the general population of the former Soviet Union. Int J Tuberc Lung Dis 1999; 3:582–588. 56. Kimerling ME, Kluge H, Vezhnina N, et al. Inadequacy of the current WHO re-treatment regimen in a central Siberian prison: treatment failure and MDR-TB. Int J Tuberc Lung Dis 1999; 3:451–453. 57. Pfyffer GE, Strassle A, van Gorkum T, et al. Multidrug-resistant tuberculosis in prison inmates, Azerbaijan. Emerg Infect Dis 2001; 7(5):855–861. 58. Stern V. Problems in prisons worldwide, with a particular focus on Russia. Ann NY Acad Sci 2001; 953(5):113–119. 59. Tuberculosis control in prisons. A manual for programme managers. WHO/CDS/ TB/2000.281. 60. Shemyakin IG, Stepashina VN, Ivanov IY, et al. Characterization of drug-resistant isolates of Mycobacterium tuberculosis derived from Russian inmates. Int J Tuberc Lung Dis 2004; 8:1194–1203. 61. United Nations Development Programme. ‘‘Reversing the epidemic: facts and policy options’’ report on the HIV/AIDS epidemic in the 28 countries of east and southeastern Europe. The Baltics and CIS, 17 February 2004. 62. Ministry of Health of the Russian Federation. Central Research Institute on Epidemiology. HIV infection. Inform Bull Moscow 2003; 25 (in Russian). 63. Ministry of Health of Ukraine. Bull ‘‘HIV in Ukraine’’ 2003; 22:14 (in Ukrainian). 64. De Colombani P, Banatvala N, Zaleskis R, et al. European framework to decrease the burden of TB/HIV. World Health Organization 2003, EUR/03/5037600, ISBN 9289010894. 65. Kazionny B, Wells CD, Kluge H, et al. Implications of the growing HIV-1 epidemic for tuberculosis control in Russia. Lancet 2001; 358:1513–1514. 66. HIV/AIDS surveillance in Europe. End-year report 2003. Euro-HIV Report 2004, No. 70, p. 42. 67. 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. 68. World Health Organization. Interim policy on collaborative TB/HIV activities. WHO/HTM/TB/2004.330. 69. Coker RJ, Atun RA, McKee M. Health-care system frailties and public health control of communicable disease on the European Union’s new eastern border. Lancet 2004; 363(9418):1389–1392. 70. Hargreaves S. Time to prioritize tuberculosis laboratory services. Lancet Infect Dis 2003; 3(10):606. 71. Kruuner A, Danilovitsh M, Pehme L, et al. Tuberculosis as an occupational hazard for health care workers in Estonia. Int J Tuberc Lung Dis 2001; 5(2):170–176. 72. Yurasova Y, Zaleskis R, Jakubowiak W, et al. Social support of tuberculosis (TB) patients and treatment outcomes. Int J Tuberc Lung Dis 2003; 7(11, suppl 2):267. 73. Enserink M. European expansion. Outwitting TB on the E.U.’s eastern frontier. Science 2004; 304(5668):199.

29 Tuberculosis Control in Low-Prevalence Countries of Europe

GIOVANNI BATTISTA MIGLIORI and ROSELLA CENTIS World Health Organization Collaborating Centre for Tuberculosis and Lung Diseases, Fondazione Salvatore Maugeri, Care and Research Institute, Tradate, Italy

I. The Framework for Tuberculosis Control: An Evolving Strategy In the 1980s, Styblo conceived, in Tanzania, the International Union Against Tuberculosis and Lung Disease (IUATLD) model to control tuberculosis in developing countries (1). In 1991, the World Health Assembly (WHA) established the targets (to diagnose 70% of existing infectious tuberculosis cases and cure 85% of them) to be reached by the year 2000, and in 1993, the World Health Organization (WHO) declared tuberculosis a global emergency (2). In 1994, WHO published the ‘‘Framework for Effective Tuberculosis Control,’’ the key document summarizing the strategy, control policy package, and key technical operations of a national tuberculosis program in countries with a high incidence of tuberculosis (3). This document encapsulated the five essential elements of the strategy of tuberculosis control, launched in 1995 as the WHO-recommended strategy (coined the ‘‘DOTS’’ strategy, at the time translated as directly observed therapy, short course) (4,5): political commitment to tuberculosis control; diagnosis based on bacteriology (sputum smear microscopy) and case 747

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finding among symptomatic patients presenting to health services; standardized short-course chemotherapy provided under proper case-management conditions, including DOT; the provision of a regular supply of essential anti-TB medications; and the establishment and maintenance of a recording and reporting system with evaluation of treatment outcome (6,7). This document has greatly contributed to international consensus on what the prime focus of any national tuberculosis control program should be: the prompt identification and documented cure of infectious cases (6,8), allowing a reduction of the period of transmissibility of infection in the community (9), and a reduction in the risk of emergence of drug resistance (10). Following other relevant achievements toward tuberculosis control [e.g., Stop TB partnership launched in 1998 (11); Amsterdam declaration in 2000, postponing the deadline to reach the global targets in 2005 (12,13); and implementation of the Stop TB working groups, Global Drug Facility (14), Global Fund Against AIDS, Tuberculosis and Malaria (GFATM) (15,16) and Millennium Development Goals (MDG) in 2001] (11). WHO launched in 2002 the Expanded Framework and DOTS as a brand name (17,18). This document emphasized the role of the five key elements in allowing resource-limited countries to control tuberculosis, encouraging programs with sufficient resources to complete the basic strategy with additional elements (e.g., culture and drug susceptibility testing (DST), active screening in high-risk groups, etc.). The WHO Frameworks (3,17), focusing on countries with a high incidence of tuberculosis, were not sufficiently comprehensive for low-incidence countries, where technical sophistication and resources allow a much more intensive approach. The existing framework documents also addressed necessarily the most important elements of tuberculosis control, but excluded components necessary when embarking on an elimination strategy (19). To summarize the essential elements of tuberculosis control in lowincidence countries for those industrialized countries of Europe already achieving a low incidence of the disease through the consistent application of existing technologies, a policy document was published in 2002 (20) by WHO, IUATLD, and the Royal Netherlands Tuberculosis Association (KNCV), following a series of workshops jointly organized in Wolfheze, the Netherlands, since 1990. These have aimed at reorienting tuberculosis control in Europe with the help of both tuberculosis-control experts and representatives of ministries of health (19,21). At the third European Workshop on Tuberculosis Control in Low Prevalence Countries (Wolfheze, 1997), it was proposed to explore the need for and feasibility of developing a framework document for countries with a low incidence including those approaching the elimination phase of the disease, still compatible with the global strategy for tuberculosis control advocated by WHO (19). It has been estimated that, without additional efforts, the elimination phase may still take up to 50 to 60 years before the actual point of elimination in these countries will be reached (19).

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The framework for tuberculosis control and elimination in lowincidence countries (20) was mainly intended to: (i) alert and strengthen the political commitment of governments, and, specifically, of Ministries of Health in Europe, to the changes required in policy setting and prioritization of activities; (ii) encourage national tuberculosis control authorities and professional societies to incorporate elements of the framework into their efforts, adopting those appropriate to the local epidemiological and socio-economical situation; and (iii) support educational programs for medical, public health, nursing, and laboratory workers pointing out the specific requirements of tuberculosis control in the elimination phase of tuberculosis. The content of this document is the ideal frame to discuss how countries at low incidence should reorient their efforts to control and eliminate tuberculosis. To underline the natural evolution of the DOTS strategy, the Director of WHO Stop TB Department, during the 2004 meeting of the DOTS Expansion Group, presented the main directions to accelerate expansion and adapt the DOTS strategy to reach all patients: (i) keep expanding and sustaining DOTS achievements, supporting countries to build capacity and to mobilize human and financial resources, within strengthened health systems; (ii) advocate for DOTS, as the recognized public health strategy for TB control, and the importance of individual patient care within DOTS; (iii) engage all care providers, both public and private, to increase access and use of a universal standard of care, especially among the poorest groups; (iv) promote community participation and mobilize societies to increase demand for proper care and involvement in care; (v) adapt DOTS to high-HIV and multidrug-resistant TB (MDR-TB) settings, and strengthen capacity to diagnose and manage sputum smear–negative tuberculosis and drug-resistant cases; (vi) strengthen monitoring and evaluation for problem solving and to measure achievements vis-a`-vis WHA and MDG targets; and (vii) sustain the Stop TB Partnership and its Working Groups. II. Definitions To allow a common understanding, the following working definitions (consistent with earlier documents) are used: Latent tuberculosis infection is subclinical infection with tubercle bacille without clinical, bacteriological, or radiological signs or symptoms of manifest disease (19,22). Tuberculosis is defined as the clinically, bacteriologically, and/or radiographically manifest disease (19). Low–tuberculosis incidence countries have been defined as those with a crude case notification rate below 20 (all cases) per 100,000 inhabitants and declining. Tuberculosis elimination is the point at which less than one infectious (sputum smear positive) case per 1,000,000 inhabitants emerges annually in the general population (19).

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Tuberculosis control strategies aim at reducing the incidence of new tuberculosis cases by rapid identification of the sources of infection and their effective treatment. Tuberculosis elimination strategies include additional elements to reduce the prevalence of latent tuberculosis infection such as preventive therapy for persons with an increased risk of progression from latent infection to overt clinical tuberculosis. Preventive therapy is the treatment of latent tuberculosis infection to reduce the risk of progression to overt clinical disease (19). A risk factor for tuberculosis is the presence of a factor in a person with latent tuberculosis infection that increases the risk of progression to disease compared with the risk for a person without such a condition (23). High-risk groups are those population segments at increased risk of exposure to tuberculosis infection [arbitrarily, those with a notification rate of more than 100 cases per 100,000 population (19)]. Some countries may prefer to consider the relative rather than the absolute risk in these groups. Definite cases of tuberculosis are those with culture-confirmed disease due to Mycobacterium tuberculosis complex (8). Active case-finding is the deliberate search for tuberculosis disease or infection by means of clinical and radiographic examination, supplemented by tuberculin skin testing (19). Case-finding among symptomatic individuals presenting to health services relies on patients with symptoms taking the initiative to attend health services. A definite case has been defined as cured if the patient has completed the prescribed regimen and there is, at least once, a documented negative culture during the continuation phase of treatment. If the bacteriological evidence (negative culture) is not available, the case is defined as treatment completed. The sum of cases whose final outcome is cured or treatment completed is the treatment success. A treatment failure is a case who fails to achieve bacteriological conversion within five months after starting treatment, or becomes culture positive again after previous conversion. Death means a case that died of any cause during treatment. Treatment interrupted (default) is a case in which treatment was interrupted for more than two months or the standard six-month regimen was not completed within nine months. A case of tuberculosis transferred to another unit with the agreement of the treating physicians has been defined as transfer out (6). Although the six outcome categories must be respected, further stratification might be useful, such as death from and death with tuberculosis (6). III. Context: New Challenges for Tuberculosis Control in Low-Incidence Countries Most low-incidence industrialized countries are confronted with very specific problems and challenges as a result of the successful shift from high

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to low incidence over the past 50 years. These specific problems and challenges are a direct consequence of: (i) the steadily declining tuberculosis incidence in the native population; (ii) the gradually increasing relative and absolute importance of latent tuberculosis infection and tuberculosis imported from other countries (Figs. 1–3) (24); (iii) the emergence of groups at particularly high risk of tuberculosis (e.g., HIV-infected patients, prisoners in certain settings, refugees, homeless and poor persons, etc.); and (iv) the importation of drug-resistant and, particularly, MDR cases from Eastern European and other countries (i.e., strains resistant to at least isoniazid and rifampicin) (25). Table 1 summarizes epidemiological indicators and available information on drug resistance in Europe and other selected low-incidence countries. In most low-incidence countries, tuberculosis morbidity among the native population has dramatically declined in the 20th century (23), yet notification data indicate that the regular decline previously observed slowed down or halted in several low-incidence countries of Europe in the 1990s (Fig. 3) (26,27). In Europe, the proportion of immigrants among tuberculosis cases notified in 2002 exceeded 50% in Belgium, Denmark, Israel, Norway, Sweden, Switzerland (notified as foreign-born), and the Netherlands (notified as foreign citizens) (24). This phenomenon is particularly highlighted by increased international migration from high- to low-incidence countries (21,28). Segments of the population at high risk of HIV infection (e.g., commercial sex workers, injection drug users, and prisoners) frequently also have higher tuberculosis incidence rates than the general population. New challenges to treatment and management of patients harboring MDR strains are emerging and pose substantial constraints on infrastructure, policy, and resources (25,29). As tuberculosis declines in a community, groups at particularly high risk become more visible, providing an opportunity for targeted intervention.

Figure 1

Reported tuberculosis cases in Sweden by country of birth, 1980 to 2003.

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Figure 2 Ref. 24.

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Proportion of tuberculosis cases of foreign origin, 2002. Source: From

Figure 3 Standardized notification rates are declining again after slowing down in the 1990s. Source: Courtesy of C. Dye, Stop TB Department, WHO, Geneva, Switzerland.

2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002

Czech Republic Denmark England and Wales Northern Ireland Scotland Estonia Finland France Germany Italy Latvia Netherlands Norway Poland Russian Federation

Slovakia

Country

Year notification data

9.3

40 7.5 3.1d 5.9 2.8h 55.6 4.8 4.2 14.6 –

53.3 9.1 10.3 9.3 7.3 79.6 8.7 5.7 27.1 93.6 19.5

55.3c

3.9b

12.5

1.1

19.6 9.1 40.6e 38.1g 30.7 6.1 61i 76.2 – 0.4i

13.7 61.3

% foreign born

7.4 6

Incidence of notified definite cases pulm Cþ (per 100,000 pop)

11.7 7.8

Overall incidence notified cases (per 100,000 pop)

2000 1997 2002 2002 2002 2002 2002 2002 2002 2002 2001 Tomsk Oblast 2002 Orel Oblast 2002 2002

2002 2002

Year resistance data

Table 1 Summary of Surveillance and Resistance Data from Selected Countries/Territories in Europe

(Continued )

0.9 0.3 17.1a 0.9a 0.9f 1.5a 6.1f 9.9a 0.3a 3.8a 1.2 13.7 2.6 0.3a

1.8a 0.4a

3.6a 5.3a 6.0 3.7 25.1a 3.1a 4.7f 7.2a 15.8f 26.8a 2.8a 10.9a 4.1 29.1 17.9 2.8a

% any MDR % any H

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2002 2002 2002 2002

17.6 18.6 4.6 9.2

Overall incidence notified cases (per 100,000 pop) 14.7 9.4 4 7.2

Incidence of notified definite cases pulm Cþ (per 100,000 pop) 22 5.8j 71.8 60.6

% foreign born 2002 2002 2002 2002

Year resistance data

% any MDR 0.4a 0.4f 1.3a 0.8a

% any H 1.9a 4.7f 8.8a 3.5a

Note: Only countries providing resistance data stratified for previous treatment status were included. The overall incidence of notified cases per 100,000 population was derived from Ref. 24. The incidence of notified definite cases (pulmonary culture positive, Cþ) was calculated from Refs. 24 and 26 (population data). The proportion of foreign born (or foreign citizens) was derived from Ref. 14. Resistance data for cases that have not received treatment for as much as one month were derived from Refs. 24 and 25. a Culture/drug susceptibility testing (DST) performed routinely; national data on all notified/representative samples of TB cases. b Clinician reporting only (68% result unknown). c 18% missing data. d 60% of cases with culture results not available. e 17% of cases with missing information. f Culture/DST not routinely performed, data on selected cases/areas. g 9% with geographic origin unknown. h 50% of cases with culture unknown. i Foreign citizens. j 53% of cases missing information on origin.

Slovenia Spain Sweden Switzerland

Country

Year notification data

Table 1 Summary of Surveillance and Resistance Data from Selected Countries/Territories in Europe (Continued )

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The global dynamics of the tuberculosis epidemic means that a common approach to tuberculosis control policies and activities in lowincidence countries will be more likely to hasten the approach of the overall goal of tuberculosis elimination (19). IV. Aims of the Elimination Strategy Tuberculosis control and elimination strategies must aim at diminishing the incidence and prevalence of subclinical, latent infection with M. tuberculosis to reduce the pool of those infected from which future cases of tuberculosis diseases will emanate. This can be accomplished using two different approaches, the first being to reduce the incidence of new tuberculosis infection, and the second to reduce its prevalence (30). In the low–tuberculosis incidence countries, the oldest generations of the indigenous population have the highest prevalence of latent tuberculosis infection (20), having been born at a time when the risk of tuberculosis infection was high and having had a long cumulative probability of acquiring infection, whereas the youngest generations have a very low prevalence and risk of tuberculosis infection. With the passage of time, as long as the risk of infection in the general population continues to decline, each generation will be replaced by a generation with less and less infection. To ensure that this remains the case, it is essential to minimize the risk of new generations becoming infected through early identification and cure of newly emerging transmitters of infection, i.e., infectious cases. Furthermore, should they become infected, their infection must be prevented from progressing to overt disease. This combined approach is recommended to hasten progress toward elimination of tuberculosis from countries with low incidence of tuberculosis. V. Approach to Control and Eliminate Tuberculosis The basic tuberculosis control strategy in low-incidence countries aims at minimizing transmission of tuberculosis by maintaining high case-finding and cure rates, especially among potentially infectious, bacteriologically confirmed cases (definite cases). It includes some important elements of a more aggressive approach additional to those advocated by the basic WHO framework (Fig. 4A and B) (3): 1.

Ensuring early detection of tuberculosis patients and their treatment until cure and preventing avoidable death from tuberculosis. The clinician’s duty is to ensure that any patient with tuberculosis is promptly diagnosed and treated in order to reduce human suffering and avoidable death. Despite availability of diagnostic tools and efficacious treatment, some patients continue to remain undiagnosed until death from or with tuberculosis (20). The decline in disease incidence adversely affects the

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Figure 4

2.

Problems and challenges in tuberculosis control (A) and elimination (B).

clinical index of suspicion, and points to the need for continuing professional education in the field. Reducing the incidence of infection by risk-group management and prevention of transmission of infection in institutional settings. The incidence of tuberculosis infection in the community is most effectively reduced by identification of potential sources of infection in the community at the earliest possible time and interruption of the chain of transmission. Risk-group management. Although there are significant differences between countries, a large proportion of cases in

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3.

757

low-incidence countries arises from groups with a high prevalence of latent tuberculosis infection (and of active disease): immigrants from countries with a high incidence of tuberculosis (24,28), ethnic minorities, residents of jails and prisons, hospital wards, nursing homes, and homeless shelters, the elderly, and household contacts of recent tuberculosis cases (20). Risk-group management involves active rather than solely opportunistic case-finding aimed at detecting both those with active disease and those with latent infection. These activities need to be in concert with provision of effective treatment, and preventive therapy as appropriate. Prevention of the transmission of infection in institutional settings. Transmission of tuberculosis infection in institutional settings such as jails and prisons, hospitals, nursing homes/long-term residential homes for the elderly, and shelters for the homeless and for new immigrants (both within the institutionalized population and to the staff) makes infection prevention in institutional settings a public health priority in low-incidence countries. Administrative measures such as protection of health-care workers, active screening by chest radiography, and tuberculin testing among residents and staff may be considered as well as the development of policy for rapid diagnostic services and medical examination of suspects, ventilation, isolation of suspects, and training of staff. Reducing the prevalence of tuberculosis infection through outbreak management and provision of preventive therapy for specified groups and individuals. The tuberculosis elimination strategy in low-incidence countries aims at reducing the prevalence of latent infection with M. tuberculosis particularly among those at high risk of progression to manifest disease. Such individuals include recently infected contacts of cases (19), HIV-infected individuals (31), and persons with fibrotic lesions from previously untreated but spontaneously healed tuberculosis (32). Outbreak management. An important group of people with recent infection are persons associated with a common source case in a recognized outbreak of tuberculosis. Outbreak management requires the identification of people with probable recent transmission (starting with close household contacts of the index case or equivalent but extending the circle, if necessary, according to the ‘‘stone in the pond’’ principle) (33), followed by adequate treatment and preventive chemotherapy for those found to be infected (34). Identifying related cases using DNA fingerprint technology opens the way to identify transmitters and to improve control by identifying the so-called ‘‘cluster epidemics’’ (35). Furthermore, this technique allows

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Migliori and Centis study of which tuberculosis cases, within the native population, are more likely due to reactivation of remotely acquired infection or to recent transmission (21,24,36). Provision of preventive therapy for specific groups and individuals. It has been demonstrated in numerous prospective clinical trials that preventive chemotherapy with isoniazid of 6 to 12 months duration is efficacious in reducing the risk of tuberculosis among persons with latent infection (20,32,34,37,38). VI. Prerequisites to Implementation of the European Framework

Maintenance of effective tuberculosis control in low-incidence countries and achievement of elimination will depend on the implementation of a tuberculosis policy package, which includes: (i) government and private sector commitment toward control and elimination; (ii) case detection through casefinding among symptomatic individuals presenting at health services and active case-finding in special groups; (iii) access to tuberculosis diagnostic and treatment services; (iv) standard approach to treatment of disease and infection; and (v) surveillance and treatment-outcome monitoring. A. Government and Private Sector Commitment Toward Elimination

Efficient tuberculosis control and ultimate elimination will not be possible without government commitment, demonstrated by provision of the necessary basic infrastructure (funding, human resources, and facilities), effective technical leadership, adequate legal framework, and development of a coherent, consensus-based national policy. Guidelines for the implementation of risk-group management, outbreak management, infection prevention in institutional settings, and provision of preventive therapy should be developed, based on the national epidemiology and cost-effectiveness evaluation. Guidelines for occupational protection should also be produced and distributed, and their application monitored. In a context characterized by lowering incidence of TB, advocacy is a key activity to ensure both governmental and private sector commitment toward elimination. Although in intermediate- and high–TB burden countries the provision of adequate funding for TB control is in part ensured by international funding sources (e.g., GFATM, bilateral and multilateral funding), in low prevalence settings proper mechanisms should be identified to fund the elimination phase of tuberculosis. For example, in countries experiencing a change in the insurance coverage system, it is important to keep TB high in the list of priorities. Free access to both first- and second-line drugs should be ensured, independently from census, insurance coverage, and legal status, to all individuals. The system of refunding health services

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should take into account the increased absorption of resources caused by MDR-TB and other (rare) complicated TB cases. A suboptimal funding of the reference centers designated to treat few complicated (and expensive) TB cases may lead to mismanagement and further development of drug resistance. The key technical operations to sustain and implement the framework for low-incidence countries include the following: 1.

2.

3.

4.

National schemes for the control and elimination of tuberculosis. With the decline of tuberculosis incidence, the previous ‘‘vertical’’ approach toward tuberculosis control is no longer sustainable, and a national scheme (or ‘‘program’’) is necessary to ensure tuberculosis control and elimination, particularly when loss of expertise on tuberculosis management and control occurs. The key activities should be planned, co-coordinated, supervised, and evaluated by a core group of experienced professionals belonging to governmental as well as nongovernmental agencies (including professional and scientific societies). Within the team, identification of specific responsibilities (including a central co-coordinator) and a balance among the different components of the control effort (surveillance, prevention, diagnosis, including the laboratory network, and treatment) should be ensured. National tuberculosis control policy. Because priorities change rapidly, the development of a system (a ‘‘national tuberculosis policy committee,’’ with adequate representation of all major stakeholders) to establish and continuously update a consensusbased national tuberculosis control policy is crucial. Although the national scheme for tuberculosis control involves essentially technical units, the policy committee needs a balance of technical, political, and administrative members. The implementation of the national tuberculosis control policy at regional level in several countries could be evaluated by the development of a quality assurance system complemented by regular external (if required multidisciplinary) audit. The national policy guidelines are to be based on scientific evidence. National tuberculosis network. (Re-) establishment and/or maintenance of a national tuberculosis network in terms of funding, human resources, and facilities are vital. Bacteriological laboratories and specialist nursing support are an integral part of this network. Public and private sectors should collaborate within the network. The network, identified and co-coordinated within the national scheme, is responsible for the different tuberculosis control activities, based on the national tuberculosis control policy. Legal framework. The legal framework is one expression of government commitment. A committed government supports

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5.

6.

7.

tuberculosis control and elimination activities with appropriate legislation. A legal framework is composed of laws, orders, circular letters, and other different acts in different countries. A good legal framework should allow updating of policies in a flexible manner, in order to respond quickly to the changing priorities of tuberculosis control and elimination. Essential elements of the legal framework for low-incidence countries include compulsory notification of individual tuberculosis cases (8), costfree access to diagnostic and treatment services for all patients (including illegal immigrants) (28,29,39), and limitations to the use of rifampicin in the open market (40). Human resources development. Adequate graduate and postgraduate education plans for staff involved directly (control officers, public health nurses, chest physicians, and bacteriologists) as well as indirectly (e.g., physicians and nurses involved in the patient care of asylum seekers and prisoners) in tuberculosis control and elimination should be developed in collaboration with universities, training institutes, professional societies, and other nongovernmental agencies, within the aims of the national program and the framework of the national policy (39,41). Because the provision of a socially and culturally sensitive environment is essential to ensure rapid diagnosis and effective treatment of tuberculosis patients (immigrants in particular), contacts with community leaders should be taken to ensure translation and support during case-management from the first contact to the final cure, and specific on-the-job training should be planned for nonmedical personnel (from charity organizations, religious groups, retired persons, volunteers, etc.) to be involved on a voluntary basis in the provision of DOT. Health education. Modern health education materials (brochures, videos, etc.) should be developed to facilitate the execution of tuberculosis control and elimination activities. Leaders of foreignborn communities should collaborate in developing educational materials in the original language of the community. Culturally adapted material is part of an overall approach aimed at identifying, designing, and evaluating the tools for reliable communication between health-care professionals, tuberculosis patients, their families, and their community. Tuberculosis managers should seek the help of social scientists for building and implementing such tools, and evaluating them (20). Research. Operational and epidemiological research should address key constraints in the implementation of control and elimination policies and evaluate the impact of specific interventions and the introduction of new technologies and tools. Priorities include research projects, which focus on the operational aspects of tuberculosis control (e.g., how to ensure adherence to

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9.

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treatment in certain parts of the tuberculosis population, and preventive and treatment services for immigrants, how to document the outcome of screening activities, and how to optimize collaboration with other programs such as national HIV control activities). International collaboration. Tuberculosis is a global problem. Expertise in tuberculosis management and control can be maintained and increased in low-incidence countries by collaborating in tuberculosis control programs in high-incidence countries. Tuberculosis elimination will never be reached without a co-coordinated global approach by low-incidence countries toward tuberculosis control in high-incidence countries. International audit. Independent audit performed by professionals from low-incidence countries as ‘‘peer review’’ may contribute to increasing expertise, improving program monitoring, and creating awareness of the need for a global approach to tuberculosis control.

B. Case Detection Through Case Finding Among Symptomatic Individuals Presenting at Health Services and Active Case Finding in Special Groups

As the incidence of tuberculosis declines, prompt diagnosis of tuberculosis cases will require good quality laboratory services and sensitized professional and ancillary staff in the health service and elsewhere. Although case-finding limited to symptomatic individuals presenting at health services (considered the most cost-effective approach) remains the basis of the casedetection policy, a more aggressive approach in countries with low incidence of tuberculosis is justified, including active screening performed on special groups with an incidence of tuberculosis higher than that of the general population. Diagnosis and treatment-outcome monitoring should be based on bacteriological confirmation (8). Laboratories should use standard methods for DST with a quality assurance program including national and international proficiency testing (42). Proficiency-testing procedures should also be developed to maintain good standards in direct microscopy, particularly when the incidence of new sputum smear–positive cases is declining. Similarly, quality control programs should be designed for radiology and pathology (histology) services. C. Standard Approach to Treatment of Disease and Infection

To maintain high cure rates, the main goal is to achieve completion of treatment using modern chemotherapy with standardized regimens. A six-month regimen has been determined to be the most efficacious (43,44). This regimen is appropriate in most countries in the elimination phase (29,43–45). However, the overall resistance situation and the nature of the most important risk groups in a country will influence the national recommendations for the first-line treatment regimen (46). It is recommended that the

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treatment of MDR tuberculosis cases is based on DST results, including at least two, preferably three, drugs to which the organism is susceptible in an individualized regimen. Multidrug-resistant cases should be referred to specialist centers with: validated laboratory proficiency and biosafety measures as well as expertise in clinical management of drug-resistant tuberculosis cases; availability of adequate methods to prevent transmission of resistant strains to patients and health staff (e.g., negative pressure rooms) (47); and intensive patient monitoring (with all therapy normally directly observed) during both the intensive and the continuation phase of treatment, in order to ensure treatment and early detection and management of adverse reactions (10,29,45). A policy of DOT is recommended at least for patients whose adherence to treatment is in doubt and for all patients during the intensive phase of treatment (10). A policy of preventive chemotherapy in selected patients, according to the principles and recommendations outlined in this chapter, is essential in low-incidence countries approaching the elimination phase. The regimen and the management strategy should be elaborated at the national level, and recommendations based on evidence from clinical trials (20,32,34,37,38,48). A review of bacille Calmette–Gue´rin (BCG) vaccination policy is necessary. Evidence of the effectiveness of BCG in protecting infants from disseminated and meningeal tuberculosis, and death from tuberculosis is overwhelming. The protective efficacy in other situations is much more variable. It is thus important to evaluate the cost-effectiveness of BCG vaccination programs in low-incidence countries continuing its use, including an assessment of the frequency of adverse effects, and the need for selective BCG immunization programs/policies in case universal vaccination is discontinued (49). D. Accessibility to Tuberculosis Diagnostic and Treatment Services

Provision of health care in general and tuberculosis services in particular must take into account of the fact that tuberculosis preferentially strikes the poorest segments of the population, and provide services that are either free of charge or covered by comprehensive insurance schemes. As an increasing proportion of tuberculosis cases emerges among foreign-born persons, culturally sensitive services are essential if the elimination strategy is to succeed (21,28). Furthermore, coordination between tuberculosis- and HIV-dedicated services is recommended from the national to the local level. To ensure the same quality of health care for all tuberculosis patients, close collaboration among the civilian, military, and prison health services is necessary, to comply with standards defined on a national level. E. Surveillance and Treatment-Outcome Monitoring

Among others, the Wolfheze consensus documents ‘‘Surveillance of Tuberculosis in Europe’’ (8), ‘‘Standardized Tuberculosis Treatment-Outcome Monitoring in Europe’’ (6), and ‘‘Standardization of Antituberculosis Drug Resistance Surveillance in Europe’’ (42) provide the basic components for

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such a surveillance and monitoring in low-incidence countries. Surveillance must ensure that a minimum set of nine variables (date of starting treatment, place of residence, date of birth, sex, country of origin, site of disease, bacteriological status, and history of previous antituberculosis treatment) is collected in a timely manner on all tuberculosis patients on an individual basis. Physicians’ compulsory notifications should be supplemented by laboratory notifications and the two systems be linked (8). Treatmentoutcome monitoring is based on six mutually exclusive categories (cure and treatment completion, the sum of which represents the treatment success, death, failure, treatment interruption, and transfer out), evaluated by cohort analysis (6,50). The proportion of cases resistant to first-line drugs and of multidrugresistant cases among incident cases should be routinely evaluated within surveillance activities, or, where not feasible, by means of representative surveys or sentinel studies (42,51,52). Because MDR-TB represents a threat for tuberculosis control, the prevalence of multidrug resistance at country level is a useful indicator of the performance of the treatment program and for planning proper public health action, if necessary. In countries where drug resistance surveillance is not routinely carried out, a national register of multidrug-resistant cases should be considered. A set of indicators is necessary to assess the progress in tuberculosis control toward elimination at national level, and to allow international comparisons among different countries. Suggested indicators include indicators of government commitment (e.g., availability of a national tuberculosis control policy); coverage of the policy (e.g., proportion of the country implementing the national strategy); indicators of control performance (e.g., proportion of definite cases and proportion of definite pulmonary tuberculosis cases with successful and unsuccessful outcome); indicators of the functioning of the surveillance system (e.g., time trends in tuberculosis notifications, for all and for pulmonary cases); number of cultures and proportion of cultures positive for M. tuberculosis complex among all examinations requested for mycobacterial investigation; number of direct smear microscopy examinations and proportion of positive results; estimate of patient’s and doctor’s delay in diagnosis and treatment; and prevalence of MDR-TB in new and retreatment tuberculosis cases. Additional examples of input indicators include indicators of training, supervision, and other managerial aspects of tuberculosis control. A reasonable target for low–tuberculosis incidence countries is to reduce the proportion of patients with a potentially bacteriologically unsuccessful outcome (failure, default, and transfer) to less than 10%. In high-risk groups, the proposed targets are to screen 95% of the population at risk and to treat 95%. VII. Conclusions Low–tuberculosis incidence countries of Europe are committed to the elimination of tuberculosis (19). This commitment requires a clear strategy and

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the technical capacity to implement it. This chapter provides a framework to pursue better control and foster elimination of tuberculosis in low-incidence settings where resources are available. A balanced combination of traditional principles and innovative technologies is necessary to achieve this aim. Acknowledgments The authors of this chapter are indebted with all coauthors of the original document (20). References 1. Styblo K. Overview and epidemiological assessment of the current global tuberculosis situation with an emphasis on control in developing countries. Rev Infect Dis 1989; 11(suppl 2):S339–S346. 2. WHO. 44th World Health Assembly: Resolutions and Decisions-Resolution WHA 44.8 (WHA44/1991/REC/1). Geneva: World Health Organization, 1991. 3. World Health Organization. WHO Tuberculosis Programme framework for effective tuberculosis control. WHO document 1994; WHO/TB/94.1:1–7. 4. World Health Organization. Tuberculosis Handbook. World Health Organization Document 1998; WHO/TB/98.253:1–222. 5. Raviglione MC, Dye C, Schmidt S, et al. Assessment of worldwide tuberculosis control. Lancet 1997; 350:624–629. 6. Veen J, Raviglione M, Rieder HL, et al. Standardized tuberculosis treatment outcome monitoring in Europe. Recommendations of a Working Group of the World Health Organization (WHO) and the European Region of the International Union Against Tuberculosis and Lung Disease (IUATLD) for uniform reporting by cohort analysis of treatment outcome in tuberculosis patients. Eur Respir J 1998; 12:505–510. 7. Migliori GB, Ambrosetti M, Besozzi G, et al. Prospective multicentre study on the evaluation of antituberculosis treatment results in Italy: comparison of the cultureversus the smear-based methods. Eur Respir J 1999; 13:900–903. 8. Rieder HL, Watson JM, Raviglione MC, et al. Surveillance of tuberculosis in Europe. Recommendations of a Working Group of the World Health Organization (WHO) and the European Region of the International Union Against Tuberculosis and Lung Disease (IUATLD) for uniform reporting on tuberculosis cases. Eur Respir J 1996; 9:1097–1104. 9. Styblo K. Tuberculosis control and surveillance. In: Flenley DC, Petty TL, eds. Recent Advances in Respiratory Medicine. Number 4. Edinburgh: Churchill Livingstone, 1986:77–108. 10. 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: 1179–1184. 11. WHO. Stop TB Partnership: Annual Report 2001 (WHO/CDS/STB2002.17). Geneva: World Health Organization, 2001. 12. WHO. Stop TB Initiative. Amsterdam March 22–24, 2000: Tuberculosis and Sustainable Development. Conference Report (WHO/CDSSTB/2000.6). Geneva: World Health Organization, 2000. 13. WHO. 53rd World Health Assembly: Resolutions and Decisions-Resolution WHA 53.1 (WHA53/2000/VR/7). Geneva: World Health Organization, 2000. 14. WHO. Stop TB Initiative: Global TB Drug Facility—Prospectus (WHO/CDS/STB/ 2001.10a). Geneva: World Health Organization, 2001.

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15. Brugha R, Walt G. A global health fund: a leap of faith? BMJ 2001; 323:152–154. 16. Elzinga G, Raviglione MC, Maher D. Scale up: meeting targets in global tuberculosis control. Lancet 2004; 363:814–819. 17. WHO. Stop TB: An Expanded DOTS Framework for Effective Tuberculosis Control (WHO/CDS/TB2002.297). Geneva: World Health Organization, 2002. 18. Raviglione MC, Pio A. Evolution of WHO policies for tuberculosis control, 1948– 2001. Lancet 2002; 359:775–780. 19. Clancy L, Rieder HL, Enarson DA, et al. Tuberculosis elimination in the countries of Europe and other industrialized countries. Based on a workshop held at Wolfheze, Netherlands, 4–9 March 1990, under the joint auspices of the IUATLD (Europe region) and WHO. Eur Respir J 1991; 4:1288–1295. 20. Broekmans JF, Migliori GB, Rieder HL, et al. European framework for tuberculosis control and elimination in countries with a low incidence. Recommendations of the World Health Organization (WHO), International Union Against Tuberculosis and Lung Disease (IUATLD) and Royal Netherlands Tuberculosis Association (KNCV) Working Group. Eur Respir J 2002; 19(4):765–775. 21. Tala E, Kochi A. Elimination of tuberculosis from Europe and the world (editorial). Eur Respir J 1991; 4:1159–1160. 22. 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(suppl):S221–S247. 23. Rieder HL. Epidemiologic Basis of Tuberculosis Control. 1st ed. Paris: International Union Against Tuberculosis and Lung Disease, 1999:1–162. 24. EuroTB (InVS/KNCV) and the national coordinators for tuberculosis surveillance in the WHO European Region. Surveillance of tuberculosis in Europe. Draft Report on tuberculosis case notified in 2002. http://www.eurotb.org/rapports/2002/ report_2002htm. 25. World Health Organization. Anti-tuberculosis Drug Resistance in the World. Third Global Report. WHO Document 2004; WHO/HTM/TB/2004.343:1–299. 26. World Health Organization. Global Tuberculosis Control. WHO Report 2004. World Health Organization Document 2004; WHO/HTM/TB/2004.331:1–218. 27. Raviglione MC, Sudre P, Rieder HL, et al. Secular trends of tuberculosis in Western Europe. Bull WHO 1993; 71:297–306. 28. Rieder HL, Zellweger JP, Raviglione MC, et al. Tuberculosis control in Europe and international migration. Report of a European Task Force. Eur Respir J 1994; 7:1545–1553. 29. Migliori GB, Raviglione MC, Schaberg T, et al. Tuberculosis management in Europe. Recommendations of a Task Force of the European Respiratory Society (ERS), the World Health Organization (WHO) and the International Union against Tuberculosis and Lung Disease (IUATLD) Europe Region. Eur Respir J 1999; 14:978–992. 30. Styblo K, Meijer J, Sutherland I. The transmission of tubercle bacilli—its trend in a human population. Tuberculosis Surveillance Research Unit Report No. 1. Bull Int Union Tuberc 1969; 42:1–104. 31. Antonucci G, Girardi E, Armignacco O, et al. Tuberculosis in HIV-infected subjects in Italy: a multicentre study. AIDS 1992; 6:1007–1013. 32. 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. 33. Veen J. Microepidemics of tuberculosis: the stone-in-the-pond principle. Tuberc Lung Dis 1992; 73:73–76. 34. Ferebee SH. Controlled chemoprophylaxis trials in tuberculosis. A general review. Adv Tuberc Res 1969; 17:28–106.

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35. Van Soolingen D, Borgdorff MW, De Haas PEW, et al. Molecular epidemiology of tuberculosis in the Netherlands: a nationwide study from 1993 through 1997. J Infect Dis 1999; 180:726–736. 36. Mackay AD, Cole RB. The problems of tuberculosis in the elderly. Quart J Med 1984; 212:497–510. 37. Pape JW, Jean SS, Ho JL, Hafner A, Johnson WD Jr. Effect of isoniazid prophylaxis on incidence of active tuberculosis and progression of HIV infection. Lancet 1993; 342:268–272. 38. Whalen CC, Johnson JL, Okwera A, et al. A trial of three regimens to prevent tuberculosis in Ugandan adults infected with the human immunodeficiency virus. N Engl J Med 1997; 337:801–808. 39. Migliori GB, Casali L, Nardini S, et al. Evaluation of the impact of guidelines on tuberculosis control in Italy. Monaldi Arch Chest Dis 1996; 51:204–209. 40. Norwegian Government. Forskrifter om godtgjørelse av utgifter til viktigere legmidler [Regulations on refund of expenses for important drugs]. Oslo: Ministry of Social Affairs, 1996. 41. World Health Organization. Tuberculosis Control and Medical Students. WHO document 1998; WHO/TB/98.236:1–53. 42. Schwoebel V, Lambregts-van Weezenbeek CSB, Moro ML, et al. Standardization of antituberculosis drug resistance surveillance in Europe. Recommendations of a World Health Organization (WHO) and International Union Against Lung Disease (IUATLD) Working Group. Eur Respir J 2000; 16:364–371. 43. British Thoracic Association. A controlled trial of six months chemotherapy in pulmonary tuberculosis. First report: results during chemotherapy. Br J Dis Chest 1981; 75:141–153. 44. British Thoracic Association. A controlled trial of six months chemotherapy in pulmonary tuberculosis. Second report: results during the 24 months after the end of chemotherapy. Am Rev Respir Dis 1982; 126:460–462. 45. World Health Organization. Treatment of Tuberculosis: Guidelines for National Programmes. 2nd ed. 1997. World Health Organization Document 1997; WHO/TB/ 97.220:1–66. 46. Iseman MD. Treatment of multidrug-resistant tuberculosis. N Engl J Med 1993; 329:784–791. 47. Moro ML, Errante I, Infuso A, et al. Effectiveness of infection control measures in controlling a nosocomial outbreak of multidrug-resistant tuberculosis among HIV patients in Italy. Int J Tuberc Lung Dis 2000; 4:61–68. 48. Gordin F, Chaisson RE, Matts JP, et al. Rifampin and pyrazinamide vs isoniazid for prevention of tuberculosis in HIV-infected patients. An international randomized trial. JAMA 2000; 283:1445–1450. 49. Tala-Heikkila¨ M, Tuominen JE, Tala EOJ. Bacillus Calmette–Gue´rin revaccination questionable with low tuberculosis incidence. Am J Respir Crit Care Med 1998; 157:1324–1327. 50. Borgdorff MW, Veen J, Kalisvaart NA, et al. Defaulting from tuberculosis treatment in the Netherlands: rates, risk factors and trend in the period 1993–1997. Eur Respir J 2000; 16:209–213. 51. Helbling P, Altpeter E, Raeber PA, et al. Surveillance of antituberculosis drug resistance in Switzerland 1995–1997: the central link. Eur Respir J 2000; 16:200–202. 52. Loddenkemper R. The need of antituberculosis drug surveillance in Europe (editorial). Eur Respir J 2000; 16:195–196.

30 Tuberculosis in the United States: Toward Elimination?

MICHAEL F. IADEMARCO and 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.

I. Introduction From 1953, when national reporting of U.S. incident tuberculosis (TB) cases was first fully implemented, through 1984, the number of cases reported to the Centers for Disease Control and Prevention (CDC) decreased from 84,304 to 22,255. This average annual decline of 5% to 6% was only interrupted by a transient increase in 1980, attributed to cases arising from a large influx of refugees from Southeast Asia (1). This steady decline from 1953 through 1984 led to optimism that tuberculosis could be eliminated from the United States. In 1987, the Secretary of the U.S. Department of Health and Human Services (DHHS) called for the establishment of an Advisory Committee (now Council) for the Elimination of Tuberculosis (ACET), whose purpose would be to provide recommendations for eliminating tuberculosis as a U.S. public health problem. In 1989, ACET published a strategic plan for the elimination of tuberculosis in the United States, establishing a goal of tuberculosis elimination (defined as a case rate of less than one per one million population) by the year 2010 (2). However, in the midst of this planning, it became apparent that something was amiss: an unprecedented reversal occurred in the long-standing 767

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trend of tuberculosis cases. From 1985 through 1992, reported cases increased by 20.1%, from 22,201 to 26,673; this represented a 13% increase in the case rate, from 9.3/100,000 population to 10.5/100,000 population. On the basis of an extrapolation of tuberculosis case trends observed from 1980 through 1984, an estimated 52,000 excess cases of tuberculosis occurred from 1985 through 1992 (3). These increases were primarily seen among persons with human immunodeficiency virus (HIV) infection and included outbreaks of drug-resistant tuberculosis, which resulted in prolonged illnesses and deaths, and resulted in a renewed U.S. government commitment and mobilization of new resources to improve tuberculosis prevention and control activities. Subsequently, from 1992 through 2005, the number of reported tuberculosis cases in the United States decreased to 54% (4). This chapter discusses the factors associated with the increase in tuberculosis cases, the impact of public health actions intended to reverse the epidemic, and future challenges for the prospects of elimination. II. Factors Associated with the Tuberculosis Epidemic in the United States The stagnation in the declining tuberculosis cases and case rate in 1985 and the subsequent epidemic peak in 1992 were primarily associated with five factors (5). Although all of these factors were operative at the national level, there was substantial geographic variability. First was the deterioration of the infrastructure for case finding and effective treatment. During this time, U.S. health-care professionals gradually experienced decreasing capacity to diagnose, appropriately treat, and prevent cases of tuberculosis. This relative loss of proficiency was probably the result of the decades of decreasing tuberculosis case rates. This was compounded between 1972 and 1981 by the shift of federal support away from categorical tuberculosis resources to more discretionary block grants for public health funding to state and big city governments (6–9). With decreasing trends, tuberculosis programs and services were curtailed and resources redirected to address other public health needs. Second, the concurrent epidemic of acquired immunodeficiency syndrome (AIDS) and a rising number of persons infected with HIV placed a significant number of people at greatly increased risk of progressing to tuberculosis disease if infected with Mycobacterium tuberculosis complex (defined as a set of several closely related species: M. tuberculosis, Mycobacterium bovis, Mycobacterium africanum, Mycobacterium microti, Mycobacterium canetii, Mycobacterium caprae, Mycobacterium pinnipedii). A substantial body of evidence linking the epidemics of tuberculosis and HIV infection has accumulated (10–14). HIV infection has both an amplifying and accelerating effect on the natural history of tuberculosis; it is often prevalent among populations with M. tuberculosis infection, and M. tuberculosis infection tends to rapidly progress to active tuberculosis disease among those with HIV infection.

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Third, the tuberculosis epidemic coincided with the immigration of people from countries with a high prevalence of M. tuberculosis infection, reflecting the commonality of tuberculosis throughout the world (4,15–17). The country of origin for persons with tuberculosis was first collected as part of tuberculosis surveillance in 1986, at which time 4925 cases (22% of all reported cases) occurred in persons born outside of the United States. From 1986 to 1992, there was a continuous increase in the number of tuberculosis cases reported in foreign-born persons and in the proportion of cases accounted for by them: in 1992, 7270 cases (27%) occurred in foreign-born persons. Cases in foreignborn persons accounted for approximately 60% of the increase in cases reported in the United States from 1986 to 1992 (3). By 2005, 54% of all tuberculosis cases for which the birthplace is known were foreign born. Fourth, lapses in the implementation of infection control practices in health-care settings and other congregate facilities contributed to the recent increase in tuberculosis, by facilitating transmission of M. tuberculosis (18,19). Poverty, crowded housing, homelessness, substance abuse, and incarceration in correctional facilities all contribute to the creation of environments that facilitate the transmission of tuberculosis (20–26). Concomitantly, a health-care infrastructure lacking appropriate infection control practices, and having inadequate access to care, contributed to delayed diagnosis and treatment of persons with tuberculosis, which, in turn, prolonged infectiousness and increased transmission. An indicator of recent transmission of M. tuberculosis is the occurrence of tuberculosis outbreaks. During the recent tuberculosis epidemic, a number of outbreaks occurred in a variety of settings, including health-care facilities, correctional institutions, shelters for homeless persons, long-term care facilities, substance abuse treatment centers, residential facilities, and schools (8,27–56). Fifth, increased transmission as a result of inadequate laboratory capacity for prompt recognition and diagnosis of multidrug-resistant tuberculosis led to inappropriate treatment regimens and, in turn, led to an increase in the number of patients who remained contagious with drug-resistant strains of M. tuberculosis. Patients with a drug-resistant disease were more complicated and costly to treat, and experienced higher morbidity and mortality. Outbreaks of drug-resistant cases greatly strained the existing public health infrastructure, created great public concern, and brought significant attention to the national tuberculosis epidemic. Although affecting the entire country, the scope and nature of the epidemic varied across the country, indicating that there were different operative combinations of these contributing factors in different regions. III. The Response to the Epidemic and Associated Reversal in Trend A decision to address the problem through a comprehensive strengthening of tuberculosis control activities, including the availability of large, sustained increases in TB-specific federal and local support, is credited with

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reversing the tuberculosis case rate, from 10.5/100,000 population in 1992 to 4.8/100,000 population in 2005 (4,57–60). A. Surveillance

One of the pivotal tuberculosis control activities that brought about these fundamental changes was an enhancement of the national tuberculosis surveillance system, which provided information that allowed state and local health department and the CDC to better monitor and target groups at increased risk for tuberculosis disease. tuberculosis surveillance was updated in 1992 to systematically include the collection of data on the patient’s history or risk of coinfection with HIV, substance abuse, homelessness, residence in long-term care or correctional facilities, type of provider, type of drug regimen, drug resistance, the use of directly observed therapy, and subsequent completion of therapy. Although the U.S. tuberculosis surveillance system has been shown to have a high level of completeness and accuracy (61), work to improve surveillance continues. Investment in a five-year public health research project, National tuberculosis Genotyping and Surveillance Network (62–64) and translation of the findings into new program action paved the way for the establishment, in January 2004, of the tuberculosis Genotyping Program (65). This program, developed in collaboration with the National tuberculosis Controllers Association (NTCA) and other stakeholders, was initiated to enable rapid genotyping of isolates from every patient in the United States with an M. tuberculosis isolate. Tuberculosis control programs in all 50 states and two large cities (New York and San Diego) provided protocols and were approved for participation. The CDC program contracts with laboratories in California and Michigan to provide results within 10 working days from two polymerase chain reaction (PCR)-based genotyping tests: mycobacterial interspersed repetitive units typing (66) and spoligotyping (67). In combination, these two tests provide a highly discriminatory method to identify M. tuberculosis complex strains. An additional genotyping method, IS6110-based restriction fragment length polymorphism fingerprinting (68), is available to provide further discrimination between strains for isolates with identical PCR results. The Mycobacteriology Laboratory Branch at CDC also participates in the tuberculosis Genotyping Program by performing genotyping testing for quality-control purposes. In 2004, NTCA and CDC published the Guide to the Application of Genotyping to tuberculosis Prevention and Control (69). tuberculosis genotyping is a tool which helps tuberculosis control programs identify recent transmission of tuberculosis, detect outbreaks sooner, identify false-positive M. tuberculosis cultures, evaluate completeness of routine contact investigations, and monitor progress toward tuberculosis elimination (Chapter 2: Molecular Epidemiology: Its Role in the Control of tuberculosis) (69,70). B. The Conduct and Management of Outbreaks

Another important intervention implemented at the time of the resurgence included an expanded capability of local health departments to investigate

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tuberculosis outbreaks with the assistance of state governments and CDC, especially in congregate and institutional settings. This work has been extensively documented (27,30,32–56,71,83). However, the lack of standardized definitions of outbreaks leads to a critical need to advance our systematic approach to the conduct of tuberculosis cluster investigations. To this aim, CDC has established an Outbreak Evaluation Unit to better coordinate investigative skills and program expertise to meet the needs and demands of state and local tuberculosis control programs in an effective and efficient manner (84). The conduct of this unit is based on a written plan. The primary goal of the Outbreak Response Plan is to assist in discovering, interrupting, and preventing tuberculosis transmission. Nine secondary goals include: (i) building expertise in tuberculosis epidemiology, diagnosis, and treatment at all health agencies; (ii) integrating the contribution of tuberculosis programs and tuberculosis laboratories; (iii) assessing the impact of investigations and interventions carried out; participating in the evaluation of tuberculosis program functions, costs, and effectiveness; (iv) establishing an accountable system of communication, response, and tracking of tuberculosis transmission; (v) helping to determine training and education needs for implementing the interventions and preventing future outbreaks; (vi) helping partner agencies in obtaining resources for implementing interventions, including training to build skills, to evaluate, and to make strategic programmatic changes; (vii) determining the mediumand long-term national intervention needs for the interruption of tuberculosis transmission; (viii) contributing to the training of Epidemic Intelligence Service Officers and other professional staff; and (ix) contribute to the understanding of tuberculosis transmission dynamics, diagnostic tools, therapeutics, M. tuberculosis virulence, and human tuberculosis immunity. C. The Standardization of Contact Investigations

In the United States, prompt case identification and treatment of infectious cases is the highest priority (Chapter 17: Tuberculosis Control Interventions: A Stepwise Approach). The second priority and important intervention to prevent tuberculosis outbreaks includes contact investigations (Chapter 20: The Role of Contact Tracing in Low- and High-Prevalence Countries). We actively investigate persons deemed to be the source case of tuberculosis using basic principles of epidemiology with a focus on the who, when, and where of close contacts. Increasingly, the use of locations is being realized as an important adjunct to the close contact approach (86). Contact investigation is a tool to find, diagnose, and treat those infected with M. tuberculosis, both latent infection and tuberculosis disease (86–90). In low-incidence settings, these investigations are an efficient source of case finding. Local approaches to tuberculosis contact investigations have not been uniformly standardized. Contact investigations are complicated undertakings that typically require hundreds of interdependent decisions, the majority of which are made on the basis of incomplete data, and dozens of time-consuming interventions.

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Decision-making during a contact investigation requires use of a complex, multifactor matrix rather than simple decision trees. In an effort to standardize the approach, CDC in collaboration with NTCA issued national guidelines in 2005 for the conduct of contacting investigations (91). This guidance is structured to cover 13 fundamental domains (Table 1). This first national attempt to provide basic guidance is forward looking and covers issues such as data management, confidentiality and consent, human resources, cultural competency, and social network analysis. CDC is sponsoring and conducting several major studies to understand the essential and effective components of contact investigations. The resultant knowledge will be used to design interventions to improve the practice of effective contact investigations. Further, more basic research is embedded in these studies with several local health departments, to develop diagnostic approaches, genetic and epidemiologic characteristics of contacts to predict which exposed contacts are most likely to be infected and who is most likely to progress from latent infection to disease. The knowledge gained from these studies might allow us to further focus contact investigation efforts and gain insights useful to the development and evaluation of an effective vaccine. D. Development of National Guidance

In the United States, state and local governments establish public health laws and regulations. CDC promulgates national evidence-based guidelines and recommendations, which are used by states, in partnership with local governments, to develop and implement state-specific tuberculosis control policies. An unprecedented number of evidence-based public health tuberculosis guidelines have been published since 1992 (157). The national guidance spans a spectrum of tuberculosis control principles, from clinical medicine to public health practice. The development of this national guidance has been pursued through expanded collaborations with partners Table 1 Fundamental Aspects of Contact Investigations Decisions to initiate a contact investigation Index patient and sites of transmission Assigning priorities to contacts Diagnostic and public health evaluation of contacts Medical treatment for contacts with LTBI When to expand a contact investigation Communicating through the news media Data management and evaluation of contact investigations Confidentiality and consent in contact investigations Staffing and training for contact investigations Contact investigations in special circumstances Source-case investigations Cultural competency and social network analysis Abbreviation: LTBI, latent tuberculosis infection.

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such as the American Lung Association, Association of Public Health Laboratories (APHL), the American Thoracic Society (ATS), ACET, the Infectious Diseases Society of America (IDSA), the American Academy of Pediatrics, the International Union Against Tuberculosis and Lung Disease, the National Coalition for the Elimination of Tuberculosis (NCET), the Royal Netherlands Tuberculosis Association, the World Health Organization (WHO), and the U.S. Agency for International Development (USAID) (59). The process of establishing consensus, at times challenging, has required a comprehensive and inclusive approach, substantial time and resources, and flexibility (93). Essential elements of policy guidance development process include the need to be sufficiently robust, flexible, and act quickly and correctively. A recent example of the need to act correctively in the United States included the reports of severe adverse events such as deaths and hospitalizations due to drug-induced hepatitis in patients with latent tuberculosis infection (LTBI) who had been prescribed an effective treatment regimen, the combination of two months of rifampicin and pyrazinamide. Prompt action required calling attention to the problem in the context of incomplete information (94), issuing updates and interim recommendations (95,96), and making final recommendations on the basis of additional data (i.e., the combination of two months of rifampicin and pyrazinamide should not generally be offered for the treatment of LTBI in the United States) in collaboration with partners (97), supported by studies (97–99). A particular challenge is the need to allocate resources for the development of guidelines considering both the time of experts and capacity to convene, often at a relatively short notice. Some efforts are enormous and time-consuming [e.g., four years to revise the guidelines for preventing the transmission of M. tuberculosis in health-care settings CDC. Guidelines for Preventing the Transmission of Mycobacterium tuberculosis in Health Care settings, 2005–MMWR 2005; 54 (No. RR17, 1–141) and three years for guidance on controlling tuberculosis in the United States (100)]. Other efforts require keeping up with fast-paced technologic developments [e.g., guidelines 1 for the use of QuantiFERON -TB Test for detecting M. tuberculosis infection which needed to be replaced shortly thereafter with guidance on the use of QuantiFERON-TB Gold Test for both latent infection and tuberculosis disease (101,102)]. Still others, although seemingly confined to a specialized clinical niche, are also very important with the added necessity of building new relationships with nontraditional partners [e.g., recommendations for tuberculosis associated with blocking agents against tumor necrosis factor-a (103)]. People and groups in the United States dedicated to eliminating tuberculosis must increasingly reach out to other communities and persons affected by tuberculosis (a lesson derived most poignantly from public health activities combating HIV infection; Chapter 22: Involving Community Members in tuberculosis Care and Control) and primary care health professionals (to enforce the message, ‘‘Think TB,’’ especially as the incidence in the United States continues to decrease) (104).

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Table 2 Four U.S. Regional Training and Medical Consultation Centers Francis J. Curry National Tuberculosis Center (107) Heartland National Tuberculosis Center (108) Northeastern National Tuberculosis Center (109) Southeastern National Tuberculosis Center (110)

E. The Importance of Education, Communication, and Training Efforts

Publication of national guidelines is necessary but insufficient to make rapid progress toward tuberculosis elimination. The development and implementation of consensus as manifest in guidelines must be translated and disseminated through efforts in education, communication, and training. The approach to this translation is best rooted in formal processes, which include formative research and formative evaluation, to optimize and best ensure that the products delivered are appropriate for the needs and as efficacious as possible (105). At a national level, this effort is the mandate of a specific unit in CDC’s Division of tuberculosis Elimination and provides necessary leadership and guidance (92). In addition, CDC created and consistently supported three national tuberculosis model centers through 2004. These centers were the cornerstone of the effort to respond to the resurgence. The focus of their efforts was the provision of state-of-the-art care, training and education of program staff and providers, development of innovative approaches to tuberculosis control, application of the innovation in their own program and collaboration with CDC. These accomplishments were associated with a decrease in morbidity in the respective areas (106). In 2005, CDC sought to translate this success to a broader national scope, in an attempt to be more responsive to the needs of all state and local health departments. Four Regional Training and Medical Consultations Centers were established on the basis of competitive applications and available resources. These centers, which cover the entire country, will serve as sources of excellent medical consultation and training for tuberculosis programs. The centers will also serve as a national resource, but with assigned responsibility to provide regional coverage. The goal of each center is (i) to increase human resource development for the prevention and control of tuberculosis through education and training activities and (ii) to increase the capacity for appropriate medical evaluation and management of persons with tuberculosis and latent infection in their assigned region. The centers offer training curricula, course materials, and technical assistance. For a list of these four centers, see Table 2. F. Epidemiologic Trends in the Progress Toward Elimination

From 1992 through 2005, tuberculosis case rates declined every year. This trend has been associated with a measured increase in the essential activities for tuberculosis control. These activities include increasing the percentage

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of those persons diagnosed with tuberculosis who are started on standard four-drug regimen (41–82%, 1993–2004), are given only directly observed therapy (22–55%, 1993–2002), and complete treatment in less than one year’s time (64–80%, 1993–2002) (106). These achievements were accomplished along with high rates of reporting (61), and a recognition of the obligation of the United States to contribute to global tuberculosis control (Chapter 1: The Global Tuberculosis Epidemic: Scale, Dynamics, and Prospects for Control) (59). In addition, there have been substantial improvements in the rates of HIV testing (46–67% in persons aged 25–44 years; and from 30–54%, in persons of all ages, 1993–2003); and a decrease in the rates of tuberculosis and HIV co-infection if HIV tested (29–16% in persons aged 25–44 years old; and 15–9% in persons of all ages, 1993– 2003); and in the numbers of cases with drug resistance (from 1564 to 832 isolates resistant to at least isoniazid, and from 485 to 124 isolates resistant to at least isoniazid and rifampicin, 1993–2004). However, after 12 years of decline in the tuberculosis case rate from 1993 to 2005, the United States finds itself at crossroads. In 2004, the rate of decline in both the rate and number of cases was slower than previous declines. From 1993 to 2000, the annual rate of decrease of the number of cases averaged 6.0 (range 3.6–7.4%) and the decrease in the rate per 100,000 population averaged 7.1 (range 4.8–8.5%). From 2000 through 2005, the average of the annual in the number and the rate has been less: 2.9% and 3.8%. The declines in four of these last fours have been the smallest over the 13 years of decline. This trend may be the harbinger of stagnation in our efforts toward elimination, and may reflect a slow erosion in the ability to sustain long-term progress as resources to prevent and control tuberculosis in the United States have remained relatively fixed and have not kept up with inflation. IV. The Choice Between Elimination and Stagnation: Another Cycle of Neglect? In this era of renewed optimism for tuberculosis elimination, there have been two recent milestones: ACET issued a revised tuberculosis elimination plan, and the Institute of Medicine published Ending Neglect: The Elimination of Tuberculosis in the United States (59,111). The fundamental challenge is whether as a nation we will take decisive action to eliminate tuberculosis in the United States, or fall again into the cycle of neglect and resurgence. It has long been acknowledged that as the numbers of persons with tuberculosis decrease, there is an accompanying complacency and lack of political will required to provide long-term, sustainable support (8,18,58). Even if the overall trend from 1993 continues, elimination will not be achieved for the next several decades (59). The most compelling argument favoring efforts to eliminate tuberculosis was advanced by ACET in declaring the following: ‘‘because eliminating tuberculosis from the United States will have widespread economic, public health, and social benefits, committing

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to [tuberculosis elimination] will also fulfill an obligation to persons throughout the world who have this preventable and curable disease.’’ Furthermore, in 1999, one decade after the publication of the original strategic plan, ACET reaffirmed its call for the elimination of tuberculosis in the United States (111). V. The Way Forward In attempting to prevent another cycle of neglect, to accelerate the decline in tuberculosis, and to proceed at a reasonable pace toward elimination, we must avoid the substantial risk of renewed complacency in the face of declining tuberculosis cases in the United States. This is especially important in the setting of the current global tuberculosis emergency (112–116). However, the opportunity to eliminate tuberculosis in the United States is impaired by several converging factors: (i) the persistence of the global tuberculosis epidemic, (ii) the retreat of tuberculosis into high-risk populations at the margins of society, (iii) the limitations of current control measures, including diagnostic tests and treatments, and the absence of a highly effective vaccine, and (iv) changes in the health-care system that make the current context of tuberculosis elimination very different from that of a decade and a half ago (59,111,117). To end the cycle of neglect that has characterized tuberculosis control in the United States, the Institute of Medicine report, Ending Neglect, recommended an aggressive strategy to: (i) maintain control of tuberculosis; (ii) accelerate the decline in tuberculosis incidence; (iii) develop new tools for tuberculosis diagnostics (Chapter 46: New Diagnostics for Tuberculosis), treatment (Chapter 47: New Drugs for Tuberculosis), and prevention (Chapter 48: The Future of Tuberculosis Vaccinology); (iv) increase efforts in the United States to help fight the global epidemic; and (v) mobilize and sustain public support for tuberculosis elimination, and track progress (58). As a first step toward addressing these issues, CDC has prepared a response to the Institute of Medicine’s report (117) which outlines goals and objectives (Table 3) that will move us toward elimination. In addition, the Federal tuberculosis Task Force has drafted a more comprehensive response that incorporates the role and responsibilities of other federal agencies involved in TB-related activities, such as the Food and Drug Administration, the National Institutes of Health (NIH), the Agency for Health Care Policy and Research, the Federal Bureau of Prisons, the Health Care Financing Administration, USAID, the Occupational Safety and Health Administration, the Department of Veterans Affairs (VA), the Department of Housing and Urban Development, and the U.S. Marshall Service (118). A. Elimination in Low-Incidence Areas

In 2002, CDC published ACET’s recommendations to address tuberculosis in low-incidence areas (119). In 2004, 24 states had tuberculosis incidence rates less than or equal to the ACET year-2000 interim objective of 3.5 cases per 100,000 population. This rate is defined as low incidence (2). Health

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Table 3 Centers for Disease Control and Prevention’s Response to Ending Neglect: The Elimination of TB in the U.S. Summary of Goals and Objectives Goal I: Maintain control of TB Objectives: Maintain and enhance local, state, and national public health surveillance for TB Support the infrastructure needed for laboratory-based identification and treatment of TB Ensure that patient-centered case management and monitoring of treatment outcomes are the standard of care for all TB patients Develop community partnerships, and strengthen community involvement in TB control Improve the timely investigation and appropriate evaluation and treatment of contacts with active TB disease and LTBI Ensure appropriate care for patients with multidrug-resistant TB, and monitor their response to treatment and their treatment outcomes Ensure that health care facilities maintain infection-control precautions Develop improved engineering and personal protective techniques to prevent TB transmission Improve TB control in foreign-born populations entering or residing in the United States Educate the public and train health care providers to maintain excellence in TB services Goal II: Accelerate the decline Objectives: Increase the capacity of TB control programs to implement targeted testing and treatment programs for high-risk persons Promote the appropriate regionalization of TB control activities in high, intermediate, and low TB-incidence areas of the United States Characterize circulating Mycobacterium tuberculosis strains using DNA fingerprinting methods Develop national, state, and local capacity to respond to outbreaks of TB Goal III: Develop new tools Objectives: Develop a coordinated plan for TB research Develop new methods to diagnose persons with LTBI and to identify infected persons who are at high risk for developing active TB Develop and assess new drugs to improve TB treatment and prevention Develop a new and effective TB vaccine Develop and implement a program of research on behavioral factors related to TB treatment and prevention Rapidly transfer findings from research studies into practice (Continued)

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Table 3 Centers for Disease Control and Prevention’s Response to Ending Neglect: The Elimination of TB in the U.S. Summary of Goals and Objectives (Continued ) Goal IV: Increase involvement in global efforts Objectives: Provide leadership in public health advocacy for TB prevention and control Provide technical support and build capacity for implementation of DOTS, especially in those countries that contribute significantly to the U.S. TB burden Develop models for the diagnosis and treatment of patients with multidrug-resistant TB Provide technical, programmatic, and research support aimed at reducing the incidence of TB as an opportunistic disease in high HIV-burden countries Goal V: Mobilize and sustain support Objectives: Develop and implement a health communications campaign focusing on the resources and support needed to eliminate TB Help communities foster nontraditional, multisectoral, public–private partnerships to improve the effectiveness of their communications activities, with particular attention to culturally appropriate materials Support the development of state- or area-specific TB elimination plans that contain communications activities to build support for TB elimination Goal VI: Track progress toward elimination Objectives: Develop innovative analyses for examining surveillance data to help focus elimination efforts Develop novel indicators of progress toward elimination Conduct periodic evaluations of TB program performance at federal, state, and local levels Conduct an annual progress review Abbreviation: LTBI, latent tuberculosis infection. Source: From Ref. 116.

departments in low-incidence states, and those in low-incidence counties within other states, need distinctive, area-specific strategies, for maintaining the skills and resources required for finding increasingly rare tuberculosis cases, containing outbreaks, and ending cycles of transmission (119). The capacity for conducting all the essential components of a tuberculosis prevention and control program must be retained at local, state, and national levels. Alternatively, these resources could be regionalized for prompt mobilization to areas of need. Such an approach would require preparedness to provide sustained support to areas whenever tuberculosis cases occur. Essential needs which must be met include contact investigations and assurance of treatment completion for both persons with tuberculosis disease and latent infection. Failure to do so increases the risk of additional outbreaks

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and a new resurgence of tuberculosis. In low-incidence areas, it is especially important to have an adequate public health infrastructure and creative integration of resources, some of which until now have not played a important role in tuberculosis control. An essential component to the infrastructure is an effective, comprehensive laboratory network (Chapter 18: The Laboratory Network in Tuberculosis Control in High-Prevalence Countries). Since the mid-1990s, public health laboratories have improved tuberculosis test performance, which has substantially contributed to the decline in incidence. However, further improvements are needed in laboratory services to overcome current challenges (Table 4). A critical step is the development of an integrated system that ensures prompt and reliable laboratory testing and flow of information among laboratory staff, clinicians, and tuberculosis control officials. The recently created APHL Task Force presented a orientwork, backed up subsequent CDC Guidelines, to improve the future of tuberculosis (120,121). Further operational research is needed to help determine the most efficient control measures. Eventually, with a series of local successes in eliminating tuberculosis, low incidence will be attainable in all states, and the nation will profit from the lessons gained in current low-incidence states. In parallel these efforts have recognized changes in health-care delivery, such as the movement toward managed care, and addressed the formulation of model contractual language for assessing comprehensive tuberculosis services (122). B. The Entanglement Between Tuberculosis in the United States and the Global Epidemic

The proportion of tuberculosis cases among foreign-born persons has increased since CDC began collecting these statistics in 1986. In 2005, this proportion was 54% (3). This resembles the trend in similar analyses in many other industrialized countries, where the proportion is significantly greater than 50% (Chapter 29: Tuberculosis Control in Low-Prevalence Countries of Europe) (123–127). In the United States, five countries— Mexico, the Philippines, Vietnam, China, and India—account for 56% of the ‘‘foreign-born’’ tuberculosis, although local epidemiological profiles Table 4 Challenges to Developing an Integrated Laboratory System Establishing lines of communication among laboratory technicians, clinicians, and tuberculosis control officials Expediting reporting of laboratory results, which can avoid delayed or inappropriate treatment and missed opportunities to prevent transmission Developing evidence-based recommendations for use of new laboratory technologies Maintaining staff proficiency in light of declining numbers of specimens to test, workforce shortages, and loss of laboratory expertise Upgrading laboratory information systems and connecting all partners Source: From Refs. 120, 121.

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vary (128–132). Given this epidemiologic reality, the elimination of tuberculosis in the United States will necessitate adequate control of tuberculosis throughout the world. Overseas U.S. investment in global tuberculosis control is perhaps the most cost-effective long-term strategy to reduce tuberculosis among migrants to the United States (133,134). Since 1995, the United States has substantially and materially increased its involvement in the global effort to control tuberculosis through a number of efforts, including the WHO-hosted Stop tuberculosis Partnership (Chapter 25: Advancing Tuberculosis Control Globally Through the Advocacy Network of the Stop Tuberculosis Partnership). In collaboration with the U.S. Departments of State and Defense and international partners and donors, CDC and other DHHS agencies are providing direct technical assistance and financial support to improve the capacity of national tuberculosis control programs, with the following priorities. First, assist countries where most of the U.S. foreign-born tuberculosis patients originate (e.g., Mexico, Philippines, and Vietnam). Second, expand the implementation of the WHO Tuberculosis-control strategy (i.e., DOTS, see Chapter 27: Fundamentals of tuberculosis Control: The DOTS Strategy) in selected high-burden countries. Third, mitigate the expanding HIV-TB syndemic (i.e., converging pandemics), most pronounced in sub-Saharan Africa. CDC’s Global AIDS Program, The President’s Emergency Plan for AIDS Relief (135), and the multinational Global Fund to Fight AIDS, TB, and Malaria are tangible efforts to address these dual epidemics (136). Fourth, control and prevent multidrug-resistant tuberculosis in countries identified by the WHO as having high rates of resistance (137– 141), and apply lessons gained during the 1985–1992 U.S. resurgence with high rates of multidrug-resistant tuberculosis. Ongoing efforts focus on screening persons who apply to enter the United States as refugees or immigrants prior to and after entry. These activities represent an enormous effort (129,142–144), complicated by the epidemiology in the country of origin (145) and legal issues (146), and has been challenged as an effective priority (147,148). C. The Development of New Tools

An acknowledgment of the need to develop new tools in order to facilitate the control and eventual elimination of tuberculosis has prompted a renewal of interest in TB-related research. The tools currently available for tuberculosis control and prevention are effective but are labor intensive and frequently underutilized in resource limited settings. Therefore, improvements in these tools and the development of new tools are urgently needed (58,149). In response to these needs, research efforts toward developing such tools are under way in epidemiology (including statistical modeling), biology, molecular biology, immunology, diagnosis, treatment, preventive therapy, behavioral studies, and operational research into factors associated with improvements in tuberculosis program management. NIH has increased its funding for tuberculosis research, and is currently supporting

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investigator-initiated research, Small Business Innovation Research, training, and increasingly, international collaborations (150). An important development with far-reaching research potential was the recent sequencing of the genome of M. tuberculosis (151). In 1960, CDC was given the responsibility for tuberculosis control in the United States. Some years later, the U.S. Public Health Service trials in tuberculosis were also transferred to CDC for the conduct of clinical trials to evaluate tuberculosis treatments. However, the conduct of clinical trials in tuberculosis had come to a virtual standstill following Study 21, an evaluation of six-month, short-course treatment that began in 1981 (152). It was not until 1995, when CDC and investigators at academic medical centers, health departments, and VA hospitals (comprising the CDC tuberculosis Trials Consortium) initiated U.S. Public Health Service Study 22, a randomized trial to evaluate once-weekly rifapentine and isoniazid in the continuation phase of treatment. The findings demonstrated the efficacy of once-weekly treatment during the continuation phase of anti-TB therapy for selected tuberculosis patients (153), and have been used to update tuberculosis treatment recommendations being issued jointly by CDC, ATS, and IDSA (154,155). Study 27 and 28 are phase II trials which are examining the safety of the fluoroquinolone moxifloxicin with the aim of designing a phase III trial to evaluate the efficacy of shortening the now required minimum treatment (two or four months instead of six months) for tuberculosis. Another trial, Study 26, is a randomized placebo controlled study comparing the U.S. preferred regimen for the treatment of LTBI (nine months of daily isoniazid) to 12 weekly dose of the combination of isoniazid and rifapentine (a long acting rifamycin). In 2000, a nongovernmental organization was formed as a partnership of industry, government, academia, private foundations, and the WHO to develop the Global Alliance for tuberculosis Drug Development (156). Due to renewed interest and increased basic science research funding, a number of promising new agents are emerging from the pharmaceutical pipeline. We are at a critical point because new compounds are insufficient, and because we urgently need new effective regimens for shorter courses of treatment, including for persons with multidrug-resistant tuberculosis or co-infection with HIV. Based on the experience of the British Medical Research Council and the U.S. Public Health Service clinical trials in tuberculosis, it takes a few decades to capitalize on the use of new, highly effective agents. Without prompt substantial expansion of clinical trials capacity, we risk failing to develop and deliver these new tools, urgently needed to save the lives of millions. In 1998, ACET recommended renewed efforts toward development of new safe and effective vaccines for tuberculosis (91). A 20-year Blueprint for Vaccine Development was published (150). By 2005, four candidate vaccines were in phase I clinical trials (158–160). In 2001, CDC established the tuberculosis Epidemiological Studies Consortium, composed of 22 collaborative research groups, each consisting of a formal partnership between an academic institution and a state or metropolitan tuberculosis control program. In 2001, the National Institute

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of Allergy and Infectious Diseases of NIH issued its Global Health Research Plan for HIV/AIDS, Malaria, and tuberculosis (150). Optimally, these combined efforts will result in the development of new tools, including new drugs and an effective vaccine to facilitate tuberculosis elimination. D. Social Mobilization and Public Health Advocacy

In 2002, NCET commissioned an analysis of the resources required to implement the recommendations provided in the Institute of Medicine report, Ending Neglect. The NCET report, Tuberculosis Elimination: The Federal Funding Gap (161), estimated a total of US $528 million was necessary. In 2004 update, NCET identified priority areas for intensified support (162). These respond to current epidemiologic trend, and include efforts to: (i) reduce racial and ethnic disparities in the incidence of tuberculosis; (ii) prevent, detect, and treat tuberculosis in persons who cross the U.S. Mexico border; (iii) intensify use of universal genotyping for all culturepositive tuberculosis cases to improve our understanding and ability to interrupt transmission dynamics; and (iv) research to improve the diagnosis and treatment of tuberculosis. The report Ending Neglect concludes with the following thought: ‘‘As has been demonstrated in the past century of control efforts, social mobilization is critical to sustaining tuberculosis control programs. Moreover, the tuberculosis control community must pay as much attention to social mobilization efforts as it pays to the technical, medical, and scientific issues’’ (59). As a result of increased attention, unparalleled since the early part of the 20th century, there has been a significant and measurable growth in interest in tuberculosis prevention and control. These advocacy efforts are challenged by the fact that a majority of those who contract tuberculosis are disenfranchised and at the margins of societies (Chapter 45: Tuberculosis in the Poverty Alleviation Agenda). This reality complicates their access to health care and the preventive benefits of public health, and is accompanied by a limited ability to influence and guide our nation’s decisions on health priorities. Therefore, bringing people with tuberculosis and their views to the forefront is a necessary step to raise awareness of the problem and to address unmet needs. This can only happen through mobilization and active partnership with communities of persons at high risk for tuberculosis, health-care professionals (private and public), industry, media, and policy makers (111,128). Also, the elimination of tuberculosis is necessarily tied to increased and sufficient financial resources to accomplish the requisite tasks (59,117). A recent report published by the NCET posited, ‘‘Resurgence is again a threat. Given the huge resources required to reestablish control in the 1990s, the prudent action now is to provide the funding needed to accelerate progress toward eliminating tuberculosis in the United States The alternative is to allow people in this country and around the world to suffer unnecessarily from this terrible, yet preventable and treatable, disease’’ (162). Furthermore, U.S. engagement and significant participation in broad global efforts to improve health is necessary to reap global tuberculosis control.

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Specific objectives and actions steps are outlined in the Global Plan to Stop tuberculosis, published by the WHO-hosted Stop tuberculosis Partnership (163). This document is now being updated to be consistent with Millennium Development Goals, 2006–2015 (164) and describes the ubiquitous nature of tuberculosis, its global toll in illness and death—along with its socio-economic impact, and acknowledges that ‘‘threats to effective tuberculosis control are threats to global health.’’ The crucial role of advocacy at the global, national, and local level is described. The agreed-upon mission of this global partnership consists of four parts: ‘‘to ensure that every tuberculosis patient has access to effective diagnosis, treatment, and cure; to stop the worldwide transmission of tuberculosis; to reduce the inequitable social and economic toll of tuberculosis; and to develop and implement new preventive, diagnostic, and therapeutic tools and strategies to eliminate tuberculosis.’’ It has become increasingly clear that the successful elimination of tuberculosis necessitates going beyond technical remedies and must include socioeconomic interventions aimed at improving the overall welfare of individuals and communities. VI. Summary Eliminating tuberculosis from the United States will require: (i) sustained and increased efforts such as those that have been initiated over the past several years, (ii) continued support to rebuild and update the country’s health-care infrastructure, and prevent it from deteriorating again; (iii) continued direct involvement and support for global tuberculosis control; (iv) the maintenance of an effective surveillance system to enable rapid identification of changes in disease trends and to adjust and target our prevention and control strategies accordingly; (v) continued epidemiological studies to improve our understanding of the dynamics of tuberculosis transmission and to use the data to model effective interventions; and (vi) research for the development of new diagnostic tests, therapeutics, and a safe and effective vaccine. To succeed in eliminating tuberculosis, we must build an expanding coalition of governmental and nongovernmental partners to increase the impact of our prevention and control activities. Because people with tuberculosis are commonly afflicted with other health or social problems, tuberculosis control programs’ efforts should ideally facilitate referrals and access to other needed services, such as HIV treatment and care, drug rehabilitation services, and correctional and immigrant/refugee health services. We must also establish priorities for activities and increase their efficiency. With adequate attention to the problem and resources, the elimination of tuberculosis in the United States will eventually be achieved. Acknowledgments The foundation of this chapter is derived in part from a chapter in the second edition of Tuberculosis by William N. Rom and Stuart M. Garay (165), which

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was in the first edition written by Samuel W. Dooley and Dixie E. Snider. Original contributions from these authors have been retained in the current chapter. Also, we would like to acknowledge and thank Ann Lanner for editorial assistance. We are grateful to John Oeltmann, Wanda Walton, William Burman, Neil Shlugger, and Andrew Vernon for their creative suggestions. References 1. Rieder HL, Cauthen GM, Kelly GD, Bloch AB, Snider DE Jr. Tuberculosis in the United States. JAMA 1989; 262(3):385–389. 2. CDC. A strategic plan for the elimination of tuberculosis in the United States. Morb Mortal Wkly Rep 1989; 38(suppl 3):1–25. 3. Cantwell MF, Snider DE Jr, Cauthen GM, Onorato IM. Epidemiology of tuberculosis in the United States CDC. Trends in Tuberculosis–United States, 1985 through 1992. JAMA 1994; 272(7):535–539. 4. CDC. Trends in Tuberculosis United States, 2005. Morb Mortal Wkly Rep 2006; 55(11):305–308. Available at http://WWW.cdc.gov/mmwr/preview/mmwrhtml/ mm5511a3.htm. 5. Bloom BR, Murray CJ. Tuberculosis: commentary on a reemergent killer. Science 1992; 257(5073):1055–1064. 6. Binkin NJ, Vernon AA, Simone PM, et al. Tuberculosis prevention and control activities in the United States: an overview of the organization of tuberculosis services. Int J Tuberc Lung Dis 1999; 3(8):663–674. 7. Leff DR, Leff AR. Tuberculosis control policies in major metropolitan health departments in the United States. VI. Standard of practice in 1996. Am J Respir Crit Care Med 1997; 156(5):1487–1494. 8. Snider GL. Tuberculosis then and now: a personal perspective on the last 50 years. Ann Intern Med 1997; 126(3):237–243. 9. Stone R. Tuberculosis rebounds while funding lags. Science 1992; 255(5048):1064. 10. Corbett EL, Steketee RW, ter Kuile FO, Latif AS, Kamali A, Hayes RJ. HIV-1/ AIDS and the control of other infectious diseases in Africa. Lancet 2002; 359(9324):2177–2187. 11. Mukadi YD, Maher D, Harries A. Tuberculosis case fatality rates in high HIV prevalence populations in sub-Saharan Africa. AIDS 2001; 15(2):143–152. 12. Girardi E, Raviglione MC, Antonucci G, Godfrey-Faussett P, Ippolito G. Impact of the HIV epidemic on the spread of other diseases: the case of tuberculosis. AIDS 2000; 14(suppl 3):S47–S56. 13. Glynn JR. Resurgence of tuberculosis and the impact of HIV infection. Br Med Bull 1998; 54(3):579–593. 14. Telzak EE. Tuberculosis and human immunodeficiency virus infection. Med Clin North Am 1997; 81(2):345–360. 15. CDC. Tuberculosis among foreign-born persons who had recently arrived in the United States—Hawaii, 1992–1993, and Los Angeles County, 1993. Morb Mortal Wkly Rep 1995; 44(38):703–707. 16. Talbot EA, Moore M, McCray E, Binkin NJ. Tuberculosis among foreignborn persons in the United States, 1993–1998. JAMA 2000; 284(22):2894–2900. 17. World Health Organization. Global Tuberculosis Control. WHO Report 2006. WHO/HTM/TB/2006.362. Geneva, Switzerland, 2006. 18. 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(4):745–749.

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31 Tuberculosis Transmission and Infection Control in Congregate Settings

EDWARD A. NARDELL

KEVIN P. FENNELLY

Division of Social Medicine and Health Inequalities, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, U.S.A.

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.

I. Introduction Tuberculosis (TB) infection control in congregate settings such as hospitals, clinics, jails, prisons, hostels, and residential treatment facilities may be the most neglected aspect of global TB control. Although occupational infections with Mycobacterium tuberculosis have been well documented in the United States and Europe over the past century, institutional (including patients, prisoners, students, and other institutional residents) TB transmission in high-prevalence, resource-limited settings has only recently begun to be reported with increasing frequency. From reports limited to hospital workers and outbreaks in other settings, it is difficult to extrapolate the full impact of institutional transmission on the total disease burden at the local, regional, or global level. Yet, there is good reason to believe, especially in high-prevalence settings, that institutional occupants are routinely becoming infected and reinfected at high rates, usually from persons with unsuspected TB. Institutional transmission of TB threatens the health of an already tenuous workforce, especially in areas where HIV/AIDS prevalence is also high. Ultimately, institutional TB transmission undermines efforts to decrease the disease burden in the community. In a rural area of KwaZulu Natal, 793

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South Africa, an analysis of the first 50 cases of extensively resistant Mycobacterium tuberculosis cases showed that 64% had no prior treatment, implying that their infection had been transmitted already highly resistant, and not acquired by erratic treatment as might have been be predicted. Twenty-two percent of these cases had completed therapy and were considered cured, and only 14% had defaulted or failed treatment. Where did this transmission occur? It is always difficult to be sure where transmission occurs, but 56% of these cases had been previously hospitalized and in a rural setting, the hospital would be the most likely place (1). In Lima, Peru, fully 10% of an initial cohort of patients in a community-based multidrugresistant tuberculosis (MDR-TB) treatment program were health-care workers (HCWs), reflecting exposure and infection in local hospitals and clinics (2) (Farmer PE, personal communication. November, 2005). Interns and residents in teaching hospitals in the same city confirm a high risk of nosocomial transmission: an annual infection rate of 17% with 2% active TB (3). In Brazil, the prevalence of TB infection among medical students during the three years of clinical training was 4.6%, 7.8%, and 16.2%, respectively, but in engineering students of the same socioeconomic status the prevalence remained 4.2% to 4.4%, indicating transmission primarily in the hospital setting rather than in the community setting (4). In Malawi, the active TB case rate among 2979 HCWs was 3.2%, or 3200 cases per 100,000 population, compared to 1.8% among primary school teachers (5). At a chest hospital in Estonia, 49 health workers developed TB between 1994 and 1998, with 18 (38%) due to MDR organisms (6). These latter disturbing data recall the U.S. TB resurgence of 1985–1992, where one epidemiologic investigation of 357 genotype-linked cases (one quarter of all MDR-TB cases in the United States at the time) concluded that 96% had likely been transmitted nosocomially, predominantly in just four New York City hospitals (7). When costly interventions reversed the U.S. resurgence, improved case holding as well as improved infection control was credited (8). Similarly, hospital transmission accounted for 68 (88%) of 77 MDRTB cases among HIV patients in a Buenos Aires hospital, and as in the United States, basic infection control measures have greatly reduced spread (9). The problem is not geographically localized, or limited to hospitals or HIV-associated TB. Using extensive contact evaluations and molecular epidemiology, Barnes et al. identified the likely source case and the site of transmission for 79 of 249 TB cases in central Los Angeles, only 27% of which were HIV related. Of the 79 instances of transmission, 55 (70%) were traced to just three homeless shelters (10). Population-based molecular epidemiological studies in New York City and San Francisco have identified a greater proportion (30–40%) of cases due to recent infection than was previously thought possible (11,12). Among recent immigrants to the United States, the rapid decline after arrival in case rates observed among immigrants of all ages has been interpreted as indicating an important role for recent infection and reinfection in the pathogenesis of their disease (13). Although transmission occurs in homes and other noninstitutional

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environments, nowhere is transmission more efficient than in congregate settings, and nowhere is there a greater opportunity for interventions to prevention transmission. In a high-prevalence community of South Africa, a molecular epidemiological study estimated that in only 19% of cases was the disease transmitted within the household (14). Given the above data, the importance of controlling TB transmission in institutions cannot be overstated. As indicated in Figure 1, TB infection control in hospitals, prisons, and other institutions should be considered an integral part of TB control in the community. Persons with infectious TB from the community transmit their disease in institutions when admitted just as surely as persons infected in institutions contribute to disease in the community when discharged. Control efforts in one sector contribute to control in the other. In Tomsk, Siberia, for example, integration of TB control efforts between the civilian and prison sectors assures continuity of treatment when prisoners are released (16). In Lima, Peru, community-based treatment of MDR-TB reduces hospitalization and thereby reduces the opportunity for nosocomial transmission in hospitals (17). The main thesis of this chapter, therefore, is that community TB control and ultimately global TB control will not likely be achieved without strategically implementing institutional infection control in a programmatic fashion.

Figure 1 Tuberculosis transmission in hospitals and other institutions should be considered an integral component of TB transmission in communities, and institutional infection control an integral component of public health TB control in the community. Source: From Ref. 15.

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Previous chapters in this book on the epidemiology and pathogenesis of TB (Chapters 1, 4, 5, and 6) assume that the disease spreads with human populations from person to person, but the details of transmission have not as yet been considered. This chapter, therefore, begins with a brief review of airborne transmission, essentially the only way TB is spread, before addressing the means available for control. Consistent with the international focus of the book, this chapter considers TB infection control for HCWs and other high-risk groups in both high- and low-prevalence settings. Whereas infection control has been the focus of considerable attention in the United States in the years following the 1985–1992 resurgence, it was emphasized much less in Western Europe and in high-prevalence parts of the world until the threat of MDR disease and HIV coinfection became apparent—the very same factors that combined to call attention to institutional transmission in the United States two decades ago. Unfortunately, settings with the highest prevalence of TB usually have the most limited resources for TB infection control (Table 1). Recent TB infection control guidelines for both high- and lowprevalence settings are available on the Internet from national and international health agencies, notably from the U.S. Centers for Disease Control and Prevention (CDC), the International Union Against Tuberculosis and Lung Disease (IUATLD), and World Health Organization (WHO) (Box 1). Rather than duplicate these recommendations, we highlight those aspects that we consider most important, controversial, or in need of added emphasis. We also attempt to add practical suggestions based on our own experience and research. The CDC document is a comprehensive reference source. The WHO and IUATLD guidelines are more applicable to moderate- and low-income settings. Readers should consult the original documents and the literature sited for additional details. Finally, Web-based documents are usually updated more often than are textbooks, so the guidelines should be consulted after reading this chapter for additional details and for the most recent changes. II. Tuberculosis Transmission Koch’s isolation of M. tuberculosis in the late 19th century and proof that he could transfer infection from one animal to another and then recover the organism in pure culture (Koch’s postulates) soon put to rest theories that TB was caused by heredity, bad humors, or other causes. Still, the mechanism by which TB spreads from one person to another remained unclear until well into the next century when it was confirmed to be spread by the airborne route. Public health posters in the early 20th century cautioned against spitting on the street, sharing bottles, and the dangers of dry sweeping, reflecting the current thinking of the time that direct contact with contaminated objects and dust was important. These concepts persist in some high-burden countries today. In the 1930s, Wells and his student, Richard Riley, proposed that some contagious respiratory infections (measles, TB, etc.)

Resources generally available for treatment, case finding, and infection control (prioritized, mandated by law, and monitored, but still not always implemented effectively) High—harder to detect institutional transmission; Low—easier to detect institutional transmission by tuberculin skin testing; greater potential for less potential for transmission due to some transmission due to lack of previous infection protection (incomplete and counterbalanced by or BCG, and greater use of immunosuppressive HIV coinfection, malnutrition, etc.) drugs Controversial—little used due to DOTS priority on Widely used although epidemiological impact unclear due to poor treatment adherence and smear-positive cases, concerns about engendering low specificity of TST resistance, and reinfection potential Limited protection or enforcement of guidelines In the United States, institutions subject to inspection and fines for noncompliance with OSHA regulations Generally less crowded, but modern, smaller, lowCrowded, but sometimes older buildings with ceiling rooms conducive to airborne spread; larger, high-ceiling rooms in use with, in some more mechanical ventilation but less natural locations, abundant natural ventilation during the ventilation day, depending on outside climate; limited mechanical ventilation

Limited resources; WHO priority has been DOTSimplementation guidelines for infection control, but no plan for implementation or monitoring

Low TB prevalence populations

Abbreviations: BCG, bacille Calmette–Gue´rin; TST, tuberculin skin testing; INH, isoniazid; OSHA, Occupational Safety and Health Administration.

Institutional building structure and use

TST and use of INH treatment of latent infection Legal protection of workers

Background rate of TB infection and BCG (partial protection)

Resources and WHO priorities

High TB prevalence populations

Table 1 Factors that Contribute to the Different Emphasis on Tuberculosis Infection Control in Low- and High-Prevalence Parts of the World

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Box 1 Web-Based Tuberculosis and TB/HIV Infection Control Resources Guidelines for the prevention of TB in health care facilities in resource-limited settings, Geneva: World Health Organization, 1999. http://www.who.int/docstore/gtb/ publications/healthcare/PDF/WHO99–269.pdf. Note: A supplement to these guidelines focused on ambulatory care in the context of expanded HIV testing and treatment was under review at the time of this publication Guidelines for preventing the transmission of Mycobacterium tuberculosis in Health-Care Settings. MMW, Centers for Disease Control and Prevention, 2005. http:// www.cdc.gov/mmwr/PDF/rr/rr5417.pdf Interim policy on collaborative TB/HIV activities. WHO, 2004. http://whqlibdoc.who.int/ hq/2004/WHO_HTM_TB_2004.336.pdf Strategic framework to decrease the burden of TB/HIV. Geneva: World Health Organization, 2002. http://www.who.int/docstore/gtb/publications/tb_hiv/2002_296/ pdf/tb_hiv_2002_296_en.pdf A guide to monitoring and evaluation for collaborative TB/HIV activities. Geneva: World Health Organization, 2004. http://whqlibdoc.who.int/hq/2004/ WHO_HTM_TB_2004.342.pdf TB/HIV: A Clinical Manual. 2nd ed. Geneva: World Health Organization, 2004. http:// whqlibdoc.who.int/publications/2004/9241546344.pdf The following guidelines were developed for U.S. domestic situation but contain useful material: Curry FJ. National Tuberculosis Center, Institutional Consultation Services. A guideline for establishing effective practices: identifying persons with infectious TB in the emergency department. 1998. http://www.nationaltbcenter.edu/catalogue/downloads/ emergencyRoomGuidelines.pdf Curry FJ. National Tuberculosis Center, Institutional Consultation Services, and California Department of Health Services. TB in homeless shelters: reducing the risk through ventilation, filters, and UV. 2000. http://www.nationaltbcenter.edu/catalogue/ downloads/tbhomelessshelters.pdf Isoniazid Preventive Therapy Policy statement on preventive therapy against tuberculosis in people living with HIV. Report of a meeting held in Geneva, 18–20 February 1998. Geneva: World Health Organization, 1998. http://www.who.int/docstore/gtb/publications/ TB_HIV_polstmnt/PDF/tbhivpolicy.pdf Correctional Institutions Tuberculosis Control in Prisons: A Manual for Program Managers. Geneva: World Health Organization, 2000. http://www.who.int/docstore/gtb/publications/prisonsNTP/ PDF/tbprisonsntp.pdf The following guidelines were developed for U.S. domestic situation but contain useful material: Curry FJ. National Tuberculosis Center and California Department of Health Services. Tuberculosis Infection Control Plan Template for Jails, 2002. http:// www.nationaltbcenter.edu/jailtemplate/docs/tb_section1.pdf Laboratory Issues World Health Organization. Communicable Diseases Prevention and Control. Laboratory Services in Tuberculosis Control. 1st ed. Geneva: World Health Organization, 1998

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were likely spread by the dried residua (droplet nuclei) of larger respiratory droplets generated by coughing and other respiratory maneuvers (18). To prove their droplet nuclei theory, Riley et al. conducted a landmark air-sampling experiment at the Baltimore Veterans Administration Hospital, where over a period of four years (1958–1962), hundreds of guinea pigs breathed the air exhausted from a six-bed TB ward; this provided quantitative data on the infectiousness of TB patients and the variability due to clinical characteristics, chemotherapy, and drug resistance (19,20). Previous animal experiments had demonstrated that the guinea pig could be infected by as few as one to three particles (containing no more than three tubercle bacille) inhaled deep into the lung (21). Larger particles ( > 3 mm), which tend to impact on the upper airways, were much less likely to cause infection. This is because M. tuberculosis initially infects the alveolar macrophages while the upper airways are relatively resistant. Because predominantly 1to 3-mm particles are required to reach the alveolus and these are small enough to remain suspended indefinitely on room air currents, TB is almost exclusively an airborne infection. Most respiratory viruses, however, can infect the nasal and upper airway mucosa and can be spread by direct contact through fingers contaminated by larger respiratory droplets, although this does not exclude the more efficient airborne route. Many common bacteria (and probably viruses) first colonize the pharynx where they are then aspirated into the lungs, sometimes in numbers large enough to overcome normal host defenses and cause pneumonia. Table 2 lists some of the distinctions between airborne and large droplet–borne (contact) infections, although considerable overlap exists for many infections, and in many cases (rhinovirus, influenza, smallpox, for example), the relative importance of the two modes of transmission remains unclear (22). A. Infectiousness of Tuberculosis

Infectiousness is often considered to be a dichotomous state; a patient is either infectious or is not. Although this concept is convenient from a policy or programmatic perspective, it is not consistent with available data. In fact, considerable variability of infectiousness was documented on Riley’s experimental TB ward. In one study, 8 of 61 (13%) patients occupied the ward only 1% of the total patient days, but infected 29 of the 63 infected guinea pigs. Of the 29 infections, 15 were due to one patient with TB laryngitis (19). In an earlier study, 3 of 77 (4%) patients produced 73% of the infections in the animals (23). Data from an epidemiological study conducted in Rotterdam in 1967–1969 were coherent with these experimental data. Overall, only 28% of smear-positive patients transmitted infections to household contacts. However, age was an important predictor of transmission from source cases, because household transmission was attributed to 57% of those under the age of 40, but to only 9% of those over 60 years (24). Recent molecular epidemiology data from the Netherlands have confirmed the decreased transmission risk associated with older age among adults (25). Conversely, children are usually less infectious than adults due

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Table 2 Comparison of Airborne and Large Droplet–Borne Infections Airborne droplet nuclei (1–3 mm) transmission

Large droplet (contact) transmission

Beyond the immediate vicinity of Limited to surfaces contaminated the source case, facilitated by air by the source case, spread dependent on source case currents and recirculated mobility and direct contacts mechanical ventilation, and source case mobility Source control (administrative, Control Source control (administrative, surveillance, treatment, surgical strategies surveillance, and treatment), mask, etc.), isolation, barrier engineering controls (isolation, protection, hand washing dilution, directional airflow, air disinfection, etc.), personal respiratory protection Examples Tuberculosis, measles (rhinovirus, Respiratory viruses such as rhinovirus, RSV, and influenza, influenza, smallpox, SARS, all SARS coronavirus, smallpox. have airborne potential); Bacteria such as staphylococci environmental infections such as and streptococci anthrax, histoplasmosis, coccidiomycosis, and Hanta virus

Extent of spread

Abbreviations: SARS, severe acute respiratory syndrome; RSV, respiratory syncytial virus.

to a preponderance of lymphatic rather than cavitary lung disease, but older children may be infectious if they present with an ‘‘adult’’ radiographic picture, e.g., parenchymal disease with cavitation (26). Although men may transmit the disease at a slightly higher rate than women, in practice gender is generally not relevant for decisions on isolation. The strongest indicator of infectiousness in a newly diagnosed patient is a positive sputum smear, as it generally indicates a high bacillary load in the sputum (27). However, it is a misconception that sputum smear–negative patients are noninfectious. In San Francisco, 17% of transmission was attributed to sputum smear– negative cases (28). In one outbreak report, 10 of 13 HCWs were infected in a poorly ventilated intensive care unit (ICU) after exposure to a smearnegative patient who was intubated endotracheally and had bronchoscopy (29). Thus, if there is a high clinical suspicion, TB suspects should be isolated until the diagnostic workup has confirmed or ruled out TB. Cavitation on the chest radiograph is a risk factor for transmission, and chest radiographs are often obtained more easily and before the sputum smears in the diagnostic evaluation. However, the sputum smear is generally more useful than the chest radiograph. The chest X-ray is neither sensitive nor highly specific. Old cavities, cystic changes, or blebs are sometimes misinterpreted as cavities, prompting unnecessary isolation, whereas patients with advanced HIV infection may have little or no radiographic evidence

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of disease. For this reason, AIDS patients may be less likely to have a positive sputum smear, as already noted, and they too may have other infections or noninfectious conditions causing lung cysts or cavities, further complicating the evaluation. In high-risk settings, however, such patients should be presumed to have TB until proven otherwise. Cough frequency is positively associated with transmission, so patients with forceful, frequent coughing should be considered to be more infectious than others (27). Understanding the factors associated with infectiousness is fundamental to a rational approach to isolating suspect patients, especially under resource-limited conditions. Nosocomial TB transmission may be iatrogenic due to the lack of diagnostic suspicion or due to inadequate evaluation. Under high-prevalence conditions, the problem of underdiagnosis can be addressed by educating doctors and nurses, and by the implementation of administrative procedures, such as routine questioning of patients about new, persistent coughs on admission to hospitals, clinics, and other institutions. As discussed later, the problem of potentially missing cases is harder to correct under low-prevalence conditions, where heightened diagnostic suspicion and rigorous administrative screening strategies are rarely validated by finding actual cases, and where clinical experience with the disease is lacking. Under these circumstances, inevitable overdiagnosis and overisolation of TB suspects contribute to unnecessary concern and expense, and may compromise patient care. In suspect patients, active TB can usually be diagnosed by two or three expectorated sputum samples (30). If there is little or no sputum production, inducing sputum with hypertonic saline is recommended. However, by stimulating cough, sputum induction can generate infectious aerosols, requiring that this procedure be done in a properly functioning isolation room or booth, or in a well-ventilated area away from susceptible patients. In temperate climates, sputum can be collected in a protected area outside the institution. Bronchoscopy can be helpful in making a diagnosis of TB, but, as noted, this procedure can also generate infectious aerosols (29). Furthermore, because coughing may persist after the procedure, transmission may occur during the recovery phase and during transport back to the ward, and precautions are required. Three induced sputa had the same diagnostic yield as a bronchoscopy in one study, suggesting that it is usually safest to request up to three sputum inductions before proceeding to bronchoscopy (31). Extensive transmission of TB has also occurred during postmortem examinations and the embalming process. Clinicians should inform pathologists when disseminated TB is suspected, and carefully consider the risks and benefits of the autopsy if MDR-TB is anticipated. In all patients who had been immunosuppressed from HIV, cancer, or advanced age, pathology and mortuary staff should take extra precautions against airborne transmission (32). High-risk procedures such as autopsies and bronchoscopies should be done only in facilities designed with appropriate engineering controls (enhanced air disinfection and negative pressure to

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assure airflow away from adjacent occupied areas) while wearing properly fitted personal respiratory protection (PRP). In facilities where MDR-TB is found, positive-pressure respirators that reduce face-seal leaks (discussed later in this chapter) should be considered. Although there is intense basic science interest in the role of strain variability on transmissibility and virulence, at this time there is no practical role for genotyping in guiding infection control, as all strains must be considered equally infectious. Whereas there is evidence that some strains of drug-resistant TB are less ‘‘fit,’’ i.e., cause less disease in the population than wild strains, there is also evidence that highly drug-resistant strains have been highly virulent, especially in institutional settings and among immunocompromised hosts (i.e., strain W) (33,34). Moreover, the consequences of transmission of drug-resistant strains are so great that heightened precautions are warranted. B. Factors that Have Been Associated with Institutional Mycobacterium tuberculosis Transmission

1.

General 

2.

Inadequate infection control practices or resources (35) Source factors



Sputum smear–positive for acid-fast bacille (AFB) (as an indicator of bacillary load) (36) Lung cavitation or laryngeal TB (27) Frequent, strong cough (27) Watery, easily aerosolized sputum (theorized, no direct evidence) Sputum induction, bronchoscopy, and other cough-inducing procedures (36) Ineffective treatment (early in the course of effective treatment, or drug resistance) (35,37,38)

     3.

Environmental factors   

4.

Closed environment, little dilution (39,40) Crowding Possibly high humidity and air pollution (including smoking) (41) Organism factors



5.

M. tuberculosis strains especially resistant to environmental stresses, highly virulent, and prone to cause hematogenous dissemination and lung cavitation (speculative, little direct evidence) Exposed host factors 

Individuals or populations with increased innate or acquired susceptibility to initial infection or reinfection (42) (we have no ability to identify such host susceptibility factors)

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 Lack of effective vaccination [bacille Calmette–Gue´rin (BCG)] or prior infection with M. tuberculosis or environmental mycobacteria (43,44) C. Modeling TB Transmission in Rooms

Leaving aside for the moment the important parameters of host susceptibility and organism virulence, the probability of becoming infected by M. tuberculosis in a room shared with an infectious source has been modeled mathematically using a relatively simple mass balance equation, incorporating the following variables: number of infectious source cases, generation rate of infectious ‘‘quanta’’ or doses, number of exposed susceptibles, pulmonary ventilation rate of susceptibles, duration of exposure, and room ventilation rate. There are several examples where estimates of transmission parameters have permitted the calculation of the average generation rate of infectious quanta (29,40,45,46). These estimates range from one to several hundred per hour, depending on clinical features. Modeling of this type, while useful in analyzing the relative importance of various transmission factors, such as ventilation, when other factors remain constant, assumes perfect air mixing and steady state equilibrium, which are not likely to exist in real life. Therefore, caution is warranted in extrapolating the results of modeling to actual exposures. III. TB Infection Control in Low-Prevalence, Resource-Rich Settings We first discuss institutional infection control in low-prevalence, resourcerich settings even though the need for infection control is far greater in places where the prevalence is high and resources inadequate. This approach allows us to mention the full array of possible interventions, some of which will be broadly applicable, but others, such as high-volume, negativepressure room ventilation, are not likely to be widely available in many high-risk settings in the foreseeable future. Later, we discuss issues especially relevant to high-risk settings where resources are limited. However, the fundamental infection control components are similar wherever persons with TB share indoor space with susceptible hosts. These are listed below. 1. 2. 3. 4. 5.

Designation of ‘‘administrative responsibility,’’ authority, and resources for infection control for the institution ‘‘Assessing the level of risk’’ for the institution or population served Development, adoption, and implementation of an ‘‘institutional infection control plan’’ ‘‘Training of institutional staff ’’ for the prompt identification and treatment of infectious TB suspects and cases Enhancement of ‘‘laboratory capacity’’ for rapid processing and reporting of specimens sent for TB, both for prompt diagnosis and to efficiently remove isolated patients from isolation rooms

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7.

8.

9. 10.

‘‘Triage and separation or isolation’’ of infectious persons and suspects from susceptible persons, including attention to optimal directional airflow to maintain separation/isolation Optimal ‘‘utilization of institutional space’’ to reduce potential exposures from known or unsuspected persons with infectious TB Maximum ‘‘dilution of potentially infectious air’’ by room volume, ventilation, air filtration, or ultraviolet (UV) air disinfection. This applies to isolation areas for known or suspected cases as well as general areas where unsuspected infectious persons may spend time ‘‘PRP’’ for isolation rooms and high-risk procedures ‘‘Monitoring of institutional staff ’’ for infection, and treatment of latent infection

The apparent simplicity of the 10 interventions listed here is deceptive. In the 2005 revision of the CDC guidelines, the details of these fundamental interventions with supporting information occupy 147 manuscript pages (47). The length is explained in part by an effort to provide guidance for a wide variety of complex institutional settings, from autopsy suites to pharmacies as well as detailed guidelines on each of the categories listed above, including guidelines on the use of one of the new gamma interferon release assays. In addition, the revised guidelines strive to be substantially self-contained, providing pertinent details that would otherwise require referral to other documents. The reader is referred to this comprehensive reference document for detailed discussions and recommendations beyond the scope of this review. A. The Key Components of Infection Control

It is common to rank these interventions using the industrial hygiene model, where administrative controls are considered the most important, followed by engineering controls, and finally PRP—although all three categories are applied simultaneously, not sequentially. Moreover, the classification is somewhat artificial because all of the interventions listed have important administrative or managerial components, including engineering controls and personal respirator protection. Respiratory isolation, for example, includes the policies and procedures for triaging patients into isolation, and also for its discontinuation, as well as the structural and mechanical aspects of maintaining effective separation of infectious air. From this perspective, effective institutional infection control, like effective TB control in the community, is essentially a problem of effective management, especially in resource-rich settings. In poor settings, unfortunately, good administrative policies and practices may not succeed if resources for diagnosis or respiratory isolation (separation) are lacking. But even where resources are available, there are several inherent problems in infection control for which there are no easy answers.

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B. The Problem of Unsuspected Cases and Overisolation Under Low-Prevalence Conditions

Inherent barriers to effective TB infection control include the nonspecific symptoms and signs of the active pulmonary TB and the laboratory delays in making a definite diagnosis. In high-risk hospitals during the 1985–1992 resurgence, approximately seven patients were isolated as TB suspects for every patient ultimately diagnosed with TB (48). That appears to be as precise as current clinical judgment and diagnostic tests allow. At the other extreme, using standard signs and symptoms associated with TB as criteria to isolate suspects, a prominent Midwestern medical center serving a lowrisk population estimated that in their facility approximately 92 TB suspects (having one or more symptoms associated with TB) would need to be placed in respiratory isolation for every patient who actually had the disease (49). The U.S. case rate is now much lower than when that analysis was published, suggesting an even greater potential for the excessive use of isolation. Yet, barring new rapid and highly-specific tests for TB, there seem to be few options. Reducing the number of patients isolated, a normal response to low-yield procedures, will inevitably lead to missed cases and transmission, as the following scenario illustrates. An episode of widespread TB transmission was discovered in an ICU in a community hospital in Massachusetts, United States (TB case rate 4 per 100,000 population), after routine annual tuberculin testing revealed that the skin test in a nurse had converted from negative to positive. A chest radiograph revealed a small infiltrate, but she was asymptomatic, and initially sputum acid-fast–smear negative. Her sputum culture turned positive, however. Both her husband and child were tuberculin skin test negative, confirming that her disease was early and probably noninfectious. Further testing of personnel and other workers associated with the unit revealed that a total of 23 had new skin test conversions, but none had active disease. They included 12 other nurses or nurses’ aides, 5 respiratory therapists, and both a minister and computer technician who frequented the ICU. One of the nurses had worked on the unit only a few months, which helped narrow the window of when transmission must have occurred—about four months prior to identifying the index case. However, there were no known or suspected TB patients in the ICU during the likely transmission period, and public health records revealed no cases in the area served by the hospital that might have been responsible. The source case was assumed to have been an ICU patient who died with undiagnosed TB or of unrelated causes. The records of all ICU patients with abnormal chest radiographs during that period were reviewed. Three elderly patients who had died with abnormal chest radiographs were considered suspicious (in retrospect) for active TB, and their time in the ICU could account for the staff infections. One patient who was thought to have died of biopsy-proven lung cancer had a formalin-fixed lung tissue specimen tested retrospectively for TB by nucleic acid amplification, and it was positive. However, the pleural biopsy of one of the other two patients also tested positive for TB by the same

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technique, although the histology was nonspecific. Nucleic acid extracted from both specimens had the same spoligotype fingerprint pattern, suggesting that the two cases were related to each other and to the index case (the nurse). It was not possible to identify which, if either, of the patients was the source of transmission, and which might have been a secondary case, along with the nurse. All three suspect patients had been in single-bed ICU cubicles with negative-pressure capacity, but none were turned on because TB was not suspected in these critically ill, complicated patients with no known TB risk factors. PRP was available, but not in use for the same reason. On the other hand, the hospital’s practice of routine annual tuberculin skin testing of ICU staff uncovered this outbreak before the ICU nurse became symptomatic and possibly contagious. Although ventilation rates in the ICU met recommended standards, less transmission might have resulted had there been additional air disinfection in each cubical, for example, by upper-room UV germicidal irradiation (UVGI). In any ICU, patients are routinely admitted with fever and nonspecific chest X-ray abnormalities that could be TB, but in low-risk settings and without specific individual risk factors, usually are not, and TB is (appropriately) not often considered. If TB were to be routinely ruled out by protocol in such circumstances perhaps hundreds of patients would be needlessly isolated while awaiting three negative sputum examinations. Clearly more rapid, sensitive, and specific tests for TB would help solve this problem and such tests are likely to become available. Under current clinical conditions, however, rare TB cases will inevitably be missed with the potential for institutional transmission. However, more than half the cases reported in the United States are from populations born in high-risk countries. Clinicians should not ignore such epidemiological clues when they are present. Knowing the risk factors for TB in the community served by a given institution is the basis of a rational infection control plan. Greater attention to general air disinfection wherever patients congregate or receive care is one intervention that could, in theory, reduce transmission from unsuspected TB cases as well as reduce seasonal airborne infections such as influenza, but there is only indirect evidence to support this approach (50–52). C. Preventing Transmission from Unsuspected Source Cases: A Greater Role for General Ventilation and Germicidal UV

As noted above, if the current trends continue in the United States and other low-prevalence regions, the increasingly uncommon cases of TB are more likely to be missed unless diagnostic methods greatly improve. Even then, clinicians will have to think of ordering the tests; the tests are likely to require sputum or blood specimens, and are unlikely to be done on every patient or institutional resident with a cough, fever, or lung infiltrate. In a study of risk factors associated with TB transmission to HCWs in Canada, Menzies et al. found relatively little risk associated with working with patients in isolation rooms (reference odds ratio 1.0), even though ventilation

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rates in isolation rooms were often substandard. However, there was increased risk for hospital workers in other clinical areas where general ventilation was less than two air changes per hour (odds ratio 3.4), and for certain other worker categories (respiratory therapists, odds ratio 6.1; nursing, odds ratio 4.3; housekeeping, odds ratio 4.2; and physical therapists, odds ratio 3.3) (53). These findings are consistent with the notion that under the low-prevalence conditions found in Canada, TB is likely to go undiagnosed, resulting in transmission in waiting rooms, radiology suites, emergency rooms, and clinics, thereby posing a relatively greater risk to workers than suspect patients on treatment in isolation rooms where few workers are exposed and where air disinfection is enhanced. Increasing general ventilation rates throughout institutions is one, albeit expensive, solution to this problem. Single-pass (non-recirculated) ventilation is especially expensive in very cold and very warm climates where energy losses are an important constraint on ventilation rates. Moreover, beyond comfort-level ventilation rates, increasing ventilation becomes progressively less and less efficient as a way to sterilize air (40). This is because each doubling of ventilation reduces the risk of infection by approximately half. Thus, while each increment in ventilation is harder and more expensive to achieve in practice, the increment in protection gained is progressively smaller and smaller. An alternative approach to single-pass ventilation throughout large buildings is the greater use of UVGI to increase the rates of germ-free ‘‘equivalent’’ ventilation (52,54). High-efficiency particulate air (HEPA) filtration can also render room air less infectious and should be considered for certain applications, as discussed below (55). UVGI can be applied in three different ways to disinfect room air: direct high-intensity UVGI, UVGI in ventilation ducts and portable room units, and upper room UVGI. In some parts of the world (Russia, for example), unshielded (bare) UVGI lamps are turned on in unoccupied rooms to sterilize both room surfaces and room air. Unfortunately, this approach fails to consider that airborne transmission usually rapidly decreases once the source case leaves the room, and M. tuberculosis is not spread via contaminated surfaces (56,57). Direct (unshielded), high-intensity UVGI has been used with great success in orthopedic operating rooms to prevent infection of prosthetic joints with ordinary bacteria, but occupants must wear protective clothing and follow strict protocols to avoid eye burns from even brief direct exposures. This approach would not be applicable to air disinfection for TB, where patients and workers would be overexposed to UV. UVGI lamps are also used within ventilation ducts to sterilize recirculating air, thereby increasing the ‘‘equivalent’’ outside air–ventilation rate. Although irradiated air may be equivalent to outside air in terms of being free of specific pathogens, UVGI does not remove odors or air pollutants, and adequate outside air mechanical ventilation or passive infiltration is still required. Like UVGI, HEPA filters can be used to disinfect air in ventilation ducts, and portable room units using UVGI, HEPA filters, or both modalities, are widely available as low-cost interventions to increase

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germ-free dilutional ventilation within rooms (55). The advantage of UVGI over HEPA in ventilation ducts or portable room air cleaners is that they offer little or no airflow resistance. In contrast, HEPA filters offer considerable airflow resistance, requiring larger, noisier blowers, and greater energy costs. As they age and accumulate material, airflow resistance increases until flow all but stops, and high-pressure gradients encourage leakage around the filter. HEPA filters in ventilation ducts should always be tested in place to be sure that leaks have not developed around them. HEPA filters are expensive to replace and a strict maintenance schedule is required. On the other hand, UVGI enclosed in ventilation ducts or portable room units can fail with no outward sign that anything is wrong. Warning lights to indicate lamp failure can obviate this problem, but they are neither standard nor foolproof. A major limitation of UVGI or HEPA filters in ventilation ducts or portable units is that their efficacy is dependent on the number of mechanical air changes achievable in the room, which in turn is limited by duct and blower size as well as by occupant tolerance of ventilation noise and drafts. Moreover, like mechanical ventilation itself, increased numbers of air changes are progressively less efficient as a means of infection control (58). The third application method for UVGI is in the upper room using shielded fixtures designed for this purpose. The air above room occupants’ heads is effectively irradiated, but UV intensities in the lower occupied space remain well below the threshold limit value (TLV) for 254 nm UV of 6.0 mJ/cm2 (59–61). Effective air disinfection in the lower room depends entirely on good vertical air mixing within the room to carry contaminated air from the breathing zone up to the irradiated zone, displacing air disinfected by UVGI, which slowly drifts back down into the occupied space. Body heat normally produces a plume of heat around the room occupants, which helps with this process, but slow paddle fans and ventilation registers can also assure good vertical room-air mixing. Several room studies have now shown very high levels of equivalent ventilation with properly installed upper-room UVGI and good air mixing, commonly achieving 10 to 12 equivalent air changes without noise, drafts, or extra energy costs other than the modest cost of fluorescent UV lamps and simple fans (62,63). However, there are no practical ways to demonstrate that upper-room UVGI UV systems are working effectively. Assurance of their efficacy depends entirely on the proper design of the UV air-moving system, and practical validated guidelines are only now being compiled (64,65). Although upper-room UVGI poses a potential hazard for room occupants, the risks are minor compared to the risks of TB transmission. For occupant safety, exposure of the eye, the most sensitive structure, must be less than 6.0 mJ/cm2 over any eight-hour period. A personal monitoring study has recently reported eight-hour exposures for nurses, teachers, and hospitalized patients that are well below the TLV despite point measurements at eye level that would have predicted overexposure (59,66). This is because the eyes are normally protected by facial features and by occupant motion within the lower room. Good fixture design and installation planning are

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important for safety as well as efficacy, but qualified planners are currently in short supply. The application of computed-assisted design to upper-room installations is being investigated as an aid to planning UV installations. D. Personal Respiratory Protection

PRP refers to the use of face masks and other devices intended to prevent the wearer from inhaling airborne hazards, in this case, from airborne M. tuberculosis. The use of respirators in health care is a relatively new concept based on occupational health and safety principles and practices. In the late 1980s and early 1990s in the United States, the deaths of nine HCWs and well-documented transmission to HCWs during outbreaks of MDR-TB raised concerns about the adequacy of protective measures. Just prior to this time, data had emerged demonstrating the lack of efficacy of surgical masks, which have traditionally been worn in health-care settings. The most common type of PRP used in health care is the disposable particulate respirator, which is intended to prevent the inhalation of particles in the air but will not prevent the inhalation of toxic gases or odors. The protective filter of a typical disposable particulate respirator is the whole mask or face piece. These respirators are held tightly against the face by two elastic straps that may or may not be adjustable; many models are available with an exhalation valve that allows for the removal of warm, expired air, thus offering more comfort. Many appear similar to a surgical mask, which is an advantage regarding acceptance in the health-care settings (67). There are many other types of respirators available for industrial uses, but, in the health-care environment, the most commonly recommended alternative is the powered air-purifying respirator (PAPR) hood. These expensive devices offer a greater level of protection than disposable particulate respirators, so they are especially useful for protection against aerosol-inducing procedures such as bronchoscopies and autopsies where there may be high concentrations of infectious aerosols that cannot be easily removed by engineering controls. PAPR hoods are loose fitting and have a battery-driven fan that pulls air through a HEPA filter and then pushes this filtered air through the hood over the head of the wearer, cooling the wearer. The air is then exhausted out the edges of the hood. The air between the respirator and the face is under positive pressure, whereas disposable particulate respirators rely on negative pressure generated by the inspiration of the wearer. The chance of a face-seal leak is greatly reduced with a positive-pressure respirator, even if the wearer has facial hair. PAPR hoods have a large clear face shield that provides protection against splash exposures and allows patients to see the HCWs whole face. Respirators are certified in the United States by the National Institute of Occupational Safety and Health of the CDC (68). In the U.S. system, the most commonly used disposable particulate respirator is certified as a N95. The ‘‘N’’ means that it has been tested against aqueous aerosols. The ‘‘95’’ means that the filter material is certified to remove 95% of a test aerosol of particles 0.3 mm in size.

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The weakest link in the performance of negative-pressure respirators in general and disposable particulate respirators in particular is not the filter material itself but rather the face seal, i.e., the seal between the face and the mask. Unfortunately, the current methods of certifying respirators do not provide information about the fit of respirators. A contentious aspect of PRP against TB in the United States has been the regulatory requirement to do annual fit testing to confirm that the respirator appropriately fits the wearer. Although there are theoretical data to support this practice, there is no data documenting its effectiveness in protecting against TB. Recent data suggest that very well-designed respirators without fit testing may provide better PRP than some respirators with fit testing (69). This could potentially improve the cost-effectiveness and acceptance of PRP by eliminating the need for fit testing. Annual fit testing may be counterproductive in diverting limited infection control and employee health resources away from higher priority practices such as administrative controls. ‘‘Qualitative’’ fit testing is the easiest and least expensive approach. It involves the ability of the wearer to detect aerosols of saccharin (sweet) or Bitrex1 (bitter), and so is limited by variability of special senses. ‘‘Quantitative’’ fit testing is more objective but requires expensive specialized instruments, greater operator expertise, and test respirators with probes so that the number of particles inside and outside the mask can be counted. Major respirator manufacturers offer kits for both types of fit tests. A major issue raised early in the debate about the use of PRP to prevent TB in HCWs is cost-effectiveness. Shortly after the recommendation to use HEPA-filtered disposable respirators, two studies questioned the costeffectiveness of this intervention, suggesting that it would cost up to US $7,000,000 to prevent one case of occupational TB (70,71). However, these studies assumed fairly broad distribution of respirators to workers in hospitals that had low rates of TB compared to many facilities in high-prevalence areas. Furthermore, these studies may have been premature due to the lack of data about efficacy and effectiveness. Due to the ethical and logistical problems of experimentally studying the effectiveness of PRP, several groups of investigators have used mathematical modeling to estimate the efficacy of various types of PRP (46,72–74). These authors generally concluded that PRP would be likely to prevent occupational TB, but were unable to provide true cost-effectiveness estimates. Our modeling data suggested that the use of relatively simple respiratory protection (e.g., N95 respirators) in isolation rooms with good ventilation is probably efficacious, but that the use of more sophisticated devices (e.g., PAPR hoods) for high-risk aerosolproducing procedures such as bronchoscopies may be needed to provide a similar reduction in risk. Studies comparing TB infection rates in HCWs with and without PRP and other interventions will probably never be done in the United States due to ethical concerns and the decrease in TB cases. A central issue to the cost-effectiveness of PRP as well as other TB infection control measures is our limited ability to target infectious cases. It is likely that only 25% to 33% of patients with active pulmonary TB

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are infectious, i.e., able to transmit infection. Improved assessment of patient infectivity could considerably improve the cost-effectiveness of control measures. Moreover, respirators only work while worn during suspected exposures. Although PRP may decrease the risk of infection when used in a suboptimal isolation room, infection may occur when respirators are removed in a hallway that may contain contaminated air (75). A PRP program cannot protect workers from exposures to unrecognized cases (e.g., the failure of administrative controls on admission) or from exposure due to inadequate engineering controls (e.g., poor ventilation). In these situations, respirators may provide only a false sense of security or an excuse for administrators to not invest in the implementation of appropriate administrative and engineering control measures. Finally, respirators only protect HCWs, whereas patients are also exposed in health-care environments, as are the inmates in prisons and jails. Protection of these people depends on administrative and engineering controls. There is general agreement that PRP should be recommended for workers engaged in high-risk aerosol-producing procedures, including sputum induction, bronchoscopy, and autopsies. More data are needed about the efficacy and effectiveness of PRP as well as the feasibility and cost-effectiveness of its use, especially in high-prevalence areas with limited resources. E. Progress in TB Testing of Institutional Workers: The Gamma Interferon Release Assays

For more than a century the only way to detect latent TB infection has been the TB skin test. Although it is a useful epidemiologic tool, its use as a diagnostic tool is fraught with problems. Despite precautions to avoid boosting, workers who convert to positive are more likely to have been vaccinated with BCG or be hypersensitive to antigens of environmental mycobacteria (76). However, there are now two commercial blood tests available for detecting TB infection and disease that have several advantages over skin testing, including no cross-reactivity with BCG vaccination (77–79). These tests are discussed in Chapter 9. Despite their advantages, gamma interferon–release blood tests are technically demanding and will find greatest application in their present form in low-prevalence, resource-rich settings where skin testing is currently commonplace among certain institutional workers. Hopefully, in the near future, technical advances will allow these tests to be used routinely to detect infection and disease in high-prevalence settings where they are most needed (80). In the meantime, the tuberculin skin test, with all its limitations, will remain an important tool for detecting TB infection in many parts of the world. IV. High-Risk, Resource-Limited Settings In Tomsk, Siberia, in 2002, 13.7% of newly diagnosed TB cases were MDR-TB, and the rate among previously treated cases was 43.6%. Throughout Russia being hospitalized with TB is thought to be a major risk factor for

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developing MDR-TB although this has not yet been proven. This is not surprising to anyone who has seen the conditions in Russian TB hospitals, civilian or prison, which are not dissimilar to conditions in hospitals in many other parts of the world where the disease burden is high and resources are limited. In Russia, the hospitals are likely to be old and in disrepair. Ceilings are usually high, heating is by radiator, and usually there are no mechanical ventilation system. In patient rooms, the windows must be closed most of the year, and the door to the hallway is always closed. There is no air turnover except for infiltration of outside air through cracks, and the air entering when doors are opened. An ordinary four-bed hospital room will often be crowded with six or seven beds in close proximity to each other. When a newly diagnosed, infectious TB patient is admitted to one of these beds, there is a high probability that the other TB patients will be exposed and possibly reinfected. Increasingly, in Russia, some of the other patients will likely be HIV-infected and at high risk for progression to active TB. In Latin America and subSaharan Africa, and other milder climates, open windows are likely to provide substantial air exchange on most days, but they are likely to be shut tight at night for warmth and security. Conditions in general hospitals are similar, but there is a greater chance in that setting for persons with TB to not be diagnosed, as discussed below. The same is true in prisons, jails, hostels, and shelters. Outbreaks have been better documented in hospitals because records are better, not because transmission is likely to be much less in other congregate settings. The situation is dire and likely to worsen as HIV spreads in Asia, Latin America, and the former Soviet Union. However, the welldocumented experiences in Buenos Aires, previously cited, suggests that attention to basic infection control principles can be highly effective in controlling transmission in resource-limited settings (9). Similarly, in a hospital in Thailand where in 1995 there were 536 active TB cases per 100,000 health workers, basic infection control interventions have reduced the infection rate from 9.3 to 2.2 per 100 person years despite increases in patients with HIV and TB (81). What more needs to be done? In many countries, prolonged hospitalization for TB is the norm and a community-based treatment infrastructure does not exist. However, community-based ambulatory TB treatment would greatly help reduce the numbers of patients hospitalized (2). This is applicable to treating MDR-TB as well as drug-susceptible strains. Prison reform is reducing prison populations in some countries and reduced TB transmission is one unmeasured benefit. Still, TB cases will continue to occur in congregate settings. Practical infection control guidelines already exist for middle income and poor countries (82) (see previous Web address), but they appear not to be widely implemented for lack of resources and for lack of emphasis. In a 1997 address to the North American Region IUATLD, Paul Farmer, addressing ‘‘Poverty, Inequality, and Drug Resistance,’’ commented on the role of transmission in perpetuating drug-resistant TB, and, among 11 recommendations to address the MDR-TB crisis, he noted, ‘‘In the global era, new strategies to prevent transmission of MDR-TB to HCWs

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are necessary. Currently, enormous efforts are made to protect workers in settings with relatively low levels of risk, while no efforts are made to follow even rudimentary precautions in high-risk settings.’’ He continued, ‘‘A first step, then, will be to share protective technologies so that degree of protection reflects degree of risk. Distribution networks developed for anti-TB drugs, can also serve to level the playing field as far as precautions are concerned’’ (83). As MDR-TB and antiretroviral treatment programs emerge with funding from international sources such as the Global Fund for AIDS, TB and Malaria (GFATM), both the need and the resources for TB infection control programs in poor and middle-income settings are growing. What is needed, in addition to infection control guidelines, however, is a global TB infection control implementation strategy supported by an organizational structure comparable, for example, to the current international program to develop laboratory capacity in poor countries. A strategic plan to develop infection control capacity in poor countries will have to be linked to adequate resources and have well-defined goals, regional training programs, measurable end points for both processes and outcomes, and regular progress reports. As suggested by Farmer, centrally organized purchase and distribution networks for respirators, UV fixtures and lamps, and other infection control consumables should also be considered, accompanied by expert consultation. Training and training materials are already available from WHO but a proactive strategy for dissemination and implementation is needed. As noted, the essential components of TB infection control in highprevalence, resource-limited settings are similar to those in low-risk environments, although the emphasis on specific interventions sometimes differs. A. Known or Suspected Cases

It is often said that administrative controls are the least expensive and the most effective of the available interventions to reduce TB transmission in hospitals. Although this is true, the fundamental task is the prompt identification and separation of potentially infectious TB suspects. There are several administrative approaches to improving surveillance, but it has been our experience that the process often comes to an impasse when the overcrowded hospital or institution simply cannot identify suitable space for separating suspects until TB can be ruled out, much less isolating them individually. Although finding a suitable isolation area away from children and other vulnerable persons seems relatively simple, the goal becomes increasingly complex when separate isolation wards are needed for males and females, for TB/HIV-infected patients, and for those with known or suspected MDR-TB. Administrative solutions can go only so far in creating suitable space in an underfunded, overcrowded facility. However, even in the absence of properly engineered isolation rooms, there is some evidence that physical isolation can be effective. In Italy, for example, a MDR-TB outbreak was brought under control by moving potentially infectious

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patients to rooms separated from other patients, even though these rooms did not have advanced environmental control measures and PRP was not used (84). Similarly, administrative controls alone, without enhanced environmental controls or PRP, appeared to prevent further TB transmission at a large U.S. city hospital (48). International guidelines for low- and middleincome countries also recommend affordable environmental controls, such as open windows, directional airflow, outdoor waiting areas, and where appropriate, separate structures for MDR-TB patients (82). Under highprevalence conditions, high-risk procedures such as sputum induction can often be done outdoors in warm climates, away from waiting areas, visitors, and other patients. Bronchoscopy can be done in a low-cost procedure room with an exhaust fan (discharging to a safe area) used to increase air disinfection as well as assure directional airflow away from adjacent occupied areas. In cold climates, such as during winter, in much of the former Soviet Union, dilution of contaminated air cannot depend on open windows, and fresh-air ventilation is often limited. Under these circumstances, the most practical environmental intervention may be upper room UVGI, as discussed earlier in this chapter. Surveillance for TB suspects means screening patients for cough (persisting for three weeks or more), weight loss, or fever, at several possible entrance points into the facility, including ambulatory care. This must be followed by: (i) the means (sputum acid-fast smears and chest radiography) to quickly confirm or rule out TB disease, and (ii) a suitable place for isolation or separation while awaiting test results. The WHO guidelines suggest that district and local facilities might have more infection control interventions based on greater risks. For example, a relatively large district hospital might consider hiring a ‘‘ward cough officer’’ whose job is to focus on identifying chronic cough, collecting specimens, delivering them to the laboratory, and following up on results to be sure that no active case goes undiagnosed (82).

B. The Unsuspected Case Under High-Prevalence Conditions

An important problem in both high- and low-prevalence settings is the unsuspected TB patient admitted for other reasons. In a hospital in Lima, Peru, for example, 250 of 349 women admitted to a general medical ward over the course of a year were actively screened for TB by history, physical examination, radiography, and sputum smear and culture (85). Forty (16%) of the patients had positive TB cultures, and of those, two-thirds were smear positive, and one-third of those were unsuspected cases. Of the 40, eight had MDR-TB and of these, six were unsuspected and three were sputum AFB— smear positive. If that ward is at all representative, over 1% of general medical patients sharing the ward with other patients and staff had unsuspected, smear-positive MDR-TB. HIV-AIDS was low in that setting, but the potential for transmission in a high HIV-AIDS prevalence setting would be even greater. Education leading to greater awareness of unsuspected TB can help,

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but only if the tools for rapid diagnosis are available and used. Prompt sputum smears on all patients with cough could help identify the most infectious inpatients and outpatients before much transmission occurs, assuming separation is possible until effective treatment renders them noninfectious. C. PRP Under High-Prevalence Conditions

Although properly worn PRP can exclude a high percentage of infectious droplet nuclei, respirators cannot be worn at all times, and their role under high-prevalence conditions may be limited. In the hospital ward in Lima, Peru, detailed above, workers would be unlikely to wear respirators while caring for the 16% of patients with unsuspected TB. Generally, the use of personal respirators should be limited to caring for new suspect cases before effective treatment is started, high-risk procedures (sputum induction, bronchoscopy, and autopsy), and routine care of MDR cases until they are known to be responding to therapy and have been sputum-culture negative on three separate specimens. Where PRP is needed, workers should be carefully instructed on their use to minimize face-seal leak. At a minimum, U.S.-certified N95 or European Union–certified FFP2 respirators should be used. For protection during highrisk procedures, for example, with MDR-TB patients, powered air purifying respirators (PAPR) offer greater protection. These respirators are designed to fit the face snugly. For performing high-risk procedures on MDR-TB patients, positive-pressure respirators should be used to further minimize face-seal leak. Surgical masks are designed to prevent the wearers’ respiratory droplets from contaminating the surgical field, not to protect the wearer, and should not be substituted for personal respirators because they are not designed to prevent face-seal leakage. Surgical masks can be used temporarily on patients who cannot cover coughs with a tissue when they are required to be outside of isolation. They are stigmatizing, uncomfortable, and should not be routinely used as a means of infection control. V. TB Infection Control in Prisons Much of what has been presented applies to some degree to most institutional settings where TB transmission is likely. Space does not permit in-depth discussion of nuances that characterize each of the varied settings generally considered under the term, ‘‘institutional’’ or ‘‘congregate settings.’’ By virtue of their mission, health-care facilities in high-burden areas are inevitably at risk for TB transmission, to both patients and care givers, and for the same reason, should be most amenable to control measures. Yet, effective TB infection control in health-care facilities cannot be assumed to occur, and usually proves difficult to achieve. In contrast, the mission of prisons, defined broadly by WHO as any place of detention, including such diverse places as pretrial facilities, immigration detention camps, police stations, and prisoner of war camps, to name but a few, has little to do with health, and their structures and functions often serve

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to facilitate and not reduce the transmission of TB and other communicable diseases. TB rates up to 100 times those in the general population are common, in part due to the high-risk populations concentrated in prisons, and in part due to institutional transmission and reactivation. The previously cited document published by WHO in 2002 (86) provides comprehensive TB control technical guidance for prison managers and public health authorities. The following list summarizes some of the key points of this excellent WHO resource:  The spread of TB is made worse by the late diagnosis and treatment of infectious cases, and poor prison living conditions such as overcrowding.  Due consideration of the level of occupancy and to general ventilation rates can reduce the transmission of airborne infections.  HIV infection dramatically increases the risk of developing active TB. HIV in a prison population therefore significantly increases the number of TB cases.  TB can be effectively treated with DOTS-based strategies in prisons. However, badly managed TB treatment does not cure patients, prolongs transmission of infection, and promotes MDR-TB.  MDR-TB is caused by incorrect treatment of TB. Treatment for MDR-TB is expensive, difficult, and prolonged.  MDR-TB is infectious. Patients with drug-susceptible TB can be reinfected with drug-resistant strains.  Close cooperation between prison health services and community public health services is critical for effective TB control.  Reducing rates of incarceration through penal reform is fundamental to improving TB control and prison health. The basic components of TB control are, of course, similar to those in communities and civilian institutions, and the greatest challenge is generating the political will and resources adequate to achieve effective control. VI. Summary We have presented evidence that TB transmission in institutions and other congregate settings contributes importantly to TB in the community. Although transmission in low-burden, resource-rich countries is generally well controlled, increasingly uncommon unsuspected TB cases will continue to transmit infection because of the limitations of case detection and the increasing burden of overisolation based on nonspecific symptoms. Better diagnostic tools for active disease could improve the situation greatly. In the meantime, in addition to continued vigilance, prompt diagnosis, and effective treatment, greater emphasis on general air disinfection might reduce the impact of transmission from unsuspected TB cases. For highburden, resource-limited countries, the contribution of institutional transmission to the community case rate, although poorly documented, is likely

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to be great. The impact of nosocomial TB transmission and the fear of MDR-TB transmission on the availability of HCWs in some countries is a serious concern, especially where HIV infection is prevalent. A shift toward less hospitalization for TB and more community-based treatment would help greatly, but requires both a major policy shift and the development of ambulatory community-based infrastructure. Although administrative controls are critically important, improved surveillance, diagnosis, and treatment must be combined with innovative use of existing and new space to permit effective separation of suspect cases. Again, because cases will continue to be missed (until there are affordable breakthroughs in diagnostics), greater reliance on improved general air disinfection will help to limit transmission from unsuspected cases. Maximal use of natural ventilation, window fans to direct airflow away from adjacent areas, and use of relatively low-cost germicidal UV should be considered. PRP should be prioritized for high-risk procedures and for areas where administrative and engineering controls are suboptimal. Excellent guidelines exist for both high- and low-burden settings, including health-care facilities, prisons, homeless shelters, and other facilities, but their implementation has been slow due to a lack of emphasis and hands-on guidance from international authorities, a lack of local expertise, and a lack of resources. The GFATM, PEPFAR, and other new funding sources are providing new opportunities for resource-limited programs, but implementation will require new programmatic approaches similar to DOTS to be effective, including training, purchasing, and reporting of progress toward goals. Combined with DOTS expansion and an increased focus on both HIV-TB and MDR-TB, reducing transmission in hospitals, clinics, prisons, jails, and shelters will reduce human suffering, support the large institutional work force, and accelerate progress toward global TB control. References 1. Moll A, Gandhi NR, Pawinski R, et al. Presented at: 13th Conference on Retroviruses and Opportunistic Infections [abstr]. Denver, CO, 2006; 5–8. 2. Mitnick C, Bayona J, Palacios E, et al. Community-based therapy for multidrugresistant tuberculosis in Lima, Peru. N Engl J Med 2003; 348:119–128. 3. Bonifacio N, Saito M, Gilman RH, et al. High risk for tuberculosis in hospital physicians, Peru. Emerg Infect Dis 2002; 8:747–748. 4. Silva VM, Cunha AJ, Oliveira JR, et al. Medical students at risk of nosocomial transmission of Mycobacterium tuberculosis. Int J Tuberc Lung Dis 2000; 4:420–426. 5. Harries AD, Hargreaves NJ, Gausi F, Kwanjana JH, Salaniponi FM. Preventing tuberculosis among health workers in Malawi. Bull World Health Organ 2002; 80:526–531. 6. Kruuner A, Danilovitsh M, Pehme L, Laisaar T, Hoffner SE, Katila ML. Tuberculosis as an occupational hazard for health care workers in Estonia. Int J Tuberc Lung Dis 2001; 5:170–176. 7. 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.

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8. Frieden TR, Fujiwara PI, Washko RM, Hamburg MA. Tuberculosis in New York City—turning the tide. N Engl J Med 1995; 333:229–233. 9. 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. 10. Barnes PF, Yang Z, Pogoda JM, et al. Foci of tuberculosis transmission in central Los Angeles. Am J Respir Crit Care Med 1999; 159:1081–1086. 11. Alland D, Kalkut GE, Moss AR, et al. Transmission of tuberculosis in New York City. An analysis by DNA fingerprinting and conventional epidemiologic methods. N Engl J Med 1994; 330:1710–1716. 12. 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. 13. Cohen T, Murray M. Incident tuberculosis among recent US immigrants and exogenous reinfection. Emerg Infect Dis 2005; 11:725–728. 14. Verver S, Warren RM, Munch Z, et al. Proportion of tuberculosis transmission that takes place in households in a high-incidence area. Lancet 2004; 363:212–214. 15. Nardell EA. Environmental control of tuberculosis. Sem Respir Infect 2003; 18: 307–319. 16. Shin SS, Pashechnikov AD, Gelmanova IY, et al. Treatment outcomes in an integrated civilian and prison multi-drug resistant tuberculosis treatment program in Russia. Inter J Tuberc Lung Dis 2006; 10(4): 402–408. 17. Shin S, Furin J, Bayona J, Mate K, Kim JY, Farmer P. Community-based treatment of multidrug-resistant tuberculosis in Lima, Peru: 7 years of experience. Soc Sci Med 2004; 59:1529–1539. 18. Wells W. On air-borne infection: II Droplets and droplet nuclei. Am J Hyg 1934; 20:611–618. 19. Riley RL, Mills CC, O’Grady F, Sultan LU, Wittstadt F, Shivpuri DN. Infectiousness of air from a tuberculosis ward. Ultraviolet irradiation of infected air: comparative infectiousness of different patients. Am Rev Respir Dis 1962; 85:511–525. 20. Riley R, Wells W, Mills C, Nyka W, McLean R. Air hygiene in tuberclosis: quantitative studies of infectivity and control in a pilot ward. Am Rev Tuberc Pulmon Dis 1959; 75:420–431. 21. Wells W, Ratcliff H, Crumb C. On the mechanism of droplet nuclei infection II: quantitative experimental airborne infection in rabbits. Am J Hyg 1948; 47:11. 22. Kundsin RB. Airborne Contagion. New York: The New York Academy of Sciences, 1980. 23. Sultan L, Nyka C, Mills C, O’Grady F, Riley R. Tuberculosis disseminators—a study of variability of aerial infectivity of tuberculosis patients. Am Rev Respir Dis 1960; 82:358–369. 24. van Geuns HA, Meijer J, Styblo K. Results of contact examination in Rotterdam, 1967–1969. Bull Int Union Tuberc 1975; 50:107–121. 25. Borgdorff MW, Nagelkerke NJ, de Haas PE, van Soolingen D. Transmission of Mycobacterium tuberculosis depending on the age and sex of source cases. Am J Epidemiol 2001; 154:934–943. 26. Curtis AB, Ridzon R, Vogel R, et al. Extensive transmission of Mycobacterium tuberculosis from a child. N Engl J Med 1999; 341:1491–1495. 27. Loudon RG, Spohn SK. Cough frequency and infectivity in patients with pulmonary tuberculosis. Am Rev Respir Dis 1969; 99:109–111. 28. Behr MA, Warren SA, Salamon H, et al. Transmission of Mycobacterium tuberculosis from patients smear-negative for acid-fast bacilli. Lancet 1999; 353:444–449. 29. Catanzaro A. Nosocomial tuberculosis. Am Rev Respir Dis 1982; 125:559–562.

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30. Leonard MK, Osterholt D, Kourbatova EV, Del Rio C, Wang W, Blumberg HM. How many sputum specimens are necessary to diagnose pulmonary tuberculosis? Am J Infect Control 2005; 33:58–61. 31. Anderson C, Inhaber N, Menzies D. Comparison of sputum induction with fiberoptic bronchoscopy in the diagnosis of tuberculosis. Am J Respir Crit Care Med 1995; 152:1570–1574. 32. Templeton GL, Illing LA, Young L, Cave D, Stead WW, Bates JH. The risk for transmission of Mycobacterium tuberculosis at the bedside and during autopsy [see comments]. Ann Intern Med 1995; 122:922–925. 33. Cohen T, Sommers B, Murray M. The effect of drug resistance on the fitness of Mycobacterium tuberculosis. Lancet Infect Dis 2003; 3:13–21. 34. Cohen T, Murray M. Modeling epidemics of multidrug-resistant M. tuberculosis of heterogeneous fitness. Nat Med 2004; 10:1117–1121. 35. Maloney SA, Pearson ML, Gordon MT, Del Castillo R, Boyle JF, Jarvis WR. Efficacy of control measures in preventing nosocomial transmission of multidrugresistant tuberculosis to patients and health care workers. Ann Intern Med 1995; 122:90–95. 36. Malasky C, Jordan T, Potulski F, Reichman LB. Occupational tuberculous infections among pulmonary physicians in training. Am Rev Respir Dis 1990; 142: 505–507. 37. Fridkin SK, Manangan L, Bolyard E, Jarvis WR. SHEA-CDC TB survey. Part I: status of TB infection control programs at member hospitals, 1989–1992. Society for Healthcare Epidemiology of America. Infect Control Hosp Epidemiol 1995; 16: 129–134. 38. Fridkin SK, Manangan L, Bolyard E, Jarvis WR. SHEA-CDC TB survey. Part II: efficacy of TB infection control programs at member hospitals, 1992. Society for Healthcare Epidemiology of America. Infect Control Hosp Epidemiol 1995; 16: 135–140. 39. Hutton MD, Stead WW, Cauthen GM, Bloch AB, Ewing WM. Nosocomial transmission of tuberculosis associated with a draining abscess. J Infect Dis 1990; 161: 286–295. 40. Nardell EA, Keegan J, Cheney SA, Etkind SC. Airborne infection. Theoretical limits of protection achievable by building ventilation. Am Rev Respir Dis 1991; 144: 302–306. 41. Ko G, First MW, Burge HA. Influence of relative humidity on particle size and UV sensitivity of Serratia marcescens and Mycobacterium bovis BCG aerosols. Tuber Lung Dis 2000; 80:217–228. 42. Stead WW. Variation in vulnerability to tuberculosis in America today: random, or legacies of different ancestral epidemics? Int J Tuberc Lung Dis 2001; 5: 807–814. 43. Kritski AL, Marques MJ, Rabahi MF, et al. Transmission of tuberculosis to close contacts of patients with multidrug-resistant tuberculosis. Am J Respir Crit Care Med 1996; 153:331–335. 44. Fine PE. The BCG story: lessons from the past and implications for the future. Rev Infect Dis 1989; 11(suppl 2):S353–S359. 45. Ko G, Burge HA, Nardell EA, Thompson KM. Estimation of tuberculosis risk and incidence under upper room ultraviolet germicidal irradiation in a waiting room in a hypothetical scenario. Risk Anal 2001; 21:657–673. 46. Gammaitoni L, Nucci MC. Using a mathematical model to evaluate the efficacy of TB control measures. Emerg Infect Dis 1997; 3:335–342. 47. CDC. Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care settings, 2005. Morb Mort Wkly Rep 2005; 54:1–147.

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48. Blumberg HM, Watkins DL, Berschling JD, et al. Preventing the nosocomial transmission of tuberculosis. Ann Intern Med 1995; 122:658–663. 49. Scott B, Schmid M, Nettleman MD. Early identification and isolation of inpatients at high risk for tuberculosis. Arch Intern Med 1994; 154:326–330. 50. Wells WF, Wilder TS. The environmental control of epidemic contagion: I. An epdidemiologic study of radiant disinfection of air in day schools. Am J Hyg 1942; 35: 97–121. 51. McLean R. The effects of ultraviolet radiation upon the transmission of epidemic influenza in long-term hospital patients. Am Rev Resp Dis 1961; 83(suppl):36. 52. Riley RL. Ultraviolet air disinfection: rationale for whole building irradiation. Infect Control Hosp Epidemiol 1994; 15:324–325; discussion 326–328. 53. Menzies D, Fanning A, Yuan L, FitzGerald JM. Hospital ventilation and risk for tuberculous infection in Canadian health care workers. Canadian Collaborative Group in Nosocomial Transmission of TB. Ann Intern Med 2000; 133:779–789. 54. Nardell EA. Interrupting transmission from patients with unsuspected tuberculosis: a unique role for upper-room ultraviolet air disinfection. Am J Infect Control 1995; 23:156–164. 55. Rutala WA, Jones SM, Worthington JM, Reist PC, Weber DJ. Efficacy of portable filtration units in reducing aerosolized particles in the size range of Mycobacterium tuberculosis. Infect Control Hosp Epidemiol 1995; 16:391–398. 56. Loudon RG, Bumgarner LR, Lacy J, Coffman GK. Aerial transmission of mycobacteria. Am Rev Respir Dis 1969; 100:165–171. 57. Houk VN, Baker JH, Sorensen K, Kent DC. The epidemiology of tuberculosis infection in a closed environment. Arch Environ Health 1968; 16:26–35. 58. Nardell EA. Fans, filters, or rays? Pros and cons of the current environmental tuberculosis control technologies. Infect Control Hosp Epidemiol 1993; 14:681–685. 59. First MW, Weker RA, Yasui S, Nardell EA. Monitoring human exposures to upperroom germicidal ultraviolet irradiation. J Occup Environ Hyg 2005; 2:285–292. 60. Brickner PW, Vincent RL, First M, Nardell E, Murray M, Kaufman W. The application of ultraviolet germicidal irradiation to control transmission of airborne disease: bioterrorism countermeasure. Public Health Rep 2003; 118:99–114. 61. Riley RL, Nardell EA. Clearing the air. The theory and application of ultraviolet air disinfection. Am Rev Respir Dis 1989; 139:1286–1294. 62. Ko G, First MW, Burge HA. The characterization of upper-room ultraviolet germicidal irradiation in inactivating airborne microorganisms. Environ Health Perspect 2002; 110:95–101. 63. Nicas M, Miller SL. A multi-zone model evaluation of the efficacy of upper-room air ultraviolet germicidal irradiation. Appl Occup Environ Hyg 1999; 14:317–328. 64. First M, Nardell E, Chaission W, Riley R. Guidelines for the application of upperroom ultraviolet germicidal irradiation for preventing transmission of airborne contagion—Part II: design and operations guidance. ASHRAE Transact 1999; 105:877–887. 65. First M, Nardell E, Chaission W, Riley R. Guidelines for the application of upperroom ultraviolet germicidal irradiation for preventing transmission of airborne contagion—Part I: Basic principles. ASHRAE Transact 1999; 105:869–876. 66. NIOSH. Criteria for a Recommended Standard for Occupational Exposure to Ulturaviolet Radiation. Cincinnati, Ohio, U.S.: National Institute for Occupational Safety and Health, HHS, CDC, 1972. 67. Centers for Disease Control. NIOSH Guide to the selection and use of particulate respirators certified under 42 CFR 84. [DHHS (NIOSH) Pub No. 96–101]. Cincinnati, Ohio, U.S.: National Institutes for Occupational Safety and Health, HHS, CDC, 1996.

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68. NIOSH. Respiratory protective devices, 42 CFR Part 84. Cincinnatti, Ohio, U.S.: National Institute for Occupational Safety and Health, HHS, CDC, 1995. 69. Coffey CC, Lawrence RB, Campbell DL, Zhuang Z, Calvert CA, Jensen PA. Fitting characteristics of eighteen N95 filtering-facepiece respirators. J Occup Environ Hyg 2004; 1:262–271. 70. Adal KA, Anglim AM, Palumbo CL, Titus MG, Coyner BJ, Farr BM. The use of high-efficiency particulate air-filter respirators to protect hospital workers from tuberculosis. A cost-effectiveness analysis. N Engl J Med 1994; 331:169–173. 71. Nettleman MD, Fredrickson M, Good NL, Hunter SA. Tuberculosis control strategies: the cost of particulate respirators. Ann Intern Med 1994; 121:37–40. 72. Nicas M. Respiratory protection and the risk of Mycobacterium tuberculosis infection. Am J Ind Med 1995; 27:317–333. 73. Fennelly K, Nardell E. The relative efficacy of respirators and room ventilation in preventing occupational tuberculosis. Inf Control Hosp Epidemiol 1998; 19: 754–759. 74. Barnhart S, Sheppard L, Beaudet N, Stover B, Balmes J. Tuberculosis in health care settings and the estimated benefits of engineering controls and respiratory protection. J Occup Environ Med 1997; 39:849–854. 75. Kenyon TA, Ridzon R, Luskin-Hawk R, et al. A nosocomial outbreak of multidrugresistant tuberculosis. Ann Intern Med 1997; 127:32–36. 76. von Reyn CF, Horsburgh CR, Olivier KN, et al. Skin test reactions to Mycobacterium tuberculosis purified protein derivative and Mycobacterium avium sensitin among health care workers and medical students in the United States. Int J Tuberc Lung Dis 2001; 5:1122–1128. 77. Mori T, Sakatani M, Yamagishi F, et al. Specific detection of tuberculosis infection: an interferon-gamma-based assay using new antigens. Am J Respir Crit Care Med 2004; 170:59–64. 78. Mazurek GH, Villarino ME. Guidelines for using the QuantiFERON-TB test for diagnosing latent Mycobacterium tuberculosis infection. Centers for Disease Control and Prevention. MMWR. Recomm Rep 2003; 52(RR-2):15–18. 79. 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; 286:1740–1747. 80. Pai M, Gokhale K, Joshi R, et al. Mycobacterium tuberculosis infection in health care workers in rural India: comparison of a whole-blood interferon gamma assay with tuberculin skin testing. JAMA 2005; 293:2746–2755. 81. Yanai H, Limpakarnjanarat K, Uthaivoravit W, Mastro TD, Mori T, Tappero JW. Risk of Mycobacterium tuberculosis infection and disease among health care workers, Chiang Rai, Thailand. Int J Tuberc Lung Dis 2003; 7:36–45. 82. WHO. Guidelines for the prevention of tuberculosis in health care facilities in resource-limited settings. Geneva: WHO, 1999. 83. Farmer PE, Bayona J, Becerra MC, et al. Poverty, inequality, and drug resistance: meeting community needs. Proc Int Union Against Tuberc Lung Dis North Am Reg Conf 1997:88–102. 84. Di Perri G, Cadeo GP, Castelli F, et al. Transmission of HIV-associated tuberculosis to healthcare workers. Infect Control Hosp Epidemiol 1993; 14:67–72. 85. Willingham FF, Schmitz TL, Contreras M, et al. Hospital control and multidrugresistant pulmonary tuberculosis in female patients, Lima, Peru. Emerg Infect Dis 2001; 7:123–127. 86. http://www.who.int/docstore/gtb/publications/prisonsNTP/PDF/tbprisonsntp.pdf.

32 Tuberculosis Drug Resistance in the World

FRANC ¸ OISE PORTAELS, LEEN RIGOUTS, ISDORE CHOLA SHAMPUTA, and ARMAND VAN DEUN

MOHAMED ABDEL AZIZ

Department of Microbiology, Institute of Tropical Medicine, Antwerpen, Belgium

Stop TB Department, World Health Organization, Geneva, Switzerland

I. Introduction Tuberculosis (TB), the disease caused by Mycobacterium tuberculosis, discovered by Robert Koch in 1882, is today as devastating as ever. TB is widespread throughout the world, affecting all races and ages without exception and is prevalent under all types of climatic conditions. The World Health Organization (WHO) (1) 2004 estimates indicate that about one-third of the world’s population is infected with TB bacilli and that nine million patients have developed active disease. In addition, WHO estimated that two million deaths resulted from TB in the year 2002. The highest number of TB-related deaths is forecast for the Southeast Asia region, but the highest mortality per capita has been registered in the African region, mainly due to HIV infection. Combined TB/HIV infection significantly increases the likelihood of TB deaths. Since 1985, Iseman made constant efforts to encourage laboratory services and operational researchers to combat the threat of drug-resistant TB, which he defined as the result of ‘‘inadvertent genetic engineering’’ (2). Indeed, development of drug resistance is a man-made phenomenon

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following inadequate treatment, resulting from ineffective TB control programs, physician mismanagement, or patient noncompliance. Drug-resistant M. tuberculosis isolates first appeared in the 1940s to 1960s soon after the introduction of various chemotherapeutic agents such as streptomycin (S), p-aminosalicylic acid, and isoniazid (H) used in mono- or bitherapy (3,4). The discovery of rifampicin (R) and the implementation of short-course chemotherapy (SCC) using a combination of drugs were milestones in the fight against TB. SCC appeared successful in treating drug-susceptible strains as well as H- and/or Sresistant strains (5), but also allowed the medical community to continue to ignore the underlying factors that promote the appearance of drug resistance. Murray et al. in 1990 called the magnitude of the TB problem ‘‘simply staggering’’ and pointed out ‘‘TB has been ignored by much of the international health community’’ (6). In the early 1990s, several reports were published on the increasing risk of multidrug-resistant tuberculosis (MDR-TB) (7–11), defined as TB incurable by the current firstline drugs, i.e., TB caused by M. tuberculosis isolates resistant to at least H and R, the two most potent anti-TB drugs and the key components in SCC (12–14). At the close of the 20th century, we published a book on MDR-TB (15). The book provided an overview of MDR-TB by a variety of internationally renowned experts including epidemiologists, clinicians, pharmacologists, microbiologists, molecular biologists, and public health specialists. Many aspects of MDR-TB were addressed, such as the epidemiology in industrialized countries and in low-and middle-income countries, the link in some outbreaks with HIV infection, the factors that contribute to the development of MDR-TB including clinical mismanagement and program deficiencies, methods for the detection and treatment of MDR-TB, and management of health-care workers and other individuals exposed to MDR-TB patients. Tools for the management of MDR-TB are available in high-income countries but rarely elsewhere. A lack of data on several aspects of the epidemiology of MDR-TB and its treatment were also identified. During the last decade, the situation has changed partly due to a greater awareness of the medical and scientific communities of the threat of drug resistance for worldwide TB control. International organizations, nongovernmental organizations (NGOs), and pharmaceutical companies paid more attention to the problem of (drug-resistant) TB. Some remarkable achievements were mentioned in the preamble of the book: the rapid adoption of the DOTS strategy and the establishment by the WHO of the ‘‘Stop TB Initiative’’ (later becoming the ‘‘Stop TB Partnership’’) and of successful initiatives such as the Global Drug Facility and the Green Light Committee (GLC). In this chapter, an overview of the current worldwide situation of drug-resistant TB will be presented, with special emphasis on the areas of greater concern.

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Causes of (multi)drug resistance and risk factors for its development as well as the importance of the clinical laboratory in the diagnosis will be discussed. The impact of MDR-TB on control efforts will be mentioned. II. Extent of the Worldwide Drug Resistance Problem In contrast to the increasing availability of data on notification rates and incidences of pulmonary TB, only sporadic data on drug resistance was available before 1994. In 1994, WHO joined forces with the International Union Against Tuberculosis and Lung Disease (IUATLD) and launched the Global Project on Anti-TB Drug Resistance Surveillance. The aims of the Global Project were ‘‘to measure the prevalence and monitor the trend of anti-TB drug resistance worldwide, using a standardized methodology, and to study the correlation between the level of drug resistance and treatment policies in different countries.’’ The overall goal of the Project was ‘‘to improve the performance of national TB programs (NTPs) through policy recommendations on drug management.’’ The initiative of the WHO/IUATLD Global Project on Anti-TB Drug Resistance Surveillance was a result of dramatic outbreaks of MDR-TB, the fact that drug resistance constitutes a potential major threat to TB control, and the lack of representative and comparable data on the extent of the problem worldwide. The project is based on three principles: accurate representativity of the sample studied and careful calculation of its size, data collection and analysis differentiating between new and previously treated cases, and internationally accepted methodology and quality assurance of drug-susceptibility tests (DST) (16). Three reports of the Global Project have been released so far. They concern surveillance of resistance to the first-line drugs R, H, S, and ethambutol (E). The first report covered 35 geographical areas surveyed between 1994 and 1997 (14,17). Drug-resistant TB was present in all areas surveyed, and the prevalence of MDR-TB was significant in six areas (Argentina, Dominican Republic, Estonia, Latvia, Coˆte d’Ivoire, and the Ivanovo Oblast in the Russian Federation). The second report provided data on 58 geographical areas studied between 1997 and 1999 (18,19) and confirmed the worldwide occurrence of drug resistance. The third report was released in 2004 and contained new data from 77 areas or countries (20). It provided a comprehensive overview of the problem in six WHO regions, analyzed trends of TB drug resistance between 1994 and 2002, searched for determinants of rate disparities, estimated the magnitude of the MDR problem in the participating countries, and described drug resistance patterns. Data from 55,779 new cases were collected in 75 settings and from 8405 previously treated cases in 65 settings. Data from combined cases (i.e., new and previous by treated cases) was available for 68 settings.

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Table 1 Prevalence Rate (%) of Resistance to Any Antituberculosis Drug Worldwide from 1999 to 2002 Resistance to

New cases Minimum Maximum Median Previously treated cases Minimum Maximum Median Combined cases Minimum Maximum Median

Overall resistance

1 drug

2 drugs

Multidrug 3 or 4 drugs resistance

0 57.1 10.2

0 21.7 7.0

0 17.8 2.2

0 25.3 0.8

0 14.2 1.1

0 82.1 18.4

0 27.6 8.7

0 21.2 4.5

0 62.4 4.5

0 58.3 7.0

0 63.9 10.4

0 22.4 6.9

0 15.5 2.3

0 42.8 1.3

0 26.8 1.7

The third Report of the Global Project represents the most recent and accurate document on the situation of anti-TB Drug Resistance in the world. The most important findings from this report are presented below. A. Prevalence Rate of Resistance to Any Antituberculosis Drug

The prevalence rates of resistance to any drug among new TB cases as well as previously treated and combined cases from 1999 to 2002 are presented in Table 1. New Cases

The rate ranged from 0% in some West European countries (Andorra, Iceland, and Malta) to 57.1% in Kazakhstan with a median value of 10.2%. The resistance rate to only one drug ranged from 0% to 21.7% (Egypt) with a median value of 7.0%. The resistance rates to two and three or four drugs ranged from 0% to 17.8% and 25.3%, respectively (Kazakhstan), with a median value of 2.2% for two drugs and 0.8% for three drugs. Six countries had no MDR-TB (Oman, Andorra, Iceland, Luxembourg, Malta, and Slovenia), and the highest rates of MDR-TB (14.2%) were found in Israel and Kazakhstan, whereas the median rate was 1.1%. Previously Treated Patients

The rate of resistance in previously treated patients ranged from 0% in three European countries (Iceland, Luxembourg, and Malta) to 82.1% in Kazakhstan, with a median value of 18.4%. The resistance rate to only one drug ranged from 0% to 27.6% (Honduras), with a median value of 8.7%.

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The resistance rates ranged from 0% to 21.2% for two drugs in Denmark to 62.4% for three drugs in Kazakhstan, with a median value of 4.5% for two or three drugs. There was no MDR-TB among previously treated patients in eight countries (Gambia, Iceland, Luxembourg, Malta, Netherlands, Norway, Slovenia, and New Zealand) and one setting (Belgrade, Yugoslavia). However, the number of retreated cases in each of these settings was very small (1–38 cases). The highest rate of MDR-TB (58.3%) was found in Oman, but only 12 retreated cases were tested in this country. The median rate of MDR-TB among previously treated patients was 7.0%. Previously treated patients frequently involve very low numbers of cases. Therefore, results of resistance rates among previously treated patients should be interpreted with caution, taking into account the proportion of previously treated cases among the total number of cases and the low number of new cases in countries such as Andorra, Iceland, Malta, and Luxemburg. Combined Cases

The prevalence rate of resistance to any drug among combined (new and previously treated cases) TB cases ranged from 0%, in four countries (Iceland, Luxemburg, Malta, and Gambia), to 63.9% in Kazakhstan (median 10.4%). Resistance rates to one, two, and three or four drugs ranged from 0% to 22.4%, 15.5%, and 42.8%, respectively, with median values of 6.9%, 2.3%, and 1.3% to one, two, and three drugs, respectively. MDR-TB was not observed among combined cases in six countries (Andorra, Iceland, Luxembourg, Malta, Slovenia, and New Zealand). The highest rate of MDR-TB (26.8%) for combined cases was found in Kazakhstan. The overall median value of MDR for combined cases was 1.7%. B. Prevalence Rate of Drug Resistance to Specific Drugs

Single drug resistance rates to specific drugs among new cases as well as previously treated and combined cases are presented in Table 2. New Cases

Monoresistance rates to specific drugs ranged from 0% for all drugs to 12.8% for H (India–North Arcot), to 3.5% for R (Egypt), to 5.0% for E (Norway) and to 15.5% for S (China–Liaoning), with overall median values of 2.6% for H, 0.2% for R, 0.0% for E, and 3.3% for S. Monoresistance to H was only absent in three European countries and monoresistance to R was absent in 38 out of the 77 settings covered. Any resistance rates to specific drugs ranged from 0% for all drugs to 42.6% for H, 15.6% for R, 24.8% for E, and 51.5% for S, with overall median values of 5.7% (H), 1.4% (R), 0.8% (E), and 6.3% (S). In three West European settings, there was no resistance to H or R, and in four additional European countries, there was no resistance to R. The median values confirmed higher rates of resistance for S and H than for R and E.

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Table 2 Prevalence Rate (%) of Resistance to Specific Antituberculosis Drugs from 1999 to 2002 H

New cases Minimum Maximum Median Previously treated cases Minimum Maximum Median Combined cases Minimum Maximum Median

R

E

Mono

Any

Mono

Any

0 12.8 2.6

0 42.6 5.7

0 3.5 0.2

0 15.6 1.4

0 12.5 4

0 71 14.4

0 9.8 0

0 7.7 2.7

0 58.8 6.6

0 4.4 0.2

Mono

S Any

Mono

Any

0 5 0

0 24.8 0.8

0 15.5 3.3

0 51.5 6.3

0 61.4 8.7

0 6.7 0

0 54.2 3.5

0 13.8 3.2

0 77.1 11.4

0 27 2.2

0 5.1 0.1

0 32.1 1.3

0 14.9 3.1

0 57.9 5.8

Abbreviations: H, isoniazid; R, rifampicin; E, ethambutol; S, streptomycin.

Previously Treated Cases

Monoresistance rates to specific drugs ranged from 0% for all drugs to 12.5% for H (Israel), 9.8% for R (Ecuador), 6.7% for E (Belgrade and Yugoslavia), and 13.8% for S (Honduras), with overall median values of 4.0% (H), 0% (R and E), and 3.2% (S). Resistance rates to specific drugs ranged from 0% for all drugs to 71.0% for H, 61.4% for R, 54.2% for E, and 77.1% for S, with overall median values of 14.4% (H), 8.7% (R), 3.5% (E), and 11.4% (S). As for new cases, higher rates of resistance were observed in previously treated patients for S and H and relatively lower rates for R and E. Combined Cases

Monoresistance rates to specific drugs ranged from 0% for all drug to 7.7% for H, 4.4% for R, 5.1% for E, and 14.9% for S. Any resistance rates to specific drugs ranged from 0% for all drugs to 58.8% for H, 27.0% for R, 32.1% for E, and 57.9% for S. The median monoresistance rate to specific drugs ranged from 0.1% for E to 3.1% for S and for any resistance from 1.3% for E to 6.6% for H. C. Trends of Drug Resistance (1994–2002)

Analysis of drug resistance trends is important for the evaluation of program performance. The three global reports allowed to analyze temporal dynamics of resistance. For some settings, only two data points were available, whereas for others, at least three data points were available.

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Evaluation of trends may, however, be hampered in some settings by laboratory errors, misclassification of patients, changes in coverage, or by other factors such as selective migration (20,21). Therefore, factors responsible for temporal changes should be carefully analyzed in each setting. New Cases

Twenty settings reported two data points and 26 settings three or more data points. Trends of resistance against any anti-TB drug between 1994 and 2002 among new cases were significant for seven settings. Significant increases in the rates of any resistance were observed in Botswana, New Zealand, Norway, The Russian Federation (Tomsk Oblast), whereas significant decreases were found in Argentina, China (Hong Kong), Cuba, and Germany. Four settings showed significant changes in prevalence rates of MDRTB. A significant increase was observed in the Russian Federation (Tomsk Oblast) and a decrease in China (Hong Kong), Latvia, and in the United States (slight decrease). Previously Treated Cases

Two data points were reported from 19 settings, whereas 23 had at least three data points. Significant decreases for any resistance were observed in four settings (Cuba, Latvia, Switzerland, and the United States). Prevalence rates of MDR-TB increased in Estonia, Lithuania, and in the Russian Federation (Tomsk Oblast) and decreased in Latvia, Slovakia, and the United States. Combined Cases

Two data points were presented from 20 settings, and 26 settings had three or more data points. Significant increases in prevalence rates of any resistance were observed in Israel, Lithuania, New Zealand, and Norway, whereas a significant decrease was observed in China (Hong Kong) and The Netherlands. MDR-TB rates for combined cases increased in China (Hong Kong), Lithuania, and the Russian Federation (Tomsk Oblast) and decreased in the United States. For each setting, factors responsible for these changes should be analyzed carefully. We recently observed that changes between periodic surveys were better revealed by combined resistance rates than by its group components, and may thus be a reliable indicator of program performance (22). Combined resistance rates are not influenced by misclassification of patients into new and previously treated patients and reflect the total reservoir of drug-resistant cases. D. The Magnitude of Multidrug-Resistant Tuberculosis

Before 1990, most cases of MDR-TB were found in patients in whom it was acquired during prolonged inappropriate treatment (13,23), and only

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occasional outbreaks of MDR-TB were reported in which MDR bacilli were transmitted to contacts (24,25). Until then, the potential public health impact of MDR-TB concerned only a few cases of primary drug resistance (25). Several major outbreaks of MDR-TB occurred in hospitals and other institutions in the United States, mostly among HIV-positive patients during the early 1990s (25–31). Similar nosocomial outbreaks of MDR-TB were subsequently reported in Europe and in South America (32–34). In response to these MDR-TB outbreaks, a nationwide survey of drug-resistant TB was carried out in the United States (27). Of 3256 combined cases, 3.5% were MDR-TB. New York City, however, accounted for 61.4% of the nation’s MDR-TB cases. Adequate interventions were initialized (35), resulting in a significant reduction in MDR-TB in the United States from 2.8%, in 1993, to 1.6%, in 1996 (36). The rate of MDR-TB in the United Kingdom between 1994 and 1996 was 1.5% (37). Studies during the 1990s in Belgium, France, and Germany found MDR-TB rates between 0.9% and 1.5% (38,39), but higher rates were reported from Southern Europe (40). Cohn et al. (41) reviewed all reports of drug resistance surveys published between 1985 and 1994. High rates of MDR-TB were reported in several developing countries (10–48%) However, the surveys often used nonstandardized laboratory techniques and/or sampled small nonrepresentative groups of patients. Moreover, in many studies, there was no distinction between new and previously treated patients. The Global Project of the WHO/IUATLD has attempted to address these deficiencies. In the first Global Report (14,17), ‘‘hotspots’’ (i.e., areas with a high prevalence of MDR-TB among new cases) were identified. In the second Global Report (18,19), a prevalence rate of 3% among new cases was considered as a reference point, indicating a high MDR-TB level. A hotspot was thus defined as an area with at least a 3% MDR-TB prevalence rate. In the third Global Report (20), the statistical validity of such a cutoff point was examined. The distribution of MDR-TB prevalence rates in 75 settings showed that 6.5% was the natural departure point of ‘‘extreme values.’’ As shown in Figure 1, a prevalence rate of MDR-TB among new cases higher than 6.5% was observed in 10 settings: China (Liaoning and Henan Provinces), Ecuador, Estonia, Israel, Kazakhstan, Latvia, Lithuania, the Russian Federation (Tomsk Oblast), and Uzbekistan. Absolute numbers of cases must also be taken into consideration in the identification of hotspots. High-prevalence rates of MDR-TB in lowburden TB countries could reflect a very low number of MDR-TB cases. This is the situation in the majority of Western and Central European countries where the estimated incidence of MDR-TB cases did not exceed 10 cases per country. The estimated number of MDR-TB cases was five or less in seven countries (Andorra, Iceland, Luxembourg, Malta, New Zealand, Scotland, and Slovenia) Conversely, low rates of MDR-TB in TB highburden countries such as South Africa could reflect a very high number of MDR-TB cases.

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Figure 1 Prevalence of multidrug-resistant tuberculosis among new TB cases, 1994–2002.

In the third Global Report, the findings on the number of MDR-TB cases in the samples have been extrapolated to estimate the annual incidence of MDR-TB in the most recent phase of the Global Project. The total estimated number of MDR-TB cases in these settings was 15,106. Figure 2 shows that the highest estimated numbers of MDR-TB

Figure 2 Estimated total number of multidrug-resistant tuberculosis cases for countries included in the third phase of the Global Project, 1999–2002.

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cases are to be found in Kazakhstan and in South Africa, with more than 3000 MDR-TB cases per year. Kazakhstan, however, has a lower burden of disease, whereas South Africa has a lower rate of MDR-TB. These countries were followed by China (Hubei, Henan, and Liaoning Provinces), with more than 1000 estimated cases of MDR-TB. It should be noted, however, that the Global Project surveyed only one-third of the notified TB cases worldwide. Many information gaps still remain in many important areas, particularly in countries with a high TB burden and those suspected of having high MDR-TB rates. It is thus possible that many more unidentified settings with high MDR-TB rates do exist. These MDR-TB cases, if not treated properly, represent an important threat to TB control in their respective areas, and drug resistance surveillance needs to be expanded to many other countries. MDR-TB cases need to be managed by NTPs, through application of the DOTS-plus strategy. The GLC showed that DOTS-plus is feasible under routine DOTS-program conditions in mid- and high-prevalence countries. By August 2004, the GLC approved 25 projects worldwide, covering more than 8000 patients, with over 5000 new patients to be added in 2005. Regular DOTS programs should be introduced in countries with a high level of MDR-TB, and the DOTS-plus strategy should be fully integrated into the regular DOTS program. Application of this full DOTS strategy should stop the creation of new MDR-TB cases as well as the transmission of MDR-TB. III. Drug-Resistance Surveillance Smear microscopy remains the first priority for NTPs in high-prevalence countries. Effective control of TB and of any form of drug resistance, however, also implies drug-resistance surveillance, although its implementation may be difficult in some high-TB-burden settings. The third Global Report confirmed that drug resistance exists almost everywhere but with great variations in regional prevalence rates. The areas surveyed from 1994 until 2002 accounted for more than 100 sites on all continents, representing only about 40% of the world sputum-positive TB cases. As shown in Figure 3, more than half of the settings conducted only one survey, 19 countries provided two data points and 23 provided three or more data points. Figure 4 shows the high-TB-burden countries. Comparison of Figures 3 and 4 clearly shows that for several high-TB-burden countries, data on drug resistance is lacking. This lack of data is mainly due to shortcomings in the minimum requirement to conduct surveys, such as inadequate laboratory capacity or the absence of a functioning National Reference Laboratory. It should be noted that optimal laboratory performance must be attained, using a quality assurance program including an international exchange of strains.

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Figure 3 World Health Organization/International Union Against Tuberculosis and Lung Disease Global Project coverage, 1994–2002.

Strengthening laboratory capacity is required to detect TB patients effectively and to carry out drug-resistance surveillance. Recognizing the pressing need to improve laboratory performance in 2002, a Subgroup on Laboratory Capacity Strengthening (SLCS) has been established within the DOTS Expansion Working Group (DEWG). The ultimate goal of the SLCS is to improve TB case detection and cure rates in all countries, to reach and maintain the targets of 70% case detection and 85% cure rate and the millennium development goals (MDG).

Figure 4

Twenty-two tuberculosis high-burden countries.

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Organizing drug-resistance surveys requires a reasonable level of capacity of the TB control services, especially the laboratory services, and, in general, the support of a Supranational Reference Laboratory. Although case detection remains the first priority for NTPs, continuous surveillance should also be prioritized in some nonsurveyed areas. Given the low number of settings surveyed, data on trends in drug resistance are very scarce in some high-TB-burden countries. Nationwide surveys are underway or planned in several high-burden countries. These surveys are not easy to carry out and are expensive. The technical staff of the TB Division of the IUATLD have proposed continuous monitoring of drug resistance in a representative sample of isolates from previously treated patients as a more accurate and efficient alternative (21). IV. Causes of (Multi)drug Resistance and Risk Factors for Its Development Resistance to an anti-TB drug results from a spontaneous mutation in M. tuberculosis. A strain becomes MDR, through the sequential occurrence of individual mutations, each conferring resistance to a single drug or a class of drugs. The mechanisms of action of most drugs have been elucidated, as well as the mutations causing resistance (42,43). The circumstances in which drug resistance emerges are also well known from the first clinical TB treatment trials (44). Drug-resistant mutants are selected when anti-TB drugs are not properly used, e.g., if monotherapy is applied. The factors contributing to the development of drug resistance may be classified under two headings: clinical mismanagement (e.g., inadequate initial treatment, failure to recognize a preexisting drug resistance, addition of a single drug to a failing regimen, malabsorption due to other diseases, inadequate communication with patients, and poor compliance) and program factors (e.g., weak political commitment, irregular drug supply, poor quality drugs, and illicit sale of drugs). The extent of amplification in a given area reflects the quality of treatment practices. Amplification of resistance through addition of a new drug to a failing drug regimen is a well-known mechanism. In 1998, Farmer et al. first described the ‘‘amplifier effect’’ of short-course chemotherapy (45). Amplification of resistance to first-line drugs was clearly illustrated in a penitentiary hospital (Colony 33) in Mariinsk (Siberia), where Me´decins sans Frontie`res—Belgium—supported the care of about 2000 patients in 1996 (46). All patients received the WHO-recommended eight-month Category II retreatment regimen (i.e., 2HRZES/1HREZ/5HRE) under direct supervision. In 1998, a cohort study on 234 consecutive newly admitted patients with pulmonary TB was started. Microbiological examinations consisted of direct smear examination, culture testing, drug-susceptibility testing, and DNA-fingerprinting by IS6110-RFLP (Restriction Fragment Length Polymorphism). Sputum samples were collected before the start of treatment (T0), three months later (T3), and after completion of

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Table 3 Initial Drug-Susceptibility Pattern and Treatment Outcome of 234 Patients on a Category 2 Treatment Regimen in the Penitentiary Hospital, Colony 33, Mariinsk (Siberia) Final phase Initial phase Susceptible or monoresistant Polyresistant HS HES HE MDR HRS HERS Total

Cured

Cultþ

129 (55.1%)

109 (84.5%)

11 (8.5%)

9 (7.0%)

61 (26.1%) 30 30 1 44 (18.8%) 6 38 234

49 (80.3%) 25 23 1 13 (29.5%) 2 (33.3%) 11 (28.9%) 171 (73.1%)

8 (13.1%) 3 5

4 (6.6%) 2 2

26 (59.1%) 2 (33.3%) 24 (63.1%) 45 (19.2%)

Died (D)

Released (R)

N

2 2 2 (0.9%)

3 (6.8%) 3 16 (6.8%)

Abbreviations: MDR, multidrug resistance; H, isoniazid; R, rifampicin; E, ethambutol; S, streptomycin.

treatment (T8). As shown in Table 3, of the 234 patients, 129 (55.1%) had pan-susceptible or monoresistant disease, 61 (26.1%) carried polyresistant but non-MDR isolates, and 44 (18.8%) had MDR-TB. Eighteen (7.7%) patients did not complete treatment because they died (2) or were released from the colony (16) before treatment completion. Of 120 patients initially infected with pan-susceptible or monoresistant strains, 11 were culture positive at eight months (Table 3) Reinfection with a MDR strain in eight patients or a polyresistant strain in one patient was confirmed by RFLP analysis (Table 4). The remaining two patients carried pan-susceptible strains before treatment and after eight months, but with a different RFLP pattern. This change in RFLP type can result from specimen mislabelling, laboratory errors, or patients cheating to remain at the penitentiary hospital rather than in the regular penitentiary institutions. Fifty-seven patients with polyresistant strains who completed treatment, had initial HS-, HE-, or HSE-resistant isolates. After eight months, 8 of 57 patients were culture positive (Table 3). Clinical and microbiological records, including DNA-fingerprinting, documented acquired R resistance in 5 of 28 (17.9%) initially HSE-resistant cases, and reinfection with a MDR-TB strain in two of 28 (7.1%) initially HS-resistant patients (Table 4). The remaining patient with a pan-susceptible final isolate showing a different RFLP profile and was considered to result from a laboratory error or patients cheating. Of 39 patients with an MDR strain at T0 (35 HRES-and 4 HRS resistant), 26 (66.7%) remained culture positive after eight months of treatment (Table 3). DNA-fingerprints documented treatment failure in 22 (57.9%) cases among which two acquired E resistance (Table 4).

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Table 4 Drug-Susceptibility Testing and DNA-Fingerprinting Results for 45 Patients in Colony 33 with Positive Cultures After Eight Months Treatment DNA-fingerprinting N Susceptible or monoresistant

Identical failure

Different reinfection 8 ! HRES

11

Other 2 ! susceptiblea

1 ! HES Polyresistant HS HES MDR HRS HRES

8 3 5

5 ! HRESb

26 2 24

2 ! HRESb 20 ! HRES

2 ! HRES

1 ! susceptiblea

3 ! HRESa 1 ! HRESc

a

Cases of lab error, cheating? Cases of amplifier effect. c Cases of a mixed infection? Abbreviations: MDR, multidrug resistance; H, isoniazid; R, rifampicin; E, ethambutol; S, streptomycin. b

In this study, resistance amplification was demonstrated among partially resistant cases (polyresistant and MDR). The relative importance of the ‘‘amplifier effect’’ is dependent on the choice of the denominator. Among the candidates for amplification, i.e., isolates resistant to at least three drugs, the general amplification rate was 21.9% (7/32): five initially HES-resistant isolates became additionally resistant to R, and two initially HRS-resistant isolates acquired E resistance. This means that on a total of 216 patients who completed treatment, 3.2% (7/216) showed resistance amplification. However, among the 27 ‘‘true’’ failure cases, i.e., culture-positive patients at T8 showing unchanged DNA fingerprints, the amplification rate was 25.9% (7/27) The candidates for amplification (i.e., initially resistant to three drugs), who remained culture positive (seven patients), developed additional resistance. The ‘‘amplifier effect’’ also affects second-line drugs. These drugs are now used everywhere in the world, including in high-TB-burden countries where hotspots of MDR-TB have been detected and where a rational programmatic approach to diagnosis and treatment of MDR-TB is lacking. Emergence of resistance to second-line drugs due to their inappropriate use is increasing in these areas. Addition of a second-line drug to a failing treatment regimen with first-line drugs is responsible for the creation of resistance to the second-line drug. Some second-line drugs have also been administered alone (monotherapy), resulting in resistance.

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Frequency of resistance to second-line drugs among MDR and nonMDR isolates has been studied in some settings with high MDR-TB levels. Our convenience sample comprised isolates from the general population of Armenia, Bangladesh, Congo—Kinshasa, Benin, Kazakhstan, and Peru, and from the prison population in Baku (Azerbaijan), Mariinsk (Siberia), and Tbilisi (Georgia) (46). In general, resistance to second-line drugs was limited or absent in regions with a low MDR-TB prevalence and lack of second-line drugs, such as Bangladesh, and the frequency was significantly lower among non– MDR-TB patients compared to the MDR-TB population. The highest resistance frequencies were observed for kanamycin, with up to 46.7% of the MDR isolates being resistant in a prison in Georgia. This observation is alarming but not surprising considering the widespread and uncontrolled use of this drug in some areas of the former Soviet Union. Resistance to ofloxacin (OFL), the most frequently used fluoroquinolone for MDR-TB treatment, was not detected in the samples from Kinshasa, Kazakhstan, Azerbaijan, Georgia, and Siberia. In these settings, systematic MDR-TB treatment was not available at that moment. In Peru, Armenia and Bangladesh, however, MDR-TB treatment including the use of OFL has been implemented to some extent (47–49). Up to 10% of the MDR-TB patients harbored OFL-resistant strains in Peru and Armenia. It appeared recently that resistance to OFL could reach 51.4% among MDR-TB patients in some areas in the Philippines (50). These authors conclude that quinolones are now a significantly less effective alternative to treat MDR-TB cases in their country due to their widespread use in the treatment of TB and possibly in other infections as well. These alarming findings on the prevalence of resistance to second-line drugs, especially among MDR-TB patients, highlight the risk of producing resistance to second-line drugs if MDR-TB patients receive DOTS-plus, creating incurable TB strains. The amplifier effect could also occur if second-line drugs are used together with some first-line drugs to reduce the duration of therapy. Promising results in India seemed to indicate that replacing E with a fluoroquinolone could reduce the duration of therapy by two to three months (51). In view of this, phase III clinical trials are planned, using, e.g., gatifloxacin or moxifloxacin in combination with first-line drugs to treat patients in four months instead of six months. MDR-TB patients should absolutely be excluded from such trials to avoid amplification of resistance to fluoroquinolones. Great vigilance is also imperative when new drugs are introduced. Due to amplification of resistance, these new drugs could rapidly become ineffective, if administered in combination with first-line drugs to partially resistant or MDR-TB patients. Among newer anti-TB candidate drugs, some belong to known families (e.g., moxifloxacin, gatifloxacin, rifapentin) (52,53), whereas others belong to new classes of compounds such as nitroimidazopyrans (PA-824) (54) and diarylquinolones (R 207910) (55).

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Selection of resistant mutants through monotherapy sensu stricto or monotherapy by the addition of a single drug to a failing regimen may be quite frequent and constitutes an ‘‘excellent’’ way of amplifying the problem of drug resistance.

V. Role of the Laboratory Activities in Drug-Resistance Surveillance The global targets for TB control are the detection of 70% of all new infectious, sputum smear positive cases and curing at least 85% of these by 2005. Several new strategies have been developed to reach these 2005 targets (56). TB diagnosis and monitoring of treatment progress rely on bacteriological examination of clinical specimens, in particular sputum microscopy. Moreover, culture-and drug-susceptibility testing are useful to conduct drug resistance surveillance. Unfortunately, serious problems with the execution of all these techniques exist in a number of high-burden countries, and the NTP may lack capacity to solve them all at the same time. In this case, improvement of the microscopy network will constitute the first priority, because it is essential for early diagnosis and correct treatment monitoring of the majority of all TB cases. The third Global Report on anti-TB drug resistance in the world illustrates the lack of data on drug resistance in many high-TB-burden countries, partly due to inadequate laboratory capacities or lack of functioning National Reference Laboratories. The impact of MDR-TB became clearer through the three Global Projects on drug resistance surveillance (14,17–19). The DOTS-plus strategy was launched to address the issue of MDR-TB. Treatment of MDR-TB cases is now feasible everywhere, even in resource-poor settings, through the Global Fund to Fight AIDS, TB, and Malaria, and the GLC for access to second-line drugs (57). The DEWG of the Stop TB Partnership has recently developed a Global DOTS Expansion Plan. The NTPs should adopt a new approach combining prevention and treatment of MDR-TB by using the DOTS strategy for drug-susceptible TB cases and expanding the DOTS strategy via DOTS-plus and the GLC to properly manage MDR-TB cases (58). But this ‘‘full DOTS’’ strategy, i.e., adding a DOTSplus component to a regular DOTS programme, requires, among other prerequisites, well-functioning laboratory services that are able to perform culture and DST. Furthermore, the risk of amplification of drug resistance underlines the need for rapid tests to determine first-and second-line drugs resistance patterns before including patients in any new phase III clinical trial. Rapid detection of drug resistance to first-and second-line drugs can be done using culture-independent and culture-dependent techniques. Both techniques must be applicable to clinical specimens. Culture-independent techniques are based on polymerase chain reaction (PCR), and results are available

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within a few days. These methods reveal drug resistance in M. tuberculosis by detecting mutations in genes associated with the development of drug resistance. They are, however, sophisticated and expensive (when commercialized), and may not detect all drug-resistant isolates. Some drugs such as H and S target different genes; other drugs such as R and OFL are mostly restricted to a single gene, but, yet, resistance may also be due to mechanisms that remain to be elucidated (59). Several rapid culture-dependent techniques can also be applied directly on clinical specimens. They are cheaper than the molecular techniques and can detect resistance to first and second-line drugs within one week (60–63) (see also Chapter 46). Fingerprinting techniques must be used to differentiate failures, relapses, and reinfections, and to confirm the amplification of resistance (46,59). These techniques are generally applied on isolates, but some seem to work directly on smear-positive specimens (fresh or from slides). Promising results have been obtained with the Mycobacterial Interspersed Repetitive Unit–Variable Number of Tandem Repeats (MIRU–VNTR) method (64), but more testing is needed to validate the usefulness of this technique directly from specimens. The need for laboratory tests for the detection of drug resistance, and, in some cases, for fingerprinting analyses illustrates the importance of strengthening laboratory capacities in some high-TB-burden countries. There is an urgent need to improve the laboratory conditions and reinforce laboratory networks in countries with a high burden of TB and with suspected or existing high prevalence of drug resistance. High-quality laboratory activities complement other strategies and participate in better control of TB worldwide. Recognizing the urgent need to improve the laboratory performance in most of the high-burden countries, the SLCS was established. The major objective of the subgroup is to assist high-TB burden and other countries in strengthening TB laboratory capacity and to provide NTPs with reliable and high-quality diagnostic services. Microscopy remains the main tool for TB diagnosis in high-prevalence settings. Culture might provide more reliable results, but unfortunately culture on classical media takes long and is not accessible to the majority of patients. Molecular techniques at a referral center may offer alternatives for specific indications, which are not yet clearly defined. These indications might include species identification, rapid determination of R resistance, differentiation of acquired resistance from reinfection, and investigations of nosocomial transmission of TB. However, the use of these techniques will be limited to a few settings in the foreseeable future. It is the task and the responsibility of all of us, including international NGOs, bilateral development agencies, foundations, public and private organizations, technical agencies, and other United Nations agencies to strengthen laboratory capacities. Collaboration among partners is a key issue that will contribute to improve TB control worldwide (65,66) and to reach the MDG to halt TB and reverse its incidence by 2015 (53).

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33 Programmatic Control of Multidrug-Resistant Tuberculosis

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.

¨ NDAL-VINK and KAI BLO KITTY LAMBREGTS-VAN WEEZENBEEK KNCV Tuberculosis Foundation, The Hague, The Netherlands

ERNESTO JARAMILLO Stop TB Department, World Health Organization, Geneva, Switzerland

I. Background and Introduction Drug resistance emerged as a central issue in tuberculosis (TB) control beginning with the earliest human trials of the first anti-TB drug, streptomycin (SM), in 1947 (1). SM-treated patients improved over three to six months, but SM resistance developed in 85% of them, and long-term outcomes were little better than for untreated patients. Once para-aminosalicylic acid (PAS) became available in 1948, British researchers carried out the first-ever randomized controlled clinical trials comparing SMþPAS to each drug alone (1,2). Depending on the dose, the combination gave better results and SM resistance arose less frequently than either drug alone. A similar story unfolded when isoniazid (INH) was introduced in 1952 (3). INH was highly effective in the short term, but patients relapsed within months with INHresistant Mycobacterium tuberculosis. SMþINH together proved to be the most effective two-drug combination. By studying isolates from relapses 845

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and treatment failures, microbiologists developed methods to identify drugresistant bacille (4,5). These methods were soon put to use because concerns over transmission of drug-resistant TB to the population led the British to conduct the first national drug resistance survey, 1955 to 1956. Resistance to SM, PAS, and INH was identified in 2.5%, 2.6%, and 1.3% of previously untreated patients. As a result, the British Medical Research Council (BMRC) introduced the concept of triple drug therapy to ensure that patients received at least two effective drugs. Numerous subsequent clinical trials demonstrated that three drugs, given for sufficient periods of time, cured over 90% of patients and almost eliminated the development of drug-resistant TB (1,6). The principle of multidrug treatment was firmly established, and it was thought at the time that the problem of acquired drug resistance had been overcome. In the late 1980s and early 1990s, notorious outbreaks of drugresistant TB shattered that illusion and roused health professionals from their complacency (7). Resistance to combined INHþrifampicin (RIF) was especially lethal and came to define multidrug-resistance. Since then, it has become clear that multidrug-resistant tuberculosis (MDR-TB) is ubiquitous and poses a serious challenge to TB control programs in many countries (8–10). In affluent countries, the cost to treat such cases can exceed US $100,000 per patient and outcomes are substantially worse than in drug-susceptible TB (11). In low-income countries, the necessary drugs and diagnostic services may be unaffordable or simply unavailable (12). Consequently, the expertise and infrastructure to diagnose and treat MDR-TB may not be highly developed in such countries. MDR-TB patients may go untreated or inadequately treated. After years of highly contentious debate, these circumstances are changing rapidly. Since 2000, the cost of treating MDR-TB with so-called second-line drugs (SLDs) has declined sharply through the work of the Stop TB Partnership’s Working Group on MDR-TB (13). Since 2002, the Global Fund to Fight AIDS, TB, and Malaria (GFATM) has made funding available for MDR-TB control, and pilot projects for the treatment of MDR-TB in national or regional TB control programs have multiplied rapidly. Through May 2006, 41 countries had pilot projects for the management of MDR-TB representing over 14,000 patients (14) and WHO, unpublished data]. Based on these projects, data and experience have accumulated from a wide variety of circumstances and patients. These projects, built around core principles of TB control, have helped define a framework for MDR-TB control programs, which can be adapted with flexibility to a wide variety of situations. This chapter focuses on the organization and operation of public health programs for the control of MDR-TB, in middle- and low-income countries. The next section reviews recently developed, standardized definitions for classifying MDR-TB cases and their outcomes. The third and fourth sections discuss salient features of the etiology and epidemiology of drug-resistant TB from the program management perspective. These considerations lead naturally to an overview of the global response to

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MDR-TB that has demonstrated both the feasibility of and obstacles to implementing services for MDR-TB as part of national or regional TB control programs. To enable services for MDR-TB to expand, the World Health Organization (WHO) led the development of comprehensive, up-todate guidelines for MDR-TB control programs in middle- and low-income countries, described in Section 6 (15). These guidelines delineate a framework for MDR-TB control programs as well as a range of options that may be suited to different epidemiological, political, and economic circumstances. Although evidence-based to the extent possible, scientific evidence does not exist for many situations encountered in the management of MDR-TB. Given the vast body of TB research from Sylvius and Villemin to the present, the paucity of data on MDR-TB is surprising (16). Research is urgently needed to fill these gaps. In these situations, strategies are based on the experience from: ongoing projects for MDR-TB; analogy to DOTS; extrapolation from the pre-rifampicin era; extrapolation from other mycobacterial infections; in vitro and experimental animal studies; and fundamental principles of microbiology, pharmacology, clinical medicine, epidemiology, and related scientific disciplines. The chapter concludes by describing emerging issues as MDR-TB control programs scale up to fulfill their part of the Global Plan to Stop TB, 2006–2015 (14).

II. Drug-Resistant TB: Definitions and Program Implications One of Karel Styblo’s landmark achievements was to develop a practical, standardized system of registering and reporting cases and analyzing their outcomes (17). His system became a cornerstone of the DOTS strategy and provided the means to monitor incidence, mortality, and evaluate program performance. Because it was based on microscopy, short-course chemotherapy, and 12 to 15 months outcomes, it was not suited for MDR-TB. Prior to 2002, no existing system took into account drug-susceptibility testing (DST), treatment with SLDs, and the two-year duration of treatment needed for MDR-TB. Building on the pioneering work of Partners in Health (PIH), a Harvard University-based nonprofit organization, demonstrating the feasibility of MDR-TB management in a project in the slums of Lima, Peru, from 1996 to 2000, the Bill and Melinda Gates Foundation (BMGF) funded the ‘‘PARTNERS’’ project—a consortium of several organizationsa—to extend the project to the rest of Peru, export the MDR-TB control strategy to at least one other site, disseminate the knowledge and lessons learned, and generalize the strategy for global applicability (18). PARTNERS helped a Harvard Medical School/Partners in Health, the Peruvian Ministry of Health, the World Health Organization, the U.S. Centers for Disease Control and Prevention, and the Task Force for Child Survival and Development.

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catalyze a transformation in the international approach to MDR-TB in middleand low-income countries, which is discussed later in this chapter. One key contribution was a clear, practical, and standardized taxonomy for case registration, reporting, and outcomes analysis of drug-resistant TB based on broad international consensus (19). These standardized definitions are crucial for programs to register cases, classify and tabulate case counts, and analyze treatment outcomes by case classification and by cohort in a manner that can be understood easily and compared across programs. Drug resistance is defined bacteriologically as growth of M. tuberculosis on (or in) well-defined artificial nutrient media despite a specific concentration of one of the anti-TB drugs under carefully controlled laboratory conditions. Thus, drug-resistant TB is diagnosed exclusively in the laboratory. This broad definition does not specify which drug or how many drugs are ineffective at blocking mycobacterial growth in vitro. ‘‘Monoresistance’’ means that exactly one drug is ineffective. ‘‘Polyresistance’’ means that two or more drugs are ineffective. But neither term indicates which drugs. The term ‘‘multidrug-resistance’’ specifically refers to INH and RIF with or without other drugs. Thus, MDR-TB may be resistant to ‘‘only’’ two drugs, INHþRIF, or it may be resistant to three, four, or more drugs. Drug resistance can also be classified as primary or secondary. Drug resistance is primary if the patient was never treated with anti-TB drugs, or treated for less than one month before the specimen was collected. Drug resistance is secondary if the patient was treated for one or more months at any time before the specimen was obtained. Programmatically, the implications of these two types of resistance differ. Primary resistance implies that individuals with infectious, drug-resistant TB remain at large in the community and are transmitting the disease to others in the population. Control measures should focus on finding and curing infectious cases and on preventing transmission in institutions and other high-risk environments. Secondary resistance implies that resistance may have developed during or as a consequence of previous treatment. Control measures should focus on rapid diagnosis of drug-resistance, appropriate chemotherapy, and diligent case management to assure adherence to treatment. In the past, ‘‘acquired resistance’’ was the term used instead of secondary resistance, but this is incorrect. Acquired resistance means the patient’s isolate was known to be susceptible to a given drug at one point in time and resistant at a later point in time during the same course of treatment. The isolates must also be the same strain, i.e., not reflecting a mixed infection or exogenous reinfection. Thus, the diagnosis of acquired resistance requires serial isolates with the same genotype; it implies that resistance developed due to inadequate treatment. Outside affluent countries, most TB control programs do not perform culture and DST routinely at the start of treatment; those that do typically wait until treatment fails. It would be impossible to know if resistance to a given drug was present previously. Programs like those in Eastern Europe are noteworthy exceptions, but in these countries genotyping may not be available routinely.

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Patients with confirmed or suspected MDR-TB who are treated with SLDs constitute WHO Category IV. Within Category IV, three registration groups are defined according to the treatment history: (i) no previous treatment with anti-TB drugs (or treatment for less than one month) (ii) previous treatment (for greater than or equal to one month) with only first-line drugs, and (iii) previous treatment (greater than or equal to one month) with one or more SLDs (with or without first-line drugs). Previously treated patients should be further classified according to the outcome of the most recent treatment—failure, default, or relapse—as defined by WHO (20). The last two registration groups are ‘‘Transfer In,’’ for patients starting MDR-TB treatment elsewhere, and ‘‘Other’’ for Category IV patients who do not fit these definitions, including Category IV patients who were treated outside DOTS programs (14,19). In addition, patients should be stratified by the presence or absence of coexisting HIV infection. Outcomes for Category IV patients were defined based on monitoring both microscopy and culture and on the roughly two-year duration of treatment but otherwise they parallel the six standard DOTS outcomes for drug-susceptible TB (20). Patients who complete a full course of treatment (following the program’s protocol) are defined as ‘‘cured’’ if they remain culture-negative for the last 12 month of treatment provided a sufficient number of samples (at least five) are cultured. In patients with too few, the outcome is defined as ‘‘treatment completed.’’ The outcome ‘‘died’’ is defined as death for any reason during treatment. ‘‘Treatment failure’’ is defined as two or more positive cultures in the last 12 months of treatment or any one of the last three cultures. In addition, treatment failure can be recorded if a clinical decision has been made to terminate treatment due to the clinical course of the disease or adverse events. These failures should be separated from microbiologically confirmed failures to do sub-analyzes. ‘‘Default’’ is defined as treatment interruption for two or more consecutive months for any reason. Finally, ‘‘transfer out’’ is for patients who transfer to another MDR-TB treatment program and for whom the treatment outcome is unknown. From a program management perspective, these definitions determine how cases are registered and reported, assigned appropriate treatment regimens, and evaluated. Second, they form the basis for cohort analysis, carried out at 24 to 36 months, to evaluate program performance based on incidence trends and outcomes of patients with MDR-TB. Cohort analyses must be stratified by registration groups to interpret the distribution of outcomes relative to international norms and relative to previous cohorts in the same program (21). Third, they establish the requirement for service level II and level III laboratory servicesb. Fourth, epidemiological analysis of case registration and outcomes data will suggest strategies for preventing MDR-TB.

b

Level I ¼ AFB microscopy; level II ¼ level I þ culture for mycobacteria; level III ¼ level II þ mycobacterial species identification, drug susceptibility testing, and oversight of levels I and II.

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Programs with a large proportion of new, previously untreated Category IV patients may want to focus on better case finding to prevent transmission in the community, for instance, through contact tracing, rapid diagnosis of drug resistance, and possibly infection control measures in institutions (22). Programs with a large proportion of Category IV patients treated previously with only first-line drugs should strengthen services for Category I, II, and III patients, for example, by ensuring 100% DOT, using fixed-dose combination drugs, increasing cooperation with the private sector, and expanding or improving DST at the start of treatment. Similarly, programs registering many patients previously treated with SLDs, in addition to the foregoing measures, may consider implementing DST for selected SLDs, revising treatment protocols for drug-resistant TB, attention to side effects if nonadherence is a problem, and controlling the distribution and ensuring the quality of SLDs. III. Etiology of Drug Resistance and Program Implications MDR-TB is caused by both microbial and human factors. The microbial factors are discussed in Chapter 2 briefly, drug resistance occurs naturally but infrequently through spontaneous genetic mutations. The proportion of resistant mutants in a wild-type population of M. tuberculosis ranges from 10
5 to 10
7 depending on the specific drug and mutation. A drug-resistant strain comes to predominate under the selective action of an anti-TB drug. The drug kills the susceptible bacille, and the resistant bacille continue to grow. Unlike many pathogens, mycobacteria do not exchange genetic material horizontally, so mutations are independent. The probability of two simultaneous mutations is vanishingly small, from 10
11 to 10
14, far less than the number of bacille in a patient. The number in a pulmonary cavity may reach 109. Two or more bactericidal drugs in combination should eliminate the entire population of bacille in an individual patient. The microbiology parallels precisely the early human data with two-drug combinations of SM, PAS, and INH. Resistance to two or more drugs arises by serial accumulation of individual mutations, often in more than one patient, over months to years of inadequate treatment. This traditional model oversimplifies, however, because M. tuberculosis inhabits a range of microenvironments in patients where drug concentrations and drug activity differ (23,24). Even if two drugs are administered together, they may not attain effective concentrations at the same time and for sufficient periods of time at each site of infection. Drug concentrations can be affected differentially by impaired gastrointestinal absorption, for example, due to HIV infection, enteric infections, malnutrition, and other substances in the GI tract (food, antacids, other drugs) (23). Drugs also affect different bacterial subpopulations differently, depending on their phenotype. Three phenotypes have been described based on their metabolic state: (i) actively growing and dividing, (ii) ‘‘latent’’ or ‘‘persistent’’ with minimal metabolic activity, and (iii) slowly or intermittently active (24). These subpopulations are the same

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strain genetically but differ in their susceptibility to different drugs. For example, SM and INH are highly active against rapidly growing extracellular bacille, for instance, in the lining of a pulmonary cavity, reducing such bacterial populations by orders of magnitude within days to weeks. Pyrazinamide (PZA) works well inside the phagolysosome, but SM works poorly at this low pH. RIF is highly effective, against all sub populations including latent bacteria, but INH is not. Even if two or more drugs are effective against an isolate in vitro, they may not be equally effective against different subpopulations of that same strain in a patient (24). In practical terms, one concludes that three or more bactericidal drugs with complementary modes of action are needed to eradicate large bacterial populations consistently in every patient. As noted earlier, BMRC studies in the 1950s demonstrated SMþPASþINH to be superior to any two-drug combination. It should be self-evident that a high prevalence of poly- and multidrugresistant TB is due to inadequate treatment of drug-susceptible and monoresistant TB for whatever reason: delayed or inaccurate diagnosis, inappropriate drug combinations, poor-quality drugs, improper case management, or otherwise inappropriate program conditions. In programmatic terms, TB control services for MDR-TB cannot compensate for improper management of drug-susceptible TB patients. In other words, a poorly functioning TB program can create MDR-TB much faster than expensive, specialized services can detect and treat it. Interventions to control MDRTB must place the highest priority on correcting deficiencies in diagnosis, treatment delivery, and program operations for uncomplicated TB cases as a prerequisite to implementing services for MDR-TB. A program that does not achieve its targets for case detection by smear microscopy and successful treatment using six to nine month regimens of relatively benign drugs is not likely to succeed with complex laboratory services and 24-month treatment regimens that are more toxic and less effective. In contrast, well-functioning programs often find it to be a natural, albeit challenging, extension of their operations to develop specialized services for the relatively small fraction of patients with or at risk of MDR-TB. IV. Epidemiology of Drug-Resistant Tuberculosis MDR-TB could not have existed before rifampicin was introduced in 1966. Forty years later, an estimated one million people have MDR-TB and 430,000 people develop it every year (25). The magnitude of the problem, however, was not recognized until the 1990s. Highly lethal outbreaks of MDR-TB in several countries affecting especially HIV-infected persons called attention to an epidemic that had been developing for at least 10 years (26–29). In 1999, Harvard Medical School published an extensive treatise on the global impact of MDR-TB, which summarized reports of MDR-TB in 104 countries and provided in-depth case studies of four countries with exceptionally intense epidemics (30). Many of the reports, however, were limited by problems with laboratory quality and epidemiological methods.

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In truth, the incidence and prevalence of MDR-TB in representative populations were unknown. In 1994, the WHO and the International Union Against Tuberculosis and Lung Disease (IUATLD) launched the Global Project on Anti-TB Drug-Resistance Surveillance (DRS) to determine the levels of resistance to INH, RIF, ethambutol (EMB), and SM in nationally (or regionally) representative populations using standardized bacteriological and epidemiological methods (31,32). More than 20 top mycobacteriology laboratories around the world joined together to form a coordinated Supranational TB Reference Laboratory (SRL) network to provide quality assurance, establish proficiency standards for first-line DST, and validate results from national drug resistance surveys (33,34). By 2003, three rounds of the global survey were completed, the first covering from 1994 to 1996 (8), the second covering from 1996 to 1999 (9), and the third covering from 1999 to 2002 (10). Within large countries or regions, 109 countries have reported data from over 250,000 patients representing 42% of the world population and 39% of reported smear-positive TB cases worldwide. Except for small and affluent countries, drug-resistant TB was identified in virtually every country surveyed (Table 1), ranging from 0% to

Table 1 Prevalence of Drug-Resistant Tuberculosis from the WHO/IUATLD Global Project on Anti-TB DRS, 1994 to 2002 New cases, n ¼ 77,175

Previously treated cases, n ¼ 12,905

87.1% 12.9% (n ¼ 9964)

67.3% 32.7% (n ¼ 4216)

Fully susceptible Any resistance Resistance to INH RIF EMB SM INH þ RIF INH þ RIF þ 1 INH þ RIF þ EMB þ SM All MDR Other polyresistant All 2-, 3-, 4-drug resistant

% of total

% of drug-resistant cases

% of total

% of drug-resistant cases

8.2 2.6 1.6 8.0 0.5 1.1 0.7

63.3 20.2 12.6 62.3 3.8 8.8 5.3

26.1 17.8 9.2 20.2 3.3 6.7 6.4

80.0 54.5 28.3 61.9 10.0 20.4 19.6

2.3 3.0 5.3

17.9 23.2 41.1

16.4 5.6 22.0

50.0 17.7 67.7

Abbreviations: INH, isoniazid; RIF, rifampicin; EMB, ethambutol; SM, streptomycin; MDR, multidrug-resistant tuberculosis. Source: From Refs. 8–10.

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57.1% among new patients (median 10.7%) with 70% of sites (72/109) in the 5% to 20% range. Twenty sites exceeded 20%. The prevalence of MDR-TB among new cases ranged from 0% to 14.2% (median 1.2%). In 11 sites, more than 6.5% of new cases had MDR-TB, including seven in the former Soviet Union and two in China. Previous treatment increased the odds of having any type of drug resistance four-fold and of having multidrug resistance 10-fold. Moreover, the extent of previous treatment correlated with the extent of drug resistance. Among patients treated for less than one month, fewer than 3% had MDR-TB, increasing progressively to 27% among patients treated for over 12 months (35). Overall, the prevalence of drug resistance in previously treated patients ranged from 0% to 82.1% (median 23.3%), and multidrug resistance ranged from 0% to 58.3% (median 7.7%). In six sites in the former USSR and two sites in China, over one-third of previously treated patients had MDR-TB. Because repeated treatment often includes additional drugs, the spectrum of drug resistance also increases, including the possibility of resistance to SLDs. In the global DRS, one-third of MDR strains had resistance to all four drugs tested. In Latvia, 65% of MDR-TB patients with no previous treatment had PZA resistance increasing to 78% of those previously treated with first-line drugs and 83% of those previously treated for MDR-TB. Kanamycin resistance increased from 22% in the first group to 40% in the latter two groups. Successful treatment decreased and treatment failureþdeath increased across the three groups as shown in Table 2 (21). These findings also highlight the importance of subdividing Category IV registrants not only by previous treatment but also by the outcome of previous treatment. Studies from Vietnam and Brazil compared levels of drug resistance between relapses, previous treatment failures, and never treated controls. In Vietnam, only 10% of previous treatment failures had fully drug-susceptible TB, compared to 33% of relapses and 71% of controls. On the contrary, 42% of previous treatment failures had MDR-TB compared to none of the relapses or controls (36). Data from Brazil indicate Table 2 Treatment Outcomes of Multidrug-Resistant Tuberculosis Patients by Case Registration Category, Latvia, 2000 Outcome Cure Completion Death Failure Default Total

Never treated for TB 38 4 2 3 8 55

(69) (7) (4) (6) (15) (100)

Note: All figures are number (%). Source: From Ref. 2.

Previously treated for TB 76 4 10 15 14 119

(64) (3) (8) (13) (12) (100)

Previously treated for MDR-TB 13 (43) 0 2 (7) 11 (37) 4 (13) 30 (100)

Total 127 8 14 29 26 204

(62) (4) (7) (14) (13) (100)

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MDR-TB was present in less than one-tenth of relapses, but in one-third of patients in whom first-line treatment had failed, and two-thirds of patients in whom second-line treatment had failed (37). Although previous treatment failure is associated with MDR-TB, the degree of association varies between programs. Moreover, the association with MDR-TB of previous outcomes other than treatment failure is more variable between programs. Each program should establish for itself the levels of drug resistance among different types of re-treatment patients in their own population using scientifically valid epidemiological and microbiological methods, and it should be repeated periodically or monitored continuously. High levels of MDR-TB have been identified in certain prison populations (Table 3), especially in countries of the former Soviet Union, but few studies have compared MDR-TB rates in prisons and comparable civilian populations (38). Portaels compared rates of MDR-TB in five civilian populations in the former Soviet Union (two Russian oblasts plus Estonia, Latvia, Kazakhstan) with two prison systems, one in Azerbaijan and one in Russia. In the civilian populations, 4% to 11% of new TB patients and 20% to 54% of previously treated patients had multidrug resistance. In the prison populations, 24% to 26% of the new patients had multidrug resistance, as did 89% to 94% of TB patients not improving with treatment (39). Just as TB is rife in certain prison populations, MDR-TB may be more common because the same factors may contribute to both TB transmission in general and MDR-TB in particular. Certain features of prison systems may be especially important in relation to MDR-TB, including fewer resources and weaker health services; unsupervised treatment; interruptions in drug supplies resulting in inadequate treatment; barriers to seeking health services in prison; treatment interruptions due to transfers, release during treatment, and recidivism with active MDR-TB; and disincentives to effective treatment such as better conditions in the prison hospital than general prison conditions. To stem the further development of MDR-TB in prisons, these factors must be given priority, especially in prisons where MDR-TB is out of control and where treatment with SLD is being considered. MDR-TB control in prison populations is vital to controlling Table 3 Prevalence of Multidrug-Resistant Tuberculosis in Imprisoned Tuberculosis Patients Country of study Azerbaijan (n ¼ 131) Georgia (n ¼ 276) Russian Federation (Mariinsk) (n ¼ 164) Spain (Madrid) (n ¼ 203) United States (New York) (n ¼ 116) Source: From Ref. 39.

Year

Prevalence of MDR-TB (%)

1997 1997–1998 1998 1994 1991

23.0 13.0 22.6 5.9 32.0

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MDR-TB overall, not only in its own right but also because of the back and forth movement between the prison and the general population. The organization and operation of TB control programs in prison populations, including MDR-TB, has been addressed in recent publications of WHO and U.S. Centers for Disease Control and Prevention, and will not be discussed in depth in this chapter (38,40). Other than prisoners and ex-prisoners, specific social groups may be singled out as high risk for MDR-TB, but such assertions may be based on social or economic prejudice rather than on data. In some cases, specific characteristics such as poverty or alcoholism do not distinguish between the risk of MDR-TB and risk of TB in general. Data from Russia showed that homelessness was a strong risk factor for MDR-TB, but alcoholism and unemployment, apart from their association with homelessness, were not independent risk factors (41). The value of these data for MDR-TB program management is that it enables programs to target specific risk groups to maximize the cost-effectiveness of expensive and limited diagnostic services, and possibly of empiric treatment pending DST results. It also enables programs to plan the types of case-management issues that will arise during long-term treatment such as housing, substance abuse, boredom, and social support. V. The Global Response to Multidrug-Resistant Tuberculosis In response to high or increasing levels of MDR-TB in many countries, WHO and its many partners launched the ‘‘DOTS-Plus’’ initiative beginning in 1999 with the goals of developing and evaluating strategies to: (i) prevent further development and spread of MDR-TB, and (ii) provide adequate diagnosis and treatment for patients with drug-resistant M. tuberculosis by building upon, not detracting from existing TB control services (12,13). Thus, DOTS-Plus represented the pilot phase of a new public health program-based strategy for the systematic detection, diagnosis, treatment, and prevention of MDR-TB, which is consistent with WHO TB control guidelines and built on the solid foundation of a well-functioning DOTS program (42). The basic concept was that the program’s performance with diagnosis, treatment, drug management, and information management for TB under the DOTS strategy may be the best predictor of performance with the more difficult strategies and services required for MDR-TB. The DOTS-Plus initiative was spearheaded initially by WHO through an open working group of stakeholders and experts in TB control, leaders in public health, international and bilateral donor agencies, and representatives of industry, especially the pharmaceutical industry. Recognizing the high cost of second-line anti-TB drugs as a major barrier for less affluent countries, in 1999, Me´decins Sans Frontie`res, WHO, PIH, and their partners negotiated major price concessions on second-line anti-TB drugs from several pharmaceutical companies through a pooled procurement mechanism for drug quantities sufficient for 2000 patients over two years

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(12). For the first time, the cost of these drugs was within the reach for middle-income and some lower-income countries. After the Stop TB Partnership was established in the year 2000, the group officially became the ‘‘Working Group on MDR-TB,’’ one of seven working groups. As such, the rationale, purpose, specific objectives, and resource needs were delineated in the Global Plan to Stop TB, 2006–2015, (43). Because uncontrolled access to these drugs would inevitably result in the rapid development of resistance to these same drugs, the Working Group chose to offer this limited supply of high-quality, low-cost drugs to programs that would be most likely to use the drugs properly without generating even worse drug resistance. Access to these drugs is offered through the Green Light Committee mechanism (GLC) (13,42,44). Of course, procurement of SLD through preexisting, normal commercial channels outside of the GLC process remains unchanged and continues to account for the large majority of production and consumption of SLDs. The GLC, formally a subcommittee of the Working Group, is an independent group of experts whose role is to evaluate applications from potential projects for management of MDR-TB; and monitor the approved projects. Programs wishing to purchase reduced-price drugs apply to the GLC according to published guidelines and procedures describing their current TB situation, laboratory capacity, and proposed strategies to manage MDR-TB (15,42,44). Applications are approved if they meet the criteria set out in the Guidelines (15). For projects that are not approved, the GLC assists the applicants to improve their TB services and to reapply. Starting in 2002, the same pricing agreement was renewed thrice, each time for two years. As the market has evolved, additional production capacity is being developed and stringent quality assurance mechanisms are being put in place. Drug registration issues, however, continue to be a major hurdle to the distribution of drugs procured through this mechanism. Over time, the lowest possible prices have been ensured increasingly through market competition. Limited quantities of capreomycin and cycloserine continue to be made available through concessional pricing with one of the manufacturers. In 2003, WHO evaluated the first five GLC-approved DOTS-Plus pilot projects, in Estonia, Latvia, Lima (Peru), Manila (the Philippines), and Tomsk Oblast (Russian Federation) (Table 4) (45). Patients were eligible for inclusion if they started treatment before the end of 2001 to ensure they had time for at least 24 months of treatment. Case finding strategies differed. The three Eastern European projects routinely cultured all patients at the start of treatment and, if culture positive, performed DST. In Lima, DST was performed in patients at high risk of MDR-TB, generally those having previously received Category I, Category II, and standardized treatment for MDR-TB through the national TB program. In Manila, treatment histories varied, but most patients came after treatment failure or with MDR-TB documented in the private sector. All five projects treated with individualized regimens based on DST results and previous treatment history, including at least four drugs thought to be effective. The majority of patients received more than four drugs to

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Table 4 Treatment Outcomes of New and Previously Treated Multidrug-Resistant Tuberculosis Patients Enrolled in Five DOTS-Plus Pilot Projects from 1999 to 2001

Estonia Cured Completed Default Failed Died Transferred Total Treatment success

28 2 7 4 5 0 46 30

Latvia

(60.9) 165 (67.3) (4.3) 3 (1.2) (15.2) 40 (16.3) (8.6) 28 (11.4) (10.9) 9 (3.7) 0 (100.0) 245 (100.0) (65.2) 168 (68.6)

Lima (Peru) 351 0 40 17 99 1 508 351

(69.1)

Manila (The Tomsk Philippines) (Russia)

61 1 (7.9) 14 (3.3) 12 (19.5) 16 (0.2) 1 (100.0) 105 (69.1) 62

(58.2) 118 (82.5) (1.0) 0 (13.3) 9 (6.3) (11.4) 9 (6.3) (15.2) 7 (4.9) (1.0) 0 (100.0) 143 (100.0) (59.0) 118 (82.5)

Total 723 6 110 70 136 2 1047 729

(69.1) (0.6) (10.5) (6.7) (13.0) (0.2) (100.0) (69.6)

Note: All figures are number (%). Source: From Ref. 45.

ensure at least four were effective. Regimens included an aminoglycoside (or capreomycin) and a fluoroquinolone whenever possible. The injectable agent was continued for three to six months after cultures converted to negative, but oral drugs were continued for 18 to 24 months. The Eastern European projects routinely hospitalized patients until they were noninfectious, while in Lima and Manila, patients were hospitalized only if they were severely ill or had complications. Just over 1000 patients were included in this evaluation. Almost 90% of them had been previously treated, slightly less than one-half with only firstline drugs and slightly more than one-half with SLDs. Less than 3% of isolates were resistant to only INHþRIF; two-thirds were resistant to both first-line drugs and SLDs. HIV-infection was rare. Treatment was successful in 70% of patients, ranging from 59% to 83%. Treatment failed in 3% to 11% of patients, 4% to 19% died, and 6% to 16% defaulted from treatment. In Estonia and Latvia, previously untreated patients had a higher treatment success rate (80% vs. 61%) and a lower treatment failure rate (4% vs. 15%) than previously treated patients. Only 3% of patients discontinued treatment due to adverse drug reactions ranging from 0% to almost 9% at the different sites (46). Through January 2006, 58 applications to the GLC were received from 49 different project sites in 36 countries. Of these, 47 applications were approved, representing 12,215 patients in 29 countries. In addition, reapplications were received from nine projects for cohort expansion; all of these reapplications were ultimately approved. Although an optimal approach to MDR-TB from a clinical perspective might be to base treatment on rapid, accurate DST results obtained at the start of treatment, this approach is unrealistic in many regions of

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the world. Therefore, pilot projects and national programs are assessing alternative approaches to achieving the best possible results for their patients, taking practical considerations into account, with resources that often are grossly inadequate. In South Africa, a standardized regimen was devised based on DRS data and is being administered to a large cohort of patients with MDR-TB, without further DSTs, to evaluate the costs, feasibility, and outcomes of this approach. Currently about 4000 MDR-TB patients are on treatment. In Nepal, recent surveillance data demonstrated that 80% to 90% of patients in whom Category II treatment failed have MDR-TB. Such patients are being treated empirically for MDR-TB without bacteriological confirmation of DST results in each new case. In Latvia and Estonia, the initial DOTS-Plus cohorts included only patients with confirmed MDR-TB as noted above. More recently, patients at risk for MDR-TB have broth-based culture and DST, and selected patients undergo rapid screening with a nucleic acid amplification test for RIF resistance. Patients may be treated empirically for MDR-TB based on their previous history of TB and TB treatment or based on detection of mutations in the rpoB gene pending the results of new DST. Critical evaluation of these projects will guide future improvement of international guidelines and delineate a range of potential measures to control MDR-TB, including strategies for low-income countries and for highrisk groups such as retreatment cases in situations where real-time DST results may not be available (15,45). One of the most important developments has been the GFATM, established in 2002. The GFATM awards grants to countries for TB control (as well as for HIV/AIDS and malaria), including for MDR-TB. The GFATM has selected the GLC as the mechanism for procuring SLDs. Recipients of GFATM awards are therefore required to obtain approval by the GLC before spending funds on these drugs. This helps ensure that the proposed services for patients with MDR-TB follow international guidelines and aims to prevent the development of even worse drug resistance. In addition to evaluation and approval, these programs receive technical assistance from, and are monitored by, the GLC. Through 2005, 15 applicants to the GFATM were also approved by the GLC for SLDs, representing approximately 60% of patients in GLC-approved projects. For the first time, adequate funding was available to provide services for MDR-TB, and economic barriers to MDR-TB control programs diminished. Given the availability of financial resources and evidence of feasibility, the pressing issues have become how to develop the infrastructure, human capacity, and scale-up the strategies developed through dozens of pilot projects. VI. The Framework for Multidrug-Resistant Tuberculosis Control In 2005, less than 2% of the estimated total numbers of MDR-TB patients were being treated according to WHO recommendations. The Global Plan

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to Stop TB, 2006–2015 (14) calls for scaling up detection and treatment of MDR-TB such that over 50% of incident cases are being treated properly by 2015. To hold to that trajectory, priorities for the next 10 years include: expanding DRS; strengthening capacity for high-quality culture and DST; scaling up treatment for MDR-TB; reducing the cost and increasing the supply of SLDs; developing human capacity; fostering innovation and research; and providing global leadership and coordination. At the program management level, the framework for MDR-TB control includes analogues of the five traditional elements of DOTS, plus several additional elements that have been described in the WHO Stop TB Strategy:     

The role of the government and the public health sector; Case detection and diagnosis through bacteriological methods; Treatment, monitoring, and appropriate case management; Management of drugs and commodities; Information management—monitoring and evaluation.

A. Government Commitment

Like TB in general, MDR-TB cannot be controlled unless the government commits itself to sustained and focused action. Often, government commitment is thought to mean primarily adequate financing for TB control; financing is essential, of course, but it is only one aspect of the government’s role. The government is responsible for policy, coordination, and program management. The government establishes the necessary legal and regulatory environment for MDR-TB control, including pharmaceutical regulations and quarantine laws. A strong central unit should develop an overall strategy in collaboration with local health centers and health-care providers. The strategy should cover case finding, diagnosis, appropriate treatment based on regional or local capabilities and resources, case management practices, and methods of prevention. The strategy should be based on the existing system of TB services, the infrastructure and human capacity for MDR-TB, and on the local epidemiological situation. Policies and procedures must be written, disseminated and define clearly the roles and practice standards for each participant. Flexibility is required to adapt as circumstances change, and the entire written policy needs to be reviewed periodically and revised as needed. In addition, the government’s role is to ensure an adequate work force with sufficient human expertise. B. Diagnosis of MDR-TB Through Quality-Assured Culture and DST

The availability, quality, and distribution of laboratory services determine which options are realistic for case finding and treatment. The program manager is responsible for establishing, coordinating, and supporting a laboratory network appropriate to the epidemiology of MDR-TB in the program’s geographic area, the available resources both human and financial, and the case detection and treatment strategy selected by the

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program’s leadership. In addition, infrastructure is necessary for the microbiology laboratory to integrate into the larger concept of diagnostic services. Examples include transportation, communications, financial services, and commodity suppliers and distribution. The program’s actual strategy may vary from pretreatment culture and DST in all patients as in affluent countries, to DST only for DRS or epidemiological studies to identify high-risk groups in programs without capacity to provide real-time diagnostic testing. In between, most programs in middle-income countries may choose to carry out culture and DST in selected high-risk groups such as Category II treatment failures (higher stringency, less diagnostic testing) or all retreatment cases (lower stringency, more diagnostic testing). Requiring meticulous internal quality control and external quality assurance in the laboratory is another management tool that will serve the program’s goals well. A proficiency-testing link with a supranational TB reference laboratory will be most helpful in this respect. C. Appropriate Treatment Strategies Including SLDs and Proper Case Management Conditions

A treatment strategy consists of the treatment regimen and the method to deliver this regimen under direct observation. The treatment strategy involves a comprehensive assessment of the local situation. The main factors to be considered for designing a treatment regimen include: (i) representative DRS data for new cases, and for each type of re-treatment case, (ii) the history of anti-TB drug-use in the country or region, (iii) the availability, accuracy, and timeliness of individual DST for first-line drugs and SLDs, (iv) the availability of specific drugs, and (v) options for treatment delivery. As noted, empiric treatment of certain groups of patients based on survey data, without individual DST, may be appropriate in some settings, for example, in Nepal, where 90% of Category II failures have MDR-TB, which is generally resistant to all four first-line drugs. SLD have been used very little in the past in Nepal and delivering a sputum specimen for culture may require several days walking through the Himalayas. On the other hand, in Peru, Thailand, or Latvia where SLDs have been used extensively in the past and broth-based culture and DST may be available, individualized DST-based treatment regimens may be more appropriate. The choice between hospitalization and ambulatory treatment depends on factors such as the availability and location of hospital wards with adequate infection control measures to prevent nosocomial transmission; properly trained personnel to detect and manage adverse drug reactions; a strong social support network to facilitate adherence to treatment; and acute clinical or social conditions in patients. In any case, DOT is mandatory throughout the entire course of care. This requires careful case management to prevent nonadherence to treatment. Unlike drug-susceptible TB, surgery plays an important role in the management of selected patients with MDR-TB and should be available through an experienced TB surgeon and a facility with excellent infection control measures in the operating suite, recovery room, and intensive care unit.

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D. Uninterrupted Supply of Quality-Assured Drugs

Management of second-line anti-TB drugs for MDR-TB treatment programs is complex, especially when individualized treatment regimens are used (46). Individualized regimens make forecasting drug consumption more difficult. Moreover, regimens change due to side effects, new test results, and poor response to treatment. In addition, SLD have a short shelf life, and global production may be limited for some drugs. In many countries, drug registration is a lengthy and costly process that is not attractive to drug manufacturers. Thus, careful projections of drug needs are important because, in some cases, the manufacturers depend on firm purchase orders to begin the manufacturing process that can also be lengthy. Programs should use only quality-assured drugs. E. Information System Designed for Multidrug-Resistant Tuberculosis Management

The specific characteristics of a program managing MDR-TB require an adapted recording system that is designed for MDR diagnosis (culture, DST) and monitoring of treatment response and side effects for 24 months or longer. An appropriate cohort that includes treatment outcome is essential for monitoring program performance and treatment effectiveness. The Stop TB Working Group on MDR-TB has agreed on the treatment outcomes and variables definitions for projects managing MDR-TB (15,19). Recording forms and reporting instructions for monitoring morbidity, mortality, and program performance have been developed and are available for implementation (15). F. Additional Considerations for Multidrug-Resistant Tuberculosis

In the context of MDR-TB, additional measures should be incorporated into the services provided for these patients and/or the environment in which they receive their care, including       

Collaboration with HIV control programs; Infection control to prevent transmission in indoor environments; Education, training, and professional development; Integrated DRS; Epidemiological and operational research; Cooperation with private providers; and Collaboration with donors and technical agencies.

VII. Emerging Issues in Multidrug-Resistant Tuberculosis Control Programs Based on evaluating and monitoring projects proposed to the GLC over a period of six years, GLC members and consultants have observed a range of program strategies for MDR-TB under a wide variety of circumstances, for example, from the Himalayas of Nepal, where delivering a sputum specimen involves three days walking, to an apex institution of TB and lung

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diseases in New Delhi, where computed tomography and radiometric broth culture/DST are routinely available. Costa Rica’s national TB program applied to the GLC for treatment for 13 patients, while Peru’s third application to the GLC was for treatment for 6000 patients (after earlier cohorts of 200 and 750). In some parts of the former Soviet Union, 8- and 10-drug resistant TB is not rare, while in parts of Central Asia, RIF monoresistance is an important problem. GLC members have helped to adapt the MDR-TB framework to a wide variety of political, economic, social, microbiological, and epidemiological circumstances. Some salient issues, observations, and challenges have surfaced and hold true across sites. A. Feasibility

Foremost, these projects have demonstrated beyond doubt that MDR-TB can indeed be diagnosed and treated effectively in middle- and low-income countries and in ambulatory care settings, without drawing resources away from essential TB services and the traditional DOTS strategy. On the contrary, in many national or regional TB programs, pilot DOTS-Plus projects were powerful stimuli to strengthen basic TB control services in general. B. Case Detection and Diagnosis

Unlike traditional DOTS, no single strategy for case detection and diagnosis can be recommended for all programs. At one end of the spectrum, programs in Eastern Europe routinely carry out culture on all new patients and perform DST on all culture-positive patients, some using broth media and nucleic acid amplification. At the other end of the spectrum, projects use drug-resistance surveys to identify groups with high levels of drug resistance, which can be treated with a standardize regimen for MDR-TB without individual DST. Projects must determine their own approach based on the epidemiology of MDR-TB and the resources available. At the same time, diagnosis of MDR-TB is far more complex and expensive than microscopy for acid-fast bacille. The most consistent, major weakness in programs seeking to provide care for patients with or at risk of MDR-TB through the GLC mechanism has been the microbiology laboratories, especially level II and level III laboratories. In many locations, facilities, equipment, and supplies were insufficient and well-trained personnel were too few. In even more locations, however, laboratory quality, biosafety, information management, and opportunities for professional development were lacking. In general, diagnostic services were not prepared for MDR-TB control programs even though a central reference laboratory may be capable of culture and DST. In addition to the laboratories themselves, the infrastructure needed to provide valid, reliable, and timely diagnostic services, such as transportation and communications, was a steep barrier to MDR-TB control. C. Treatment and Issues Related to Second-Line Drugs

Unlike standard short-course chemotherapy for routine, drug-susceptible TB, there is no ‘‘best known’’ treatment for MDR-TB. There have been

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no controlled clinical trials to provide data on optimal treatment regimens. Without INH and RIF, treatment options are limited to drugs and drug combinations that have not been studied or have been shown to be inferior to INH and/or RIF-based regimens. No one standardized treatment can be recommended universally for patients with MDR-TB. No one empiric regimen can be recommended universally for patients at risk for MDR-TB. In the absence of solid scientific evidence, principles of treatment remain controversial. Reasonable arguments can be mounted for differing strategies, depending on the circumstances, for example: (i) standardized versus individualized regimens, (ii) fewer drugs and lower doses to minimize toxicity versus more drugs at higher doses to maximize effectiveness, and (iii) drug history versus DST for designing treatment regimens. Because of the high cost, toxicity, and irregular supply of SLDs, private practitioners are not well prepared to treat patients with combinations of four to six drugs continuously for two years. This results in variable and interrupted treatment, potentially exacerbating the MDR-TB situation in countries with large private health care sectors. Vigorous management of side effects is undervalued. Few programs put sufficient emphasis on procuring the broad range of ancillary drugs needed to protect patients from unpleasant or dangerous adverse drug reactions. As a consequence, many clinicians do not have extensive experience in managing adverse drug reactions effectively. Second-line anti-TB drugs are available in many countries without organized public health services for MDR-TB (48). For some of these commercial products, the quality may be dubious, because drug manufacturing is not stringently regulated in all countries (48). Low standards of production quality lead to low-cost products. By virtue of price and availability, these drugs have a competitive advantage over high-quality drugs produced under stringent control. These drugs are widely misused producing extensive drug-resistance in approximately 10% of MDR-TB patients (49). Together these observations regarding treatment add up to a serious lack of ‘‘human resources,’’ i.e., medical providers with expertise in the clinical management of MDR-TB. Production of quality-assured SLD is grossly inadequate to meet the global need for these drugs. Although the need is enormous, as noted above, the commercial market is small and erratic. Drug manufacturers have little incentive to produce SLD according to the quality standards of stringent drug regulatory authorities. As with other diseases of poverty, market-based systems have failed to produce and provide drugs and diagnostics for MDR-TB (12). Domestic drug production, procurement, registration, and distribution policies and practices have seriously hampered TB programs’ ability to import specific quality-assured drug products through the pooled procurement mechanism. Programs wishing to provide treatment for MDR-TB should begin drug registration procedures in advance.

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 Infection control policies and practices to prevent institutional transmission of TB in general and also MDR-TB are extremely inadequate worldwide. Medical workers and laboratory staff are at greatly increased risk for MDR-TB, and evidence suggests that nosocomial reinfection of patients may be much more common than once thought, especially with highly resistant strains of M. tuberculosis. Adequate infection control is expensive. Massive investments are needed to renovate facilities for safe patient care and diagnostic services.  Standardized, easy-to-use information management systems are sorely needed.  The ability to use data for program evaluation and improvement is extremely limited, but it can be developed without a huge investment of resources. The ability to formulate a problem, collect valid, reliable data, analyze data appropriately, and interpret the results as the basis for action to improve the operation of the system can be readily taught and fostered (50). VIII. Summary and Conclusions Preparing to implement services for MDR-TB takes time, but these services do not necessarily need to be implemented simultaneously in all parts of the region, country, or district. In large countries such as China and India, advance planning and a step-wise approach will lay a solid foundation for program implementation. As noted above, upgrading and expanding laboratory services, as a prerequisite to carry out a representative sample drug resistance survey is an important early step that consumes substantial time, effort, and resources. Human capacity building through training and education, determining infection control procedures, and registering specific SLD may proceed before applying to the GLC or the GFATM. Many countries have pilot tested their MDR-TB strategy in one national center or in selected regions or states before expanding to other parts of the country. Major challenges lay ahead for the expansion of MDR-TB control programs—human resources, laboratory capacity, the pharmaceutical industry, and financial constraints to name but a few that have been described in this chapter. The Global Plan to Stop TB, 2006–2015 (14) has clearly laid out a strategy for scaling up MDR-TB control programs, including budgetary requirements, so that the majority of detected MDR-TB cases will be treated appropriately within 10 years. At the same time, by strengthening and adapting basic DOTS programs, the proportion of retreatment cases should decrease, depleting the soil from which multidrug-resistant organisms grow. To get to that point, TB prevention and control activities will need to focus on updating national policies, training, increasing technical assistance to programs, laboratory strengthening on a massive scale and

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in all aspects, initiatives to provide low-cost quality-assured drugs for rational use and resource mobilization through innovative partnerships and advocacy. References 1. 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(suppl 2):S231–S252. 2. Medical Research Council: Treatment of pulmonary tuberculosis with streptomycin and para-aminosalicylic acid. Br Med J 1949; 2:1521–1525. 3. Medical Research Council: Various combinations of isoniazid with streptomycin or with PAS in the treatment of pulmonary tuberculosis. Br Med J 1955; 7:435–445. 4. Rist N. The application to clinical practice of the laboratory experience with combinations of antituberculosis drugs. Bull Int Union Tuberc 1953; 23:416–427. 5. Wolinsky E, Reginster A, Steenken W Jr. Drugresistant tubercle bacilli in patients under treatment with streptomycin. Am Rev Tuberc 1948; 58:335–343. 6. Iseman MD. Tuberculosis chemotherapy, including directly observed therapy. In: Iseman MD. A Clinician’s Guide to Tuberculosis. Philadelphia: Lippincott Williams and Wilkins, 2000:271–322. 7. Dooley SW. Multidrug-resistant tuberculosis. Ann Int Med 1992; 117:257–258. 8. The WHO/IUATLD global project on anti-tuberculosis drug resistance surveillance Anti-tuberculosis drug resistance in the world. First global report. Geneva: World Health Organization, 1997 (WHO/TB/97.229). 9. The WHO/IUTLD global project on anti-tuberculosis drug resistance surveillance. Anti-tuberculosis drug resistance in the world. Second global report. Geneva: World Health Organization, 2000 (WHO/CDS/TB/2000.278). 10. The WHO/IUATLD global project on anti-tuberculosis drug resistance surveillance. Anti-tuberculosis drug resistance in the world: third global report. 1999–2002. Geneva: World Health Organization, 2004 (WHO/HTM/TB/2004.343). 11. Iseman MD. Treatment and implications of multidrug-resistant tuberculosis for the 21st century. Chemotherapy 1999; 45(suppl 2):34–40. 12. Gupta R, Kim JY, Espinal MA, Caudron JM, Farmer PE, Raviglione MC. Responding to market failures in tuberculosis: a model to increase access to drugs and treatment. Science 2001; 293:1049–1051. 13. Gupta R, Cegielski JP, Espinal MA, et al. Increasing transparency in partnerships for health: introducing the Green Light Committee. Trop Med Int Health 2002; 7:970– 976. 14. Stop TB Partnership and World Health Organization. Global Plan to Stop TB 2006– 2015. Geneva, Switzerland: World Health Organization, 2006 (WHO/HTM/ STB/2006.35). 15. World Health Organization. Guidelines for the programmatic management of drugresistant tuberculosis. Geneva, Switzerland: World Health Organization, 2006 (WHO/HTM/TB/2006.361). 16. Bates JH, Stead WW. The history of tuberculosis as a global epidemic. Med Clin North Am 1993; 77:1205–1217. 17. Styblo K. The Epidemiology of Tuberculosis. Vol. 24. of KNCVs. eds, Selected Papers. The Hague, The Netherlands: Royal Netherlands Tuberculosis Association, 1991. 18. Kim J, 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.

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37. Kritski AL, Rodrigues de Jesus LS, Andrade MK, et al. Retreatment tuberculosis cases. Factors associated with drug resistance and adverse outcomes. Chest 1997; 111:1162–1167. 38. Bone A, Aerts A, Grzemska M, et al. Tuberculosis Control in Prisons: A Manual for Programme Managers. Geneva: WHO/IFRC, 2000 (WHO/CDS/TB/2000.281). 39. Portaels F, Rigouts L, Bastian I. Addressing multidrug-resistant tuberculosis in penitentiary hospitals and in the general population of the former Soviet Union. Int J Tuberc Lung Dis 1999; 3:582–588. 40. CDC. Prevention and control of tuberculosis in correctional facilities: recommendations of the Advisory Council for the Elimination of Tuberculosis. MMWR 1996; 45(No. RR-8):1–25. 41. CDC. Primary multidrug-resistant tuberculosis—Ivanovo Oblast, Russia, 1999. MMWR 1999; 48:661–664. 42. Scientific Panel of the Working Group on DOTS-Plus for MDR-TB. Guidelines for Establishing DOTS-Plus Pilot Projects for the Management of Multidrug-Resistant Tuberculosis (MDR-TB). Geneva: WHO, 2000 (WHO/CDS/TB/2000.279). 43. Stop TB Partnership. The Global Plan to Stop Tuberculosis: Phase 1: 2000–2005. Geneva, Switzerland (WHO/CDS/STB/2001.16). 44. WHO. Instructions for Applying to the Green Light Committee for Access to Second-Line Anti-TB Drugs, 2002. WHO/CDS/TB/2001.286 Rev.1. Available at: http://whqlibdoc.who.int/hq/2001/WHO_CDS_TB_2001.286_Rev.1.pdf (accessed 23 Jan 06) and at: http://www.who.int/tb/dots/dotsplus/management/en/ index.html (accessed 23 Jan 06). 45. Nathanson E, Lambregts K, Rich M, et al. Successful management of multidrugresistant (MDR) tuberculosis (TB) in resource-limited setting. Emerging Infections Diseases (in press). 46. Nathanson E, Gupta R, Huamani P, et al. Adverse events in the treatment of multidrug-resistant tuberculosis: results from the DOTS-Plus initiative. Int J Tuberc Lung Dis 2004; 8:1382–1384. 47. WHO. Procurement Manual for DOTS-Plus Projects Approved by the Green Light Committee. Geneva: WHO, 2003 (WHO/HTM/TB/2003.328). 48. WHO. Global Tuberculosis Control: Surveillance, Planning, Financing. WHO Report 2005. Geneva: World Health Organization (WHO/HTM/TB/2005.349), p. 41. 49. Shah NS, Wright A, Drobniewski F, et al. Extreme drug resistance in tuberculosis (‘XDR TB’): global survey of supranational reference laboratories for Mycobacterium tuberculosis with resistance to second-line drugs. Abstract PS-1560–20. 36th World Conference on Lung Health, Paris, France, 18–22 October 2005. 50. Laserson KF, Binkin NJ, Thorpe LE, et al. Capacity building for international tuberculosis control through operations research training. Int J Tuberc Lung Dis 2005; 9:145–150.

34 Tuberculosis Control and Migration

SUZANNE VERVER and JAAP VEEN Head Unit Europe, KNCV Tuberculosis Foundation, The Hague, The Netherlands

I. Introduction In the mid-1980s, countries that were expecting the elimination of tuberculosis (TB) (predominantly countries of Western Europe, North America, and the South Pacific), realized that the declining trend of TB incidence halted or even reversed. Analysis showed that an increasing proportion of cases were detected among foreign-born persons. Although this was partly due to reactivation of remote infection, it became clear that recent immigration from high- to low-prevalence countries contributed to increased number of cases detected in the latter. Immigration thus was recognized as a contributing factor of increasing trends of TB notification. But migration itself, either from one high-prevalence country to another or within a country (e.g., due to civil unrest or war), can also lead to an increase of new cases. This chapter intends to describe the effect of migration on the TB epidemic and the TB control strategies that specifically target immigrants. We prepared this chapter by searching Pubmed for TB (migrant or immigrant or migration or foreign-born or refugees or displaced persons), and used published research results that were already known to us.

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The following definitions will be used: low-incidence countries have an estimated incidence of less than 20 per 100,000 (1,2); medium-incidence countries of 20 to 49/100,000, and high-incidence countries of
50/ 100,000. Definitions used for immigrants vary. The term ‘‘foreign-born’’ will be used to refer to persons born outside the country of reference, unless otherwise specified, or unless the cited paper uses a different terminology. Instead of country of birth, some countries use nationality and base this on the country of citizenship. Others use ethnicity, which is a proxy for country of birth, or birth of parents. When making comparisons between countries, differences in definitions should be taken into account. Foreign-born persons may include immigrants (legal or undocumented), refugees, asylum seekers, migrant workers, students, people who migrate for family reunion, and other visitors. For the purposes of this chapter, the definitions employed by Rieder et al. will be used (3). In this classification system, an ‘‘immigrant’’ is defined as a foreign-born person legally admitted to settle in a host country. A ‘‘refugee’’ is defined as a person who meets the refugee definition of the 1951 Convention related to the Status of Refugees and its 1967 Protocol or other relevant regional instruments. An ‘‘asylum seeker’’ is defined as a person wishing to be admitted to a country as a refugee and awaiting decision on his or her application for refugee status under relevant international instruments. A ‘‘migrant worker’’ is defined as a person who is to be, is, or has been engaged in a remunerative activity in a state of which he or she is not a national. The term ‘‘indigenous’’ will generally refer to the native-born population of the country. However, some countries such as Canada and Australia further classify the native-born population into aboriginal and nonaboriginal populations because the TB prevalence among the two may be quite different. Traditionally, TB among migrants is discussed with reference to people moving to another country. More recently, the challenge of TB control among internally displaced persons has been recognized. II. History of Migration of TB TB has been with mankind all through its existence. This was shown by the finding of Potts’s disease in an Egyptian mummy (4). More recently, the finding of a TB primary complex in a Peruvian, whose mummified remains where exhumed in 1990, demonstrated that TB existed in the Americas before Columbus (5). Of the Peruvians it is less clear, but the Egyptians were a seagoing nation, as Thor Heyerdal proved (6). It is therefore very likely that as humans traveled around the world, they carried the bacille with them (7). In the early 1600s, the incidence of TB in Western Europe increased sharply, probably due to industrialization and its concomitant urbanization and overcrowding of households, and it peaked in the 18th and 19th century (8,9). Beginning in the 18th century and increasing steadily through the

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19th century, there was a massive out-migration of the population of Western Europe to the Americas, Africa, and Asia (10). As a result, many of the migrants have carried the bacille to the New World, where rates peaked 50 to 80 years later in the white (former European) people, and to central Africa and Southeast Asia, where rates peaked some 100 years later (7). Most of these populations had no prior exposure to TB and so were highly susceptible, which resulted in devastating epidemics (11). More recently in the mid-20th century, the Inuit Eskimos of Northern Canada (12) and the natives of the highlands of Papua New Guinea have become affected (13). Migration patterns have changed. Migration in the past 50 years has been predominantly from Africa, Asia, and Latin America toward Western Europe and North America. Israel is exceptional in having high immigration rates from the former Soviet Union and Ethiopia (14,15). In 1990, the International Organization for Migration (IOM) estimated the total number of migrants to be close to 120 million or 2% of the world population (10). As was often the case when populations were threatened by contagious diseases, authorities developed a number of interventions to protect their subjects, either by putting travelers (migrants) into quarantine before allowing them to enter (16–18), or by removing diseased persons from the community as was done with leprosy patients who were sent to leprosaria (19). Numerous historical studies have demonstrated the tendencies of societies to associate dread diseases with foreigners. During the late 19th and early 20th centuries, American East Coast officials associated various contagious diseases with immigrants, and fought to limit their entry into the country. Immigrants (Mexicans) were seen as agents of the disease rather than its victims and this called for tighter border control (20). Abel showed that prohibition of entry was motivated not only by public health considerations but also by economic arguments (20). The resulting restrictive laws sent many TB patients into hiding. TB control in migrants therefore has to balance between protection of the native population against importation of the disease and avoidance of stigmatization of those coming from a high-incidence area. ‘‘Appalled and astounded’’ at the consequences that [immigration to Boston] had already produced [Lemuel], Shattuck concluded [in 1850] that it was the immigrants—the poor and unwanted from England and Ireland—who were primarily responsible for bringing disease and impoverishment to an otherwise predominantly healthy and productive native stock: ‘‘Our own native inhabitants, who mingle with these recipients of their bounty, often themselves become contaminated with diseases, and sicken and die; and the physical and moral power of living is depreciated, and the healthy social and moral character we once enjoyed is liable to be forever lost (15).’’ Barbara Gutmann Rosenkrantz, Public Health and the State (21)

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Today, countries where TB was once rare now account for the vast majority of the world’s TB cases, whereas countries that once had a high prevalence of TB now have a low prevalence. Furthermore, the same factors of overcrowding and urbanization, which contributed to the spread of TB in Europe in the past, continue to play an important role in the spread of TB in the developing world (22). III. Epidemiology A. Current Situation and Trend

In many industrialized countries, TB among the foreign-born accounts for a substantial proportion of the total number of patients, ranging from less than 10% in Finland and Japan to over 80% in Israel and Australia (Table 1). In the 32 countries of Western Europe, as defined by Euro-TB, 29% of patients in 2002 were foreign-born, reaching 40% or more in 10 countries.

Table 1 Definition of Foreign-Born and Proportion of Foreign-Born Among Tuberculosis Patients for Selected Countries Country (data 2002 unless mentioned otherwise) North America United States (23) Canada (24) (Western) Europe (1) Austria Belgium Denmark Finland France Germany Iceland Netherlands Norway Slovenia Sweden Switzerland United Kingdom Israel (14,15) Asia/Pacific Australia (25) Japan (26) New Zealand 2001 (27) a

Definition of foreign-borna

% of foreign-born among all patients

COB COB

51 67

COC COC COB COB COC COC COB COC COB COB COB COB COB COB

28 50 61 9 41 38 38 62 76 22 72 61 55 84

COB COC Ethnicity

80 3 60

COB, country of birth; COC, country of citizenship ¼ nationality.

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In 16 countries with detailed data, the proportion of foreign-born patients increased from 29% in 1996 to 36% in 2002 (1). Often rates in migrants remain the same, whereas rates in the local population decrease (Table 2) (1,28–30). The absolute number of foreign-born patients remained stable during 1998 to 2002, while the absolute number of patients among nationals in this period decreased by an average 7%. Among the foreign-born, 39% were from Africa, 28% from Asia, and 25% from other countries within the World Health Organization (WHO) European region (1). A similar pattern was seen in the United States, where during 1993 and 2002, the proportion of foreign-born patients increased from 30% to 51% (23). Increased migration from high- to low-prevalence countries has contributed substantially to halt the decline of TB incidence and in some cases to increase TB rates in many low-prevalence countries. In England and Wales, TB notification increased between 1988 and 1998. Although the rates declined among the white population and remained stable in those coming from the Indian subcontinent, it increased in all other ethnic groups (31). Also in mid-prevalence countries such as Brazil, higher rates are reported among immigrants (32). It is expected that with the current level of migration, the proportion of TB patients that is foreign-born will continue to increase and prevent elimination of TB in low-incidence countries, as was shown by a modeling study in the Netherlands (33). Figure 1A shows trends in the number of foreign-born and native-born TB patients for the United States, the Netherlands, Australia, and Canada. Figure 1B shows

Table 2 Incidence of Tuberculosis Among Foreign-Born and Native-Born for Selected Countries Country (data 2002 unless mentioned otherwise)a

Incidence rate foreign-bornb

United States Canadac (Western) Europed Australiae Japan New Zealand 1995–2001f

23.1 19.4 55.0 20.2 39.8 91.8

a

Incidence rate native-bornb 2.9 1.0–23.3 5.4 1.1–8.5 22.8 2.6–30.9

Crude rate ratio FB:NB 8.0 1–19 10.1 2–18 1.7 3–35

Sources as in Table 1. Rates are per 100,000 population. c 1.0/100,000 in nonaboriginal, 23.3/100,000 in aboriginal. d Western European countries that could provide these data: Austria, Belgium, Denmark, Finland, France, Germany, Iceland, Netherlands, Norway, Slovenia, Sweden, Switzerland, and United Kingdom. e 1.1/100,000 in nonindigenous; 8.5/100,000 in indigenous. f 2.6/100,000 among European ethnicity, 13.3/100,000 among Maori, and 30.9/100,000 among Pacific ethnicity. Abbreviations: FB, foreign-born; NB, native-born. b

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(A)

Number of cases foreign born

10,000

USA Canada Netherlands Australia

1000

100 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002

Year

(B)

Percentage of cases foreign born

90 80 70 60 Australia Canada Netherlands USA

50 40 30 20 10 0 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002

year

Figure 1 Trends in (A) number and (B) percentage of TB patients among foreignborn persons for selected countries. (Foreign-born is defined by country of birth except for the Netherlands where it is defined by country of citizenship.) Source: From Refs. 23–25 and 30. Courtesy of Dr. Melissa Phypers, Public Health Agency of Canada, Ontario, Canada.

the percentage of foreign-born patients in the four countries, and Figure 2 illustrates trends in total rates as well as the rates among the foreign-born and indigenous populations in these four countries. The increase in proportion of foreign-born cases is due partly to an increase in absolute numbers of immigrants, and partly to a decrease in incidence rates among the native-born.

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Figure 2 (Continued on next page) Tuberculosis notification rates by origin for selected countries. (A) Netherlands. (B) United States. (C) Canada. (D) Australia. (Foreign-born is defined by country of birth except for the Netherlands where it is defined by country of citizenship.) Source: From Refs. 23–25 and 30. Courtesy of Dr. Paul Roche, Australian Government Department of Health and Aging, Canbeera, ACT, Australia, and Dr. Melissa Phypers Public Health Agency of Canada, Ontario, Canada.

In the United States, the increase in TB incidence in the late 1980s and early 1990s was attributed largely to immigration (Fig. 2A). The decrease in TB incidence in the late 1990s was stronger in foreign-born patients than in U.S.-born patients. In the Netherlands, due to the strict immigration policy,

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(Continued from previous page)

the number of foreign-born TB patients and therefore the total number of TB patients in recent years has declined (Fig. 2B). Interestingly, the incidence among the foreign-born also decreased (30). This may be due to a change in countries of origin of immigrants, and/or to less transmission among immigrants. A similar pattern is seen in Canada (Fig. 2C). In Australia, the incidence among foreign-born and native-born fluctuated, but the overall incidence remained stable, probably because the incidence among foreign- and native-born does not differ as much as in other countries (Fig. 2D). Israel

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Incidence per 100,000 population

14 12 10 8 6 4 2

19 7 19 4 7 19 5 7 19 6 7 19 7 7 19 8 7 19 9 8 19 0 8 19 1 8 19 2 8 19 3 8 19 4 8 19 5 8 19 6 8 19 7 8 19 8 8 19 9 9 19 0 9 19 1 9 19 2 9 19 3 9 19 4 9 19 5 9 19 6 9 19 7 9 19 8 9 20 9 0 20 0 0 20 1 0 20 2 03

0

Year

Figure 3 Incidence rate of active tuberculosis in Israel, 1974 to 2003. Source: From Ref. 14 and Courtesy of Dr. D. Chemtob, Department of TB and AIDS, Public Health Services, Ministry of Health, Jerusalem, Israel.

shows a clear effect of migration on notification: first a peak in notifications related to Ethiopian immigrants in 1985, and then a second peak in 1991 and thereafter related to a large number of immigrants from the former Soviet Union. Since then, the notified incidence never returned to the level achieved in the late 1980s (Fig. 3) (14,15; Chemtob D, personal communication, 2004). Children

Even in children, an effect of migration on TB notification can be demonstrated. In Brussels, most TB cases among children were immigrants, although the total TB rate among children was shown to decrease between 1978 and 1988 (34). In the United Kingdom, children from the Indian subcontinent, also when born in the United Kingdom, have a higher incidence rate than the white ethnic group (35). Nondocumented Immigrants

Nondocumented immigrants are a difficult group to reach, and traditionally very little data are available. In the Netherlands, 5% of TB patients are reported to be in the country illegally, but the true proportion may be higher (36). In California, 20% of all patients were found to be undocumented; they were four times more likely to delay care seeking for more than two months than documented immigrants (37). In Texas, the proportion of nondocumented immigrants among foreign-born TB patients was 25% (38). In Italy, the prevalence of TB among undocumented immigrants who were seeking medical care was 650/100,000 (39). Being nondocumented may thus obstruct access to care for a group at high risk of TB.

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The high incidence of TB among immigrants after settling in low-incidence countries can be attributed to three processes: (i) reactivation of old TB infections, which is related to country of origin, age at migration, sociodemographic characteristics, and duration of stay in the new country; (ii) recent TB infection or reinfection due to periodic travel to the home country; and (iii) recent TB infection or reinfection within the new country, which is related to social mixing. Other factors include access to care, localization (and thus infectiousness) of the disease, drug resistance, and immune incompetence. Country of Origin

The country of origin of the foreign-born population determines what proportion of migrants has been infected in the past and thus their TB incidence in the new country. The destination to which individuals migrate depends on several factors: proximity, their country’s previous colonial ties, family, work, and ease of immigration. Countries have immigrants from different nationalities. In Canada, these are mostly people from the Latin America, Asia, and Africa (10), whereas in Australia immigrants originate mainly from Asia (40). In the Netherlands, immigrants originate from Morocco, Turkey, Eastern Europe, and Africa (33), whereas the United Kingdom has many immigrants from its Commonwealth, mainly from the Indian subcontinent (31,35). In the United States, most immigrants in the last decade were from Mexico, the Philippines, Vietnam, India, and China (41,42). Although TB rates among migrants in Canada and Australia could be predicted from the incidence in the country of origin of the migrants, the WHO estimated incidence was a better predictor than the official case notifications in those countries (43,44). Also in U.K. cities, country of origin of the population was the single best predictor of TB incidence (45). In countries with many immigrants from Africa, the incidence among foreign-born persons has been increasing, partly due to an increase of case rates related to HIV infection in their countries of origin (31). In several European countries and in Canada, Somalians have the highest TB incidence among foreign-born persons (46–50). This is probably related to the civil war in Somalia that resulted in a breakdown of the health system and caused almost half the population to seek refuge elsewhere. The comparative sizes of refugee and nonrefugee migrant populations in lowincidence countries are such that the greatest burden of migration-related TB disease will not arrive with refugee populations but rather with other immigrant groups (51). When there is a large difference in incidence between the country of origin and the host country, the difference in incidence between native-born and foreign-born population increases. Even within high-incidence countries, it was shown that migrants and refugees had a higher TB incidence than the local population, e.g., in India (52). In the United States, with more immigrants from Latin American countries that have a moderate

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incidence, the difference in incidence is smaller than in Australia, where most immigrants are from Asian countries with a high incidence (40,41). A small difference is also observed in Japan, whose immigrant population is from countries with rates similar to its own (53). Countries with large foreign-born populations, particularly those that were born in countries with a high TB prevalence, tend to have a higher proportion of foreign-born TB patients. In most countries where the foreign-born population is more than 10%, the proportion of TB patients among the foreign-born is more than 50% of all TB patients (30,42). This can also be shown within cities such as Cologne, Germany (54). Age

Age at migration determines the risk of TB: persons who migrated to a lowprevalence country at a young age tend to have rates more comparable to the host country than persons who migrated later in life (55,56). The latter had a longer exposure to the high risk of TB infection in their own country and therefore have a higher risk of latent TB infection and consequently of breakdown to an active disease. In most low-prevalence countries, foreign-born patients tend to be younger than native-born patients. In 13 Western European countries, age-specific notification rates in nationals in 2002 increased progressively with age, and were highest over 64 years (12/100,000), whereas in foreigners rates peaked in the age group 25 to 34 years (85 per 100,000), decreased in middle age and then increased again in the elderly (Fig. 4) (1). This distribution is both a reflection of the age structure of the immigrant population, because recent migrants are often young adults, and the age-specific distribution of TB in the country of origin, where TB is usually highest among young adults. Sociodemographic Factors

The TB incidence in immigrants reflects the socioeconomic status of the migrants in the country of origin. Those who migrate for study or high-level jobs have a lower incidence than those who migrate as asylum seekers, or those in search for a job or family reunion. The socioeconomic situation of migrants in the host country also plays a role. The level of unemployment in Australia was a significant predictor of TB in migrant groups (44). Unfavorable living conditions in the host country contributed to higher TB incidence among Senegalese immigrants in Italy (57). In the United Kingdom and Canada, socioeconomic circumstances were independent risk factors for TB, after correction for ethnicity or country of birth (49,58). But other studies showed that TB incidence in the country of origin is a more important predictor of TB in the new country than socioeconomic circumstances (44,45,59). In New Jersey, United States, although 47% of patients were foreign-born, the foreign-born patients were even found to live in better socioeconomic circumstances than native-born patients (60).

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Figure 4 Tuberculosis notification rates by age group, sex, and geographic origin, EU and Western Europe (countries providing population estimates by geographic origin: Austria, Belgium, Denmark, Finland, France, Germany, Iceland, Netherlands, Norway, Slovenia, Sweden, Switzerland, and United Kingdom), 2002. Abbreviation: EU, European Union. Source: From Ref. 1.

Time in New Country

The risk of TB tends to decline with the number of years after immigration, because the rate of breakdown of a disease is highest the first two years after infection and the risk of TB infection in the new country is low. The risk of becoming infected and the risk of breakdown to disease may be higher just before and just after immigration, especially for asylum seekers, due to stressful and crowded migration circumstances (7). Many studies indeed show a decline of notification over time after migration, but in most cases, the rates remain much higher than those for the indigenous population (10,31,56,61–65). The incidence seems to be highest in the first year after arrival, but this may be attributable to screening procedures at entry or to increased access to health care after entry, both of which actually reflect prevalence rather than incidence (56,66). These cases may be due to old untreated TB, as was shown in a study among asylum seekers, where the incidence after entry was highest among those with abnormal chest X-rays at entry (67). Older studies have shown that people with fibrotic lesions have a high risk of breakdown (68), and it has been recommended that they should be treated (69).

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In the first decades after labor migration started, TB among foreignborn patients was mostly detected in the first five years after migration (70,71). More recent studies in the Netherlands and Denmark show that TB incidence remains high, also more than five years after migration (46,48). This may be attributable to aging of the immigrant population. Travel to the Country of Origin

Studies in the United Kingdom, United States, and Denmark show some evidence that part of the increase in TB disease and latent TB infections among foreigners is attributable to travel to the home country (72–75). In California, children who had traveled in the 12 months preceding a tuberculin skin test were significantly more likely to be tuberculin skin test positive than children who had not (75). In Denmark, children for whom no index case could be identified often had visited their country of birth in the year before diagnosis (74,76). In the Netherlands, it was shown that the risk of TB infection in long-term travelers to high-endemic countries is of similar magnitude to the average risk of infection of the local population of those countries (77). It is likely that the same is true for immigrants who visit their home country. One may conclude that travel to the country of origin contributes to an increased proportion of TB among foreigners, but no proper prospective studies have been done to determine its magnitude. Access to Care

Many immigrants are faced with obstacles to seeking care and completing treatment, which may predispose them to a higher risk of a poor outcome. Newly arrived immigrants often live in crowded and poor conditions. Decreased access to care as a result of cultural, linguistic and socioeconomic barriers, anti-immigrant sentiments and legislation, and fear of deportation could potentially delay diagnosis and treatment (7,37,78). A study among foreign-born Hispanic Mexicans along the U.S.–Mexican border demonstrated a four-month median delay in seeking care after the onset of symptoms (79). In the Netherlands, diagnostic delay is shorter among immigrant cases than among the native-born population, probably because physicians are aware of an increased risk of TB in patients from high-prevalence countries (30). Disease Localization

Extrapulmonary TB is relatively more common among immigrants than among the indigenous populations (80). It mirrors the clinical pattern in the country of origin, having a predominance of young people with a high incidence of extrapulmonary TB (81). In southern Alberta, Canada, during a five-year period, 61% of TB disease in Asian immigrants was extrapulmonary (82). In the United Kingdom, persons from the Indian subcontinent over three decades consistently were reported to have a higher rate of extrapulmonary TB (35,83,84). The frequency of extrapulmonary TB among immigrants compared to the indigenous population was 32% versus 20% in Western Europe and 21% versus 16% in the United States (1,85). In East

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London, TB was diagnosed almost exclusively in non-Caucasian patients (89%) and there was a high percentage of extrapulmonary TB (57%), including four cases of tuberculous meningitis and five cases of osteomyelitis. Another observation was that 70% of these patients with extrapulmonary TB had normal chest X-rays (86). Lymphadenitis is the most common form of localized extrapulmonary TB in the foreign-born. In Minnesota, Somalis with TB show frequent extrapulmonary involvement; lymphadenopathy was present in 46% of cases [in the absence of AIDS (47)]. In Great Britain, lymphadenitis was the most common localization among immigrants from the Indian subcontinent (73). In British Colombia, lymphadenitis accounted for 44% of TB patients among persons born in the Philippines, but only for 10% for those born in Japan (and 6% among the indigenous population) (87). In Denmark, among the notified cases in 2003, 42% of extrapulmonary TB was found among immigrants (16% in Danes), of which 63% was lymphadenitis (14% was localized in the pleura and 10% in the bones) (88). It appears that lymphadenitis is easier to detect, as in Southern Alberta the mean period between immigration and diagnosis was 11.2 years, but the time to detection was shortest for patients with superficial lymph node disease: 7.6 years after arrival (82). Drug Resistance

Global TB control efforts are seriously threatened by increasing rates of drug-resistant TB (89). In southern Israel, the impact of immigration on TB disease, including drug-resistant strains, was assessed. Israeli immigrants from the former Soviet Union disproportionately contribute to the prevalence of drug resistance in this community; 50% of TB cases in this immigrant population had isolates that were resistant to at least one of the standard five drugs, and almost 17% were resistant to at least isoniazid and rifampicin [multidrug-resistant TB (MDR-TB)]. These rates are 22% and 8%, respectively, in a comparison population, including those born in Israel and those who immigrated prior to 1980 (90). In Madrid, Spain, during the period 1995–2001, the relative proportion of isolates from foreign-born patients increased from 4.4% to 24.2%, but no differences in resistance to any first-line anti-TB drugs were detected between immigrants and Spanish-born patients (91). Between 1993 and 1998, among immigrants to the United States, the rate of primary resistance to isoniazid was 11.6% and to both isoniazid and rifampicin it was 1.7% (41). In Minnesota, Somalis have a high incidence of active disease, but multidrug resistance was present in only 3.4% of cases (47). There is a clear association between the level of drug resistance and immigrant ethnic groups. This association may be attributable to differences in immigrant populations, including socioeconomic status, geographical origin, or differences in prearrival TB-screening practices. Thus, because the epidemiology of drug-resistant TB is local, drug resistance surveillance of foreign-born populations in each community is crucial. Although caution

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is needed to avoid possible misuse of ethnic information on patients with TB, this information can help guide treatment and prevention interventions. The evaluation of local data on drug resistance should lead to TB-treatment policy development and planning for each community to prevent the dissemination of resistant strains (92). This is confirmed by the study in East London, where hospital-based surveillance and promoting awareness of local differences were found to be essential in preventing delayed diagnosis, inappropriate management, and poor clinical outcome (86). Immune Incompetence Tuberculosis/HIV

Untreated HIV infection leads to progressive immunodeficiency and increased susceptibility to infections, including TB. HIV is driving the TB epidemic in many countries, especially in sub-Saharan Africa and increasingly in Asia, South America, and Eastern Europe (93). Early in the HIV epidemic, despite the increase in immigrants from countries with a large TB and HIV problem, in a study in the United Kingdom in the period 1991–1994, no concomitant HIV infection was found in any patient with TB (94). In 1995, however, the Centers for Disease Control and Prevention (CDC) reported that in the United States of three counties surveyed, half of the TB patients were foreign-born and a high proportion (26%) was coinfected with HIV (95). In contrast, both in Italy and in Switzerland, the HIV prevalence seemed to be lower among the immigrant TB patients than among the local TB population (96,97). A similar phenomenon was reported from Paris, France, where, as in other big cities in the world, the increase in TB cases is mainly due to immigrants, but in contrast, HIV coinfection only accounted for a small and decreasing part of cases (98). However, data from the U.K. Health Protection Agency show that immigrant-associated HIV infection in the United Kingdom is increasing and that it is mostly acquired abroad (99). It is very likely that the same pattern occurs in other countries. In the Netherlands, although the proportion of TB patients that were HIV-infected remained stable at around 4% during 1993 and 2001, among immigrants from sub-Saharan Africa, the proportion of TB/HIV increased (Haar K, personal communication). Other Immune-Compromising Conditions

Individual risk factors that compromise the immunity of the body can contribute to active TB disease. A cohort of patients requiring renal dialysis, who had migrated to the United Kingdom from TB-endemic countries, were found to have extremely high rates of TB (1187 cases per 100,000 per year), partly associated with end-stage diabetic renal disease (100). Among immigrants from the Indian subcontinent, Hindu Asians were found to have a significantly increased risk for TB compared with Muslim Asians. A vegetarian diet turned out to be an independent risk factor for TB in immigrant Asians. The mechanism is unexplained. However,

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vitamin-D deficiency, common among vegetarian Asians in south London, is known to affect immunological competence (101). IV. Contribution of Migration to Transmission in the Host Country A. Transmission of TB from Foreign-Born to Native-Born Populations

The risk of TB transmission from immigrants to the local population is small. Two factors are relevant for transmission: the interaction between both groups, which is mostly limited, and the relatively more frequent and less transmissible extrapulmonary disease localization in immigrants. The main evidence for the limited risk of transmission is the continued decrease of TB incidence among the native-born populations in low-incidence countries. In Croatia, the natural decline in incidence did not change despite the high TB rates among refugees and displaced persons who comprised 10% of the population during the war period 1992–1994 (102). A tuberculin skin test survey in Canada failed to demonstrate a relationship between skin test positivity and contact with the foreign-born populations (103). In the United States, the proportion of close contacts who are tuberculin skin test positive is higher than among native-born index cases than among foreign-born index cases (104). This may indicate higher transmission among immigrants, but also that a high proportion of contacts had been infected in the past. Additional evidence comes from studies employing DNA fingerprints of Mycobacterium tuberculosis using restriction fragment length polymorphism. Clustered fingerprints are usually interpreted as attributable to recent transmission, whereas unique fingerprints are considered to be attributable to reactions of old infections or transmission from a strain outside the study area. In the Netherlands, 17% of cases among Dutch TB patients were attributable to recent transmission from a non-Dutch source (105). In contrast, in San Francisco, the country of origin was less important than the ethnic group: U.S.-born TB patients generated more secondary cases than immigrants and young blacks appear to be a risk group for transmission (106,107). In the same city, only 2 of the 115 U.S.-born patients were infected by a foreign-born patient (108). In Denmark, only 0.9% of all Danish patients were most likely infected by Somalis (46,109). In most low-incidence countries, foreign-born patients had less clustered strains than native-born patients (28,110–115). This is often interpreted as reflecting the development of TB in foreign-born patients due to reactivation of a remote infection acquired in the country of origin. However, a large proportion of unique DNA fingerprints among foreigners do not necessarily mean that the incidence of recently transmitted disease is low, only that they are at greater risk of reactivated disease (116). Some smaller and more recent studies showed a higher risk of clustering among immigrants (117–120). The longer the stay in the country, the more often

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immigrants show clustered DNA fingerprints of their TB strains (96,121). In London, persons born in the United Kingdom and the black Caribbean ethnic group born outside the United Kingdom had an increased risk of clustering, as compared to persons born elsewhere (122). The authors concluded that TB in London was largely caused by reactivation of a remote infection among those born in the United Kingdom, or importation of TB infection by recent immigrants. In the United States, the incidence rate of both clustered and nonclustered cases among foreign-born persons remained constant between 1991 and 1997, while the incidence rates of both clustered and nonclustered cases among native-born persons decreased in the same period (123). This indicates limited transmission from the foreign-born to the native-born population. Interestingly, Asian ethnicity was associated with a decreased odds ratio of clustering both in Texas (114) and in San Francisco (124), or being first case in a cluster in the Netherlands (125). This suggests even less social mixing as with other immigrant groups or less transmissible strains. In Germany, asylum seekers more often showed clustering than foreign-born patients who were not asylum seekers. This may indicate that asylum seekers more often have TB attributable to recent transmission (126). B. Transmission of TB Within Immigrant Groups

It is likely that transmission takes places within foreign-born populations. Increasing rates of pediatric TB in the United States were partly related to transmission from household contacts to U.S.-born children of immigrants (127). In the United Kingdom, children from the Indian subcontinent, also when born in the United Kingdom, have a higher incidence rate than the white ethnic group (35). It is often unclear if such a transmission has taken place before or after migration. Even DNA fingerprint studies can hardly elucidate this question, especially when the variety of strains in the country of origin and/or new country is small. Increased transmission among immigrant groups within the Netherlands is largely attributable to the relatively young age of immigrant source cases (128). In Hamburg, Germany, recent transmission within foreign-born populations does not play an important role (126). Studies comparing molecular links with epidemiologically linked case pairs give more insight. Epidemiologically linked case pairs in the United States were often not confirmed by DNA fingerprints when the secondary case was foreign-born, indicating that the epidemiological link was not a causal link, and TB among foreign-born persons is more often due to remote infections (45,129). In the Netherlands, epidemiologically linked DNA fingerprint–clustered cases were more frequently documented among Dutch than among non-Dutch patients (130,131). V. Interventions In 1994, a European Task Force for TB control and international migration recommended that: (i) surveillance of TB patients needs to be able to

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identify risk groups, (ii) screening among immigrants needs to be considered for both active disease and latent TB infection, (iii) health services should be culturally appropriate, (iv) comprehensive curative and preventive services should be provided, and that (v) evaluation of efficacy and efficiency of screening procedures should be ongoing (3). A similar series of recommendations for use by state and local health departments have been developed in the United States (132). Many low-incidence countries now include country of birth or citizenship in their surveillance system, and have included outcome monitoring to measure the impact of interventions (1). In this section, we describe the strategies currently being used by low-prevalence countries for screening for TB disease and latent TB infection, and present the available data from the yield of such screening. Some of the obstacles encountered in the provision of curative and preventive services in foreign-born persons are identified. A. Screening

In low-prevalence countries, three screening strategies are employed, either alone or in combination. These strategies include prearrival screening, postarrival screening, and screening of foreign-born populations for other purposes (e.g., school based or preemployment screening). Postarrival screening can take place at the port of entry or at a later stage. In most countries, screening focuses on foreign-born persons who apply for immigration or who have recently arrived. Screening is carried out for two reasons: TB rates are highest among recent arrivals and the application for immigration or long-term residence provides a unique opportunity for screening and may represent one of the few reliable points of contact with new arrivals. The populations screened and the methods used vary considerably (Table 3). Most countries limit their screening to persons intending to become long-term visitors. In Canada, every immigrant who intends to stay for more than six months has to undergo screening, whereas in the United States and the Netherlands this period is three months. Such intervals are needed because it is impossible to screen the large number of persons who enter low-incidence countries each year. Screening Prearrival

Some countries, including United States, Canada, Australia, and New Zealand, require pre-entry screening. Prospective immigrants found with active infectious TB first need to complete their TB treatment or at least be smear negative before they will be allowed to enter the country of destination (40,132,134–140). Current Methods

Prearrival screening only targets disease, not latent TB infection. The method of prearrival screening is a chest X-ray. When the X-ray suggests active TB, sputum samples are taken for smear (and in the case of Canada, also for culture). When TB is confirmed, treatment has to be taken, and

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Table 3 TB Screening Programs for Immigrants and Refugees for Selected Countriesa

Country North America Canada (85) United States (85) European Region Austria (3,133) Belgium (3,99,133) Czech Republic (3,99,133) Denmark (3,99,133) Estonia (133) Finland (3,133) France (3,99) Germany (3,85) Greece (3,99) Hungary (3,133) Iceland (3,99,133) Latvia (99,133) Malta (99,133) N. Ireland (3,133) Netherlands (3,99,133) Norway (3,99,133) Portugal (3,99,133) Russian Fed. (133) Slovenia (3,133) Sweden (3,133) Switzerland (3,99,133) Ukraine (133)

Time of screeningb

Target groupc

Methods usedd

Treatment for latent TB infection in immigrantse

P, E

Stay > 6 mo All except A

CXR

Y

B

Y

E E

A, FW A, FW

B B

Y Y

N Y

E, R

A

B

N

Y

E

All

X

N

N

E A E E E, R E

A, FW All A, FW A

X X X B B B

C C C Y

N N N N N N

A, R

All

B

Y

Y

R R E

A A A

B B T

Y Y < 34 yr

N Y N

E, R

All

B

C

Y

E, R

All

B

Y

N

E, R

A

B

C

N

P, E

A E, R A E, R A

X

A, FW All

B B B B

Systematic collection and reportinge Y

N

Y Y

N Y Y (Continued )

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Table 3 TB Screening Programs for Immigrants and Refugees for Selected Countriesa (Continued )

Country United Kingdom (3,99,133) Israel (3,88,133) Australia (85) New Zealand (85)

Time of screeningb

Target groupc

Methods usedd

Treatment for latent TB infection in immigrantse

E

All

B

C

N

E P, E P, R

All All All

B X X

Y N

Y Y N

Systematic collection and reportinge

Note: Different references can give contradictory information on screening policies in the same country. This may reflect a change in policy over time, different policies within the same countries, and differences in interpretation of the questions. a Additional information: countries in the European region that indicated to screen only those that ask for a residence permit: Azerbaijan, Belarus, and Slovakia. Countries in the European region that have no active screening: Albania, Armenia, Bosnia Herzegovina, Bulgaria, Croatia, Italy, Kyrgyzstan, Macedonia, Moldova, Poland, Romania, Spain, Turkey, Uzbekistan, and Yugoslavia (133). b E ¼ at entrance (within two weeks); A ¼ afterward; R ¼ when receiving residence permit, P ¼ prearrival. c A ¼ asylum seekers including refugees; FW ¼ foreign workers; All ¼ all entering foreigners from countries with high and/or middle incidence (selection of countries differs). d X ¼ chest X-ray; T ¼ tuberculin skin test; B ¼ both (often this means tuberculin skin test only in children). e Y ¼ yes; C ¼ only to children; N ¼ no.

repeated negative smears have to be shown before entry is allowed when the pre-entry X-ray shows abnormalities consistent with active TB, but the sputum samples are negative, or when the chest X-ray abnormalities are consistent with inactive TB, the immigrant is allowed to enter. In the United States, these two groups of immigrants are classified as B notifications that are required to report to a local health department for the evaluation of the TB disease. In the case of Australia and Canada, immigrants with a history of and/or chest X-ray abnormalities consistent with past TB need to sign a declaration before arrival (a so-called health undertaking) that they will visit a health department within four weeks after arrival. The advantages of pre-arrival screening include prompt identification and treatment of infectious cases, the possibility of contact tracing among contacts in the home country, and a decrease of the burden of screening for the health infrastructure of the host country. The disadvantages include the difficulty to provide adequate supervision at the screening sites, varying diagnostic and laboratory capabilities, the potential falsification of

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information, and the possible change in TB status during the interval between the medical examination and the arrival in the country of destination. Yield of Prearrival Screening

The yield of screening in terms of cases of active TB detected varies by country of origin of the immigrant, the screening criteria used, and the aggressiveness of follow-up. In 1996, 1.4% of the 421,405 newly arrived immigrants in the United States were considered to have radiographs compatible with active TB and 2.1% with inactive TB (85). However, these percentages differed widely by country of origin. The number of cases that are smear positive and undergo partial or complete treatment prior to arrival is small. Among those whose radiographs are compatible with suspect-active or -inactive TB upon follow-up, 3.3% to 14%, and 0.4% to 3.8%, respectively, were diagnosed as having TB on laboratory and or clinical grounds (141). (The range indicates differences between states, which can partly be explained by the use of different definitions.) Overall, B notifications accounted for 38% of all foreign-born patients in California within one year after arrival (141). But in Los Angeles, fewer than 5% of TB patients from Mexico and other Central American countries, who had been in the United States less than a year at the time of diagnosis, had been identified through prearrival screening (142). Thus the system of clinical evaluation of B notifications does not identify the majority of recently arrived cases (40,143). The reasons include temporary visitors who do not need screening, nondocumented entry, patients missed by the pre-entry screening, or persons developing TB between pre-entry and postentry screening. Compliance with screening in Australia was high although it differed between regions (40,144). Among immigrants who had a prearrival history of TB, or chest X-ray abnormalities indicating past TB, 0.5% had active TB postarrival (40). Factors influencing the outcome of screening were unnecessary health undertakings due to low quality of X rays or other disease conditions, and default from follow-up. Screening Postarrival Current Methods

Most Western European countries screen foreign-born populations, including refugees and other immigrants; this is usually mandatory and after arrival (3,61,145,146). A recent survey among 51 Eastern and Western European countries, of whom 26 responded, showed that of 13 countries, predominantly from Western Europe, three conducted TB screening at ports of entry and 10 in other centers (99). All programs used chest X-rays to find active disease. Often a tuberculin skin test is used in children as an additional screening tool to find latent TB infection. No two countries took the same specific clinical approach. The United States, Canada, and Australia perform postarrival screening for persons who have entered the country on entry visa categories other

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than for residence permit or who enter as asylum seekers (40,135,136,140, 141,147,148). Qatar has a screening program using chest X-rays at entry for all expatriates (149). Canada’s and Australia’s postarrival screening methods include a medical history and examination, combined with a chest radiograph to find active disease (10,40,135,136,147,148). Screening policies are often carried out without coercion (138). Compliance with screening is ensured in several ways. In most of Western European countries and Israel, immigrants must undergo screening for active disease to obtain permission to stay, to obtain access to health care and social benefits, and/or to obtain permission to work. Asylum seekers are often screened at the centers where they stay, sometimes with mobile X-ray units (67,150,151). In the United Kingdom, immigrants are screened at the port of entry (152–154). But this covers only half the immigrants, because many immigrants do not arrive through ports with operative chest X-ray machines, and follow-up at the address given at entry is often unsuccessful because it may only be a temporary address (152,155,156). The crucial part of all methods of screening is the referral for further investigation or treatment at local centers near the place of residence (40,132,157). Screening for latent TB infection by a tuberculin skin test is often limited to children. Some countries, such as the United States, Australia, and Canada, also screen some adults for latent TB infection (132,134,148, 158–160). In the United States, these are persons who apply for permanent residence and have lived in the country for a number of years (134,143). In Canada, skin testing is limited to immigrants with a history of TB or contact with TB, or certain medical conditions (137,148). In Israel, immigrants younger than 18 years are screened and given treatment for latent TB infection if found to be skin test positive (14,15). The advantages of postarrival screening are better quality assurance of the examination process; a broader range of laboratory services (e.g., culture and susceptibility testing) resulting in a better diagnosis, and more focused and supervised treatment. Yield of Postarrival Screening

In Europe, the yield of postarrival screening for active disease is mostly in the range of 0.1% to 0.7%. In the Netherlands in 1994 to 1997, 0.2% of asylum seekers were found to have active TB at entry, the prevalence being higher among those coming from a country at war and among those with a history of imprisonment (67). In Switzerland in 1993, 0.3% of asylum seekers had active TB (150). The yield of chest X-ray screening at London’s Heathrow airport in 1990 was approximately 0.1% (155). Active case finding by visiting the new arrivals at their home has a much higher yield: regional data in England gave 0.6% active disease. A positive tuberculin skin test was found in 70% of immigrants and in 12% among children (156). In Hackney, United Kingdom, only 19% of the 1262 new entrants invited for screening at the hospital attended, and the prevalence of TB

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among these people was 1.5% (or 1546 per 100,000) (152). (These high rates are probably due to self-selection.) In Denmark, 14 of 1936 (0.7%) screened Vietnamese refugees had TB on arrival (61). In Belgium, the yield of screening 4794 asylum seekers for active disease at entry was at least 0.4% (161). In Israel, the yield of entry screening for active disease among Ethiopian immigrants was almost 1.9% (162). As many as 400,000 persons undergo postarrival screening in the United States each year (85), but limited data about the results are available. In an older study in Denver, among 7500 predominantly Mexicans evaluated, only five had TB (0.07%), whereas 42% had latent TB infection (145). In San Diego County, the yield of postarrival screening among 658 immigrants (including refugees) who were TB suspects in their countries of origin was 7% active TB patients and 76% persons with latent TB infection (148). The difference between the two studies is probably due to the difference in the immigrant population (total versus suspects). The Netherlands is the only country where the screening at entry is followed-up by a six monthly periodic screening for two years, also for those that have a normal chest X-ray at entry (125,163,164). But even with a sixmonth screening periodicity, almost half the foreign-born patients with pulmonary TB are detected in the interval between the screening rounds, probably because the preclinical detectable phase is highly variable. [The preclinical detectable phase is the phase in which a patient has no symptoms yet but can be detected with screening (165).] It is not clear what the efficacy of this follow-up screening is, although it seems to lead to less serious disease, to less hospitalizations, and to reduce the infectious period and therefore transmission (125,163). Limitations of Screening

Despite the number of people screened being very high, all screening programs will miss temporary visitors and nonlegal immigrants, which may constitute a large proportion of the foreign-born patients. For example, in Tarrant County, Texas, nonimmigrant visitors were found to constitute 40% of the foreign-born TB patients (38). Undocumented immigrants are the most difficult target group (3), but in Italy, it was shown that screening is even possible among undocumented immigrants (39). Screening for disease among the foreign-born will find only a small proportion to have active TB and therefore it has limited effectiveness (65,148,166). A large proportion of immigrants will have a latent TB infection at the time of entry and may develop disease only many years after arrival. It is estimated that about one-third of the world population is infected with TB, and this percentage is probably higher among the foreign-born from countries with a high incidence (167). These persons will not be found by screening with a chest X-ray but only by screening for latent TB infection. It may not always be ethical to force immigrants to undergo invasive diagnostic tests when their risk of TB is very low (168,169). Immigration policies may be subject to political changes, and are not always based on

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the incidence of disease in the country of origin. For example, as a result of the expansion of the European Union (EU), mandatory screening of immigrants from new EU member states is no longer allowed, while the incidence in some of these countries is higher than in other countries for which screening is mandatory. Entry screening for latent TB infection, followed by treatment for latent TB infection, may not be very effective (136,169). In the first place, there is no test for latent TB infection that can differentiate between recent and remote infection [although new serological tests will reduce the number of false-positive tuberculin skin test results that are related to bacille–Calmette–Gue´rin (BCG) vaccination and infection with mycobacteria other than TB]. Remote infection has a very small risk of breakdown to active TB (see other chapters 4 and 9). In this group, side effects of treatment for latent TB infection may not outweigh the benefits. This may be even more relevant in immigrants who have been infected with hepatitis B virus, and therefore have a higher risk of isoniazid toxicity (170,171). Secondly, the public health risk is limited because transmission to the local population is limited. Thirdly, an expanded health system is needed to ensure adherence to treatment for latent TB infection, for example, through directly observed preventive therapy (172). Furthermore, the currently available treatment regimens for latent TB infection cannot prevent the breakdown to disease from MDR strains. And lastly, treatment for latent TB infection for immigrants at entry does not prevent reinfection. Nonadherence to guidelines may be another limitation of screening. In the United States, it was shown that in 25% of applicants for permanent residence, the screening process was not executed according to guidelines; most frequently, the tuberculin skin test was omitted (173). More importantly, screening and treatment of active cases among migrants does little to reduce the incidence in the countries of origin. It is like mopping up water flowing from a tap without attempting to turn the tap off (10). For example, improved TB control measures in New York reduced drastically the number of TB patients among the U.S.-born population, but hardly caused a reduction in TB rates among foreign-born persons (174). Cost-Effectiveness of Screening

Several investigators have examined the cost-effectiveness of tuberculin skin test screening for TB (159). In the United States, an increasingly disproportionate burden of TB among the foreign-born population has led to calls for improvement of the detection and treatment of latent TB infection in new immigrants. A decision-analysis model, using a hypothetical cohort of all documented immigrants from developing countries entering the United States, was constructed (159). The model examined the efficacy and costeffectiveness of four strategies: no intervention, tuberculin skin testing followed by treatment with isoniazid, treatment with rifampicin, or treatment with rifampicin plus pyrazinamide for those with a positive test result. It was concluded that for these immigrants a strategy to detect and treat latent

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TB infection would lead to substantial health and economic benefits. The results were extensively debated (175,176). Several studies showed that entry screening for active TB can be costeffective (177,178). Screening for active disease by chest X-ray is much more cost-effective than screening for and treatment of latent TB infection, although the latter may be increased by improved adherence (159,177,179,180). Recommendations on Screening for TB in Low-Incidence Countries

As mentioned at the beginning of this chapter, groups to be screened must be selected based on epidemiological parameters. The sensitivity and specificity of the tests used should be taken into account. Screening must not be done unless it is followed by a certain action, which should be culturally acceptable. Access to screening should be made easy for immigrants, e.g., by performing it near the place of residence, preferably at the primary health-care level (40,135,152,157). When conducting screening, care should be taken to avoid stigmatization of those that are foreign-born. TB screening behaviors must be studied with culturally accepted and translated questionnaires (181,182). B. Contact Tracing Among Immigrants

Contact investigation provides an excellent opportunity to screen the foreignborn population with a high risk of active TB (104). The general approach in high-prevalence countries is not to start active case finding among contacts until a full course of adequate treatment can be assured for all patients detected. For immigrants, this condition usually is of no hindrance. Active case finding among contacts is cost-effective. In Canada, close contact investigation among immigrants resulted in a net savings of $815 for each prevalent case detected and treated and of $2186 for each future case prevented (178). However, screening for latent TB infection has a number of drawbacks. In case of a positive tuberculin skin test, it is difficult to differentiate a latent TB infection from a previous BCG vaccination, and most immigrants have been vaccinated at birth. Various countries deal with this in different ways. In the United States, previous BCG vaccination is ignored (132). In the Netherlands, until recently, people with a BCG vaccination were not tested for latent TB infection. Then there is the possibility of HIV infection and thus immune suppression in immigrants, which leads to a false-negative tuberculin skin test. Another challenge encountered in contact tracing among immigrants is the stigma of TB, preventing patients from naming their contacts (Chapter 19). C. Provision of Treatment and Preventive Services Treatment of TB

Cultural and linguistic differences put a challenge to treatment adherence in immigrants. During 1993 and 1996, the proportion of immigrants to the United States receiving some part of treatment under directly observed therapy increased from 27.3% to 59.1%, and approximately 70%

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completed therapy in 12 months (41), which is still far from the target of 85%. In Japan, despite the proportion of foreign-born among the total number of patients being only 1%, the average treatment completion rate in the period 1991–1993 among foreign-born patients was 51%, which was much lower than the national figure of 81% for the same years. Moreover the rate showed a deteriorating trend by year (183). Treatment of Latent TB Infection

Treatment adherence for latent TB infection among immigrants is often, but not always, less than among the local population. In Italy, in a multicentre, prospective, randomized, open-label study of isoniazid-preventive therapy for latent TB infection among close contacts of TB patients, Italians had a better completion rate than immigrants (184). The completion rate among undocumented immigrants was low. Supervised, clinic-based administration of treatment significantly reduced adherence. Alternative strategies to implement treatment of latent TB infection in undocumented immigrants are clearly required (172). In Los Angeles, treatment adherence for latent TB infection was higher among immigrant adolescents than U.S.-born adolescents, but factors other than immigrant status were shown to be more important (185). Highly integrated Mexicans were more likely to engage in TB prevention and control behavior than traditional Mexicans in the United States (186). A ‘‘cultural’’ case manager helped to improve adherence among immigrants (187). Immunization

BCG vaccination in many low-prevalence countries has never been part of the control strategy (United States and Netherlands) or has been discontinued (many countries in Western Europe). Yet, for immigrant children that are tuberculin skin test negative, BCG vaccination is common in many of these countries, e.g., the Netherlands or Israel (14). There is no information about the efficacy of this strategy. D. Special Populations

When discussing TB and migration, (internally) displaced persons often receive little attention. Yet, TB control among refugees is more complex than TB control among immigrants, due to the chaotic circumstances in which care has to take place, be it in low- or high-incidence countries. Increased TB rates among refugee populations as compared to the local population were reported from Tanzania (188), Congo Brazzaville (189), Georgia (190), South Sudan (191), and India (192). WHO and International Union Against TB and Lung Diseases (IUATLD) have developed special recommendations for TB control in refugee populations (193). National TB control programs and Nongovernmental Organizations (NGO) in high-incidence countries have developed successful interventions for TB patients in refugee camps and populations. Interventions include adapted treatment regimens with an extended intensive phase or thrice weekly directly observed treatment instead of daily, provision of a run-away bag in case of evacuation of staff, use

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of a four-drug fixed combination, and the provision of food packages to ensure adherence. As in regular programs, collaboration with traditional authorities and communities is extremely important. The higher incidence among refugees seems to be a temporary phenomenon. In a modeling study from 16 countries that were at war between 1975 and 1995, the risk of presenting with TB in any country 2.5 years after the war, relative to the 2.5 years before the war, was not significantly different (194). VI. Legal Aspects of TB Control Among Immigrants Access to care for undocumented immigrants is a challenge in many countries. Free treatment may be an answer. Yet, in a recent overview, most low-incidence countries stated that may be treatment may be given free of charge but this was not formalized, as in Denmark, whereas in Italy treatment is free in theory, but in practice may not be so. In Australia, treatment for undocumented immigrants is free in prisons. In Canada, Germany, and Norway, it is free for all undocumented immigrants. In the United States, theoretically treatment is free, but patients may not seek treatment due to fear of deportation (195). Increased international movements of people compel public health services to respond to the threats of communicable diseases and thus governments may consider compulsory screening of immigrants for infectious diseases like TB (167), or they may forcibly detain patients to complete their treatment. The United States recommends the postdetention completion of TB treatment for persons deported or released from the custody of the Immigration and Naturalization Service (INS) (196). The rationale is that completion of TB therapy prevents disease relapse, subsequent transmission, and the emergence of drug resistance. Integral to treatment completion are issues of security and law enforcement, involving persons who under immigration law are ineligible for legal admission into the United States. INS policies are consistent with federal law, which does not bar deportation of persons with TB disease before the completion of treatment. In the Netherlands, the law requires immigrants to undergo a TB examination before a residence permit can be obtained. For nonsuccessful applicants upon detection of TB, extradition is postponed until a full course of TB treatment is completed (164). Before supporting public health interventions through coercive measures, policy makers need to show the effectiveness of the proposed intervention (197). And obviously, ethical issues are involved such as the possibility of discrimination, notions of confidentiality (often lost when compulsion is involved), the role of clinicians as both patient advocates and protectors of public health, and stigmatization (167). VII. Epilogue Elimination of TB cannot be an activity done by countries in isolation. Elimination of TB at home means control of TB abroad. Nor is TB

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control only a medical technical intervention. It needs a multisectoral and multidimensional approach. Our mission is of the highest and noblest kind, not alone in curing the disease but in educating the people in the laws of health and in preventing the spread of plagues and pestilences. Sir William Osler (1895) (198)

Human mobility is a fact of modern life. Worldwide, 1 out of every 35 persons is an international migrant. Migration appears to be a natural reaction to cope with adverse conditions. Well-managed migrants’ health presents opportunities for improving global health, for the benefit of all societies (199). Acknowledgment This chapter is an updated version of the chapter by Mona Saraiya and Nancy J. Binkin, in the 2nd edition of this book, to whom we are highly indebted for the framework and a number of references. References 1. Euro-TB (InVS/KNCV) and the national coordinators for TB surveillance in the WHO European Region. Surveillance of tuberculosis in Europe. Report on tuberculosis cases notified 2002. Institut de Veille Sanitaire, Saint Maurice, France, December, 2004 (available on http://www.eurotb.org). 2. Broekmans JF, Migliori GB, Rieder HL, et al. European framework for tuberculosis control and elimination in countries with a low incidence. Recommendations of the WHO, IUATLD and KNCV Working Group. Eur Respir J 2002; 19(4): 765–775. 3. Rieder HL, Zellweger JP, Raviglione MC, et al. Tuberculosis control in Europe and international migration. Eur Respir J 1994; 7(8):1545–1553. 4. van Joost CRNF. Korte geschiedenis der tuberculose [short history of tuberculosis] Leerboek der tuberculosebestrijding. In: Bleiker MA, Douma J, van Geuns HA, eds. The Hague: KNCV, 1984. 5. Choraton F. Peruvian mummy shows TB preceded Columbus. Br Med J 1994; 308:808. 6. Heyerdahl T. The Ra Expeditions. New York: Doubleday, 1971. 7. Davies PDO. Tuberculosis and migration. The Mitchell Lecture 1994. J Roy Coll Phys Lond 1995; 29(2):113–118. 8. Dubos J, Dubos R. The White Plague. Tuberculosis, Man and Society. London: Victor Gollancz Ltd., 1953. 9. Davis AL. A historical perspective on TB and its control. In: Reichman LB, Hershfield ES, eds. Tuberculosis: A Comprehensive International Approach. 2nd ed. New York: Marcel Dekker, Inc., 2000. 10. Menzies D. Tuberculosis crosses borders. Int J Tuberc Lung Dis 2000; 4(12):S153– S159. 11. Bates JH, Stead WW. The history of tuberculosis as a global epidemic. Med Clin North Am 1993; 77:1205–1217. 12. Grzybowski S, Styblo K, Dorken E. Tuberculosis in eskimos. Tubercle 1976; 57(suppl 4):707–720.

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138. Harrison A, Calder L, Karalus N, et al. Tuberculosis in immigrants and visitors. NZ Med J 1999; 112(1096):363–365. 139. Mautino KS. Immigration consequences of tuberculosis. J Immigr Health 2004; 6(2):49–50. 140. Mandalakas AM, Starke JR. Tuberculosis screening in immigrant children. Pediatr Infect Dis J 2004; 23(1):71–72. 141. Binkin NJ, Zuber PL, Wells CD, et al. Overseas screening for tuberculosis in immigrants and refugees to the United States: current status. Clin Infect Dis 1996; 23(6):1226–1232. 142. Zuber PL, Knowles LS, Binkin NJ, et al. Tuberculosis among foreign-born persons in Los Angeles County, 1992–1994. Tuber Lung Dis 1996; 77(6):524–530. 143. Sciortino S, Mohle-Boetani J, Royce SE, et al. B notifications and the detection of tuberculosis among foreign-born recent arrivals in California. Int J Tuberc Lung Dis 1999; 3(9):778–785. 144. King K, Dorner RI, Hackett BJ, et al. Are health undertakings effective in the follow-up of migrants for tuberculosis? Med J Aust 1995; 163(8):407–411. 145. Blum RN, Polish LB, Tapy JM, et al. Results of screening for tuberculosis in foreign-born persons applying for adjustment of immigration status. Chest 1993; 103(6):1670–1674. 146. Joint Tuberculosis Committee of the British Thoracic Society. Control and prevention of tuberculosis in the United Kingdom: code of practice 2000. Thorax 2000; 55(11):887–901. 147. Pang SC, Harrison RH, Clayton AS, et al. Tuberculosis case-finding in Western Australia. Respir Med 1994; 88(3):213–217. 148. LoBue PA, Moser KS. Screening of immigrants and refugees for pulmonary tuberculosis in San Diego County, California. Chest 2004; 126(6):1777–1782. 149. Al-Marri MR. Childhood tuberculosis in the State of Qatar: the effect of a limited expatriate screening programme on the incidence of tuberculosis. Int J Tuberc Lung Dis 2001; 5(9):831–837. 150. Zellweger JP, Raeber PA, Desgrandchamps D, et al. Screening for Tuberculosis Among Asylum seekers Entering Switzerland. Tuberculosis Surveillance and Research Unit Progress Report 1997. The Hague, The Netherlands: KNCV Tuberculosis Foundation, 1997. 151. Breuss E, Helbling P, Altpeter E, et al. Screening and treatment for latent tuberculosis infection among asylum seekers entering Switzerland. Swiss Med Wkly 2002; 132(15–16):197–200. 152. Bothamley GH, Rowan JP, Griffiths CJ, et al. Screening for tuberculosis: the port of arrival scheme compared with screening in general practice and the homeless. Thorax 2002; 57(1):45–49. 153. Paterson R. Screening for infectious diseases. Lancet Inf Dis 2003; 3:681. 154. Van den Bosch CA, Roberts JA. Tuberculosis screening of new entrants; how can it be made more effective? J Public Health Med 2000; 22(2):220–223. 155. Hardie RM, Watson JM. Screening migrants at risk of tuberculosis. BMJ 1993; 307(6918):1539–1540. 156. Ormerod LP. Tuberculosis screening and intervention in new immigrants 1983–88. Respir Med 1990; 84(4):269–271. 157. Ormerod P. Issues facing TB control [1.1]. Tuberculosis in United Kingdom immigrants/organisation of tuberculosis control services. Scott Med J 2000; 45(5 suppl):22–23. 158. Pang SC, Harrison RH, Brearley J, Jegathesan V, Clayton AS. Preventive therapy for tuberculosis in Western Australia. Int J Tuberc Lung Dis 1998; 2(12): 984–988.

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35 Tuberculosis Control in Refugee and Displaced Populations

´ IRE A. CONNOLLY MICHELLE GAYER and MA Disease Control in Humanitarian Emergencies, Communicable Diseases, World Health Organization, Geneva, Switzerland

I. Introduction Refugee and displaced populations are at high risk of many communicable diseases including tuberculosis (TB). These populations face increased disease threats due to inadequate shelter and water, poor sanitation, overcrowding, and malnutrition. This is further compounded by a breakdown in health services, lack of regular drug supplies due to logistic difficulties, and ongoing conflict limiting access to populations. TB is becoming an increasingly important cause of morbidity and mortality in these populations. Conflict can affect large numbers of refugee and displaced populations, and in acute situations with a combination of war or civil strife and food shortage can result in significant excess mortality and morbidity (1). An increasing number of civilians have been affected by conflict over the last decade. By the end of 2003, there were almost 10 million refugees and 20.6 million displaced people worldwide, an increase from 19.8 million reported in 2002 (2). In addition, conflict has affected entire countries such as the Democratic Republic of Congo (DRC) and Afghanistan. At present, more than 200 million people live in such countries.

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Several issues must be considered before initiating a TB control program in such settings. Firstly, whether TB is a problem; secondly, whether an effective long-term, resource-intensive program can be implemented, in settings with weak health infrastructure, poor basic health and laboratory services, lack of qualified staff, supply and logistic difficulties, and often ongoing conflict and political instability. The priority should be to provide adequate shelter that avoids overcrowding, safe water, sanitation, and food, and to attend to the major causes of mortality before considering TB control. In addition, the public health risk posed by the possibility of interruption of TB programs (which is worse than no treatment) due to population movement or insecurity from open conflict, leading to the development of multidrug-resistant TB (MDR-TB) in patients already on treatment, must be considered. Certain preconditions must be in place before TB control programs can be set up in refugee and displaced populations, and the feasibility of implementing safe and effective programs should be assessed separately for each setting on an ongoing basis as the situation changes. This chapter will highlight the importance and challenges of carrying out TB control programs in refugee and displaced populations living in conflict situations, consider criteria for initiating TB control programs, provide insight into novel means of improving case detection and completion rates, and provide outcome indicators for monitoring and evaluation. II. The Changing Context of Conflict Situations It is increasingly being recognized that refugees and displaced populations now exist in a wide variety of settings beyond the traditional refugee camp that was common toward the end of the last millennium. Conflict may affect entire countries, can entail refugees and displaced persons living in camps/settlements or dispersed among host communities, with the majority of TB control services being provided by nongovernmental organizations (NGOs) with or without the National TB Control Program (NTP). Approaches to TB control must therefore be locally adapted to each setting (Table 1). III. Risk Factors The risk of TB is significantly increased in refugee and displaced populations. Overcrowding in temporary shelters increases the risk of transmission of TB and malnutrition increases the risk of progression to TB disease. In addition, poor access to health care services leads to low case detection, delays in diagnosis and, therefore, increased numbers of infectious cases and higher transmission rates. Furthermore, population mobility can result in high defaulter and low cure rates, thereby increasing the number of chronic cases and encouraging development of MDR-TB.

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Table 1 Conflict Situations and Tuberculosis Control Programs Refugees in camps/settlements with host (NTP) implementing TB control programs with support of UNHCR and partners (e.g., Burundian and Congolese refugees in The United Republic of Tanzania) Refugees in camps/settlements with UNHCR partners implementing TB control programs using NTP protocols (e.g., Somali, Sudanese, and Eritrean refugees in Ethiopia) Refugees dispersed among local population with host NTP implementing TB programs (e.g., Chechen refugees in Ingushetia, Kosovar refugees in Macedonia) Displaced populations in noncamp settings with NGOs implementing TB control programs (e.g., southern Sudan) Unstable country with weak NTP; NGOs implementing TB control programs for national and displaced populations but poorly coordinated (e.g., Afghanistan) Large country with weak government where TB control programs are implemented in some provinces by NGOs including faith-based organizations (e.g., DRC) Country with collapsed NTP where TB control activities are severely compromised by ongoing insecurity (e.g., Iraq) Abbreviations: NTP, national TB control program; DRC, Democratic Republic of the Congo; UNHCR, United Nations High Commissioner for Refugees.

In an NGO-run TB control program in Abkhazia, 25% of retreatment cases were MDR-TB in 2003 (3). MDR-TB, already very difficult to treat, is all the more so in a conflict setting such as the Caucasus, given the lack of regular drug supply, poorly trained staff, and multiple agencies being involved in TB control. Furthermore, HIV infection increases the lifetime risk of latent TB infection progressing to active TB disease from 5% to 10% to 50% (4), and also increases the risk of severe side effects from anti-TB drugs. The lack of HIV prevention and control programs for refugee and displaced population increases this burden as HIV has until recently been considered to be a development issue by many NGOs. This, however, is changing, particularly with increasing awareness among donor agencies, NGOs and governments of the importance of early implementation of HIV control programs as outlined in the recently updated interagency guidelines for HIV/AIDS control in emergencies (5). IV. Burden of TB Globally, there were an estimated 2 million deaths from TB worldwide in 2002, of which 98% occurred in the developing world. Of the annual 8.8 million estimated new cases worldwide, 80% occur in 22 high-burden countries, two of which are conflict-affected countries—DRC and Afghanistan.

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The region with the greatest burden is Southeast Asia, which accounts for 33% of incidence globally. However, the estimated incidence per capita in sub-Saharan Africa is nearly twice that of the Southeast Asia at 350 cases per 100,000 population, where coinfection with HIV has led to rapid increases in the incidence of, and the likelihood of dying from, TB. TB is now a leading cause of death among people who are HIV positive and accounts for about 13% of AIDS deaths worldwide. The burden of TB is particularly high among refugee and displaced populations given the increased risk of transmission and lack of treatment in such settings. In 1985, 26% of deaths among adult refugees in Somalia and between 38% and 50% of all deaths among refugees in camps in eastern Sudan were attributed to TB (6,7). In northeast Kenya, in 1994, the incidence of smear positive TB was four times higher in refugees than in the local population. In Ingushetia in 2000, the TB notification rate for displaced Chechens was almost twice as high as the resident Ingush population (8). Similarly, the TB incidence rate in refugees and internally displaced persons (IDPs) temporarily residing in Zagreb during the war period (1992–1994) was significantly higher (96/100,000 vs. 54/ 100,000 in 1992, 53/100,000 vs. 68/100,000 in 1993) than in the local population in Croatia (9). Screening of IDPs with the tuberculin skin test and symptom questionnaire in Tbilisi, Georgia, found a high incidence of 537 per 100,000 population (10). In East Timor in 1999, 3% of East Timorese refugees screened in Darwin, Australia were treated for TB. A very high TB burden was found (point prevalence of 542/100,000 for smear-positive and 2060/100,000 for culture-positive cases), as well as high resistance to anti-TB medications (17.2% resistance to isoniazid and 8.6% resistance to both isoniazid and streptomycin) (11). The countries of origin of many refugee populations already have a high TB incidence and some of the largest refugee populations in the world are hosted in the DRC, Ethiopia, Kenya, the Islamic Republic of Iran, Pakistan, United Republic of Tanzania, and Uganda—many of which are also high-burden TB countries themselves (Table 2). Factors associated with the emergence of drug-resistant Mycobacterium tuberculosis such as poor program implementation, frequent or prolonged shortages of drugs, inadequate resources, ongoing insecurity, or lack of political commitment are common in conflict situations. Furthermore, the sale of anti-TB drugs of unproven quality over the counter and on the black market is also a major risk factor. Moreover, incorrect case management due to poorly trained health staff, difficulties in diagnosis and selecting the appropriate chemotherapeutic regimen, and patient nonadherence due to population movement all contribute to anti-TB drug resistance in these settings (13). A recent study in Kenya comparing TB treatment in camp and noncamp populations showed that there were high levels of drug resistance in the camps (18% of samples were resistant to one or more drugs, with

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Table 2 Estimated TB Burden 2003 in Main Conflict-Affected and Refugee-Hosting Countries Incidence all cases

New SMþ cases

Country

Number

Rate (per 100,000)

Number

Rate (per 100,000)

Afghanistana Burundia DRCab Ethiopiab Eritreaa Iraqa Kenyab Pakistanb Sudana Thailandb Ugandab United Republic of Tanzaniab

79,656 25,585 194,627 251,685 11,233 39,552 195,207 278,392 73,802 89,351 106,201 137,260

333 346 369 356 271 157 610 181 220 142 411 371

35,845 10,083 84,667 109,452 4946 17,797 83,822 125,172 32,614 39,683 46,176 58,235

150 148 160 155 119 71 262 82 97 63 179 157

a

Conflict-affected country. Refugee-hosting country. Source: From Ref. 12. b

3% MDR), combined with evidence of transmission of strains resistant to streptomycin in the refugee population (14). V. Constraints to Implementing TB Control Programs for Refugee and Displaced Populations There are many constraints to implementing TB control programs in this setting. Firstly, an unstable government or no government at all, and thus a lack of Ministry of Health structure, precludes the political commitment essential for implementing TB control programs. NTPs may have collapsed, or there may be a weak health infrastructure with even weaker links to TB control programs. In many circumstances, basic health and laboratory services are destroyed due to conflict or may have collapsed, there is a lack of qualified laboratory and health staff, and a concurrent increase of private practitioners involved in TB control in the absence of appropriate training and supervision. Ongoing conflict and political instability not only reduce access of population to health services but also render drug distribution, supply and logistic operations very difficult, in some cases with TB drugs ending up on the black market. Furthermore, multiple agencies, often poorly coordinated,

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are involved in providing health care in to refugee and displaced populations. Their focus is principally on primary health care with little priority given to TB control and their donors may opt to spend limited resources on shorterterm programs. Stigmatization of TB patients and poor community involvement in TB control activities is often a major constraint to achieving high case detection rates. In addition, patients may be highly mobile and as a result, it may be difficult for them to remain at one site long enough to complete treatment. Furthermore, the link between HIV and TB in high HIV burden settings may increase the stigmatization of TB patients. Finally the increase in proportion of TB patients coinfected with HIV and emergence of MDR-TB have made case detection and treatment all the more challenging. The WHO global TB control strategy known as DOTS was being implemented in 182 out of 211 countries in 2003 and DOTS population coverage (defined as the percentage of national population living in areas where health services have adopted DOTS) had increased to 77%. Global new case detection rate (a more precise indicator than coverage) in 2002 was 46% of that estimated, with the sputum smear positive case detection rate of 44% (12). The status of DOTS implementation in conflict-affected and refugeehosting countries is variable and depends on several factors including the level of political commitment at all levels, status of health and laboratory infrastructure and drug distribution systems, insecurity as well as availability of qualified staff and community awareness. DOTS coverage, detection, and treatment success and defaulter rates for these countries are shown in Table 3. In Afghanistan, constraints to DOTS implementation include weak health sector infrastructure, weak NTP capacity due to insufficient personnel and poor training, low community involvement in TB control, social stigma about TB and unwillingness to seek treatment, and increasing private sector involvement, unregulated and of variable quality, in TB control (3,12). In the DRC, delays in the implementation of the national plan for TB control were experienced due to an underdeveloped primary health care system, political instability, ongoing conflict, and lack of political commitment to TB control at provincial level. Furthermore, lack of financial and human sources, an inefficient drug distribution system, and limited laboratory capacity with poor microscopy quality were impeding DOTS expansion (2,12). However, good progress has been made in improving DOTS coverage and case detection rates with expansion of health network from 306 health districts to 515 to improve access, better coordination, extensive training at all levels, improved capacity of laboratories, and collaborative HIV/TB activities. Despite chronic lack of resources in some areas in Kenya, such as staff and laboratory facilities, TB control services have improved as a result of strong managerial and operational central structures. DOTS is implemented in all primary health care units, giving a DOTS coverage of

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Table 3 DOTS Coverage, Detection, Treatment Success, and Defaulter Rates for Key Conflict-Affected and Refugee-Hosting Countries

Country Afghanistan DRC Kenya Pakistan Sudan United Republic of Tanzania Uganda

DOTS population coverage % (2003)

Detection rate new ssþ cases % (2003)

Treatment success new ssþ cases % (2002 cohort)

Defaulter rate new ssþ cases % (2002 cohort)

53 75 100 63 99 (2002)a 100

18 63 46 17 34 43

87 78 79 77 78 80

5 8 9 14 7 4

100

44

60

19

a DOTS coverage not reported for 2003. Abbreviations: DRC, Democratic Republic of the Congo. Source: From Ref. 12.

100%; however, there is still a low case detection rate. A major constraint in Kenya, also, is the increase in the proportion of TB patients infected with HIV (51% in 2002) (12). There has been a steady progress toward achieving the national strategic plan objectives in Pakistan, which includes the large Afghan refugee population of 2 million in 2004 (number). Whilst case detection rates and treatment outcomes have improved, they remain below global targets. In addition, there is a very high defaulter rate of 14%. Pakistan also reports a high proportion of smear-negative pulmonary cases causing concern for the quality of diagnosis (at least 65–85% of pulmonary TB should be smear positive). The main challenges to TB control program expansion in Pakistan include weak management and supervisory capacity at provincial and district levels, nonstandardized smear microscopy, nonstandard drugs and poor drug supply, and poor integration of TB control into urban primary health care facilities (12). In both the southern part of Sudan, with an estimated number of IDPs above 4 million Office for Coordination of Humanitarian Affairs (OCHA Nairobi, 2002), and the three western Darfur states with an estimated IDP population of 1.45 million (OCHA 2005), health services are provided to a large extent through multiple international and local NGOs. Political instability and conflict, lack of financial and human sources, difficult logistics and drug supply, and limited laboratory capacity have made implementation of TB control programs difficult (3). Although DOTS coverage appears high, probably as the lowest administrative units cover

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large geographical areas, case detection rates remain low due to poor access to health services. In the United Republic of Tanzania, which hosts almost half a million refugees from Burundi and the DRC, TB control services are coordinated by the National TB Leprosy Program (NTLP) and implemented through the primary health care system. UNHCR in collaboration with the NTLP provide TB control services to the refugee population in camps in the western provinces. Constraints to fully achieving set targets include high turnover of district coordinators and lack of diagnostic centres and qualified laboratory personnel at district level shortage of staff at national level to provide overall monitoring and supervision is also a problem. VI. Management of TB in Refugee and Displaced Populations Given the complexity of TB control, the number of implementing agencies and constraints in conflict situations, certain preconditions must be fulfilled prior to implementing TB programs in these settings (summarized in Table 4). The acute phase of the emergency must be over, i.e., the crude mortality rate must be less than one death per 10,000 per day (this is equal to double the baseline mortality rate for countries in sub-Saharan Africa). The population’s basic needs for water, food, shelter, and sanitation must be met. A lead agency for coordination must be identified with a clear policy for TB control adapted to the local setting with written long-term commitment from all parties involved, and funding secured for a minimum of one year. In particular, regular drug supply, laboratory facilities to perform smear microscopy and appropriate supervision must be ensured. Once these criteria are met, several key steps are required in implementing TB programs for refugee and displaced populations (Table 5). Mobilizing Table 4 Preconditions for Implementing Tuberculosis Programs for Refugee and Displaced Populations General issues: Acute phase of the emergency is over (CMR < 1 death per 10,000 per day) Basic needs of the population are met (food, water, shelter, sanitation) Essential clinical services including drugs and trained health staff available Security and stability of population envisaged for at least 6 mo TB-specific issues: TB is an important health problem Lead agency identified with full-time TB coordinator with a well-trained team Long-term commitment of all parties Regular supply of drugs and laboratory material ensured Laboratory facilities able to perform sputum smears with quality control system Funds available for minimum of one year of program implementation Abbreviation: CMR, crude mortality rate.

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Table 5 Key Steps in Implementation of Tuberculosis Control Programs for Refugee and Displaced Populations Carry out situational analysis and evaluation of capacity Confirm prerequisite criteria Mobilize/confirm political commitment and support from relevant authorities Ensure collaboration with National TB Control Program Establish Interagency Coordination Mechanism and appoint TB coordinator Develop clear policy for TB control program Develop and agree on Memoranda of Understanding between all implementing partners with clearly defined responsibilities Agree TB treatment regimens and protocol Develop work plan and budget Ensure referral facilities available for severe TB cases Ensure laboratory services for quality control of sputum smear examinations Establish registration and reporting system Establish system for monitoring and supervision Procure drugs and supplies Secure storage facilities for drugs and supplies Recruit staff Implement training for staff Implement workplan Perform program evaluation

political commitment and support from relevant authorities is critical to the success of the program and collaboration with the NTP, where one exists, is crucial. A workplan and budget must be developed, with responsibilities of all actors defined. Local TB treatment regimens and protocols must be agreed, all staff must be properly trained, referral facilities for severe TB cases ensured and drugs and supplies procured and stored safely, including buffer stocks. In particular, an appropriate registration and reporting system must be set up with regular monitoring and supervision of the program. Outcome indicators, such as smear conversion rates, cure rates, treatment success rates, deaths, and treatment failure and defaulter rates as outlined in the DOTS strategy should be used for program evaluation (Table 6). VII. TB Control Successes in Refugee and Displaced Populations Despite the constraints of implementing TB control programs in these situations, there have been several successful examples from which lessons can be learned. For example, the introduction of short-course chemotherapy in Nicaragua, despite conditions of war and increasing poverty, achieved cure rates of 70% in 1980s. This success was attributed to political commitment, good supervision and well-trained staff (15).

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Table 6 Outcome Indicators for Tuberculosis Programs in Refugee and Displaced Populations The following are expressed as a percentage of the number registered in a cohorta: Smear conversion ratesb
80% at end of 2 mo of fully supervised treatment Treatment success ratesc
85% Deathsd 8% Treatment failurese 2% Defaultersf 6% a

Group of TB cases diagnosed (and in principal notified and started on treatment) during a specified time, for example, the cohort of new smear-positive cases for calendar year 2004. This group forms the denominator for calculating outcomes. b Sputum smear-positive patient that became smear negative. c Percentage of new smear-positive patients cured (initially smear positive who were smear negative in the last month of treatment, and on at least one previous occasion) PLUS the percentage that completed a course of treatment but without bacteriological confirmation of a cure (and not meeting criteria for failure). d Patients who died for any reason during treatment. e Smear-positive patient that remained positive at five months or later during the treatment). f Patient whose treatment was interrupted for two consecutive months or more. Source: From Ref. 12.

Similarly, an overall treatment success rate of 70% and the smear conversion rate of 93% was achieved over 1994 to 1996 in patients in Somalia. Measures such as more evenly distributed TB control programs, improved coordination between programs, introduction of cross-border programs, and facilities where nomadic patients remain for the duration of chemotherapy could enhance TB control (16). Implementation of DOTS programs amidst civil unrest in northeast India from 1998, in an IDP population with high TB and HIV rates, achieved an overall 91% success rate and a low 3% defaulter rate. Success was attributed to strong local community support, the use of outreach workers from each ethnic group to allow access to all areas and patients, the use of thrice weekly instead of daily treatment, and the limiting of distances travelled by outreach workers and patients (17). VIII. Challenges for the Future Many challenges are faced in implementing TB control programs for refugee and displaced populations. Firstly, there is a need to increase awareness of the importance of TB by the international community. Secondly, given that nongovernmental and international organizations and increasingly private practitioners are major providers of health services in these settings, their involvement in TB control programs is vital and requires encouragement. Nevertheless, linkages to NTPs (however weak) are crucial to ensure that agencies do not operate independently, that standardized, evidence-based, effective, accessible, and sustainable programs are in place. These linkages

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are important in coordination of the different components of TB control programs, standardization of protocols, ensuring a regular drug supply, quality control, prevention and management of MDR-TB, access to laboratory and hospital referral services, community involvement, training of health staff, supervision, and monitoring and evaluation. Although many NGOs may have the funds for TB drugs, they may not necessarily have the technical expertise for implementation of TB control programs. In addition, the time frame of projects carried out by health NGOs for refugee and displaced populations is often short, with the danger of contributing to MDR-TB if a program is interrupted. In addition to training local staff, NGOs themselves require training and technical support on TB control to ensure their capacity to run TB programs, as well as provide primary health care services. At the same time, conflict-affected countries need more targeted technical assistance in coordinating the work of the numerous NGOs, international organizations and the private sector. Community involvement needs to be fostered in order to improve early case detection and treatment compliance. The added challenge in these settings is to improve access and utilization of primary health care services and to integrate TB control programs within them. Finally, certain added elements are crucial such as ensuring clear memoranda of understanding for all agencies involved in TB control, stockpiling of supplies for periods of insecurity, contingency plans for open conflict, population movements, repatriation, transfers and regular crossborder movements, and adequate plans for handover to the NTP. The Global Fund to fight AIDS, TB and Malaria (GFATM), set up to finance control of these diseases on a national level, needs to ensure special provision for conflict-affected countries as epidemiological data are often limited, there are multiple implementing partners and the infrastructural capacity needed to absorb funds are not in place. In addition, proposals by national programs to the GFATM must include refugee and displaced populations. The Global Drug Facility, set up to ensure access to TB drugs for resource poor countries, should target these countries as a priority. In addition, as more HIV/AIDS control projects are set up for refugee and displaced populations, it will be essential to ensure linkages to TB control programs. There are also clear research challenges. Given the poor laboratory infrastructure, lack of trained technicians and difficulties in maintaining quality control for sputum microscopy, and also in monitoring MDR-TB, a rapid diagnostic test for TB could greatly improve TB control. New drugs with less frequent dosing and shorter regimens would greatly improve adherence, cure and help to avoid drug resistance. IX. Conclusions Globally, increasing numbers of people are affected by war and civil strife, with entire populations of some conflict-affected countries living in difficult

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conditions. These refugee and displaced populations face increased communicable disease threats due to inadequate shelter and overcrowding, lack of clean water and sanitation, and food shortages leading to malnutrition. Destroyed or collapsed infrastructure, a breakdown in heath services, and poor access to health care compounds this risk. TB is becoming an increasingly important cause of morbidity and mortality in these populations. Implementing TB control programs in populations affected by conflict calls for new partnerships and approaches. Certain preconditions must be met before TB programs can be implemented in such settings given the need for microscopy diagnosis, long duration of supervised treatment, and importance of compliance in achieving cure and preventing drug resistance, and TB programs should not be undertaken if these conditions are not fulfilled. Strategies adopted for controlling TB in conflict situations need to enhance local capacity to expand and sustain the implementation of TB programs without compromising the quality of case detection and treatment. Integration into primary health care services is required, but TB control needs to be specifically adapted to each settings so as to enable effective and sustainable delivery of services. Nongovernmental and international organizations play a crucial role in implementation of such strategies and linkages to the NTP are essential to ensure such programs are sustainable. Finally, better community involvement in TB care and a patient-centered approach must be facilitated in order to improve access and utilization of health services, particularly in refugee and displaced populations. References 1. Salama P, Spiegel P, Talley L, et al. Lessons learned from complex emergencies over past decade. Lancet 2004; 364:1801–1813. 2. UNHCR statistics 2003. http://www.unhcr.ch/cgi-bin/texis/vtx/home?page¼ statistics (accessed November 2004). 3. World Health Organization. Report of the technical meeting on TB control in complex emergencies, 23–24 February 2004. WHO, Geneva, Switzerland. 4. World Health Organization. TB/HIV: A Clinical Manual. 2d ed. Geneva, Switzerland: WHO, 2004; ISBN 92 4 154634 4. 5. Inter-agency Standing Committee. Guidelines for HIV/AIDS Interventions in Emergency Settings. IASC, 2003. 6. Toole MJ, Waldman RJ. An analysis of mortality trends among refugee populations in Somalia, Sudan, and Thailand. Bull WHO 1988; 66:237–247. 7. CDC. Famine affected, refugee, and displaced populations: recommendations for public health issues. MMWR 1992; 41(RR-13). 8. Government of Ingushetia and Minster of Health of the Russian Federation. TB control activities for the Ingushetia Republic and forced migrants from the Chechnya Republic for 2001–2002, 2003. 9. Pavlovic M, Simic D, Krstic-Buric M, et al. Wartime migration and the incidence of tuberculosis in the Zagreb region, Croatia. Eur Respir J 1998; 12(6):1380–1383.

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10. Weinstock DM, Hahn O, Wittkamp M, et al. Risk for tuberculosis infection among internally displaced persons in the Republic of Georgia. Int J Tuberc Lung Dis 2001; 5(2):164–169. 11. Kelly PM, Scott L, Krause VL. Tuberculosis in east Timorese refugees: implications for health care needs in East Timor. Int J Tuberc Lung Dis 2002; 6(11):980–987. 12. World Health Organization. Global Tuberculosis Control: Surveillance, Planning, Financing. WHO Report 2005, Geneva, Switzerland; ISBN 92 4 156291 9. 13. The WHO/IUATLD Global Project on Anti-TB Drug Resistance Surveillance 1999–2002. Anti-tB Drug Resistance in the World. Geneva, Switzerland: World Health Organization, 2004. 14. Githui WA, Hawken MP, Juma ES, et al. Surveillance of drug-resistant tuberculosis and molecular evaluation of transmission of resistant strains in refugee and non-refugee populations in North-Eastern Kenya. Int J Tuberc Lung Dis 2000; 4(10):947– 955. 15. Heldal E, Cruz JR, Arnadottir T, et al. Successful management of a national tuberculosis program under conditions of war. Int J Tuberc Lung Dis 1997; 1(1):16–24. 16. Agutu WO. Short-course tuberculosis chemotherapy in rural Somalia. East Afr Med J 1997; 74(6):348–352. 17. Rodger AJ, Toole M, Lalnuntluangi B, et al. DOTS-based tuberculosis treatment and control during civil conflict and an HIV epidemic, Churachandpur District, India. Bull WHO 2002; 80(6):451–456.

36 Tuberculosis Control in Prisons

MICHAEL E. KIMERLING Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, U.S.A.

A 20-year-old Russian student was screened upon entry into an American university. He had a positive tuberculin skin test and, on chest radiograph, was found to have a right-sided pleural effusion. The effusion was tapped, and the culture grew Mycobacterium tuberculosis resistant to isoniazid and streptomycin. When told of the results, he replied to the physician in dismay: ‘‘But, I’ve never been in prison! How can I have TB?’’

I. Introduction: Two Sides of the Wall As incarcerated populations continue to grow worldwide, so too have the problems of tuberculosis (TB), death from TB, and drug resistance in prisons. TB transmission among the incarcerated is an issue for every network of jails, pretrial detention centers, and prisons; for sentenced and nonsentenced inmates; and, ultimately, for general communities. To appreciate why TB control in prisons is often neglected at the global level, it is useful to consider two ‘‘images’’ of prisons and prisoners. First, there is the image of high prison walls and barbed-wired fences with incarcerated populations on one side and civil society on the other, 921

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creating a sense that such barriers not only isolate and punish the persons incarcerated, but moreover, protect society from any ills arising behind those walls. This image recalls public health posters distributed in the United States during the early 20th century, where ‘‘public health’’ walls were erected in towns to keep common afflictions and transmissible diseases of the time, such as diphtheria and measles, away from clean and unsuspecting communities. These posters carried the slogan: ‘‘How high is your wall?’’ The wall itself is shown to be built of bricks labeled as health officers, isolation and quarantine of the sick, antitoxin, disinfection, and popular education about disease. Although this public health approach has been appropriately applied to the recently discovered and highly infectious respiratory pathogens severe acute respiratory syndrome (SARS) and avian influenza, for which no cures exist, it is not appropriate for dealing with TB, especially TB in prisons. The links between prisons and the general community cannot be contained behind walls, no matter how high they may be built. A second image, less visual but certainly widespread, is one of stigma and discrimination toward the incarcerated: persons deserving of their situation and bearing responsibility for any unintended consequences of their imprisonment such as TB, rape, infection with a sexually transmitted disease, hepatitis from unclean needle use, and, more recently, infection with human immunodeficiency virus (HIV). This image reflects contempt for prisoners as ‘‘social deviants.’’ Images and reality, however, collide upon understanding the dynamics of prison-seated TB epidemics. As will be discussed throughout this chapter, TB control in prisons is directly linked to TB control in the civil sector. Control in one sector cannot be completely successful without control in the other; they are linked. DOTS in prisons should therefore become a mainstream element in the overall DOTS expansion efforts underway worldwide. II. Access to Adequate TB Care and Human Rights in Prisons Although society has the legal right to imprison members of its population through judicial processes, once individual freedoms are removed through incarceration, society assumes responsibility for the health and welfare of these individuals. In terms of prisoner rights, according to the United Nations Basic Principles for the Treatment of Prisoners (Principle 9): ‘‘Prisoners shall have access to the health services available in the country without discrimination on the grounds of their legal situation (1).’’ Consequently, persons sentenced to prison for their crimes do not deserve to develop and die of TB. Neither do they deserve to become a chronic excretor of resistant organisms due to inadequate care, with subsequent spread to their families or other community members upon release. These unintended consequences, even for the most serious crimes, are not part of the legal sentence. These rights are equally valid for those nonsentenced persons

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who are awaiting trial and investigation, and who reside either in jails or in pretrial detention centers or are mixed with sentenced populations. III. Prisons as Special Communities Besides the inmates and their associated internal power structures, prison communities consist of administrators, general staff, security personnel, and health staff, all of whom share common air with inmates, yet reside in the general community. Although prisoners originate from the greater community and will eventually return there, they disproportionately represent certain subgroups of the population, often with limited access to health services: predominately young and male, with high rates of unemployment, low education levels, low socioeconomic status, high rates of alcohol and drug abuse, high rates of mental illness, and often previous exposure to TB. Sexually transmitted diseases are also prominent (2–8). Therefore, prisoners represent a convergence of hard-to-reach groups with overlapping TB risk factors, especially given a growing HIV epidemic. The recent explosion of HIV infection among Russian prisoners, for example, from 1994 (seven infected inmates) through 2003 (36,000 infected inmates or 4.3% of the inmate population) illustrates how rapidly changes in risk status can occur (9). At a national level, much of the rise in HIV infection in Russia and Ukraine has been fanned by rising rates of intravenous drug abuse and through heterosexual spread. In prisons, unprotected sex between men (often due to sexual abuse and rape) and the sharing of needles are common but poorly quantified means of HIV spread. Almost without exception, the convergence of these risk groups occurs in the context of extreme overcrowding and violent settings associated with great mental and physical duress. Internal control is often maintained and enforced by a prisoner hierarchy system. Prison staff, including the health staff, may not be trusted because they are seen as representatives of the authorities. Such a situation can lead to the existence of numerous incentives and disincentives to participate in a TB program and even to be cured. Medicines can become currency, and sputum exchange of both positive and negative samples is well known. Conditions in a prison hospital or TB colony may be significantly better than in the general prison itself. Therefore, understanding the dynamics of a prison’s internal systems and obtaining the collaboration of its power structures are essential to developing an intervention program (10–14). IV. Epidemiology of TB in Prisons: The Convergence of Risk Groups and a Disproportionate Burden of Disease A. A Growing Population with a Disproportionate Disease Burden

Globally, inmate population and incarceration rates continue to grow (Fig. 1). Two notable exceptions are the Russian Federation and Kazakhstan, where recent penal reform has led to a marked decline in prison populations,

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Figure 1 Incarceration rates (per 100,000) in selected countries 1992 to 2004. Source: International Centre for Prison Studies. http://www.prisonstudies.org (accessed November 2004). Unpublished raw data on Thai incarceration rates obtained from the Medical Service Division, Department of Corrections, Ministry of Justice, Thailand, 2004.

often due to early releases and mass amnesties (5). Penal reform in Thailand has similarly led to a decline in incarceration rates between 2002 and 2003 (Medical Service Division, Department of Corrections, Ministry of Justice, Thailand, 2004; unpublished data). Regardless of absolute incarceration rates, a disproportionate TB burden exists among a nation’s inmates compared with the general population wherever comparable data is available. These differences can be 10- to 50-fold or greater (3,6,13,14). The extraordinarily high disease burden is a direct reflection of the high latent tuberculosis infection (LTBI) rates and convergence of risk groups discussed above. Unfortunately, LTBI rates are not known in most global settings because tuberculin skin testing (TST) is not available or utilized on a routine basis. In a recent U.S. study of 49 correctional centers in 12 states, the mean TST positivity rate was 17%, at least triple that of the general population LTBI rate. Among inmates with a known HIV result, 14.5% were HIV infected (15). Table 1 summarizes published studies of TB prevalence as determined through screening in jails and prisonsa. Some of these studies were conducted at the time of inmate entry; others were conducted as mass screenings to

a The distinction between jail and prison may not be made in all settings/countries. In large systems of incarceration, however, a jail generally refers to facilities of lawful custody designed for short-term confinement for minor cirmes or durings periods of investigation prior to trial. Jails are administered by local governments through its police or other regional law enforcement department. Prisons are facilities generally designed for persons convicted of serious crimes given long-term sentences. Prisons may be administered by either the state or the federal government.

1993 (May– CXR July) 1996 (May– Clinical July)

126,608 4172 900c

7473

9331

Entry screening

New York Entry screening City (J) (18)

Mass screening (point prevalence)

Mass screening (at national level)

Malawi (P) (19)

Republic of Georgia (P) (20)

San Francisco Entry screening (J) (21) (period prevalence)

1998

5803 (smearpositive PTB)

2707 (PTB only)

Rate (per 100K)

3667 (PTB only)

767

72.1

Sputum smear, 5995 (PTB only) culture, MMR

Sputum smear, CXR

Clinical, TST

Clinical, culture 68 (total), 53 (by MMR)

Sputum smear

CXR, sputum

Secondary

Clinical CXR, culture plus TST

1997–1998 Clinical

1992–1994 MMR

1990–1992 Clinical

Chicago (J) (17)

1861

Prospective

Ivory Coast (P) (16)

1989–1990 TST

Entry screening upon mass transfer

702c

Primary

Survey method

Barcelona (P) (3)

Study site

Number of inmates Type of survey screened Time period

Table 1 TB in Jails and Prisons: A Summary of Published Screening Studies (1989–2002)

67

NA

NA

78

50

NA

NA

(Continued )

NA

NA

73

29

29

30

42

Current diagnosis HIV of TB at coinfected screeninga (%) TB casesb (%)

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Mass screening (point prevalence)

1027

2002 (April– Clinical May) (cough)

Primary

Rate (per 100K)

Sputum smear, 3797 (2662 culture, CXR among guards)

Secondary

Survey method

51

30

Current diagnosis HIV of TB at coinfected screeninga (%) TB casesb (%)

Current diagnosis of TB at screening refers to the proportion of previously diagnosed TB cases among all cases identified at entry screening (i.e., the patient was a known case in the civil sector and had not completed therapy or was nonadherent with therapy at the time of jail entry screening). In the Botswana prison study, 20 out of 39 cases were on treatment at the time of the mass screening. b HIV testing coverage was incomplete in all studies. c Excluding previously diagnosed cases detected within the prison by routine means (prior to the screening activity). Abbreviations: TST, tuberculin skin testing; CXR, chest X ray; MMR, mass miniature radiography; PTB, pulmonary tuberculosis; NA, not applicable; P, prison site; J, jail site.

a

Botswana (P) (22)

Study site

Number of inmates Type of survey screened Time period

Table 1 TB in Jails and Prisons: A Summary of Published Screening Studies (1989–2002) (Continued )

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calculate either a period or a point prevalence. The years of study and the quality of the prison and civil TB programs also vary. Therefore, these studies are not all directly comparable; however, they do illustrate important common threads: high rates of TB at entry; high rates of TB missed by usual screening procedures; and high rates of persons entering with a current diagnosis of TB (often unknown to the prison system). Data on HIV–TB coinfection is given where reported. Table 2 provides a summary of multidrug resistant TB (MDR-TB) rates documented across a variety of prison settings with concurrent rates of isoniazid resistance. Classification of rates by primary versus acquired resistance is often difficult to ascertain in the prison setting, especially where a DOTS program is not long established. However, the overall rates of MDR-TB found are the highest recorded among any population group. To date, evidence indicates that the MDR link between the prison and civil sectors in countries with high rates of MDR-TB in both, such as Russia, is not yet as strongly developed as that for the general TB epidemic, but the bidirectional potential exists. Civilian sector–generated MDR-TB can contribute to the drug resistance problem inside prisons just as MDR-TB generated in prisons can cross into the general community (Fig. 2) (26,27). MDR-TB establishes itself wherever a TB program is inadequate, on either side of the wall. In a case–control study of primary MDR-TB (based on civilian laboratory isolates) in the Russian region of Ivanova, homelessness was identified as a significant factor, whereas previous incarceration

Table 2 Reported Rates of Multidrug-Resistant Tuberculosis in Imprisoned Tuberculosis Patients Country

Year

MDR-TB (%)

Total isoniazid resistance (%)

Azerbaijan (23) Mariinsk, Siberia (24) (Russian Federation) Republic of Georgia (20)

1995–1997 1997–1998

23a 22.6a

55 66

1997–1998

58

Thailand (8)

2000

Tomsk, Siberia (25) (Russian Federation)

2001

5.6b 15.7c 8.3b 46.7c 15.6b

36 Not reported

71.5c Note: MDR-TB is defined as resistance to at least both isoniazid and rifampicin. a In these two locations, the cases studied represented a mixed population of cases, including those with a history of undocumented or irregular TB therapy prior to transfer into a DOTS program. Due to poor record-keeping systems, further classification could not be made. b New cases. c Retreatment cases. Abbreviation: MDR-TB, multidrug-resistant tuberculosis.

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Figure 2 Development of dual and parallel tuberculosis epidemics in prisons with community spread. Note that TB, including multidrug-resistant TB, can also enter from the community.

was not (28). In another study of drug resistance among civilians in the Tomsk region, a history of incarceration was also not identified as a risk factor for MDR or polyresistant TB in the final regression model (27). Thus, each sector is generating resistance at high levels; however, it is just a matter of time before the epidemiological links are developed in the absence of effective interventions. V. The Revolving Door of Prisons and Links to the General Community A. Fluid Systems with Multiple Bridges to the General Community

The potential points for TB transmission within a detention system and between prisons and the community are multiple (Fig. 3). First, prisoners often move between institutions of a given network for purposes of investigation or security, which can lead to extensive outbreaks if active cases are not detected early and treated appropriately (29,30). HIV-infected inmates are particularly at risk, and community hospitals may become involved if sick prisoners are transferred for care. Similar outbreaks have occurred among jails (31–33). The spread of strains between prisoners and security staff has also been documented (29,31). Further, frequent family visitations can lead to a high number of prison visits and thereby increased exposure risks for the general community. Concerning this aspect, prisons may be categorized as either ‘‘restricted’’ or ‘‘open.’’ In countries of the former Soviet Union and many

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Figure 3 The civil–penal flow and links to the general community. Prisoners may be released back into the civil sector (public) from any point of the detention network. Visitors from the general community may also access the various detention sites. Source: From Ref. 26.

western countries, family member visitation rights can be modestly-toseverely restricted, even for nonhigh security inmates (i.e., visits permitted on a monthly basis or less frequently). However, overnight stays are allowed in Russia, for example. In some regions such as Latin America, prisons are considerably more ‘‘open’’ to family members on a weekly basis or greater, including spouses, children, parents, and siblings. They are also open to churches and educators, who run programs and schools within the prison. In Lurigancho prison (Lima, Peru), for example, the largest standing prison in Latin America with approximately 8000 inmates, there are three visitor days per week, two for women and children, and one for males. During a single year, there are some 600,000 adult visits and 300,000 child visits, or nearly 113 visits per inmate spot (Instituto Nacional Penitenciario, Peru, 2004; unpublished data). In Thailand, weekly visits are allowed, including child visitors (Medical Service Division, Department of Corrections, Ministry of Justice, Thailand, 2004). Thus for any given prison population, total exposure time and transmission potential to the community are multiples greater than would be thought to normally occur. Another mechanism for bridging of the inmate and general populations is the large annual turnover or exchange of prisoners entering and exiting the system. This ‘‘revolving’’ door has been described previously in the Russian Federation, where 300,000 detainees each (out of 1 million

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inmates, total) were entering and exiting the penal system as of 1999 (26). In Lurigancho prison (Lima, Peru), the average monthly intake of prisoners recorded in 2001 was 338 compared with 330 releases (Instituto Nacional Penitenciario, Peru, 2004; unpublished data). During 1995 in the United States, 521,970 inmates entered state prisons and 455,139 were released back to the community (34). In 1997, approximately 3% of the U.S. population spent time in either a jail or prison (7). VI. Establishing DOTS Programs in Prisons As the issue of undetected TB reservoirs and epidemics in prisons have been raised since several decades, so too have the calls for a comprehensive approach to its control (3,10,13,14,20,26,35,36). The recent push for expansion of modern TB control methods within the prisons of the former Soviet Union took full force with adoption of the Baku declaration in 1997 at the conclusion of a workshop organized by the World Health Organization (WHO) and the International Committee of the Red Cross (ICRC). The declaration concludes with an important warning (11): That if there is no response to our call for action, incurable tuberculosis will increase death among prisoners and their families and prison staff and their communities.

This call to action has been followed by new global momentum for assessing TB control programs in prisons. Guidelines have been released by the WHO, and there are an increasing number of prison TB control projects underway. A. Assessing the Structure of Existing Health Services for TB Control

Regardless of the country or setting and the amount of health resources available, prison and civilian TB control sectors share a common interest in working together to link activities at some level of operation. Because of the revolving or ‘‘open’’ doors between the prison and civilian communities, each in reality is a mutual stakeholder in the other’s programs, sharing the need for a ‘‘unified’’ or closely linked TB control program (Fig. 4). This need has been stated by the Committee of Ministers of the Council of Europe (37): Health policy in custody should be integrated into, and compatible with, national health policy. A clear division of responsibilities and authority should be established between the ministry responsible for health or other competent ministries, which should cooperate in implementing an integrated health policy in prison.

To determine the best approach for implementing TB control in prisons, a situation analysis must be made of the: (i) general administrative and health structures, (ii) human and financial resources available, and (iii)

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Figure 4 Linking civilian and prison directly observed therapy infrastructures. Source: From Ref. 26.

locations, types, and sizes of prisons, including the movement of prisoners, prison staff, and administrators between facilities. When evaluating the administrative and health structures to plan a program, there are a few key questions to be considered: 1.

2.

Is the prison health structure independent of and parallel to the civilian one? The organization and capacity of a prison health structure often reflect the size of a country’s prison population and/or the level of resources available to authorities for health care. In general, prison health resources (human and financial) are more limited compared with Ministry of Health (MOH) resources. Prison health services may also duplicate parallel activities readily available in the civilian sector, leading to more costly and inefficient DOTS services. Such duplication may occur with respect to inpatient care, laboratory functions [microscopy, culture, and drug susceptibility testing (DST)], recording and reporting systems, or drug management systems. Is the prison health structure part of a larger, centralized health structure? Some countries such as the Russian Federation have a large medical structure that is directed and controlled by a highly centralized, commanding medical service. Other countries with large prison populations may have medical services independently determined by each state or region. Such is the case in the

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3.

United States, where most prisoners are incarcerated as state rather than as federal prisoners. The level and quality of care may vary tremendously within a given country. Highly centralized systems tend to lead to parallel TB programs. What are the formal linkages, if any, to the civilian TB structure or general health structure? For a given state or region, some linkages may exist between the local civilian health services and the prisons within their area. For example, laboratory diagnostic services or drug supplies may come from the civilian public health sector. Civilian hospitals may also serve as referral centers for prisoners with acute medical care needs and surgical services. If such linkages already exist, expansion of DOTS activities into prisons can be greatly facilitated. However, linked civilian health structures may also have a limited capacity to support a prison program without additional resources or formal management and supervision links. It is easy to imagine that a civilian laboratory would be unable to handle a large influx of sputum specimens without expansion of their own capacities and resources, that is, microscopes, trained technicians, and quality assurance program.

B. DOTS in Prisons: Not Just Another Health Post

Regardless of structure, successful implementation of the DOTS strategy in prisons requires that the same five basic elements be in place as in a civilian program. Adjustments in the strategy, however, may be required along with consideration of additional program components. First, it would be an error to consider a prison or jail location as simply ‘‘another health post,’’ even in areas where the linkages with civilian TB programs are strong. Although such a characterization may assist in organizing civilian assistance for specific program components [i.e., staff training, civilian laboratory access for microscopy or culture/DST, drug supply management, and reporting and recording standards], prisons and jails are not representative of general communities. As noted above, incarcerated populations are special communities overrepresented by multiple, high-risk subgroups compared to the usual health-center population. Moreover, order among prisoners is often maintained through powerful internal hierarchies and/or gang affiliation, associated with strict means of prisoner–prisoner control. Precise rules exist, and prisonerimposed punishments are applied if the system is not respected. Such coercion does not exist in the general civilian sector. Consequently, the chief priority for a prison director is security rather than health, which can have a strong downstream influence on services such as access to prisoners and TB suspect/patients, interactions between prisoners and health staff, and the frequency of prisoner rotations or transfers. For all of these reasons, it would be a misjudgment on the part of a civilian

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program administrator to assume that a prison or detention center is just another health post. The basic DOTS elements as they pertain to the prison environment are as follows: 1.

2.

Political commitment: Although difficult to define, political commitment for TB control in prisons includes at least: (i) administrative support from the Ministry of Security and/or Justice and the Ministry of Health, for collaborative program development and implementation; (ii) policy formulation developed through joint prison-civilian-planning activities (tailored workplans) followed by joint evaluations, fully endorsed by policymakers at the highest levels; (iii) human resource development tied to general DOTS expansion activities; and (iv) financial support from local, regional, and national levels. Local nongovernment support may include that from community- and religious-based groups, or the sharing of income generated within the prisons (i.e., from farms, factories, concession stands, and markets). Whatever the degree of linkage and integration between prison and civilian systems, penal authorities must actively support the program down to the level of each prison director. Directors are key stakeholders and responsible for all activities within their jurisdiction. Their engagement and commitment needs to extend beyond acknowledgement of a TB problem or simply allowing a program to be developed. Their participation should evolve as that of accountable and equal partners, not peripheral collaborators. Just as prisoners may be transferred within a prison network for security reasons, the same may occur for directors. Consequently, political commitment for TB control must be fostered throughout the entire detention network. This particular lesson has been learned in several locations, including Kemerovo, Siberia, the Southern Caucasus, and Thailand (23,26, 38,39). It has been addressed successfully on a national scale in a recently implemented prison DOTS program in Honduras (40). Case detection with an emphasis on infectious cases: given the severely overcrowded conditions, concentration of risk groups and high turnover in detention settings, detection of the most infectious cases is of great importance. TB transmission to contacts of an active case is most strongly associated with a positive smear status and the presence of cavitation on chest radiograph (CXR) (41–45). Duration of exposure is another key variable with a significantly increased risk found on a per hour exposure basis (45). This factor was also noted in a large urban jail-community–linked outbreak, where TST conversion rates among jail contacts to the index case increased based on the number of exposure days: eight days of exposure or more, 48% (12/25);

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3.

4.

5.

three days or more, 24% (12/112); equal to one day or less, 15% (6/39). These differences were significant (p ¼ 0.01) (32). Another important variable is crowding. In a study of 16 state prisons in Maryland, prison-population density was the strongest factor associated with TB infection risk in a regression model (46). Finally, given the growing dual challenges of drug resistance and HIV infection among the incarcerated, more rapid laboratory methods are needed for confirmation of diagnosis and rapid detection of drug resistance (47). Adequate therapy using standardized approaches and DOT: the goals are to stop TB transmission by curing every case started on therapy and to prevent the emergence of a parallel drug-resistant TB epidemic. Unfortunately, where drug resistance already exists, primary transmission is possible as is spread into the community through the various mechanisms discussed above. Figure 2 illustrates how an uncontrolled TB situation due to inadequate treatment, frequent drug supply ruptures, and poor case management can lead to a worsening picture with development of parallel MDR and drug resistance epidemics. Given prisoner incentives to manipulate care in some settings, the need for ‘‘true DOT’’ cannot be underestimated in jails and prisons (11–14). Reliable and uninterrupted supply of all essential anti-TB drugs: the primary goal is to achieve high cure rates and prevent the emergence of drug resistance, which is already a significant issue for many countries (Table 2). Because prison health resources and capacities are often significantly less than those of the MOH, program linkages that address drug management are important. Standardized patient monitoring and recording and reporting systems: the primary goals are to closely monitor case therapy and to perform regular (quarterly) cohort analysis on treatment outcomes. Patient monitoring allows health staff and supervisors to identify individual problems early; cohort analysis allows managers to identify program problems without prolonged delays that require investigation and intervention. Depending upon the size of the program, prison TB data can be maintained at the district or regional level. A mechanism for combining prison and civilian data at some level is required to allow for a comprehensive information system and complete reporting of disease burden.

Building upon the standard DOTS strategy, TB control in prisons and jails requires two or three additional components to address the high rate of disease, large reservoir of latently infected persons, and growing threat of drug resistance: 1.

Entry screening through active case finding (ACF) combined with other routine postentry methods: Although routine case detection

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with investigation of respiratory symptomatics (RS) remains a fundamental activity in all settings, entry screening through ACF using various screening approaches is essential in prisons, jails, and pretrial detention centers (Table 1). The goal of entry screening is to keep TB out by: (i) diagnosing previously undetected cases in need of therapy, (ii) identifying previously detected cases with incomplete therapy, and (iii) reinstituting therapy for those who have dropped out of treatment in the civilian sector. The impact of effective entry screening is to reduce the pool of prevalent cases. The subsequent detection of cases through routine measures (i.e., cough registries, investigation of RS, and contact investigation of cellmates or other close contacts) is meant to identify incident cases postentry and keep the prevalent pool from refilling. Thus, screening and case finding is a continuous and overlapping process requiring multiple points of detection (Fig. 5). The optimal strategy for active case detection will vary widely across settings, based on considerations of TB program performance for case detection and cure, proposed screening frequency, and the probabilities (or burden) of key variables such as LTBI, HIV infection, TB–HIV coinfection, and other risks (48,49). It is also influenced by upfront cost and availability of resources to implement and maintain the screening activities (human and financial capacities). Consequently, it is difficult to

Figure 5 Points of detection of the respiratory symptomatic and tuberculosis cases in prisons.

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2.

compare data across settings. Moreover, most screening studies do not compare strategies concurrently. In a study of ACF methods in three prisons in the Republic of Georgia, which compared a clinical questionnaire with mass miniature radiography (MMR), the predictive value positive for MMR was higher than that of the clinical questionnaire, 17.6% and 7.5%, respectively. Using culture as the gold standard for TB diagnosis, the clinical questionnaire was more sensitive than MMR; specificity was similar (50). In a study of entry screening at a federal prison in San Diego (n ¼ 1830), where all new entrants received both a TST and a CXR (posterior–anterior view), universal CXR screening was no more sensitive than TST for detecting active TB among new foreign-born entrants (51). Symptoms were uncommonly reported. CXR screening, however, did reduce exposure time to cases by 75%. An important study limitation was the overrepresentation of foreign-born detainees (74%) in this prison, who had a TST positivity rate of 48%. DOTS program expansion to cover an entire detention network: moving beyond a single referral colony or hospital through a decentralized approach: a key challenge to the control of TB in an epidemic setting is how to rapidly extend case detection and provide adequate treatment to all those in need. This issue is relevant even when limiting an initial program to a specially designated TB colony or large referral TB hospital, which may have multiple buildings and wards scattered widely. Access to the entire population of known cases and suspects is required to prevent death and the development of drug resistance. Access to the entire incarcerated population is required to detect cases early in the periphery of the system, where adequate care may not exist and patients often rely on family members to provide drugs. The first point is well illustrated by the experiences of ICRC in Azerbaijan and Medecins sans Frontie`res (MSF) in Kemerovo, Siberia (12,23,38). The death rate in Colony 33, a large TB referral treatment colony, did not drop significantly until the colony’s entire TB population (all wards; n ¼ 1300 active cases) was accessed and placed on DOTS (26). A regionwide decline in newly detected (incident) prison TB cases occurred much more slowly than the observed decline in TB associated mortality (Fig. 6), achievable only after a mobile screening program was established for the peripheral colonies and delays to diagnosis and treatment were significantly reduced inside Colony 33 (from three months to two weeks). The latter was accomplished by addressing administrative control issues. Increasing the turnover of existing TB beds also led to a critical decompression of the system (i.e., patients completed treatment without unnecessary delays and were sent to another colony for posttreatment

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Figure 6 Tuberculosis trends in prisons, 1988 to 2001, Kemerovo Oblast, Siberia. Source: Kemerovo Regional Tuberculosis Dispensary.

surveillance, thus opening a TB bed for a new suspect/patient from a peripheral or general colony). The second point regarding access to the entire incarcerated population highlights the challenges of program expansion or decentralization throughout an entire prison network, including pretrial detention centers and jails. Again in Kemerovo, Siberia, the DOTS program was decentralized to include the second TB referral colony (for high-security prisoners) and to pretrial detention centers (SIZOs). Despite concerns that completion of therapy could not be guaranteed in such unstable settings, an evaluation of one large SIZO concluded that DOTS expansion was feasible (52). In order to reach an entire detention network, linkages to the civil sector will become increasingly important. In Thailand, despite a well-designed and implemented DOTS program in some of the country’s prisons, the reported mortality among new smear-positive patients in 16 prisons over three years was 18%, while 11% of patients were transferred out. Although concurrent mortality in the civilian program was also reported to be high (11% for the general population), the cause for the higher prison rate could not be determined; HIV testing and DST were not routinely performed. One significant barrier noted to the early diagnosis of prison cases was the nonexistence of laboratory services in prisons coupled with a limited laboratory capacity in the civil sector (at local hospitals) to support diagnosis in prisons. The problem was partially addressed in one region when

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3.

a prison laboratory service was established, and the National TB Program (NTP) trained prison nurses to examine sputum specimens. Noting that most cases released back to the community could not be found, the authors concluded that an improved civilian referral system was a priority need (39). Consideration of alternative treatment regimens and the use of standardized, empiric regimens for MDR-TB, especially for the retreatment of failure cases: given the documented levels of drug resistance in prisons (Table 2) and among some civilian populations (53), the issue of the adequacy of usual, standardized regimens in such settings must be carefully considered, particularly where there is a history of widespread and chaotic drug use (23,24). Any consideration to change treatment strategies, however, must be based on the local epidemiology of disease with availability of recent and representative drug resistance data performed by a qualified laboratory (54–56). Alternative and/or empiric MDR regimens must be based on (i) their adequacy given documentation of local, representative drug resistance data or individual case data, (ii) the availability of and access to the required drugs in-country without threat of stock ruptures, and (iii) the guarantee of continuation of therapy in the civilian sector if a patient is released prior to treatment completion. Consequently, the idea of having a MDR-TB program in the prison sector without a similar program in the civilian sector (or vice versa) poses not only logistical problems, but also ethical questions, in particular the issue that prisoners and civilians should have access to equitable care.

C. Screening in Prisons: When and How?

As discussed above, given the risk groups represented among prisoners, the high rates of recidivism in many settings, and the extraordinary rates of active TB recorded, it is essential that screening and ACF be incorporated into all prison-control programs, starting as close to the entry point into the system as feasible. Passive case detection that focuses on the respiratory symptomatic alone is inadequate. While an overview of the various points of detection is shown in Figure 5, each strategy is considered below:
Entry screening in jails and pretrial detention facilities (to detect and reduce the TB prevalence pool): As the entry point into most detention systems, high rates of TB are often detected in jails. It is not uncommon to find cases of TB upon jail entry screening, including previously diagnosed cases with incomplete therapy or lost to care (Table 1). In a large pretrial detention center in Kemerovo, Siberia, the detection rate at entry over a one-year period was 4560 (per 100,000), accounting for 84% (114/136) of all cases detected among that cohort over the same year of incarceration (52).

Tuberculosis Control in Prisons














939

Entry screening in prisons, including screening for mass transfers (to detect and reduce the TB prevalence pool): Table 1 also illustrates the high rates of undetected TB in prisons found either at entry or as part of a mass-screening campaign. In a newly opened prison in Barcelona, among 702 transfers without a history of TB and who completed a new entry-screening program, 19 culture-confirmed pulmonary TB cases were detected (2.7%) (3). A study in Botswana found a rate of undetected TB among guards that closely matched the rate among prisoners (2662 and 3797, respectively), thus illustrating that guards should be considered part of the at risk population within the prison environment (22). Routine case detection and assessment of RS (to detect new incident cases or cases missed upon entry screening): An RS may present to the staff or clinic directly, or be identified through cell monitors and other surveillance methods, i.e., establishment of cough monitors and registers. Thus, RS detection may combine ‘‘passive’’ means with ACF activities. When employed as part of a screening plan (Fig. 5), it can be effective as a means to identify postentry cases early; however, when relied upon as the primary means of TB control, it is inadequate. Contact investigations (CIs) for close prison contacts to an active case: CI in prisons is not routinely done at the international level. However, secondary cases among contacts to an active case have been identified where this information is available. In Honduras prisons, for example, CI were implemented over a two-year period (2002–2003) and accounted for 11% of newly detected TB cases (source: Gorgas TB Initiative/University of Alabama at Birmingham and the Honduran Ministry of Health; unpublished data). In a retrospective assessment of the Georgia, United States, state prison system covering a five-year period, 9% of cases detected postentry were through contact evaluation (57). Prison staff should also be included in such investigations as they can be part of an outbreak or even a source case (22,29,31). Exit screening prior to release or transfer: Although routine screening prior to release would be ideal, it is difficult to implement for logistical and administrative reasons. Releases and amnesties can occur with little or no advanced warning, and delaying a release for screening purposes would be problematic in most settings. Consequently, exit screening is more theoretical than practical. However, the possibility of missed cases being released exists, even where annual TST is performed. In a Maryland study, four new cases of pulmonary TB were reported to the state TB program within three months of release (144/100,000/year) (58). Contact investigation of family members and other community contacts: Although CI in the community is not the responsibility

940

Kimerling of prison health staff, it is important that civilian authorities be notified whenever an inmate is detected with TB to consider the need for a household investigation. This is particularly relevant for family/household members of: (i) infectious inmate cases detected at entry and (ii) cases that develop in prison postentry, especially where frequent or extended contact between inmates and their families is allowed. The crossing of TB cases (clusters) between the penal and civil sectors has been documented through analysis of matching DNA fingerprint patterns in several locations (32,59,60). Unfortunately, it is not possible to determine where the clusters originated.
Mass screening: Mass screening can be employed to identify undetected prevalent cases, especially in situations where routine screening systems are inadequate or undeveloped, or during special outbreak situations, that is, among a cohort of HIV-infected prisoners. In some settings such as the Russian Federation and other former Soviet Union republics, mass screening is employed on an annual or six-monthly basis using MMR. Such mass screening is logistically complex and costly; consequently, it is often not performed adequately. In the Republic of Georgia, in a project supported by ICRC, periodic mass screening has been introduced using a clinical questionnaire (in addition to entry screening and routine detection of RS) (61). By increasing the frequency over time (randomly in 2001, yearly in 2002 and twice yearly in 2003), they screened more inmates and found a lower proportion of sputum smear-positive cases among those screened. Although the data suggests a decline in infectious cases with six-monthly mass screening, the study’s authors also note that it is not yet a sustainable activity, neither financed nor coordinated by the Ministry of Justice. In a prior report on mass screening in Georgia, the main barriers encountered were the fixed laboratory capacity to process and test sputum samples in addition to basic challenges of sputum collection and transport (20).

Such mass-screening strategies should be distinguished from other settings, such as the United States, where annual medical screening of long-term inmates using TST is done for those who have a negative skin test. Those with a previous positive TST are screened for symptoms. The goal is to identify missed cases and assess evidence of recent transmission in order to provide appropriate therapy (36). However, in most international settings, skin testing is not routinely available or performed, and LTBI therapy is recommended only for household child contacts and the HIV-infected. Although LTBI therapy in the prison setting should ideally be offered, the choice of drug to use is complicated by high rates of drug resistance, including isoniazid resistance (Table 2).

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D. Infection Control Measures

Infection control measures for institutional settings can be classified into three main areas: administrative (managerial) controls, personal respiratory protection, and engineering controls (62,63). An infection control plan takes into account all three areas. Administrative controls are generally based on management and organizational issues that reflect the most basic commitment to implementing effective TB control. Administrative measures focus on limiting delays to diagnosis and treatment (especially of infectious cases), placing patients on adequate therapy, and educating health staff and patients about appropriate separation of infectious cases. The latter element is particularly important wherever drug-resistant TB is prevalent or HIV-infected prisoners are present. In the prison setting, separation of an infectious case should in no way be utilized or presented as a punishment for those persons (14). Personal respiratory protection measures include the use of N-95 disposable (particulate) respirators or even more efficient masks in extreme risk areas of exposure, particularly where ventilation is inadequate. Surgical masks or homemade gauze masks do not represent adequate means of personal respiratory protection. The major barrier to this infection control element is the resistance by staff to comply with such measures, despite availability of such masks. Prisoners with TB should also be instructed to cover their mouths when they cough, to reduce the number of infectious droplet nuclei expelled into the air. Engineering controls are the most complex and expensive measures to design, install, and maintain. They are normally based on equivalent air exchanges/ventilation or air recirculation with high efficiency particulate air filtration to reduce the concentration of droplet nuclei in a high-risk environment. Short-wavelength (germicidal) ultraviolet (UV) irradiation rapidly kills Mycobacterium tuberculosis upon direct exposure, but does not work unless the organism is circulated within immediate proximity to the light. To be effective, UV lights must be kept clean of dust and properly maintained; high levels of humidity above 60% also impact the effective killing power of UV irradiation (64). For these reasons, UV lights are often incorrectly utilized and relied upon in prisons and jails, providing a false sense of infection control security. In terms of human safety, UV lights should be shielded from the human eye due to the risk of corneal irritation; skin overexposure can lead to erythema. When modern engineering controls are not available, simpler measures can be taken: (i) opening of windows to create a natural cross-draft or directional airflow; (ii) designing new, open air wards; and (iii) designating special, well-ventilated sputum collection areas in front of open windows (with or without UV lights) or outside. If such systems are used, it is important that the ventilation and airflow create air exchange with the outside air rather than only blowing contaminated air into interior rooms or corridors. If ceiling fans are employed, they should be used in concert with open windows; air mixing without air dilution and exchange is not

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adequate. In regions with long, cold winters, the opening of windows and use of natural ventilation may be impractical; therefore, more expensive engineering control methods may be required. Finally, it is imperative that any prison laboratory be included in an institution’s infection control plan, because it represents a high risk environment for transmission. Other high-risk areas to consider are radiology departments, surgical suites, intensive care units, and enclosed common shower areas. E. DOTS Training, TB Education, and Information Campaigns in Prisons

Approaching prisons as ‘‘communities’’ implies that training about TB and the DOTS strategy should not be limited to the health staff and TB patient (Fig. 7). As noted above, education of the prison administration is a key initial step in soliciting sustained political commitment. Program success is equally dependent upon gaining the trust and building partnership with the general prison community, inclusive of the internal prison hierarchy. Information, education, and communication (IEC) activities also provide a means to recruit prisoner volunteers to work in the program (i.e., as treatment

Information Campaigns and Educational Activites

DOTS Action Plan Development

Infection Control

DOTS Implementation

Education and Training

Detection and Investigation of Respiratory Symptomatic

Case Detection and Treatment

Volunteer Training

Network of Program Volunteers

Figure 7 Education and training across all levels increases program momentum and commitment among the multiple stakeholders.

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observers, clinic staff, or for maintaining cough registries in each dormitory). Therefore, a well-developed IEC program provides a unique opportunity to overcome the potential distrust that may exist between prison health staff, as representatives of the prison system, and the inmates. Contrary to experience elsewhere (11), the experience in Honduran prisons has shown that inmates are open to TB education and will actively engage the IEC process through both formal and recreational channels (65,66). Events and competitions (e.g., skits, song contests, and soccer matches) can be held on World TB Day, health education programs can be developed for prison schools, and informational products used by churches and other outlets (e.g., barbershops). The IEC messages should also reach family members and community visitors. Thus, education and training is employed throughout the prison community, at all stages in the development of a program and as a means to engage all stakeholders to maintain momentum. F. Preparation for Release and Continuation of TB Treatment

The continuation of TB therapy postrelease is a key indicator of the quality of prison-civil sector linkages and coordination; it is also a key issue in the prevention of relapse and development of drug-resistant disease. The lack of a strong civilian program, for example, can limit the effectiveness of a well-organized prison program, if released prisoners do not report to a treatment center and cannot be traced. Success may require direct support upon release (i.e., access to housing, transportation, food, or other components of the social support system). Despite significant efforts, released prisoners may simply not want to be found or monitored, as was documented in Thailand (39). In a study of released prisoners on TB therapy in St. Petersburg, Russia, only 26% were subsequently found in the attendance records of the local TB dispensaries (67). Similarly, in four pilot oblasts in Kazakhstan, only 25% to 30% of released TB patients registered at a civilian TB dispensary for continuation of treatment (68). In the state of Georgia, United States, just 62% of released prisoners with TB over a five-year period completed therapy; the remainder were lost to follow-up (57). Preparation for release is therefore a key component for establishing treatment continuation in the community (10,57,68). It requires additional patient education and staff awareness of each patient’s social situation. Patients must be informed where they should go to continue their treatment, and health units should be informed of pending transfers into their program. Basic social and personal needs should be addressed, particularly for those without family support, employment opportunities, and with continuing problems of drug and alcohol addiction. A decision must also be taken whether or not to release the patient with TB medications for an interim period to allow time for the establishment of contact with a local treatment center. Finally, the reporting unit

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(usually where the TB diagnosis was made) must follow up with the transfer-in unit to determine the treatment outcome for inclusion into the cohort analysis. Ideally, a patient-tracing system should be available for finding released inmates who do not report to a civilian treatment unit. To facilitate release, all of the above-mentioned preparations should begin upon diagnosis of a prison case as administrative decisions concerning release may be made with little or no warning, thereby not allowing time for last-minute planning. It is conceivable that such releases could be held for a minimal period (24 hours) to allow for proper treatment continuation planning. However, in a well-managed system, these preparations should be initiated at time of diagnosis. Although predischarge planning often falls under the responsibility of a nurse, in Tomsk Oblast (Siberia, Russian Federation), a different approach was taken in a program supported by the organization Merlin, which was to employ a full-time social worker for this purpose (69). In Kazakhstan, in a project supported by the KNCV Foundation, monitoring committees have been established to facilitate penal–civil linkages. These committees are composed of volunteers from civil society, who visit the prisons in their regions, including human rights lawyers, journalists, psychologists, teachers, and TB physicians. Major functions are to facilitate prisoner preparation for release and the follow-up of TB cases postrelease. Similar to the Tomsk project, the monitoring committees support prisoners in accessing local means of social assistance (68). VII. Conclusions and Challenges Ahead Given the disproportionate disease burden and convergence of risk groups, TB control in jails, pretrial detention centers, and prisons is fundamental to DOTS expansion efforts globally. To implement an effective program, an understanding of both sides of the wall is required, and, despite the unique challenges, has proven to be achievable where sustained political commitment exists. Each sector (prison and civilian) is an important stakeholder in the other, sharing the goals of stopping transmission, preventing drug resistance, and controlling TB. Well-planned linkages are mandatory to guarantee appropriate and adequate therapy that will often cross sectors. However, national prison and TB program administrators must recognize and respect the differences inherent to each sector’s target populations, in particular the special challenges in establishing a program among the incarcerated. DOTS programs in prisons cannot be regarded as simply another treatment unit of the NTP. In countries where dedicated medical services serve its incarcerated population, prison authorities have a responsibility to collaborate closely with their civilian counterparts to guarantee the same level of care as found in the civilian sector and to facilitate the continuation of treatment for prisoners postrelease. DOTS expansion efforts in prisons and other detention settings must also take into account the need for additional elements, the most

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important being screening at entry to identify and reduce the prevalent pool of cases. However, entry screening should be developed as part of a comprehensive case detection and surveillance system, including the identification and investigation of RS as well as investigation of close contacts. Solely relying upon periodic mass screenings to detect active TB is not sufficient; further, it is logistically complex and wasteful of time, and human and financial resources. Given the growing and constant movement of high-risk persons into and out of detention networks, the millions of annual visits made by family members and friends from the general community and the daily contact between prisoners and staff, the reality is that TB control is dependent upon the actions and standards established on each side of the wall. If done well, TB programs developed in prisons can serve as general health and prevention models, thereby creating a conduit for other disease control and treatment initiatives. Although initially benefiting the prison community, because of the multiple bridges between the prison and civil sectors, a successful prison-based intervention will ultimately impact the larger general community. If not done well, the problems of rising TB morbidity and mortality, growing rates of TB–HIV coinfection, and untreatable drug-resistant disease will remain as threats. Finally, the role of LTBI therapy in prisons globally has not yet been addressed, reflecting in part the fact that this challenge is not well defined in corresponding civilian programs. Should LTBI therapy become routine given the high disease and infection rates, and convergence of at-risk groups? Considering the drug-resistance burden in some programs where the needs are often greatest, what regimen would be adequate? Any attempt to introduce such a program component must first seriously consider these issues and the obstacles to completion of LTBI therapy. As has been documented for postrelease TB cases, continuation of treatment remains a serious barrier.

References 1. Department of Health and the International Centre for Prison Studies. Prison health and public health: the integration of prison health services. Report from a conference at King’s College London, April 2, 2004. 2. Glaser JB, Greifinger RB. Correctional health care: a public health opportunity. Ann Intern Med 1993; 118:139–145. 3. Martin V, Gonzalez P, Cayla JA, et al. Case-finding of pulmonary tuberculosis on admission to a penitentiary centre. Tubercle Lung Disease 1994; 74:49–53. 4. Souza MMM, Costa MJM, Toledo AS, et al. The profile of TB in the penitentiary system of Rio de Janeiro, Brasil. Int J Tuberc Lung Dis 1999; 3:S19. 5. Kalinin JI. The Russian penal system: past, present and future. A lecture at King’s College, University of London, 2002. 6. National Commission on Correctional Health Care. The health status of soon-to-bereleased inmates: a report to Congress, Vol. I and II, 2002.

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7. Hammett TM, Harmon MP, Rhodes W. The burden of infectious disease among inmates of and releasees from US correctional facilities, 1997. Am J Public Health 2002; 92:1789–1794. 8. Pleumpanupat W, Jittimanee S, Akarasewi P, et al. Resistance to anti-tuberculosis drugs among smear-positive cases in Thai prisons 2 years after the implementation of the DOTS strategy. Int J Tuberc Lung Dis 2003; 7:472–477. 9. AIDS Foundation East-West. www.afew.org (accessed November 2004). 10. Abeles H, Feibes H, Mandel E, et al. The large city prison – a reservoir of tuberculosis. Am Rev of Resp Dis 1970; 101:706–709. 11. Reyes H, Coninx R. Pitfalls of tuberculosis programmes in prisons. BMJ 1997; 315:1447–1450. 12. Kluge H. Implementing a TB treatment programme in Colony 33, Marinsk, Siberia. In: Stern V, ed. Sentenced to Die? The Problem of TB in Prisons in Eastern Europe and Central Asia. London: International Centre for Prison Studies, 1999. 13. Coninx R, Maher D, Reyes H, et al. Tuberculosis in prisons in countries with high prevalence. BMJ 2000; 320:440–442. 14. Bone A, Aerts A, Grzemska M, et al. Tuberculosis Control in Prisons: A Manual for Programme Managers. World Health Organization (WHO), 2000. WHO/CDS/TB/ 2000.281. 15. Lobato MN, Leary LS, Simone PM. Treatment for latent TB in correctional facilities: a challenge for TB elimination. Am J Prev Med 2003; 24:249–253. 16. Koffi N, Ngom AK, Aka-Danguy E, et al. Smear positive pulmonary tuberculosis in a prison setting: experience in the penal camp of Bouake, Ivory Coast. Int J Tuberc Lung Dis 1997; 1:250–253. 17. Puisis M, Feinglass J, Lidow E, et al. Radiographic screening for tuberculosis in a large urban county jail. Public Health Rep 1996; 111:328–329. 18. Layton MC, Henning KJ, Alexander TA, et al. Universal radiographic screening for tuberculosis among inmates upon admission to jail. Am J Public Health 1997; 87:1335–1337. 19. Nyangulu DS, Harries AD, Kang’ombe C, et al. Tuberculosis in a prison population in Malawi. Lancet 1997; 350:1284–1287. 20. Aerts A, Habouzit M, Mschiladze L, et al. Pulmonary tuberculosis in prisons of the ex-USSR state Georgia: results of a nation-wide prevalence survey among sentenced inmates. Int J Tuberc Lung Dis 2000; 4:1104–1110. 21. White MC, Tulsky JP, Portillo CJ, et al. Tuberculosis prevalence in an urban jail: 1994 and 1998. Int J Tuberc Lung Dis 2001; 5:400–404. 22. Centers for Disease Control and Prevention. Rapid assessment of tuberculosis in a large prison system – Botswana, 2002. Morb Mort Wkly Rep 2003; 52:250–252. 23. Coninx R, Mathieu C, Debacker M, et al. First-line tuberculosis therapy and drug resistant Mycobacterium tuberculosis in prisons. Lancet 1999; 353:969–973. 24. Kimerling ME, Kluge H, Vezhnina N, et al. Inadequacy of the current WHO re-treatment regimen in a central Siberian prison: treatment failure and MDR-TB. Int J Tuberc Lung Dis 1999; 3:451–453. 25. Shemyakin AV, Isakov AM, Barnashov AV, et al. DOTS effectiveness: TB mortality and MDR-TB in the penitentiary system of Tomsk Oblast, Russia. Int J Tuberc Lung Dis 2003; 7:S140. 26. Kimerling ME. The Russian equation: an evolving paradigm in tuberculosis control. Int J Tuberc Lung Dis 2000; 4:S160–S167. 27. Kimerling ME, Slavuckij A, Chavers S, et al. The risk of MDR-TB and polyresistant tuberculosis among the civilian population of Tomsk city, Siberia, 1999. Int J Tuberc Lung Dis 2003; 7:866–872.

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28. Centers for Disease Control and Prevention. Primary multidrug-resistant tuberculosis – Ivanovo Oblast, Russia, 1999. Morb Mort Wkly Rep 1999; 48:661–664. 29. Valway SE, Richards SB, Kovacovich J, et al. Outbreak of multi-drug-resistant tuberculosis in a New York state prison, 1991. Am J Epidemiol 1994; 140:113–122. 30. McLaughlin SI, Sprading P, Drocuik D, et al. Extensive transmission of Mycobacterium tuberculosis among congregated, HIV-infected prison inmates in South Carolina, United States. Int J Tuberc Lung Dis 2003; 7:665–672. 31. Jones TF, Craig AS, Valway SE, et al. Transmission of tuberculosis in a jail. Ann Intern Med 1999; 131:557–563. 32. Bur S, Golub JE, Armstrong JA, et al. Evaluation of an extensive tuberculosis contact investigation in an urban community and jail. Int J Tuberc Lung Dis 2003; 7:S417–S423. 33. Centers for Disease Control and Prevention. Tuberculosis transmission in multiple correctional facilities – Kansas, 2002–2003. Morb Mort Wkly Rep 2004; 53:734–738. 34. Kendig N. Tuberculosis control in prisons. Int J Tuberc Lung Dis 1998; 2:S57–S63. 35. Stead WW. Undetected tuberculosis in prison: source of infection for community at large. JAMA 1978; 240:2544–2547. 36. Centers for Disease Control and Prevention. Prevention and control of tuberculosis in correctional facilities: recommendations of the Advisory Council for the Elimination of Tuberculosis. Morb Mort Wkly Rep 1996; 45(No. RR-8):1–27. 37. Recommendation No. R (98) 7 of the Committee of Ministers to member states concerning the ethical and organizational aspects of health care in prison. Council of Europe, 1998. 38. Kimerling ME. Colony 33 tuberculosis control program. Project visit consultant report for MSF-Belgium, 1998. 39. Nateniyom S, Jittimanee SX, Ngamtrairai N, et al. Implementation of the DOTS strategy in prisons at provincial level, Thailand. Int J Tuberc Lung Dis 2004; 8:848–854. 40. Arias M, Paz N, Branigan E, et al. DOTS expansion into Honduran prisons. Int J Tuberc Lung Dis 2003; 7:S142-S143. 41. Shaw JB, Wynn-Williams N. Infectivity of pulmonary tuberculosis in relation to sputum status. Am Rev Tuberc 1954; 69:724–732. 42. Grzybowski S, Barnett GD, Styblo K. Contacts of cases of active pulmonary tuberculosis. Bull Int Union Tuberc 1975; 50:90–106. 43. Rose CE, Zerbe GO, Lantz SO, et al. Establishing priority during investigation of tuberculosis contacts. Am Rev Respir Dis 1979; 119:603–609. 44. Rieder HL. Epidemiologic Basis of Tuberculosis Control. Paris: IUATLD, 1999. 45. Bailey WC, Gerald LB, Kimerling ME, et al. Predictive model to identify positive tuberculosis skin test results during contact investigations. JAMA 2002; 287: 996–1002. 46. MacIntyre CR, Kendig N, Kummer L, et al. Impact of tuberculosis control measures and crowding on the incidence of tuberculosis infection in Maryland prisons. Clin Infect Dis 1997; 24:1060–1067. 47. Hale YM, Pfyffer GE, Salfinger M. Laboratory diagnosis of mycobacterial infections: new tools and lessons learned. Clin Infect Dis 2001; 33:834–846. 48. Murray CJL, Salomon JA. Expanding the WHO tuberculosis control strategy: rethinking the role of active case finding. Int J Tuberc Lung Dis 1998; 2:S9–S15. 49. Jones TF, Schaffner W. Miniature chest radiograph screening for tuberculosis in jails: a cost-effectiveness analysis. Am J Respir Crit Care Med 2001; 164:77–81. 50. Creac’h P. Case finding strategies for prisons: rethinking approaches. Int J Tuberc Lung Dis 2004; 8:S3–S4.

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51. Saunders DL, Olive DM, Wallace SB, et al. Tuberculosis screening in the federal prison system: an opportunity to treat and prevent tuberculosis in foreign-born populations. Public Health Rep 2001; 116:210–218. 52. Slavuckij A, Sizaire V, Lobera L, et al. Decentralization of the DOTS program within a Russian penitentiary system: how to ensure the continuity of tuberculosis treatment in pre-trial detention centers. Eur J Public Health 2002; 12:94–98. 53. World Health Organization. Anti-tuberculosis drug resistance in the world: The WHO/IUATLD global project on anti-tuberculosis drug resistance surveillance, 1999–2002. WHO/CDS/TB/2004. 54. Quy HT, Lan NT, Borgdorff MW, et al. Drug resistance among failure and relapse cases of tuberculosis: the standard re-treatment regimen adequate? Int J Tuberc Lung Dis 2003; 7:631–636. 55. Espinal MA. Time to abandon the standard retreatment regimen with first-line drugs for failures of standard treatment. Int J Tuberc Lung Dis 2003; 7:607–608. 56. World Health Organization. Treatment of Tuberculosis: Guidelines for National Programmes. 3d ed. WHO/CDS/TB/2003.313. Revision approved by STAG, June 2004. http://www.who.int/docstore/gtb/publications/ttgnp/index.html (accessed November 2004). 57. Bock NN, Reeves M, LaMarre M, et al. Tuberculosis case detection in a state prison system. Public Health Rep 1998; 113:359–364. 58. MacIntyre CR, Kendig N, Kummer L, et al. Unrecognised transmission of tuberculosis in prisons. Eur J Epidemiol 1999; 15:705–709. 59. Pelletier AR, DiFerdinando GT, Greenberg AJ, et al. Tuberculosis in a correctional facility. Arch Intern Med 1993; 153:2692–2695. 60. Fernandez de la Hoz K, Inigo J, Fernandez-Martin JI, et al. The influence of HIV infection and imprisonment on dissemination of Mycobacterium tuberculosis in a large Spanish city. Int J Tuberc Lung Dis 2001; 5:696–702. 61. Schmid L, Creac’h P, Chorgoliani D, et al. DOTS programme in prisons of Georgia in 2001–2003 years. Int J Tuberc Lung Dis 2004; 8:S168. 62. Centers for Disease Control and Prevention. Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care facilities, 1994. Morb Mort Wkly Rep 1994; 43(No. RR-13):6–7. 63. Granich R, Binkin NJ, Jarvis WR, et al. Guidelines for the prevention of tuberculosis in health care facilities in resource-limited settings. World Health Organization (WHO), 1999. WHO/CDS/TB/99.269. 64. Riley RL, Kaufman JE. Effect of relative humidity on the inactivation of airborne Serratia marcescens by ultraviolet irradiation. Appl Environ Microbiol 1972; 23: 1113–1120. 65. Mangan JM. Establishing a national prison IEC program: the Honduras experience. Int J Tuberc Lung Dis 2004; 8:S4. 66. Mangan JM, Arias MS, Paz de Zavala N, et al. Examining the strengths, weaknesses, opportunities and threats within tuberculosis information, education, and communication (IEC) campaigns for prisoners in Honduras: refining campaign content and prioritizing targets for future intervention. Int J Tuberc Lung Dis 2004; 8:S115. 67. Khoshnood K, Fry R, Granskaya J, et al. Post-release TB treatment among Russian prisoners. Int J Tuberc Lung Dis 2004; 8:S173. 68. Pak S. Continuity of TB care following release from prison: monitoring committees in Kazakhstan. Int J Tuberc Lung Dis 2004; 8:S4–S5. 69. Oransky I. Tim Cullinan. Lancet 2004; 364:22.

37 Tuberculosis Control in Mines

GAVIN J. CHURCHYARD

ELIZABETH L. CORBETT

Aurum Institute for Health Research, CAPRISA, University of Kwa-Zulu Natal, Marshalltown, Gauteng, South Africa

Clinical Research Unit, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine Funded by the Wellcome Trust, London, U.K.

I. Introduction Occupational lung disease or ‘‘Miner’s phthisis’’ has been recognized for more than 2000 years (1). The distinction between noninfectious and infectious causes was not made until the early 20th century, however, when a worldwide epidemic of acute silicosis resulted from the invention of the pneumatic drill and focused attention on the hazards of dust exposure (2). Silicosis is one of a number of fibrotic lung diseases (pneumoconioses) that result from occupational dust exposure. All types of pneumoconiosis carry an increased susceptibility to mycobacterial disease, but the excess risk is small for all except silicosis, which is a potent risk factor for both tuberculosis (TB) and nontuberculous mycobacterial disease and is the main focus of this chapter (1–10). Silicosis is not unique to mining and, among miners, only those working with hard rock of a high silica content, such as granite or gold-bearing quartz, are at high risk (1,4). However, TB control can become a very special challenge when large workforces of migrant workers live in crowded conditions and are exposed to silica in settings where TB is endemic and occupational health control is suboptimal. This was the situation in 949

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America and Europe in the first half of the 20th century (2) and still applies to hard rock mines in many parts of the world today (1,3,7,11). In Africa, the HIV epidemic has now added a new dimension to these long-standing problems, as has been well documented for the gold-mining industry of South Africa (8–10,12–24). The first part of the chapter will describe the association between silica dust exposure, silicosis, and TB. The second part will describe the impact of the HIV epidemic on TB control in mines, which has been best described among South African gold miners. The third part will discuss TB control strategies in mines. II. Epidemiology A. Silicosis

Silicosis results from the inhalation of crystalline silica particles of up to 5-mm diameter. Particles of this size can impact on the respiratory mucosa of alveoli and terminal bronchioles (25). Silica is toxic to macrophages and neutrophils, particularly when freshly fractured following blasting (25–27). Clearance of silica particles from the lungs is extremely slow (28). Intense exposure results in acute silicosis, which is characterized by diffuse alveolar inflammation, rapidly progressive loss of lung function, and death from respiratory failure within months to years (2). Less intense exposure leads to chronic silicosis, typically after 15 or more years of exposure. The risk of chronic silicosis increases with cumulative silica dose, but fibrosis can progress, or become apparent for the first time, many years after exposure has ceased (3,29,30), presumably due to residual intrapulmonary silica (28). The hallmark of chronic silicosis is the development of silicotic nodules composed mainly of collagen and surrounded by fibroblasts and dust-laden macrophages (2). Nodules are detectable as rounded opacities on chest radiographs, which first appear and remain most prominent in the upper lung zones. The International Labour Organization (ILO) has produced a widely used system for radiological grading of silicosis into nodule profusion categories between 0 (none) and 3 (numerous nodules: vascular markings obscured) (31). There is, however, considerable interobserver variation both for distinguishing normal from abnormal radiographs and for severity of disease (29,32–34). Radiology has high specificity but low sensitivity (14,35). Consequently, the radiological prevalence of silicosis will tend to underestimate the true burden of disease, and cohorts of silicaexposed workers with normal radiographs cannot be considered to be free of histological silicosis. B. Silicosis and Tuberculosis Mortality

The high susceptibility of silicotic patients to TB was noted in the early part of the 20th century; the Vermont granite workers study was the first cohort study to draw attention to the high risk of death from TB in silicotics (2).

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These findings have been confirmed with the repeated demonstration that silica-exposed workers in settings where TB control is poor have markedly elevated mortality rates from TB (7,36–40). In some countries, it has also been shown that mortality rates fell following the introduction of improved dust control measures (40,41). Morbidity

In South Africa, an observational cohort of silicotic and nonsilicotic miners aged 40 years or more and with no previous history of TB treatment were followed prospectively for seven years during the 1980s (42). Miners with silicosis had an incidence of TB of 2.7 per 100 person-years, significantly higher than the incidence of 1.0 per 100 person-years in the nonsilicotic controls with a history of prolonged silica exposure. Among the silicotic group, the incidence of TB was highest (6.3 per 100 person-years) among those with more advanced silicosis (ILO grade 3) compared to those with less severe disease (2.9 per 100 person-years in men with ILO grade 2 disease, and 2.2 per 100 person-years in men with ILO grade 1 disease). HIV prevalence was low in South African miners during the study period, and the possibility of a contribution to these high rates from HIV infection was not investigated at that time. There have been two placebo-controlled trials of preventive therapy in silicotics: one in South African miners (43) and one in granite workers living in Hong Kong (5). Neither trial had a nonsilicotic control arm, but the South African study was a direct follow-on from the study discussed earlier and the general population incidence of TB in Hong Kong at the time of the trial was estimated to be about 150 per 100,000 person-years. The cumulative proportion of placebo recipients who were diagnosed with TB was 27% at five years in the Hong Kong trial, significantly higher than in recipients of the active regimens (cumulative proportion at five years of between 10% and 16% for the three regimens). The South African trial showed no significant difference between recipients of the placebo and active regimens, with an annual incidence in the order of 1.5 per 100 person-years during the four years of follow-up in both groups. There is evidence to suggest that silica dust exposure predisposes to TB in the absence of radiologically detectable silicosis (44). However, it is not possible to make a confident statement that silica dust exposure alone increases the risk of TB because of the insensitivity with which early silicotic changes can be detected by radiology and the difficulty in distinguishing a direct effect of silica from the indirect effect of increased risk of infection within the workforce. Furthermore, even very early silicosis detected postmortem has been associated with an increased prevalence of active TB (45). A study among South African gold miners demonstrated that silicosis is more strongly associated with incident TB than prevalent TB, regardless of HIV status. The duration of undiagnosed TB disease among silicotics, estimated from the ratio of the point prevalence of TB to the incidence of

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TB, was approximately one-fifth that of miners without silicosis, indicating that TB disease progresses significantly more rapidly among silicotics. Response to Treatment and Later Complications

Silicotuberculosis is a more serious illness than uncomplicated TB. Casefatality rates during treatment are higher (15), although treatment failure rates are not (15). Radiological post-tuberculous lung disease is both more frequent and more severe than in nonsilicotics at completion of TB treatment (16) and leads to an increased risk of progressive massive fibrosis (46) and premature death (37). TB recurrence rates are increased in men with radiological post-tuberculous lung disease, and both silicosis and post-tuberculous lung disease greatly increase the risk of subsequent nontuberculous lung disease in miners (9). C. Tuberculosis Among Silica-Exposed Workers in the Era of HIV

With the notable exception of South Africa, there are very few data in the public domain concerning the impact of HIV epidemics among mining workforces in sub-Saharan Africa. Judging by the reports from South Africa, however, it is likely that TB incidence has reached extremely high rates in mines across the continent. Migrant workers are at unusually high risk of HIV, and prevalence rates can reach very high levels (e.g., Triangle district in Zimbabwe: 38%, Dr. Richard Davy, personal communication). Mortality

The effect of the HIV epidemic has been to greatly increase TB case fatality rates, with HIV-infected patients having a 10-fold or higher case-fatality rate than HIV-uninfected TB patients (15,20). Among HIV-infected TB patients non-TB opportunistic infections account for the majority of deaths, particularly after the first two months of TB treatment (15,20). Morbidity

Gold miners with prevalent HIV infection have a greater risk of developing TB compared to HIV-uninfected miners (10,17). The relative risk of developing TB among HIV-infected individuals has increased since the early 1990s (Fig. 1) (10,17), probably as a result of increasing immunosuppression at a population level as the HIV epidemic has matured. The increased susceptibility to TB is evident from an early stage of HIV infection (9,10). Studies of South African mineworkers demonstrated that the risk of TB doubles soon after HIV seroconversion (47) and becomes more pronounced as the degree of immunosuppression increases (19). The incidence of TB in HIV-positive silicotics is very high, with the combined risk being a multiple of the individual risks, so that TB remains an occupational disease of miners and control of both factors is required (10). The prevalence of active TB among South African gold miners is high (48,49). In a recent study among gold miners (48), the prevalence of undiagnosed TB disease was 3.8% in HIV-positive and 2.2% in HIV-negative

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Figure 1 Unadjusted tuberculosis incidence rate ratios for HIV-infected to HIVuninfected miners.

miners: considerably less strongly HIV associated (OR 1.6; 95% CI 0.83–3.1) than incident TB (incidence rate ratio 5.5; 95% CI, 3.5–8.6). The majority (78%) of prevalent smear-positive TB cases were not HIV infected, and the point prevalence of smear-positive TB disease was actually lower for HIV-positive than HIV-negative miners (0.44% vs. 0.55%, respectively). Dividing point prevalence by incidence to estimate the duration of active TB disease before diagnosis indicated that active TB disease had presented and been diagnosed three times more quickly in HIV-positive miners than in their HIV-negative counterparts (9.6 and 28.7 months, respectively), with the difference for smear-positive disease being even more pronounced (1.8 and 13.8 months, respectively) (Fig. 2) (48). This difference in the effect of HIV on prevalent and incident TB may explain why the HIV epidemic has had relatively little impact on the prevalence of TB disease detected at routine annual radiography (Fig. 3) (48) and why TB incidence rates in HIV-negative miners have been little affected by the epidemic of HIV-associated TB in some workforces (50). The prevalence of primary and acquired drug resistance has remained stable over the past two decades, suggesting that the TB control programs have been effective in preventing drug resistance even if failing to control TB incidence itself (21,51). There has been no association between drug resistance and HIV infection (51). Response to Treatment and Later Complications

Treatment outcomes among HIV-infected gold miners who survive to the end of TB treatment are similar to that of HIV-uninfected miners (15,20).

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Figure 2 Mean tuberculosis disease duration before diagnosis by HIV and smear status. The diamonds indicate the duration before diagnosis, in months, of smear positivity and overall TB disease activity in miners who were HIV positive and HIV negative; 95% confidence intervals are represented by the horizontal lines. The difference between patients who are HIV positive and HIV negative in estimated disease duration was significant for both smear-positive and all-confirmed TB disease, as indicated by disease duration ratios that are significantly less than one for both comparisons.

In one well-described workforce, a high proportion successfully completed TB treatment (>95%), and treatment failure rates were low (< 2%) (15). DNA fingerprinting studies among gold miners have shown that despite high rates of TB transmission, reinfection is a rare cause of treatment failure (52). Recurrent TB accounts for up to a third of all treatment episodes in some workforces, despite the good initial treatment outcomes. Recurrent TB may result from relapse with the original infecting organism or reinfection with a new strain of Mycobacterium tuberculosis (24,53). High rates of exposure to reinfection, an aging workforce, the HIV epidemic, and posttuberculous lung disease have all been shown to contribute to the increasing burden of recurrent TB disease (16). Unlike in other populations, there is a major difference in recurrence rates by HIV status in miners [8.2 vs. 2.2 per 100 person-years in one study (16) and 16.0 vs. 6.4 in a second workforce (24)]. This is likely to reflect unusually high rates of reinfection, because the difference between HIV-positive and HIV-negative rates was shown to be exclusively due to increased susceptibility to reinfection with rapid progression to disease (24). Recrudescent disease also occurred, but at a rate that did not vary with HIV status. The poor prognosis following an episode of HIV-related TB is mainly attributable to preexisting high HIV load rather than to TB itself (54). Antiretroviral therapy (ART) is now available to eligible HIV-infected gold miners in some workforces, and it is anticipated that the prognosis of HIV-related TB will improve significantly as a result. Post-tuberculous lung disease in HIV-positive miners, however, increases susceptibility to other opportunistic infections including bacterial pneumonia and nontuberculous

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Figure 3 Time trends in observed new tuberculosis case-notification rates and the point prevalence of new radiologic TB at annual screening, also showing the progressive reduction in the ratio of these two indicators since 1990.

mycobacterial disease, particularly due to Mycobacterium kansasii, M. scrofulaceum, and M. avium intracellulare complex (13,55,56). D. TB Transmission

Prospective, population-based strain typing (DNA fingerprinting) studies have been conducted to characterize the molecular epidemiology of pulmonary TB among South African gold miners (22). Despite TB control programs that exceed World Health Organization (WHO) targets for cure, most TB is due to ongoing TB transmission. Although treatment failure rates were low, the effects were still considerable: Strains from individuals who remained infectious following TB treatment, particularly those with

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drug-susceptible strains, accounted for one-third of all clustered isolates. The ratio of clustered to unique strains did not vary significantly by HIV status, as has been observed in other African settings. From the results of the study of recurrent TB disease by Sonnenberg et al. (24), discussed in the section above, it is possible to estimate the minimum annual risk of TB reinfection following cure of an initial episode, because recrudescent disease did not vary by HIV status and the majority of recurrent TB among HIV-positive miners was due to reinfection. The minimum risk of TB reinfection was estimated as 9.6% per year by taking the difference in recurrence rates between HIV-positive and HIV-negative miners (57). Unless there is a major component of nosocomial exposure, for example, when attending TB clinics, the difference in recurrence rates between HIV-positive and HIV-negative miners also provides a minimum estimate of annual risk of TB infection for the whole workforce. Of note, the annual risk of TB infection is less than 0.1% per year in children in low-prevalence countries such as the United Kingdom and United States; to 0.5% to 2.5% per year for rural and urban sub-Saharan Africa; and 3.0% per year in Cape Town, which has notably high rates of HIV-negative TB disease. Although it is clear that TB transmission rates must be unusually high in gold-mining workforces, the effect of the epidemic of HIV-associated TB on transmission rates has not yet been established. No attempt has been made to directly estimate annual risk of TB infection, but there are a number of indirect indicators including rates of TB disease in miners known to be HIV negative and changes in the point prevalence of TB disease. In some cases, these appear to have been remarkably constant despite increasing TB incidence rates at the workforce level during the 1990s. In one workforce, TB case-notification rates increased four-fold, but age-specific TB incidence rates in HIV-negative cohorts remained unchanged, implying that the HIV epidemic may have had relatively little impact on TB transmission rates (50). Key observations that allow these data to be reconciled with the increasing TB incidence rates at the workforce level are that the radiological point prevalence of new TB disease (Fig. 3) has also remained relatively constant and that the point prevalence of infectious smear-positive TB disease is no higher in HIV-positive than HIV-negative miners (48). This is because HIV-related TB disease appears to be diagnosed much more rapidly than disease in HIV-negative miners, so that the period or duration of infectiousness of TB is greatly curtailed by concurrent HIV infection (Fig. 2) (48). This may well be an intrinsic feature of the natural history of HIV-related TB, because both rapid progression of HIV-related TB and apparent lack of impact of the HIV epidemic on TB transmission rates have been observed in other settings (58,59). In contrast, in another goldmining workforce that also achieved WHO targets for cure, TB casenotification rates among HIV-negative miners did increase between 1991 and 1997, while the proportion of TB attributable to HIV increased to over 40% (47). Identifying the differences that allow TB transmission to be

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controlled in some workforces but not others will be an important step forward. However, the demonstration that HIV does not inevitably result in a secondary increase in TB transmission rates is in itself heartening. III. Tuberculosis Control Even if TB transmission can be maintained at pre-HIV levels by conventional means, morbidity and mortality from TB in currently employed miners living in high HIV prevalence settings are now extremely high. Miners remain at extremely high risk of developing TB and have high rates of mortality on retirement, when they no longer have ready access to health care (34,60). There is also the strong possibility that miners contribute disproportionately to TB transmission in their home communities (61). Because of these concerns, greater attention needs to be focused on TB control strategies, and new approaches are being considered. As in other aspects of TB in miners, data publication and debate in the public domain has been essentially restricted to South Africa, but it is likely that companies in other countries with high burdens of HIV are in a similar or worse position. The first steps toward improving control must be to tighten up on all aspects of TB case finding and treatment and to reduce dust exposure (conventional measures). However, where these measures have failed to reduce morbidity and mortality to acceptable rates, there may be grounds for considering more radical options. A trial of mass case finding and preventive therapy intervention has recently been funded through the Consortium to Respond Effectively to the AIDS/TB Epidemic (CREATE) by the Bill and Melinda Gates Foundation, and will provide a valuable opportunity to reassess the magnitude and durability of the effect produced by this type of intervention in a high HIV prevalence population. A. Conventional Control Measures Dust Control

All forms of silicosis are preventable. Adequate dust control measures, such as thorough wetting of rock and ore and provision of adequate ventilation, can maintain airborne silica levels at a very low level (2). Defining a ‘‘safe’’ level of silica exposure has, however, proved difficult: Neither exposure nor outcome are easy to quantify, the latent period between exposure and disease is long, a number of physical factors affect the toxicity of silica, and there may be individual variation in susceptibility (2,4,25,62,63). The United States has two different recommendations (2,64), and the most recent statement by the American Thoracic Society stresses the need for improved worker education, and for cohort studies of workers with well-characterized exposures, including follow-up of those who are no longer exposed to silica (4). Ideally, this same approach could be used to investigate the lifetime risks of TB in endemic settings. For mines with very high rates of TB,

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however, dust levels are almost by definition ‘‘too high’’ and better control should be considered an essential part of improving TB control. Dust control is difficult to assess objectively and many countries fail to monitor compliance with existing legislation because measuring exposure is complex and technically demanding (1). Monitoring silicosis prevalence and/or TB incidence and responding to unacceptable rates may be a much more practical approach as improved control leads to reduced disease burdens within a few years (40,41). DOTS and Active-Case Finding

The mining industry is split into companies that rely on government TB control programs or, in the case of larger mining concerns, operate their own. The South African mining industry operates a DOTS-based TB control program that includes compulsory active TB case finding using routine chest radiography screening of all employees, as well as more standard passive case finding and treatment (12). Diagnosis of TB in men presenting symptomatically (passive case finding), or detected by the radiological screening program (active case finding), is based as far as possible on serial sputum smear examination and mycobacterial cultures. TB is only diagnosed in bacteriologically negative cases if there has been radiological progression unresponsive to standard antibiotics. Treatment is with shortcourse rifampicin-based regimens, administered at the workplace as directly observed therapy using fixed combination tablets. Although treatment outcomes among South African gold miners appear to be good, there may be cause for concern regarding adherence to treatment. Two studies of adherence to treatment among gold miners, based on urine testing for drug metabolites, demonstrated a lower adherence to therapy than was anticipated for both inpatients and outpatients (65,66). Even though the proportion of TB cases detected by the radiological screening program has declined with the emerging HIV epidemic, the radiological screening program still detects a sizable proportion of TB cases (12,48). Recent studies have demonstrated a reduction in post-TB scarring and mortality with increased frequency of radiological screening (18) and that the sensitivity of radiological screening can be improved by the addition of symptom screening (67). B. Controlling Tuberculosis in HIV-Affected Workforces HIV Prevention

HIV infection like silicosis is preventable. The current HIV prevention programs among South African mines include syndromic management of sexually transmitted infection (STI), use of peer educators, condom promotion and distribution, voluntary counselling and testing (VCT), and targeted sexual health services to woman at high risk of acquiring STIs and HIV in the surrounding mine communities. However, this has so far failed to control the rising HIV prevalence among miners (48).

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A recent evaluation of VCT services for South African gold miners, using a UNAIDS-validated tool, identified barriers to accessing STI and VCT services (68). These included fear of a positive HIV test result and stigmatization, lack of confidentiality, restricted accessibility of services, and judgmental attitude of staff. To improve uptake of STI and VCT services, these barriers should be addressed and the services promoted through educational and media campaigns. Integration with HIV care programs that offer preventive therapy for TB and opportunistic infection, and highly active ART, may improve uptake of VCT (69). Preventive Therapy

Primary preventive therapy with six-months of isoniazid (300 mg/day) has been shown to be cost effective in reducing TB incidence among HIVinfected mineworkers, with no prior history of TB (70,71). HIV-infected miners with a prior history of TB, who took isoniazid preventive therapy (IPT), indefinitely, compared to those that did not take IPT, had a 55% reduction in TB recurrence, with the absolute impact being greatest among individuals with low CD4 counts (19). The results are consistent with small prospective randomized trials of secondary IPT from Haiti (72) and Abidjan (73). Secondary preventive therapy is logistically easier to implement than primary preventive therapy. HIV testing should have been offered at the time of TB diagnosis; a tuberculin skin test and chest radiograph are not required and exclusion of active TB at the end of treatment, by sputum smear examination, is done routinely according to WHO TB control program guidelines. For these reasons, it seems logical to offer secondary preventive therapy to HIV-infected individuals in settings of high TB prevalence where primary preventive therapy is being offered (19). Community-Wide Tuberculosis Preventive Therapy

The use of community-wide preventive therapy was investigated in the Bethel area in Alaska in the late 1950s, where TB incidence was 1000 per 100,000 population per year prior to the intervention. A cluster-randomized study was carried out in which households in the Bethel area were randomized to receive IPT or placebo for one year. The group who received IPT experienced a 69% reduction of TB incidence (74). Based on the results of this study, IPT was provided to all residents of the Bethel area. This intervention, in addition to an ongoing TB control program of passive case finding and treatment, resulted in the sustained reduction in TB incidence (75). However, it is difficult to dissect out the exact role of the mass IPT intervention, as TB incidence and annual risk of infection were falling prior to the initiation of the intervention (Prof. George Comstock, personal observation). This strategy has not been reevaluated in the era of HIV, and before such a radical strategy can be supported, there needs to be clear evidence of effectiveness and reasonable durability. The rationale for communitywide TB preventive therapy is that all individuals at increased risk of developing TB in the population are treated; TB incidence is reduced in all

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individuals at highest risk of TB, leading to a reduction in TB transmission and improved TB control. The long-term benefit would depend on the time taken to reestablish high rates of latency and transmission following breakthrough of residual latent TB infection and reinfection from outside communities. Because the dynamics of TB infection and disease are slow, there could be a lasting benefit for a considerable number of years, but this remains to be proven. A proof-of-concept, cluster-randomized study among South African gold miners from 2006 aims to investigate whether community-wide TB preventive therapy can rapidly reduce TB morbidity and mortality. If the intervention proves to be effective and reasonably durable, this strategy could conceivably be applied to other communities with high TB morbidity rates attributable to unusually high-density living and/or working conditions, especially where HIV prevalence rates are high. Community-Wide Voluntary Counselling and Testing and Antiretroviral Therapy

Uptake of ART is increasing among workforces in South African gold mines. ART has been shown to significantly reduce the incidence of TB among HIV-infected individuals, although the incidence of TB among HIV-infected patients on ART remains well above those expected for HIV-negative persons (76). Widespread use of ART will tend to increase the prevalence of HIV infection in the workforce (by reducing rates of HIV-associated mortality and early retirement), however, and so overall impact on TB control at the workforce level is difficult to predict and may even be negative (77). A high proportion of HIV-infected miners starting ART (more than 30%) (Charalambous S, personal observation) have had a previous episode of TB. Previous TB disease appears to be a potent risk factor for recurrent TB disease in patients on ART, and so the added benefit of primary and secondary IPT needs investigation. IV. Conclusion Controlling TB disease in hard rock mines with large workforces has presented special challenges for the last century, which have now been greatly exacerbated by the HIV epidemic in African workforces. The paucity of data regarding TB control and other indicators of dust control among mines operating in most developing countries is a cause of real concern. The gravity of the situation needs to be recognized, and mining concerns in high HIV prevalence settings should reevaluate dust control and TB control programs. Monitoring and enforcement of dust control should assume a higher national and international priority than has been the case in the past. Reducing the high morbidity and mortality of TB in HIV-affected workforces requires effective dust and TB control programs and high-impact HIV prevention strategies. The role of ART and different strategies based on the widespread use of preventive therapy need to be established and

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optimized within the next decade if we are to make substantial progress toward reducing the extremely high rates of TB transmission and disease in migrant workforces in South Africa and other silica-exposed workforces in the African continent. Lessons learnt from the mines may be more widely applicable, especially if new preventive therapy regimens become available, which can safely be applied in general populations. Acknowledgments Funding support from the Consortium to Respond Effectively to the AIDS/ TB Epidemic (Bill and Melinda Gates Foundation), Centre for AIDS Programme of Research In South Africa (National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), U.S. Department of Health and Human Services (Grant #1U19AI51794)) and Safety in Mines Research Advisory Council (SA). References 1. Becklake MR. The mineral dust diseases. Tuber Lung Dis 1992; 73(1):13–20. 2. NIOSH (silicosis and silicate disease committee). Diseases associated with exposure to silica and nonfibrous silicate minerals. Silicosis and Silicate Disease Committee. Arch Pathol Lab Med 1988; 112(7):673–720. 3. Cowie RL. The epidemiology of tuberculosis in gold miners with silicosis. Am J Respir Crit Care Med 1994; 150(5):1460–1462. 4. American Thoracic Society Committee of the Scientific Assembly on Environmental and Occupational Health. Adverse effects of crystalline silica exposure. Am J Respir Crit Care Med 1997; 155(2):761–768. 5. Hong Kong Chest Service/Tuberculosis Research Centre MBMRC. A double-blind placebo-controlled clinical trial of three antituberculosis chemoprophylaxis regimens in patients with silicosis in Hong Kong. Am Rev Respir Dis 1992; 145(1):36–41. 6. Sherson D, Lander F. Morbidity of pulmonary tuberculosis among silicotic and nonsilicotic foundry workers in Denmark 11. J Occup Med 1990; 32(2):110–113. 7. Chen J, McLaughlin JK, Zhang JY, et al. Mortality among dust-exposed Chinese mine and pottery workers. J Occup Med 1992; 34(3):311–316. 8. Kleinschmidt I, Churchyard G. Variation in incidences of tuberculosis in subgroups of South African gold miners. Occup Environ Med 1997; 54(9):636–641. 9. Corbett EL, Churchyard GJ, Clayton T, et al. Risk factors for pulmonary mycobacterial disease in South African gold miners. A case-control study. Am J Respir Crit Care Med 1999; 159(1):94–99. 10. Corbett EL, Churchyard GJ, Clayton TC, et al. HIV infection and silicosis: the impact of two potent risk factors on the incidence of mycobacterial disease in South African miners. AIDS 2000; 14(17):2759–2768. 11. van Sprundel MP. Pneumoconioses: the situation in developing countries. Exp Lung Res 1990; 16(1):5–3. 12. Churchyard GJ, Kleinschmidt I, Corbett EL, et al. Mycobacterial disease in South African gold miners in the era of HIV infection. Int J Tuberc Lung Dis 1999; 3(9):791–798. 13. Corbett EL, Blumberg L, Churchyard GJ, et al. Nontuberculous mycobacteria: defining disease in a prospective cohort of South African miners. Am J Respir Crit Care Med 1999; 160(1):15–21.

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14. Corbett EL, Murray J, Churchyard GJ, et al. Use of miniradiographs to detect silicosis. Comparison of radiological with autopsy findings. Am J Respir Crit Care Med 1999; 160(6):2012–2017. 15. Churchyard GJ, Kleinschmidt I, Corbett EL, et al. Factors associated with an increased case-fatality rate in HIV-infected and non-infected South African gold miners with pulmonary tuberculosis. Int J Tuberc Lung Dis 2000; 4(8):705–712. 16. Mallory KF, Churchyard GJ, Kleinschmidt I, et al. The impact of HIV infection on recurrence of tuberculosis in South African gold miners. Int J Tuberc Lung Dis 2000; 4(5):455–462. 17. Corbett EL, Churchyard GJ, Charalambos S, et al. Morbidity and mortality in South African gold miners: impact of untreated disease due to human immunodeficiency virus. Clin Infect Dis 2002; 34(9):1251–1258. 18. Roux S, Fielding K, Grant AD, et al. [Late Breaker Session] Annual vs. 6-monthly radiological screening for the active case-finding of TB: a randomised controlled trial. 34th World Conference On Lung Health, Paris, 2003. 19. Churchyard GJ, Fielding K, Charalambous S, et al. Efficacy of secondary isoniazid preventive therapy among HIV-infected Southern Africans: time to change policy? AIDS 2003; 17(14):2063–2070. 20. Murray J, Sonnenberg P, Shearer SC, et al. Human immunodeficiency virus and the outcome of treatment for new and recurrent pulmonary tuberculosis in African patients. Am J Respir Crit Care Med 1999; 159(3):733–740. 21. Murray J, Sonnenberg P, Shearer S, et al. Drug-resistant pulmonary tuberculosis in a cohort of southern African goldminers with a high prevalence of HIV infection. S Afr Med J 2000; 90(4):381–386. 22. Godfrey-Faussett P, Sonnenberg P, Shearer SC, et al. Tuberculosis control and molecular epidemiology in a South African gold-mining community. Lancet 2000; 356(9235):1066–1071. 23. Sonnenberg P, Murray J, Glynn JR, et al. Risk factors for pulmonary disease due to culture-positive M. tuberculosis or nontuberculous mycobacteria in South African gold miners. Eur Respir J 2000; 15(2):291–296. 24. Sonnenberg P, Murray J, Glynn JR, et al. HIV-1 and recurrence, relapse, and reinfection of tuberculosis after cure: a cohort study in South African mineworkers. Lancet 2001; 358(9294):1687–1693. 25. Mossman BT, Churg A. Mechanisms in the pathogenesis of asbestosis and silicosis. Am J Respir Crit Care Med 1998; 157(5 Pt 1):1666–1680. 26. International Labour Office. Guidelines for the use of ILO international classification of radiographs of pneumoconiosis. Occupational Safety and Health. Geneva, 1981. 27. Donaldson K, Borm PJ. The quartz hazard: a variable entity. Ann Occup Hyg 1998; 42(5):287–294. 28. Nagelschmidt G. The relationship between lung dust and lung pathology in pneumoconiosis. Br J Ind Med 1960(17):247–259. 29. Hnizdo E, Sluis-Cremer GK. Risk of silicosis in a cohort of white South African gold miners. Am J Ind Med 1993; 24(4):447–457. 30. Ng TP, Chan SL, Lam KP. Radiological progression and lung function in silicosis: a ten year follow up study. Br Med J (Clin Res Ed) 1987; 295(6591):164–168. 31. International Labour Office. Guidelines for the use of ILO international classification of radiographs of pneumoconiosis, 1981:22. 32. Graham WG, Ashikaga T, Hemenway D, et al. Radiographic abnormalities in Vermont granite workers exposed to low levels of granite dust. Chest 1991; 100(6): 1507–1514.

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33. Muir DC, Shannon HS, Julian JA, et al. Silica exposure and silicosis among Ontario hardrock miners: I. Methodology. Am J Ind Med 1989; 16(1):5–1. 34. Trapido AS, Mqoqi NP, Williams BG, et al. Prevalence of occupational lung disease in a random sample of former mineworkers, Libode District, Eastern Cape Province, South Africa. Am J Ind Med 1998; 34(4):305–313. 35. Hnizdo E, Murray J, Sluis-Cremer GK, et al. Correlation between radiological and pathological diagnosis of silicosis: an autopsy population based study. Am J Ind Med 1993; 24(4):427–445. 36. Yi Q, Zhang Z. The survival analyses of 2738 patients with simple pneumoconiosis 26. Occup Environ Med 1996; 53(2):129–135. 37. Ng TP, Chan SL, Lee J. Predictors of mortality in silicosis 20. Respir Med 1992; 86(2):115–119. 38. Saiyed HN, Chatterjee BB. Rapid progression of silicosis in slate pencil workers: II. A follow-up study. Am J Ind Med 1985; 8(2):135–142. 39. Zambon P, Simonato L, Mastrangelo G, et al. Mortality of workers compensated for silicosis during the period 1959–1963 in the Veneto region of Italy 23. Scand J Work Environ Health 1987; 13(2):118–123. 40. Costello J, Graham WG. Vermont granite workers’ mortality study 18. Am J Ind Med 1988; 13(4):483–497. 41. Lou JZ, Zhou C. The prevention of silicosis and prediction of its future prevalence in China. Am J Public Health 1989; 79(12):1613–1616. 42. Cowie RL. Silicotuberculosis: long-term outcome after short-course chemotherapy. Tuber Lung Dis 1995; 76(1):39–42. 43. Cowie RL. Short course chemoprophylaxis with rifampicin, isoniazid and pyrazinamide for tuberculosis evaluated in gold miners with chronic silicosis: a double-blind placebo controlled trial 16. Tuber Lung Dis 1996; 77(3):239–243. 44. Hnizdo E, Murray J. Risk of pulmonary tuberculosis relative to silicosis and exposure to silica dust in South African gold miners 24. Occup Environ Med 1998; 55(7):496– 502. 45. Sluis-Cremer GK. Active pulmonary tuberculosis discovered at post-mortem examination of the lungs of black miners. Br J Dis Chest 1980; 74(4):374–378. 46. Ng TP, Chan SL. Factors associated with massive fibrosis in silicosis. Thorax 1991; 46(4):229–232. 47. Sonnenberg P, Glynn JR, Fielding K, et al. HIV and pulmonary tuberculosis: the impact goes beyond those infected with HIV. AIDS 2004; 18(4):657–662. 48. 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(6):673–679. 49. Murray J, Kielkowski D, Reid P. Occupational disease trends in black South African gold miners. An autopsy-based study. Am J Respir Crit Care Med 1996; 153(2): 706–710. 50. Corbett EL, Charalambous S, Fielding K, et al. Stable incidence rates of tuberculosis (TB) among human immunodeficiency virus (HIV)-negative South African gold miners during a decade of epidemic HIV-associated TB. J Infect Dis 2003; 188(8): 1156–1163. 51. Churchyard GJ, Corbett EL, Kleinschmidt I, et al. Drug-resistant tuberculosis in South African gold miners: incidence and associated factors. Int J Tuberc Lung Dis 2000; 4(5):433–440. 52. Sonnenberg P, Murray J, Shearer S, et al. Tuberculosis treatment failure and drug resistance—same strain or reinfection? Trans R Soc Trop Med Hyg 2000; 94(6): 603–607.

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53. van Rie A, Warren R, Richardson M, et al. Exogenous reinfection as a cause of recurrent tuberculosis after curative treatment. N Engl J Med 1999; 341(16): 1174–1179. 54. Day JH, Grant AD, Fielding KL, et al. Does tuberculosis increase HIV load? J Infect Dis 2004; 190(9):1677–184. [In Process Citation]. 55. Charalambous S, Day JH, Fielding K, et al. HIV infection and chronic chest disease as risk factors for bacterial pneumonia: a case-control study. AIDS 2003; 17(10): 1531–1537. 56. Corbett EL, Churchyard GJ, Hay M, et al. The impact of HIV infection on Mycobacterium kansasii disease in South African gold miners. Am J Respir Crit Care Med 1999; 160(1):10–14. 57. Corbett EL, Mallory KF, Grant AD, et al. HIV-1 infection and risk of tuberculosis after rifampicin treatment. Lancet 2001; 357(9260):957–958. 58. 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(10): 1459–1463. 59. Tuberculosis control in the era of the HIV epidemic: risk of tuberculosis infection in Tanzania, 1983–1998. Int J Tuberc Lung Dis 2001; 5(2):103–112. 60. White NW, Steen TW, Trapido AS, et al. Occupational lung diseases among former goldminers in two labour sending areas. S Afr Med J 2001; 91(7):599–604. 61. Lockman S, Tappero JW, Kenyon TA, et al. Tuberculin reactivity in a pediatric population with high BCG vaccination coverage. Int J Tuberc Lung Dis 1999; 3(1):23–30. 62. Hughes JM. Radiographic evidence of silicosis in relation to silica exposure. Appl Occup Environ Hyg 1995(10):1064–1069. 63. Rice FL, Stayner LT. Assessment of silicosis risk for occupational exposure to crystalline silica. Scand J Work Environ Health 1995; 21(suppl 2):87–90. 64. Glenn R, Amandus H, Hankinson J, et al. ORD—NIOSH prevention strategy and selected research. Am Ind Hyg Assoc J 1986; 47(11):674–680. 65. Mqoqi NP, Churchyard GA, Kleinschmidt I, et al. Attendance versus compliance with tuberculosis treatment in an occupational setting—a pilot study. S Afr Med J 1997; 87(11):1517–1521. 66. Sonnenberg P, Ross MH, Shearer SC, et al. The effect of dosage cards on compliance with directly observed tuberculosis therapy in hospital. Int J Tuberc Lung Dis 1998; 2(2):168–171. 67. Churchyard GJ, Charalambous S, Moloi V, et al. 041-PD Population based screening for active tuberculosis in a community with a high prevalence of TB. Int J Tuberc Lung Dis 2002; 6(10 suppl 1):S183. 68. Ginwalla SK, Grant AD, Day JH, et al. Use of UNAIDS tools to evaluate HIV voluntary counselling and testing services for mineworkers in South Africa. AIDS Care 2002; 14(5):707–726. 69. Day JH, Miyamura K, Grant AD, et al. Attitudes to HIV voluntary counselling and testing among mineworkers in South Africa: will availability of antiretroviral therapy encourage testing? AIDS Care 2003; 15(5):665–672. 70. Grant AD, Charalambous S, Fielding KL, et al. Effect of routine isoniazid preventive therapy on tuberculosis incidence among HIV-infected men in South Africa (a novel randomized incremental recruitment study). JAMA 2005; 293(22):2719–2725. 71. Kumaranayake L, Fielding K, Grant A, et al. [TuOrD1210] Cost-effectiveness of isoniazid preventive therapy of averting tuberculosis among HIV-infected employees in South Africa: evaluation of a randomised intervention. XV International AIDS Conference, Bangkok, 2004.

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72. Fitzgerald DW, Desvarieux M, Severe P, et al. Effect of post-treatment isoniazid on prevention of recurrent tuberculosis in HIV-1-infected individuals: a randomised trial. Lancet 2000; 356(9240):1470–1474. 73. Haller L, Sossouhounto R, Coulibaly IM, et al. Isoniazid plus sulphadoxinepyrimethamine can reduce morbidity of HIV-positive patients treated for tuberculosis in Africa: a controlled clinical trial. Chemotherapy 1999; 45(6):452–465. 74. Comstock GW, Ferebee SH, Hammes LM. A controlled trial of community-wide isoniazid prophylaxis in Alaska. Am Rev Respir Dis 1967; 95(6):935–943. 75. Comstock GW, Baum C, Snider DE. Isoniazid prophylaxis among Alaskan Eskimos: a final report of the bethel isoniazid studies. Am Rev Respir Dis 1979; 119(5):827– 830. 76. Badri M, Wilson D, Wood R. Effect of highly active antiretroviral therapy on incidence of tuberculosis in South Africa: a cohort study. Lancet 2002; 359(9323): 2059–2064. 77. Corbett EL, Currie C, Churchyard GJ, et al. [WeOrc1312] Strategies for reducing the burden of TB infection and disease in high HIV prevalence populations: modelling the impact of active case finding, antiretrovirals and preventive therapy. XIV International AIDS Conference, Barcelona, Spain, 2002.

SECTION V: NEW CHALLENGES FOR A NEW CENTURY

38 Programmatic Management of Human Immunodeficiency Virus–Associated Tuberculosis

ANTHONY D. HARRIES

PAUL NUNN

HIV Unit, Ministry of Health, Lilongwe, Malawi

Stop TB Department, World Health Organization, Geneva, Switzerland

Family Health International, Arlington, Virginia, U.S.A.

I. Introduction HIV/AIDS is the modern world’s greatest pandemic and HIV is also the most important risk factor for development of tuberculosis (TB). This chapter describes recent thinking on how control of TB needs to be adapted to assert and maintain control of TB in high HIV-prevalence settings. II. Global Burden of TB and HIV Infection Twenty-three years after first being recognized, HIV has claimed 22 million lives and created over 13 million orphans. The World Health Organization (WHO) and the Joint United Nations Programme on HIV and AIDS (UNAIDS) estimated that at the end of 2003, the number of adults and children living in the world with HIV/AIDS was 38 million, of whom the majority lived in the developing world (1). During that year, 5 million people were newly infected with HIV and over 3 million people died. Sub-Saharan Africa, especially eastern and southern Africa, bears the brunt of this epidemic. With less than 10% of the world’s population, it is home to 25 million people living with HIV/AIDS. In 2003, an estimated 3 million 967

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people became newly infected and 2.2 million died (75% of the 3 million AIDS deaths globally that year). South Asia and Eastern Europe with Central Asia have 6.5 and 1.3 million HIV-infected people, respectively. HIV, by targeting CD4-T-lymphocytes and reducing cellular immune function, is the most important driving force behind the current TB epidemic. Not only does HIV increase the risk of reactivating latent Mycobacterium tuberculosis (M. tuberculosis) (2), but it also increases the risk of rapid TB progression soon after infection or reinfection with M. tuberculosis (3). In persons infected with M. tuberculosis only, the risk of clinically significant disease within the first year after infection is approximately 1.5%, and it thereafter decreases to reach a fairly stable risk of 0.1% per annum after five years (4). Conversely, in persons coinfected with M. tuberculosis and HIV, the annual risk of active TB is 5% to 15%, with this risk increasing as the immune system becomes more compromised (5). As a result, HIV infection rates among patients with TB exceed 50% in many African countries. In 1997, it was estimated that 10.7 million people globally were dually infected with HIV and M. tuberculosis, 7.3 million (68%) of whom lived in sub-Saharan Africa (6). Among adults aged 15 to 49 years, the number coinfected with HIV and M. tuberculosis reached 11.4 million in 2000 (7). In 2000, 9% of all new TB cases in adults (aged 15–49) were attributable to HIV infection, with the proportion being highest in the WHO African region at 31% (7). In that same year, 12% of TB deaths were attributable to HIV/AIDS, the figure again being highest in the African region at 39%. The net result of the HIV/TB interaction is that TB in sub-Saharan Africa is rising faster than in any other region. The WHO Africa region already has the highest incidence of TB among all regions (8) and will soon overtake Southeast Asia with the largest absolute number of cases. HIV is also a causative factor for TB in the region with the next fastest rise, namely Eastern Europe and the Former Soviet Union (FSU), although the breakdown in health systems following the fall of communism is a more important factor in this region.

III. Current Interaction Between Tuberculosis and AIDS Programs Despite the recognition of a significant association between the two diseases, until recently there has been little formal interaction between TB and AIDS programs, either globally or at a national level. To understand why this is so, it is necessary to understand the goals, objectives, organizations, and philosophies of the two programs. A. National Tuberculosis Program

The overall aim of TB control is to reduce mortality, morbidity, and transmission of the disease, while preventing the development of drug resistance. The main intervention is standardized combination chemotherapy provided

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under direct observation—at least during the initial phase of treatment—to all identified sputum smear–positive TB patients, the main sources of infection. The DOTS strategy provides the framework within which this intervention is delivered (9). The five components of the strategy are well known (Chapter 27). Sustained political commitment is necessary to increase human and financial resources and make TB control a national priority. Access to a quality-assured TB sputum microscopy service is essential for case detection among persons presenting with symptoms of TB, particularly prolonged cough. The provision of standardized short-course chemotherapy for all cases of TB under proper management conditions, including Directly Observed Therapy (DOT), allows the best chance of ensuring a successful treatment outcome. There has to be an uninterrupted supply of quality-assured drugs with proper procurement and distribution systems to ensure cure and to prevent the development of drug-resistant TB. Finally, a standardized recording and reporting system allows the program to be systematically monitored and the identified problems to be corrected. The key operations needed for the delivery of this strategy have been presented and discussed in other chapters.

B. National AIDS Programs

The efforts of National AIDS Programs, at least in the high HIV-burden countries in sub-Saharan Africa, have centered for many years around prevention of HIV (Table 1). The strategies for preventing sexual transmission of HIV have concentrated on the use of condoms, treating sexually transmitted infections (STI) and reducing unsafe sexual behavior. Rates of mother-to-child transmission of HIV, without any intervention, are

Table 1 HIV/AIDS Prevention Activities Preventing sexual transmission of HIV Mass media campaigns Education of youth and school children Condoms, condom promotion, condom social marketing Treatment of sexually transmitted infections Preventing mother-to-child transmission of HIV ARV therapy Non-ARV interventions Elective cesarian sections (dubious role in sub-Saharan Africa) Safe alternatives to breast-feeding (difficult to find) Screening of blood for transfusion HIV voluntary counselling and testing services Whole blood rapid testing Good quality pretest and posttest counselling Abbreviation: ARV, antiretroviral.

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estimated to be 20% to 40% in sub-Saharan Africa (10). Nevirapine, a nonnucleoside reverse-transcriptase inhibitor, given as a single 200-mg dose to an HIV-infected mother at onset of labor, followed by 2 mg/kg to babies within 72 hours of birth, reduces HIV transmission to about 8% at birth (11). This regimen offers the least expensive and simplest antiretroviral (ARV) intervention for resource-poor countries, with significant efficacy maintained in breast-feeding infants up to four months of age. There is a global policy to screen donated blood for HIV. A key factor underpinning any HIV-prevention strategy is accessibility to voluntary counselling and testing (VCT) services. VCT has been shown to be cost-effective in promoting behavior change and reducing sexual transmission of HIV (12,13). Uganda is one of the few African countries to have provided low-cost, high-quality, and wide-scale VCT services, and this is believed to be one of the important factors in the country’s success in HIV prevention. In Thailand, too, HIV appears to have been contained chiefly by a strict and regulated policy of 100% condom use in brothels. Such successes, however, have been rare, and the 1990s can be seen as a decade of lost opportunity for HIV prevention. Until recently, little emphasis was laid by AIDS programs on the care and treatment of patients with HIV-related disease and AIDS. However, this is now changing, with global policy supporting the use of cotrimoxazole (CTX), and, more recently, ARV. In 2000, WHO and UNAIDS issued provisional recommendations that CTX be given to all adults and children in Africa living with symptomatic HIV-related disease (14). Although the evidence base for this intervention is gradually strengthening (see below), adoption of CTX has been slow because of a lack of good evidence of effectiveness throughout the region, concerns about resistance to the drug in commonly occurring pathogens, and possible consequences for the treatment of malaria in countries where sulfadoxine-pyrimethamine is used. Before 2000, highly active antiretroviral therapy (HAART) was considered too expensive and too difficult to manage in resource-poor countries. That position has changed dramatically, and with resources from the Global Fund to fight AIDS, TB and Malaria (GFATM), the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR), and the World Bank, as well as simplified treatment regimens and approaches to management, more and more people are able to access this life-saving intervention (see below). C. Associations Between TB and HIV

HIV adversely affects TB control in a number of ways, which are highlighted in Table 2 (15), adding to an increasing number of TB suspects and registered TB cases. HIV-positive TB patients who complete treatment are at increased risk of developing recurrent TB, either as a result of reactivation of the disease (relapse) or reinfection with a new organism, and this adds to the number of patients presenting for treatment. HIV-related morbidity is a serious management problem among patients with TB. The

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Table 2 Issues Facing TB Control in the Face of HIV and AIDS Increase in TB case numbers, especially more difficult to diagnose cases of smear-negative PTB and extrapulmonary TB Hot spots of TB transmission, e.g., prisons, households of TB contacts leading to increased case notifications Increased morbidity from HIV-related diseases Increased frequency of adverse drug reactions to anti-TB treatment Increased case fatality rates Increased risk of recurrent TB after completing anti-TB treatment Abbreviation: PTB, pulmonary tuberculosis.

causes are many and include nontuberculous bacterial infections such as Salmonella typhimurium and the pneumococcus, parasitic infections especially toxoplasmosis, Kaposi’s sarcoma, lymphoma, and the HIV wasting syndrome (16). Not surprisingly, case fatality rates in sub-Saharan Africa range from 10% in smear-positive pulmonary TB patients to 40% to 50% in smear-negative pulmonary TB patients (17). These high death rates challenge the credibility of TB control programs among health-care workers, patients, and the wider community. Adverse effects of anti-TB drugs are also more common among HIV-infected patients, of which the potentially fatal cutaneous hypersensitivity reactions to thioacetazone are the best known (18). Although most countries stopped using this drug several years ago, a recent survey by WHO revealed seven countries which still use it, including two in Africa. Although TB is one of the most common causes of morbidity and one of the leading causes of death in HIV-positive adults living in less developed countries (19,20), it is a preventable and treatable disease. Thus, TB and AIDS programs need to collaborate in order to reduce the burden of disease in their patients. Unfortunately, to date, both programs have pursued largely separate courses. Generally, in sub-Saharan Africa, TB programs focus on detection, care, and treatment, whereas AIDS programs have, until recently, largely focused on prevention. However, the ProTEST (21) projects have successfully pioneered a collaborative approach to HIV and TB service delivery at a subdistrict level in Malawi, Zambia, and South Africa. As well as expansion in these three countries, collaborative TB/ HIV activities are now being implemented in Cambodia, Ethiopia, Haiti, India, Kenya, and Tanzania. In the FSU, public health is managed in a highly vertical manner, with TB control policy set by TB Institutes, many of which have long and honorable histories, while HIV is managed by separate Infectious Disease systems. Each system has its own culture and system of promotion. Collaboration has been most marked in parts of Asia, such as northern Thailand, where day-care centers have been established to provide a ‘‘one-stop shop’’ for those with HIV (22) and its complications. But these are so far very limited in their distribution.

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If the burden of TB–HIV is to be tackled effectively, TB and HIV programs have to share mutual concerns: minimizing the impact of HIV should be a priority for TB control, and TB care and prevention should be priority concerns for HIV/AIDS programs. In 2002, WHO and its partners developed a new approach to TB control in high HIV-prevalence populations (23). The new strategy includes interventions against TB (intensified case finding and TB preventive treatment) and interventions against HIV (and therefore indirectly against TB), e.g., condoms, treatment of STI, safe injecting drug use, and HAART. The additional interventions that are required beyond effective case finding and treatment in order to control TB in high HIVprevalent populations are shown in Table 3 and are taken from the Guidelines produced by WHO and its partners for implementing collaborative TB and HIV program activities (24). V. Principles, Policies, and Guidelines for Implementing Collaborative TB–HIV Activities Three main principles underlie the development of the TB/HIV policies and guidelines. First, after small-scale operational research projects, national programs insisted on a sense of urgency in the development of policy. TB/HIV policy therefore had to include the capacity to go rapidly to national scale on the basis of what was currently known. The policy would need to adjust as more evidence became available—‘‘learning by doing.’’ Second, policy should be centered on patients, that is, all services likely to be needed by patients with TB and/or HIV infection should, ultimately, be available at the same place and at the same time. Third, TB/HIV activities should, in no sense, form a separate program, but rather, they should add HIV-related activities to National Tuberculosis Programs (NTPs) and TB-related activities to the National AIDS Control Programs (NACPs). The Guidelines (24) for implementing collaborative TB and HIV program activities reflect the lessons learnt from TB/HIV field sites with additional experience from comprehensive TB/HIV health services and interventions. With the strategic framework addressing what can be done and the Guidelines addressing how things can be done, an interim global policy was produced in 2004 describing what should actually be done to decrease the joint burden of TB and HIV (25). While there is good evidence for the cost-effectiveness of the DOTS strategy and several HIV-prevention measures, the evidence for collaborative TB/HIV activities is limited and is still being generated in different settings. For this reason an interim policy document was developed, to be continuously updated to reflect new evidence and best practices. Implementing the DOTS strategy is the core activity for TB control. Similarly, infection prevention, health promotion,

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Table 3 Interventions, Additional to the DOTS Strategy, to Control TB in Populations with High HIV Prevalence Interventions directly against TB

Interventions against HIV (and therefore indirectly against TB)

Through TB case detection and treatment By preventing HIV transmission Intensified TB case finding in highCondom promotion risk groups: Treatment of STIs Voluntary counselling and HIV testing HIV-positive voluntary Safe injecting drug use counselling and HIV Sexual behavioral changes testing clients Intravenous drug users Prevention of mother-to-child Patients with STIs transmission of HIV PLHA support groups Safe blood Home-based care patients Universal precautions by health-care Prisoners workers Household contacts of TB Targeted interventions to high-risk patients locations, e.g., brothels Through prevention of new TB cases Information, education, and Isoniazid preventive treatment for communication activities PLHA Life skills Treatment to prevent a first ever ARV treatment episode of TB By increasing immune function in PLHA Treatment to prevent a recurrent ARV treatment episode of TB By providing care for PLHA Treatment of HIV-related diseases (infections and tumors) Prevention of HIV-related infections Psychosocial support Palliative care Nutritional support Abbreviations: STI, sexually transmitted infection; PLHA, people living with HIV; ARV, antiretroviral. Source: From Ref. 24.

and the provision of treatment and care form the basis for HIV/AIDS control. The global policy does not call for the institution of a new specialist or independent disease control program, but rather enhanced collaboration between TB and AIDS programs. The policy goal is to decrease the burden of TB and HIV in populations affected by the two diseases. The objectives of the collaborative TB/ HIV activities are: (i) to establish mechanisms for collaboration between the two programs; (ii) to decrease the burden of TB in people living with HIV/AIDS; and (iii) to decrease the burden of HIV in TB patients. The collaborative activities needed to achieve these objectives are shown in Table 4.

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Table 4 Recommended Collaborative TB/HIV Activities Establish the mechanism for collaboration Set up a coordinating body for TB/HIV activities effective at all levels Conduct surveillance of HIV prevalence among TB patients Carry out joint TB/HIV planning Conduct monitoring and evaluation Decrease the burden of TB in people living with HIV/AIDS Establish intensified TB case finding Introduce isoniazid preventive therapy Ensure TB infection control in health care and congregate settings Decrease the burden of HIV in TB patients Provide HIV testing and counselling Introduce HIV-prevention methods Introduce cotrimoxazole preventive therapy Ensure HIV/AIDS care and support Introduce antiretroviral therapy

A. The Mechanisms for Collaboration

Both programs need to create a joint national TB and HIV coordinating body, to work at regional/district and local levels and oversee the direction and implementing of joint activities. In Eastern Europe and countries of the FSU, TB/HIV administrative orders, or prikaz, will need to be promulgated to mandate the new activities. The TB and HIV/AIDS programs require joint strategic planning to collaborate successfully and systematically. Either they may work together to produce joint TB/HIV plans, or they may introduce TB/HIV components into each of the national TB and national AIDS control plans. These plans should be realistic and sufficiently resourced in terms of capacity building, effective advocacy and communication, and community involvement. Collaborative activities need to be monitored, and this might be best done through the already well-tried and experienced system of quarterly monitoring, recording, and reporting, which exists in most DOTS programs. Finally, operational research is an effective way of determining the most efficient way of implementing collaborative activities (26), and should be an integral part of any development plan. Surveillance of HIV prevalence in TB patients is essential to program planning, implementation, and effective TB/HIV collaboration, and HIV testing also provides the entry point for delivery of HAART. Updated guidelines on how to conduct surveillance have recently been published (27). Surveillance can be done in three main ways: (i) periodic cross-sectional surveys, (ii) sentinel surveys (using TB patients as a sentinel group within the general HIV sentinel surveillance system), and (iii) data from routine HIV testing and counselling of TB patients. The last option is the goal to aim for, where resources are sufficient.

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B. Decreasing the Burden of Tuberculosis in People Living with HIV/AIDS

Intensified TB case finding comprises screening for symptoms and signs of TB in settings where HIV-infected people are concentrated. Early identification of TB, followed by diagnosis and prompt treatment in people living with HIV/AIDS, their household contacts, groups at high risk of HIV, and those in congregate settings (e.g., prisons, workers’ hostels, police and military barracks, and hospitals and clinics) increases the chances of survival, improves the quality of life, and reduces transmission of TB in the community. It has been shown that intensified case finding is feasible, not time-consuming, and can be done at little additional cost in existing health service settings (21). In all HIV testing and counselling settings, trained counsellors and other lay workers can be trained to administer a simple set of questions to identify suspected TB cases as soon as possible. The provision of isoniazid preventive therapy (IPT), linked particularly to counselling and HIV testing, is used to prevent the progression of latent M. tuberculosis to active disease. Several randomized trials have shown that IPT is efficacious in reducing the incidence of TB and death from TB in HIV-infected patients with a positive tuberculin skin test (28). Isoniazid is as effective and safer than rifampicin-containing regimens (and pyrazinamidecontaining regimens) and is the preferred drug. However, IPT requires several steps to be taken, including identification of HIV-positive subjects, screening to exclude active TB, and provision of information to promote adherence. For these reasons, the feasibility of this intervention in resource-poor countries is less clear (29,30). However, other structures may facilitate the application of IPT. One such is ‘‘Prevention of Motherto-Child Transmission (PMTCT).’’ HIV-positive mothers are generally well at the time of delivery, and because they should be followed up for six or more months postpartum for monitoring of safe feeding practices, childhood immunizations, and other postnatal-care issues, potentially the administration of IPT can be facilitated. However, this approach has yet to be implemented or evaluated in the routine setting. A second approach is to administer IPT through the ARV delivery system, once it is established. Because the risk of developing TB while on HAART appears to be significantly higher than in those without HIV infection (31), there is a strong rationale for this approach, although studies that directly examine the additional effect of isoniazid in preventing TB among those on HAART began only in late 2005. Several studies in sub-Saharan Africa have pointed to an increased risk of recurrent TB in patients who are HIV positive and who have completed a course of anti-TB treatment, particularly where the continuation phase does not include rifampicin (32). Studies in Haiti and South Africa have found that posttreatment isoniazid significantly reduces the rate of recurrent TB (33,34). However, this intervention has yet to find a place in the routine management of TB. If the main mechanism of recurrence is reinfection, which appears to be the case in HIV-infected individuals who

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Table 5 Tuberculosis Infection Control in Health-Care Settings Administrative measures Early recognition, diagnosis, and treatment of pulmonary TB suspects Separation of pulmonary TB suspects from others Separation of pulmonary TB cases from others Environmental protection Maximizing natural ventilation Using ultraviolet radiation (if applicable) Personal protection Protection of HIV-positive persons from possible exposure to TB Offering isoniazid preventive therapy

develop recurrent TB several months after completing treatment, then isoniazid may need to be given for life (34). As yet, the structures for delivering and monitoring such an intervention do not exist. TB infection control in health-care and congregate settings (e.g., prisons and police and military barracks) can reduce the increased risk of TB that occurs when people with TB and HIV are frequently crowded together (35). Measures to reduce TB transmission include administrative, environmental, and personal protection measures (Table 5). C. Decreasing the Burden of HIV in TB Patients

The provision of HIV counselling and testing (CT), using wherever possible rapid tests, offers an all important entry point for a continuum of prevention, care, support, and treatment for HIV/AIDS as well as for TB. The uptake of HIV testing and counselling by TB patients can be high (36), and the cost-effectiveness of CT improves significantly when testing is targeted at populations with high HIV prevalence (12). Recently UNAIDS and WHO have recommended that CT should be offered routinely to all TB patients (25,37). HIV prevention methods must accompany the process of CT. Reduction of sexual, parenteral, and vertical transmission of HIV builds on broad-based programs of education about HIV/AIDS. All clients attending TB clinics should be screened for STI using a simple questionnaire or other recommended approaches. Those with symptoms of STI should be treated or referred to the relevant treatment providers. TB control programs should implement harm-reduction measures for TB patients when injecting drug use is a problem or should establish a referral linkage with HIV/AIDS programs to do so. Finally, TB programs should ensure that vertical transmission is prevented by referral of pregnant HIV-infected clients to providers of services for PMTCT. CTX-preventive therapy is promoted by WHO and UNAIDS for the prevention of several bacterial and parasitic infections in eligible adults and children living with HIV/AIDS in Africa (14). Evidence from randomized controlled trials of CTX-preventive therapy has shown reduced

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mortality among HIV-positive smear-positive TB patients, and reduced hospitalization and morbidity among people living with HIV/AIDS in Africa (38,39). Other nonrandomized and operational studies have also shown that CTX-preventive therapy is feasible, safe, and can reduce mortality rates in TB patients (36,40,41). As in the case with IPT, whether there is a need for CTX in HIV-positive TB patients who are taking HAART in Africa and other parts of the developing world is not known. Access to HIV care and support, including good clinical management of opportunistic infections and malignancies, nursing care, nutritional support, home care, and palliative care, is feasible and helps to generate synergies and collaboration between TB and HIV/AIDS programs. The provision of HAART to HIV-positive TB patients is the intervention that is likely to have the most significant impact on improving the quality of life and reducing death rates in HIV-positive patients, whether or not they have TB. D. Thresholds for Starting Recommended HIV–TB Collaborative Activities

Unlike many other HIV-related opportunistic infections, TB can occur at all levels of immune status. Thus, countries in any HIV-epidemic state and with intersecting epidemics of TB and HIV should consider implementing collaborative TB–HIV activities as indicated in Table 6 (25). HIV prevalence among TB patients is the most sensitive and reliable indicator for when to start collaborative activities, but in the absence of this data, the national HIV-prevalence rate can be used. VI. General Overview of Initiatives to Scale Up Antiretroviral Treatment in Resource-Poor Countries The advent of HAART in 1996 lead to a revolution in the care of patients with HIV/AIDS in industrialized countries worldwide. Although HAART does not cure AIDS, and in fact presents new challenges with respect to side effects and drug resistance, the drugs have changed what was a fatal condition into a chronic and manageable disease and annual mortality rates of patients with AIDS are now well below 5% (42,43). Unfortunately, most of the 40 million people living with HIV/AIDS reside in developing countries of the world and do not share this vastly improved prognosis. WHO estimated that at the end of 2003, about six million people in the developing world were in immediate need of HAART (44). However, only about 400,000 persons were being treated, over a third of them in Brazil. At the United Nations General Assembly High-Level meeting on HIV/AIDS on 22 September 2003, WHO declared that the lack of access to HIV treatment was a global health emergency, and called for unprecedented action to ensure that by the end of 2005 at least three million people in need of HAART would have access to it—the so called ‘‘3 by 5’’ initiative (45). The provision of HAART to two million people is also a cornerstone of the U.S. President’s AIDS Initiative (46).

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Table 6 Thresholds for Countries to Start Recommended Collaborative TB/HIV Activities Criteria

Recommended collaborative TB/HIV activities

Countries in which the national Undertake all collaborative activities listed in adult HIV prevalence rate is at Table 4 or above 1% OR Countries in which the national HIV prevalence among TB patients is at or above 5% Countries in which the national Undertake all collaborative activities listed in adult HIV prevalence rate is Table 4 for the administrative areas with adult below 1% HIV rate of 1% or more AND In other parts of the country implement the following: Countries in which there are a) Joint national TB/HIV planning, particularly administrative areas with an with respect to surveillance of HIV prevalence adult HIV prevalent rate of 1% in TB patients or more b) Measures to decrease the burden of TB in people living with HIV/AIDS by intensified TB case finding, IPT, and TB infection control in health care and congregate settings Countries in which the national Implement the following: adult HIV prevalence rate is a) Joint national TB/HIV planning, particularly below 1% with respect to surveillance of HIV prevalence AND in TB patients Countries in which there are no b) Measures to decrease the burden of TB in people living with HIV/AIDS by intensified administrative areas with an TB case finding, IPT, and TB infection control adult HIV prevalent rate of 1% in health care and congregate settings or more Abbreviation: IPT, isoniazid preventive therapy.

To achieve these targets, there is a need for strong global leadership, sustained country support (particularly in the field of human resources), simplified and standardized tools for the delivery of HAART, and an effective and reliable supply of medicines and diagnostics. The GFATM is now a major player in the provision of funds to countries for the procurement of ARV drugs, but significant constraints remain in the dispersal of these funds. The prices of the drugs have come down dramatically with companies in Brazil, India, and Thailand producing cheap generic versions. With ARV drugs now a realistic option for AIDS patients in developing countries, the success or otherwise of these scale-up initiatives will depend on how well HAART can be delivered to HIV-positive eligible patients at district level. Two important simplifications of case management make success

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a real possibility. First, in industrialized countries, the initiation of HAART is usually based on measurement of the CD4-T-lymphocyte count— a laboratory test that acts as an indicator for the functioning of the immune system. Most district hospitals in Africa have no facilities to measure CD4 counts. In such hospitals where CD4-T-lymphocyte testing is unavailable, it is advised that HIV-positive patients in WHO clinical stage III or IV can be eligible for ARV treatment, which includes all patients with TB, including those with a history of TB in the previous year. Second, the drugs can now be obtained in fixed-dose combinations (zidovudine/lamivudine/nevirapine or stavudine/lamivudine/nevirapine), and this: (i) simplifies drug procurement, case management, and drug security issues, (ii) maximizes adherence to drug therapy, and (iii) minimizes development of drug resistance. Finally, there needs to be a robust system of monitoring and evaluation, and, although still to be tested at the national level, it has been suggested that the DOTS strategy and operations for monitoring TB control can be adapted for the delivery of HAART (47,48). VII. TB as an Entry Point to Antiretroviral Therapy: Benefits and Risks for TB Control As described above, all HIV-positive TB patients are potentially eligible for HAART. In theory then, HIV-positive patients with TB could make a significant contribution to reaching the targets for HIV treatment. For example, in Malawi, with the goal of providing 80,000 HIV-positive patients with HAART by the end of 2005, it was estimated that approximately 40,000 patients could be HIV-positive TB patients (Malawi registers about 28,000 TB patients per year, of whom 65–75% are HIV positive). However, these estimates presuppose that systems operate perfectly, with all TB patients counselled and HIV tested and referred to services for initiation of HAART. Unfortunately this is unrealistic, although in the first half of 2005, Malawi tested 49% (Chimzizi R, personal communication), and Rwanda tested 53% (Bah Sow O, personal communication) of all patients registered nationally for TB treatment. There are also a number of specific difficulties with providing HAART to HIV-positive TB patients who have been started on anti-TB treatment. First, there is the question of the optimal time to start HAART. Much of the mortality in HIV-positive TB patients occurs in the first two months of anti-TB treatment (17), and thus starting patients early on with HAART may seem advantageous. However, there are significant interactions between rifampicin and non-nucleoside reverse-transcriptase inhibitors as well as protease inhibitors (49). This, along with the immune reconstitution syndrome resulting from treatment with ARV drugs, poses a significant problem in terms of diagnosis and proper case management (50). Second, many TB programs in Africa have decentralized their initial and continuation phases of anti-TB treatment to health centers and the community (51). However, during the scale-up of ARV therapy, it is likely that HAART will

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be delivered initially from a hospital-based clinic. Expecting TB patients to come from remote parts of the district to the hospital to collect ARV tablets on a monthly basis is unrealistic. Solutions to these problems need to be found if HIV-positive TB patients are to reap the full benefits of ARV therapy. Clearly, one solution is the decentralization of ARV therapy as well as DOTS, but this will take time. There are large potential benefits to TB control as a result of widescale administration of HAART. In persons with HIV infection, HAART significantly reduces the risk of TB (52), and in areas endemic for TB and HIV, the administration of HAART has the potential to significantly reduce the incidence of HIV-associated TB (31). Whether HAARTwill reduce the risk of recurrent TB is unknown, although on theoretical grounds it should do so. In HIV-positive TB patients, HAART has been shown to significantly improve treatment outcomes (53). For all these potential benefits to be achieved, high levels of ARV drug coverage, early treatment, and good adherence will be necessary. The wide scaling up of ARV therapy also poses risks to TB control. These relate largely to how ARV therapy will be delivered in resource-poor settings. Among the various models of HIV care provision, one proposed model is to establish interprogram linkages and integrate HIV care and HAART provision for TB patients into existing TB DOTS programs (47,54,55) for the duration of treatment. The patients should then be referred to appropriate care services through an established referral mechanism. This would give an opportunity to: (i) initiate HIV care and HAART for patients identified as HIV-positive during anti-TB treatment, (ii) continue HAART in TB patients completing anti-TB treatment, and (iii) manage those who develop TB during HIV treatment. The integration of the two programs could potentially improve the outcome for both diseases. However, integration of TB and HIV care may put additional pressure on an already overstretched TB treatment delivery system such that the core function of providing DOTS to TB patients cannot be maintained. This may require testing in pilot districts and careful monitoring. In any event, there are many lessons for ARV scale-up in the principles underlying DOTS and in the experiences of the many staff who have successfully extended TB treatment to reach much of the developing world. Global scale-up of ARV therapy will raise many difficult issues, and risks will have to be taken at international and national levels. The AIDS pandemic, as never before, demands unprecedented actions, and provided that a responsible and ‘‘learning by doing’’ attitude is taken, these actions could shape a better future for global health. References 1. UNAIDS. 2004 Report on the Global AIDS Epidemic. 2. Selwyn PA, Hartel D, Lewis VA, et al. A prospective study of the risk of tuberculosis among intravenous drug users with human immunodeficiency virus infection. N Engl J Med 1989; 320:545–550.

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3. Daley CL, Small PM, Schecter GF, et al. An outbreak of tuberculosis with accelerated progression among persons infected with the human immunodeficiency virus. N Engl J Med 1992; 326:231–235. 4. Enarson DA, Rouillon A. The epidemiological basis of tuberculosis control. In: Davies PDO, ed. Clinical Tuberculosis. 2d ed. London, Weinham, New York, Tokyo, Melbourne, Madras: Chapman and Hall Medical, 1998. 5. Gilks CF, Godfrey-Faussett P, Batchelor BIF, et al. Recent transmission of tuberculosis in a cohort of HIV-1 infected female sex workers in Nairobi, Kenya. AIDS 1997; 11:911–918. 6. Dye C, Scheele S, Dolin P, Pathania V, Raviglione M. For the WHO Global Surveillance and Monitoring Project. Global burden of tuberculosis. Estimated incidence, prevalence, and mortality by country. JAMA 1999; 282:677–686. 7. 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. 8. World Health Organization. WHO Report 2004. Global Tuberculosis Control: Surveillance, Planning and Financing. ISBN 92 4 156264 1. 9. World Health Organization. Treatment of Tuberculosis. Guidelines for National Programmes. 3rd ed. Geneva: WHO, 2003. WHO/CDS/TB/2003.313. 10. Working Group on Mother-To-Infant Transmission of HIV. Rates of mother-toinfant transmission of HIV-1 in Africa, America, and Europe: results from 13 perinatal sites. J Acquir Immun Defic Syndr Retrovirol 1995; 8:506–510. 11. Guay LA, Musoke P, Feling T, et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for the prevention of mother-to-child transmission of HIV1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet 1999; 354:795–802. 12. The Voluntary HIV-1 Counselling and Testing Efficacy Study Group. Efficacy of voluntary HIV-1 counselling and testing in individuals and couples in Kenya, Tanzania and Trinidad: a randomised trial. Lancet 2000; 356:103–112. 13. Sweat M, Gregorich S, Sangiwa G, et al. Cost-effectiveness of voluntary HIV-1 counselling and testing in reducing sexual transmission of HIV-1 in Kenya and Tanzania. Lancet 2000; 356:113–121. 14. World Health Organization and UNAIDS. Provisional WHO/UNAIDS secretariat recommendations on the use of cotrimoxazole prophylaxis in adults and children living with HIV/AIDS in Africa. Geneva, Switzerland: WHO/UNAIDS, 2000. 15. Harries AD. Issues facing TB control: tuberculosis control in sub-Saharan Africa in the face of HIV and AIDS. Scot Med J 2000; 45(suppl 1):47–50. 16. World Health Organization. TB/HIV: A Clinical Manual. 2d ed. WHO/HTM/TB/ 2004.329. 17. Diul MY, Maher D, Harries AD. Tuberculosis case fatality rates in high HIV prevalence populations in sub-Saharan Africa. AIDS 2001; 15:143–152. 18. Nunn P, Kibuga D, Gathua S, et al. Cutaneous hypersensitivity reaction due to thiacetazone in HIV-1 seropositive patients treated for tuberculosis. Lancet 1991. 19. Lucas SB, Hounnou A, Peacock C, et al. The mortality and pathology of HIV infection in a west African city. AIDS 1993; 7:1569–1579. 20. Corbett EL, Churchyard GJ, Charalambos S, et al. Morbidity and mortality in South African gold miners: impact of untreated HIV infection. Clin Infect Dis 2002; 34:1251–1258. 21. World Health Organization. Report of a ‘‘Lessons Learnt’’ Workshop on the Six PROTEST Pilot Projects in Malawi, South Africa and Zambia. Geneva: WHO, 2004. WHO/HTM/TB/2004.336. 22. Tsunekawa K, Moolphate S, Yanai H, Yamada N, Summanapan S, Ngamvithayapong J. Care for people living with HIV/AIDS: an assessment of day care centers in northern Thailand. AIDS Patient Care STDS 2004(May); 18(5):305–314.

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23. World Health Organization. Strategic Framework to Decrease the Burden of TB/ HIV. Geneva: WHO, 2002. WHO/CDS/TB/2002.296. WHO/HIV_AIDS/2002.2. 24. World Health Organization. Guidelines for Implementing Collaborative TB and HIV Programme Activities. Geneva: WHO, 2003. WHO/CDS/TB/2003. 319. WHO/ HIV/2003.01. 25. World Health Organization. Interim Policy on Collaborative TB/HIV Activities. Geneva: WHO, 2004. WHO/HTM/TB/2004. 330. WHO/HTM/HIV/2004.1. 26. Salaniponi FML, Harries AD, Nyirenda TE, et al. TB Research. Putting Research Into Policy and Practice: the Experience of the Malawi National Tuberculosis Control Programme. The Communicable Disease Cluster of the World Health Organization, Geneva, 1999. WHO/CDS/CPC/TB/99.268. 27. World Health Organization. Guidelines for HIV Surveillance Among Tuberculosis Patients. 2d ed. Geneva: WHO, 2004. WHO/HTM/TB/2004.339. WHO/HIV/ 2004.06. UNAIDS/04.30E. 28. 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; 317:625–629. 29. 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; 9:267–273. 30. World Health Organization. Preventive Therapy Against Tuberculosis in People Living with HIV. Weekly Epidemiological Record 1999; 74:385–400. 31. Badri M, Wilson D, Wood R. Effect of highly active antiretroviral therapy on incidence of tuberculosis in South Africa: a cohort study. Lancet 2002; 359:2059–2064. 32. Harries AD, Chimzizi RB, Nyirenda TE, van Gorkom J, Salaniponi FM. Preventing recurrent tuberculosis in high HIV-prevalent areas in sub-Saharan Africa: what are the options for tuberculosis control programmes? Int J Tuberc Lung Dis 2003; 7:616–622. 33. Fitzgerald DW, Desvarieux M, Severe P, Joseph P, Johnson WD, Pape JW. Effect of post-treatment isoniazid on prevention of recurrent tuberculosis in HIV-1-infected individuals: a randomised trial. Lancet 2000; 356:1470–1474. 34. Churchyard GJ, Fielding K, Charalambous S, et al. Efficacy of secondary isoniazid preventive therapy among HIV-infected South Africans: time to change policy? AIDS 2003; 17:1–8. 35. World Health Organization. Guidelines for the Prevention of Tuberculosis in Health Care Facilities in Resource Limited Settings. Geneva: WHO, 1999. WHO/CDS/TB/ 99.269. 36. Zachariah R, Spielmann M-P, Chinji C, et al. Voluntary counselling, HIV testing and adjunctive cotrimoxazole reduces mortality in tuberculosis patients in Thyolo, Malawi. AIDS 2003; 17:1053–1061. 37. WHO/UNAIDS. UNAIDS/WHO Policy Statement on HIV Testing. Geneva: World Health Organization. http://www.unaids.org/html/pub/una-docs/hivtestingpolicy_en_pdf.htm. 38. Anglaret X, Chene G, Attia A, et al. Early chemotherapy with trimethoprim-sulphamethoxazole for HIV-I-infected adults in Abidjan, Cote d’Ivoire: a randomised trial. Lancet 1999; 353:1463–1468. 39. Wiktor SZ, Morokro MS, Grant AD, et al. Efficacy of trimethoprim-sulphamethoxazole prophylaxis to decrease morbidity and mortality in HIV-infected patients with tuberculosis in Abidjan, Cote d’Ivoire: a randomised controlled trial. Lancet 1999; 353:1469–1474. 40. Mwaungulu FBD, Floyd S, Crampin AC, et al. Cotrimoxazole prophylaxis reduces mortality in human immunodeficiency virus-positive tuberculosis patients in Karonga district, Malawi. Bull World Health Org 2004; 82:354–363.

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41. Chimzizi RB, Harries AD, Manda E, Khonyongwa A, Salaniponi FM. Counselling, HIV testing and adjunctive cotrimoxazole for TB patients in Malawi: from research to routine implementation. Int J Tuberc Lung Dis 2004; 8:938–944. 42. Palella F, Delaney K, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998; 338:853–860. 43. Mocroft A, Ledergerber B, Katlama C, et al. Decline in the AIDS and death rates in the EuroSIDA study: an observational study. Lancet 2003; 362:22–29. 44. World Health Organization. Scaling Up Antiretroviral Therapy in Resource-Limited Settings. Treatment Guidelines for a Public Health Approach. Geneva: WHO QV268.5, November 2003 (revised version). 45. Lee Jong-wook. Global health improvement and WHO: shaping the future. Lancet 2003; 362:2083–2088. 46. US Department of State. http://www.state.gov/r/prs/ps/2004/28844pf.htm. 47. Harries AD, Nyangulu DS, Hargreaves NJ, Kaluwa O, Salaniponi FM. Preventing antiretroviral anarchy in sub-Saharan Africa. Lancet 2001; 358:410–414. 48. Gupta R, Irwin A, Raviglione MC, Kim JY. Scaling up treatment for HIV/ AIDS: lessons learnt from multi-drug resistant tuberculosis. Lancet 2004; 363: 320–324. 49. Pozniak AL, Miller R, Ormerod LP. The treatment of tuberculosis in HIV-infected persons. AIDS 1999; 13:435–445. 50. Orlovic D, Smego RA. Paradoxical tuberculous reactions in HIV-infected patients. Int J Tuberc Lung Dis 2001; 5:370–375. 51. Maher D, Floyd K, Sharma B, et al. Community contribution to tuberculosis care: practice and policy. Review of experience of community contribution to TB care and recommendations to National TB Programmes. Geneva: WHO, 2003. WHO/ CDS/TB/2003.312. 52. Girardi E, Antonucci G, Vanacore P, et al. Impact of combination antiretroviral therapy on the risk of tuberculosis among persons with HIV infection. AIDS 2000; 14:1985–1991. 53. Hung C-C, Chen M-Y, Hsiao C-F, Hsieh S-M, Sheng W-H, Chang S-C. Improved outcomes of HIV-1-infected adults with tuberculosis in the era of highly active antiretroviral therapy. AIDS 2003; 17:2615–2622. 54. Friedland G, Karim SA, Karim QA, et al. Utility of tuberculosis directly observed therapy programs as sites for access to and provision of antiretroviral therapy in resource-limited settings. Clin Infect Dis 2004; 38: S421–S428. 55. Karim SS, Karim QA, Friedland G, Lalloo U, Sadr MW. On behalf of the start project. Implementing antiretroviral therapy in resource-constrained settings: opportunities and challenges in integrating HIV and tuberculosis care. AIDS 2004; 18:975–979.

39 Engaging Private Providers in Tuberculosis Control: Public–Private Mix for DOTS

¨ NNROTH MUKUND UPLEKAR and KNUT LO Stop TB Department, World Health Organization, Geneva, Switzerland

I. Introduction Traditionally, control of diseases of public health importance has been the responsibility of the public health sector in most countries. DOTSa programs for tuberculosis (TB) control in all countries are designed by the public sector and are also implemented through the public sector outlets to a large extent. However, many care providers operate outside the public health sector. Furthermore, unlike some other public health programs, in TB control there is no major difference between what public health-care providers and private medical providers contribute. Both try to do the same: diagnose and cure TB cases. Early diagnosis and effective treatment of a significant proportion of all TB cases is a cornerstone of TB control. In view of this distinct overlap of service provision, leaving some care providers out of the TB control strategy could only be to the disadvantage of TB programs. There is growing evidence of the major role of the private sector in health care in many developing countries. A large proportion of medical personnel and facilities are in the private sector (1,2). Surveys of health-seeking a

DOTS is the internationally recommended TB control strategy (see Chapter 27).

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behavior indicate widespread preference for and use of private providers. National Health Accounts consistently illustrate that private, out-of-pocket spending accounts for the bulk of health expenditures (3). The formal private providers tend to be concentrated in urban areas and often have a dominant share of outpatient care (4). The private sector typically manages a large share of TB patients (5). Engaging the private sector for DOTS is not always easy but is well justified. The shortfall in achieving the global case detection target has been widely acknowledged and documented in the World Health Organization’s (WHO) global TB control report. Apparently, even strengthened National TB Programs (NTP) fail to attract a sufficient proportion of TB patients. It is known that many poor TB patients also seek care from the private sector for a variety of reasons (5). Further, a large amount of anti-TB drugs are sold in unregulated retail private markets (6). Irrational and unsupervised drug administration by private providers could escalate the emergence of drug-resistant TB. Moreover, health sector reforms in many countries tend to promote private health-care, which makes collaboration essential. This chapter discusses engagement of private providers for global TB control. It draws heavily from the experience of the Stop TB Department of the WHO in developing and promoting its strategy termed ‘‘public–private mix’’ for DOTS (PPM DOTS) (7). The following section summarizes the findings of a global assessment undertaken by WHO to initiate private sector involvement in TB control. The guiding principles of PPM DOTS that became apparent are presented. WHO then helped set up a few ‘‘learning projects’’ in Asia and Africa. The analysis of processes and outcomes of these projects helped develop a generic model and identify practical tools to facilitate implementation of PPM DOTS. These are discussed in section ‘‘What Makes PPM DOTS Work?’’ Many countries have now begun to address private sector involvement in TB control. Section ‘‘Evidence Base’’ presents the current evidence based on the outcomes of PPM DOTS in diverse settings. This also includes known projects that supplemented WHO’s efforts. Engagement with the private sector always raises questions around cost and cost-effectiveness. The findings from an economic analysis of two PPM DOTS projects in India are discussed in section ‘‘Economic Analysis.’’ The concluding section offers a glimpse of approaches to scaling up PPM DOTS and highlights its potential contribution to meeting the Millennium Development Goals (MDG). II. Global Assessment When the work on PPM DOTS began, documentation on experiences of linking private providers to TB control programs was virtually nonexistent. To help fill this lacuna, WHO undertook a global assessment in 23 countries across the six WHO regions (8). The objectives were to understand the extent and nature of private provider involvement in TB care, identify working examples of collaboration, and develop a framework to help NTPs begin

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addressing the issue. The assessment included a mix of countries with a high, medium, and low prevalence of TB. Known ongoing collaborative initiatives between local TB programs and private providers were appraised. The assessment confirmed that a large proportion of TB suspects and cases are managed, partly or fully, in the private sector in many high TB burden countries. It underscored the need to begin actively engaging the different types of providers in TB control activities. Ignoring them would be a clear omission on part of NTPs, particularly in places where a significant proportion of TB patients consult private providers whose management practices may be questionable. Private providers pose both threats to and opportunities for improved TB control. If the private medical sector thrives and grows as an alternative and unregulated source of care, NTPs will be hampered in reaching their goals. The poor case management practices in the private sector could dilute the epidemiological impact of TB programs. Such practices, if unchecked, could contribute to the evolution and spread of multidrug-resistant TB. The private providers also offer major opportunities to further TB control. A private doctor is a valuable resource located close to, and often trusted by, the community. By involving them, NTPs can increase case detection and notification. Because many TB suspects first approach a neighbourhood private practitioner, there is an opportunity to reduce diagnostic delay with a concurrent reduction in transmission. By enlisting all care providers, NTPs can enhance patient access and acceptance, thereby improving treatment outcomes. There is also the potential to share service delivery with the private sector and thus moderate the workload of frontline health workers. Of course, this has to be traded off against the possible increase in tasks such as liaison, training, and monitoring. Most TB patients are poor and many of them use the private medical sector. There is a compelling case to address this issue through providing subsidized services through private providers in order to alleviate the health and socioeconomic burden on households. Further, TB control has to be viewed within the context of changing health systems. Health sector reforms comprise a wide range of initiatives. The common themes include a strengthening of the government role in providing information, in regulating, and in financing interventions of public health importance while partnering with the private sector to achieve a balanced public–private mix (PPM) in service delivery. For the long-run sustainability of the TB control effort, TB programs will have to adapt their strategies to these trends. A. Barriers to Collaboration

The assessment revealed major barriers to practicing PPM DOTS. Most apparent among NTP managers of high-burden countries generally was a reluctance or inertia to take on the issue of private sector involvement. This was not without reasons. First, NTP managers seemed aware but did not consider private providers a problem serious enough to divert their attention from their current activities. Second, they were too preoccupied with

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implementation of demanding public sector DOTS programs to venture into what they saw as unfamiliar territory. Third, they believed that eventually patients would turn away from ‘‘exploitative’’ and ‘‘money-minded’’ private providers. Fourth, they saw little common ground for collaboration with a largely unorganized private sector and, in the absence of working regulatory mechanisms, perceived them as an unmanageable lot. And finally, the lack of evidence, precedents, and replicable success stories on effective collaboration added to their inertia. These considerations notwithstanding, there appeared to be a general agreement on the need to act to get private providers on board. Private physicians generally complained about lack of sufficient information about TB programs. They wondered if sputum-based diagnosis and a few drug-treatment options supposedly meant for resource-starved TB programs would be in the best interest of their patients. They were critical of the disrespect and distrust shown toward them by the program staff. They were reluctant to lose their patients to the program and accused the program of discriminating against sputum-negative patients. Private practitioners were frank about their inability to undertake certain tasks such as defaulter retrieval, social support to patients, and detailed record keeping and analysis. A general view, however, was that collaboration was feasible. Some of them favoured joint care of their patients. There was no unanimity among private practitioners about providing free care to all TB patients on a permanent basis but there was a willingness to reciprocate if any support from the program was forthcoming. Likewise, many NTP managers generally disapproved providing cash incentives to the private sector, and preferred trying out nonmonetary incentives first. The assessment revealed that, regardless of the mixed perceptions and reservations on collaboration both sides, public and private had indeed acted together in some settings. The approaches used by them offered useful lessons for both sides. One such project, which proved to be successful and cost-effective as well as sustainable and possible to scale up, was undertaken in 1995 in Hyderabad, India, with support from WHO. In fact, the label PPM DOTS was first coined for this particular project. A full report of the global assessment including a review of the literature on private sector roles in TB diagnosis and treatment and working examples of the private sector involvement in TB control in low, medium, and high income countries is available (5). B. Principles Guiding the Global Strategy

Private sector involvement in TB control can be varied and wide ranging. PPM DOTS is concerned essentially with developing partnerships between NTPs and private care providers for direct provision of services under DOTS to all socioeconomic groups and especially the poor. TB suspects and patients are the obvious focus. Global strategy on PPM DOTS is guided by three basic principles. First, for TB control in any population, all TB cases should have easy access to DOTS services, regardless of the

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providers they choose to seek care from. Second, because their actions and contributions have important consequences for people’s health and welfare, private providers too have a responsibility to facilitate TB control in the communities they serve. They should be made aware of this, encouraged and supported in taking on the responsibility. And thirdly, TB control being their main mandate, it is for the NTPs to reach out, help initiate and sustain appropriate collaboration with all non-NTP providers within the DOTS framework. WHO’s expanded DOTS framework lists private provider involvement as one of the important components of the DOTS strategy (9).

III. What Makes Public–Private Mix for DOTS Work? A. Learning Projects

The global assessment provided useful insights and a framework to begin establishing PPM DOTS projects on the ground. In early 2001, WHO helped set up four such projects in Delhi, Ho Chi Minh City (HCMC), Nairobi, and Pune. The approaches were as diverse as the settings. The Pune project was in a rural setting while the rest were urban. In Delhi, the general practitioner members of the local medical association were the counterpart of the NTP and the collaboration was facilitated by a specialty institute. In HCMC, there were no intermediaries and interestingly, all the participating chest physicians were working for the public sector during the day and practicing privately in the evenings. In Nairobi, a nongovernmental organization— Kenya Association for Prevention of Lung Disease—facilitated participation of some of the chest physicians. In the Pune project, the private doctors comprised a mix of those qualified in Western and indigenous medicine. Their collaboration with the local NTP was facilitated by a research NGO. All four projects were documented systematically. External and independent resource persons carried out evaluations in association with local or international academic institutions that were also involved in the design and implementation in their respective settings. In all four settings, the intended intervention package included sensitization and training sessions in which the NTP case management guidelines were presented and discussed with private providers. Simple forms for referral, individual patient records, and reporting forms were introduced in all projects in order to improve the information systems and the system for referrals of suspects and cases. Private providers could either treat patients themselves or refer them to the NTP. In Delhi and Pune, drugs were provided free by the NTP for the patients in private clinics while they were charged for in HCMC and Nairobi. All projects planned to introduce supervision and quality control at various levels of case management in the private sector. As might be expected though, not all projects were equally successful in terms of achievements. However, there were useful lessons from the failures as well. A paper on detailed cross-site analysis and determinants of effectiveness of these projects has been published (10).

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With its clearly defined task mix, specific guidelines on procedures, standard indicators for monitoring and evaluation, built-in quality assurance, and well-defined output, PPM DOTS lends itself very well to the concept of franchising with a ‘‘brand.’’ Currently, Population Services International and the NTP of Myanmar are implementing a social marketing and franchising project. In this project, willing private general practitioners are trained and supervised under contract to provide DOTS services. Drugs are supplied by the NTP and are offered free of charge to the patients by participating doctors. Early results are very encouraging (Guy Stallworthy, personal communication). Because standardization minimizes the need for a high level of expertise, franchising is also seen as a potential tool to address the health workforce crisis in managing the dual epidemic of TB/HIV in sub-Saharan Africa. Ways to set up such projects in several countries in Africa through the involvement of international and local NGOs and the NTPs are also being explored. Franchising DOTS presents a potentially attractive scale-up mechanism. Many PPM DOTS projects are currently in progress across several country settings and successfully so. Along with the well documented projects mentioned above, these initiatives have led to three outcomes that have been extremely useful in subsequent promotion of PPM DOTS: identification of key factors that help make PPM DOTS work; a set of practical tools to help implement PPM DOTS initiatives; and a generic PPM DOTS model adaptable to most settings. These are described below. C. Success Factors

1.

2.

3.

4.

5.

6.

Government commitment to PPM is essential. The NTP need to develop clear stewardship functions for PPM. Government sector should finance or facilitate finance PPM operations, including drug costs and cost for manpower for supervision, monitoring, and evaluation activities. It is important to invest time for dialogue between all stakeholders in order to build trust and achieve a high level of agreement on common goals for PPM. When conflicts of interest exist, they need to be identified early and discussed openly. Using an NGO or a medical association as a ‘‘neutral ground’’ may facilitate collaboration, especially when there is initial distrust between NTP and private providers. Training is crucial and it is as important to sensitize NTP staff to the PPM philosophy, as it is to sensitize private providers to the DOTS strategy. Improved referral and information system through simple practical tools is essential both to secure effective operation of the PPM and to enable evaluation of the PPM process and outcome. Adequate supervision and monitoring of private providers are required, and this should ultimately be the responsibility of the NTP.

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8.

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Providing drugs free of charge to patients improves treatment outcome, promotes equity and is also a tool for steering private providers through formal or informal ‘‘drugs for performance contracts.’’ Prepayment by patients at the start of treatment is an alternative to free drugs that may yield good treatment outcomes, but may not be accessible to the poor.

D. Practical Tools

After initial input to create a mutual willingness and understanding to work together—the software for PPM—what in fact helps to commence, enhance, monitor, and evaluate collaboration is a set of a few simple practical tools— the hardware for PPM. Essentially, these include agreements, referral routines, and records (11). The rationale is simple: NTPs should have a tool for every action(s) they expect from private providers and use it. For example, what is often required first is proper orientation of private providers on DOTS. The tool for this orientation could be some locally relevant sensitization material that, among other things, explains the TB control strategy and the local organizational set-up of the NTP. Then, if private providers are expected to notify TB cases, NTPs should provide them with case notification forms along with clear instructions on what to do with them. If they are expected to refer TB suspects for quality microscopy, NTPs should distribute proper referral forms to the private providers. If the NTP staff is expected to send back the microscopy report and offer a feedback, there should be back-referral forms ready for NTP to use and so on. If agreed upon initially, monitoring proper use of these tools may in itself help build and improve upon collaboration. Table 1 provides a list of several possible tools that may be considered depending upon the tasks expected by the NTP of the private providers. Each NTP may have to choose their own set of tools appropriate for the local setting and policy, limiting them to a few relevant and essential ones. WHO has published a document describing the generic tools to facilitate PPM DOTS that can be adapted and used locally (11). E. The Generic Model

Based on the guiding principles and lessons from the learning projects, a generic model for PPM DOTS has emerged (5,10). The generic model (Fig. 1) is indicative of a suitable organization of stakeholders in PPM DOTS. The model implies that the NTP retains a strong stewardship role assuming overall responsibility for TB control. All private and public providers have a potential role to play in DOTS implementation. F. The PPM-DOTS Agency Function

At the core of the generic model is the ‘‘PPM-DOTS Agency,’’ which assumes the responsibility for delivery of TB care to a defined area or population. Specifically, this agency ensures that the essential DOTS elements such as quality assurance for sputum microscopy, provision of

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Table 1 Practical Tools to Initiate and Sustain PPM DOTS Purpose

Tool(s)

Training

Sensitization tool for private providers Sensitization tool for NTP staff

Diagnosis

Referral form for sputum microscopy Case notification form Feedback/back-referral forms

Treatment

Form of referral for diagnosed cases Adaptation of treatment card Transfer form for patients Form requesting supply of drugs Form for retrieval of defaulter tracing

Monitoring

Quality-monitoring forms Minor adaptations of NTP registers Adaptation of quarterly report forms Evaluation indicators for PPM DOTS

Agreements

Memorandum of understanding Letter of agreement

Abbreviations: NTP, National TB Program; PPM DOTS, public–private mix for DOTS.

uninterrupted drug supply, support for direct observation of treatment, retrieval of defaulting patients, and recording and reporting are in place. The PPM DOTS agency function may be taken up by the NTP’s peripheral TB unit itself, or it may be ‘‘contracted’’ to a voluntary or private hospital, institution, a medical association, or a franchise organization. An advantage of contracting this function to a nongovernmental institution is that it may be easier for them to interact with private providers. Even if the NTP keeps the PPM DOTS agency function, a nongovernmental organization could be given the task of acting as an intermediary between the NTP and private providers. An interface organization may contribute toward, for example, advocacy, sensitization, training, and supervision of private providers. G. Stewardship and Financier Function

The NTP should provide training, drugs, and supplies to the PPM DOTS agency and should be responsible for overall quality control and surveillance. The PPM DOTS agency should report on TB control activities quarterly to the NTP. The collaborative relationship may rest on a Memorandum of Understanding or a formal contract detailing responsibilities and financial conditions. Ideally, anti-TB drugs should be provided free of charge from the NTP and be dispensed to patients free of charge. This gives an opportunity to formulate ‘‘drugs-for-performance’’ contracts wherein providers get free drugs

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Figure 1 Generic PPM DOTS model. The national government provides financing and stewardship. A coordination mechanism helps to bring the public and private sectors together, agree on implementation schemes and maintain dialogue. A local PPM DOTS Agency—public, private or voluntary—implements DOTS through a network of willing health care providers in an area. Abbreviations: PPM DOTS, public–private mix for DOTS; NGO, nongovernmental organization; P, provider.

in return for following recommended guidelines in TB management. In case a national health insurance is in place and includes TB care in the benefits package, this can be used to formulate reimbursement conditions related to maintaining performance and clinical standards. Can free drugs alone be an attractive enough incentive for private providers to undertake responsibilities for notifying cases, tracing defaulters, keeping essential records, etc.? Experience in most settings suggests so. If supported adequately to carry out the non-clinical tasks such as case reporting or default retrieval, general practitioners who manage very few TB patients at one time, welcome the idea of extending free drugs received from the NTP to their patients. This helps attract TB as well as non-TB clientele to their practices. If the number of TB cases handled by the provider is high as it may be in the case of some chest physicians or private institutions, additional incentives to compensate for their services may be justifiably required. Government commitment and support need to involve both technical guidance and financial support. Ultimately, because TB control has positive externalities and most TB patients are poor, PPM DOTS should help shift financing of TB services in the private sector from private out-of-pocket to public financing. Some providers may contribute time and resources voluntarily, whereas in other situations government funding will have to cover the full cost of service delivery by contracted and subcontracted providers.

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In order to secure ongoing dialogue between stakeholders and foster a sense of common ownership of the PPM DOTS initiative, a coordination mechanism should be established. This could alleviate initial misgivings and help build, enhance, and sustain collaboration. It may be in the form of a coordination committee with formal decision making responsibility or as a more informal stakeholder or partner forum with advisory function. In any situation, the ultimate stewardship responsibility should rest with the government sector or, more specifically, the NTP. I. Collaboration with Suitable Providers

The PPM DOTS agency might implement DOTS through its own health service outlets or by ‘‘subcontracting’’ some or all the functions to a network of willing institutional or individual providers operating in the area. The task mix and contractual relationships need to be tailored to the local context. In ideal circumstances, any provider involved in treatment should be provided drugs from the NTP free of charge and any provider involved in diagnosis should have access to tools for referral and/or sputum smear microscopy free of charge or at a heavily subsidized price. A central part of planning a PPM DOTS initiative on the district level is to map health providers and investigate their current role in TB diagnosis and treatment, their capacity to perform different DOTS tasks and their willingness to participate in PPM DOTS. In order to guide this process, the NTP should define, in general terms, which provider type can take on which DOTS function. Table 2 lists some of the main tasks of DOTS implementation, divided into ‘‘clinical’’ and ‘‘public health’’ functions, and indicates how tasks may be distributed to different types of providers. The suggested task mix is indicative and needs to be adapted to local context. The NTP can obviously carry out all the tasks listed in Table 2. A private or public institution acting as PPM-DOTS agency may be able to undertake most clinical and public health tasks, while drug supply and stewardship functions may have to be retained by the NTP. Different types of health service providers can take on the other roles according to their capacity, willingness, and the acceptability of the task mix among local stakeholders. The model provides a generic framework, but stresses the need for local adaptation. In recent years, it has been applied in a variety of settings in several countries. There is a growing evidence base that further supports its feasibility and adaptability. IV. Evidence Base Sufficient evidence of the positive effect of PPM DOTS on the two key TB control indicators—treatment outcomes and case detection—is now available and is summarized below. Evidence on some of the other important potential advantages of PPM—improving equity and access to care, reducing

Abbreviations: NTP, National TB Program; PPM DOTS, Public–Private Mix for DOTS.

Table 2 Possible Task Mix in Public–Private Mix for DOTS

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delay in diagnosis, saving costs to patients and preventing emergence and spread of drug resistance—is being gathered. A. Treatment Outcomes

By end 2004, 15 PPM projects had evaluated treatment outcome for at least one cohort (Fig. 2). Treatment success rate ranged between 74% and 100% for new smear positive cases in projects that had implemented DOTS and provided drugs free of charge to patients. Treatment success was suboptimal in the hospital-linkage PPM project in Yogyakarta, Indonesia, at 75%, which probably is explained by inappropriate Directly Observed Therapy (DOT) delivery practices (12). Treatment success was similar in Cavite, Manila, which also had a hospital DOT clinic. Treatment success was very low (60%) in the PPM project in HCMC, Vietnam. This project did not apply all essential DOTS elements: treatment regimens were not fully standardized, drug costs were not subsidized (patients paid on average US $22 per month of treatment) and DOT was not used (13). In the Nairobi initiative, which used subsidized but not free drugs for DOTS patients, the treatment success was also acceptable at 84%. Treatment outcome data were also available for cases that opted for non-DOTS treatment with drugs purchased at full price in retail pharmacies. They had

Figure 2 Treatment success (cure plus treatment completion) among new sputum smear positive cases treated in evaluated Public–Private Mix for DOTS projects using directly observed therapy (DOT) and free drugs for patients (grey bars), and project not using free drugs and DOT (white bars) patient, 1995–2003. Abbreviations: HCMC, Ho Chi Minh City; DFB, Damien Foundation, Bangladesh.

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a default rate of 30% compared to 5% in the group treated by private providers under DOTS with prepaid and subsidized drugs. The default rate in the NTP was 16% during the same period (14). Available data thus demonstrate that high treatment success can be achieved in PPM DOTS. The projects used different provider types for treatment initiation and management. In Nepal, treatment was provided by a private nursing home, NGOs, and a semiprivate hospital (15). In Delhi and Mahavir PPM projects in India, all cases received DOT in private nursing homes (small hospitals) or by individual PPs (16,17). In Mumbai, individual private providers delivered DOT to about 25% of the cases that they helped detect, while public DOT centers treated the remaining cases (18). In the Damien Foundation project in Bangladesh, a majority of the cases received DOT by ‘‘village doctors’’ with limited medical training (19). In Kannur, India, 27% of the case diagnosed by PPs were managed in private clinics, the others in public facilities (20). The two projects with hospital-based DOT clinics performed slightly worse than projects with more peripheral DOT units. B. Case Detection

By end 2004, eight PPM projects had evaluated impact on case detection in detail. All these projects showed an increased case detection (Table 3). The increase of case notification of new smear positive TB cases was between 14% and 61% in different projects. Somewhat different methods were used in different assessments and the baseline case notification varied across project sites (10,15,20–23). The main conclusion is that PPM DOTS has great potential to improve case notification and case detection in a variety of settings.

Table 3 Increase in Case Detection (Registration in DOTS Program) in Different Public–Private Mix for DOTS Projects Public–private mix site (references)

Baseline rate

Increase (%)

Hyderabad (20) Delhi (21)

50/100,000 60/100,000

23 36

Kannur (19) Lalitpur (14) HCMC (22)

25/100,000 54/100,000 100/100,000

15 61 18

Punalura Thanea Mumbaia

25/100,000 50/100,000 55/100,000

50 14 19

a

Evaluation approach Compared to neighboring TU Change controlled for other areas Change in same TU Change in same area Change controlled for other areas Change in same TU Change in same TU Change in same TU

Unpublished data. Abbreviations: HCMC, Ho Chi Minh City; TU, tuberculosis unit.

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An increase in case notification under DOTS means a decrease in number of non-DOTS treatments in the private sector. In Nepal, there was a fall in the sales of anti-TB drugs in the private retail market when PPM DOTS was introduced and private providers reported that they treated fewer TB cases (15,24). V. Economic Analysis Having established its feasibility, it was necessary to determine the cost of implementing PPM-DOTS and whether or not investment in PPM-DOTS would be cost-effective. For this reason, cost and cost-effectiveness analyses of two of the PPM DOTS projects mentioned above, Delhi and Hyderabad, were undertaken. In both Delhi and Hyderabad, higher numbers of cases were notified and successfully treated when PPM-DOTS was implemented. This was true both for all types of cases, and for new smear-positive cases specifically. This treatment success rate was close to or exceeded the WHO target of 85%. The PPM-DOTS project in Hyderabad successfully treated about 40% to 85% more cases than the two alternative strategies with which it was compared, and in Delhi the PPM-DOTS project increased the number of patients successfully treated by 69%. The figures for new smear-positive cases specifically were 83% to 88% and 65%, respectively. The average cost per patient treated was similar when DOTS was implemented, at around US $110 to $120 (Fig. 3). The largest cost items were clinic visits for DOT and monitoring, general program management, and drugs (about 70% of total costs in each site). From the perspective of the public sector, the cost per patient treated was lower in PPM-DOTS projects (US $24–33 vs. US $63 for public sector DOTS). This reflected the large contribution made by private providers, mainly in the form of clinic space and staff time for DOT and project management that was provided at no charge. Patient costs were consistently about US $50 to $60. For treatment in the conventional private sector without DOTS, mean patient costs ranged from US $111 in Hyderabad to US $172 in Delhi. The main reason for higher costs compared with DOTS was much higher expenditures on drugs. From a societal perspective, the average cost per patient successfully treated was broadly similar for the two PPM-DOTS projects and the public sector DOTS program in Hyderabad, at about US $120 to $140 (Fig. 4). Non-DOTS treatment in the private sector was much less cost-effective, with an average societal cost per patient successfully treated of US $218 in Hyderabad and US $338 in Delhi. The cost-effectiveness of PPM-DOTS was much better than public sector DOTS when only public sector costs were considered (mean US $25–39 vs. US $79 per patient successfully treated). Overall, the findings showed that PPM-DOTS can be an effective, affordable, and cost-effective approach to improving TB control in India. PPM-DOTS should be scaled up alongside continued implementation

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Figure 3 Average cost per patient treated in Public–Private Mix for DOTS, public sector only DOTS, and private sector non-DOTS in Hyderabad and Delhi PPM. Note: For public sector and private providers, total cost is the sum of annualized value of start-up costs and routine implementation costs. Although total provider costs were higher for the PPM-DOTS project in Delhi compared to the PPM-DOTS project in Hyderabad, most of the difference was due to higher clinic rental costs in Delhi. When the influence of different rental costs is removed (i.e., DOT visit costs are assumed to be identical in the two projects), the average cost per patient is very similar (US $54 for Hyderabad and US $59 for Delhi). Abbreviation: PPM DOTS, Public–Private Mix for DOTS.

and expansion of the public sector DOTS program. A full report on the economic analysis of the two PPM projects is available (22).

VI. Scaling Up Public–Private Mix for DOTS The concept of PPM DOTS has evolved rapidly and its scope has been broadened in response to the ground realities. A common observation among many countries has been that several public sector care providers, such as general public hospitals and academic institutions, as well as health services provided by military, railways, mines and health insurance organizations have also been, like private providers, indifferent to the principles of DOTS in managing TB cases. Moreover, in some countries, these institutional providers manage much larger TB case loads than the private providers. The term PPM DOTS thus represents a comprehensive approach to engage not just the private sector but all relevant health-care providers in DOTS implementation. It encompasses all forms of public–private (between NTP and the private sector), public–public (between NTP and

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Figure 4 Cost-effectiveness of Public–Private Mix for DOTS, public sector only DOTS, and private sector non-DOTS in Hyderabad and Delhi PPM. Note: Provider costs are the sum of public sector provider and private sector provider costs. Societal cost is the sum of provider costs and direct and indirect patient costs. Abbreviation: PPM DOTS, Public–Private Mix for DOTS.

other public sector care providers) or private–private (between an NGO or a private hospital and the neighborhood private providers) collaborations for the common purpose of ensuring provision of standard TB care in a community. Encouraged by the positive results of early efforts, some countries have begun scaling up PPM DOTS. Expectedly though, each country has its own approach. The NTP of India has launched PPM projects in 14 cities across the country. A PPM consultant has been appointed for each city to facilitate the process of setting up public–private partnership for DOTS implementation across the city under the guidance of a National Professional Officer for PPM who is advised by experts within and outside the TB program. This initiative is seen as a pilot trial and is being used to develop and document strategies that could be applied in future expansion across the country. India’s approach to PPM is pragmatic and holistic. The aim is to link all health-care providers—public, voluntary, private, corporate, medical schools, social insurance schemes—to the NTP. In the Philippines, on the other hand, two models of PPM have been identified: one is called public sector–initiated PPM DOTS and the other

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Figure 5 Number of countries piloting and scaling up Public–Private Mix for DOTS. Abbreviation: PPM, Public–Private Mix.

is private sector–initiated PPM DOTS. Depending upon the local context and the capacity of the local public and private providers, several sites within the country have launched PPM DOTS projects with the aim to eventually cover the entire country. Early results of PPM DOTS scale-up from both India and the Philippines are indeed encouraging. In Kenya too, the Nairobi PPM initiative is being extended to three other cities in the country, as a first step. Several other countries have plans to scale up PPM DOTS with financial support from the Global Fund to fight AIDS, TB, and Malaria (Fig. 5). WHO’s PPM DOTS initiative thus provides a useful example of a systematic approach to identify a problem, build support for addressing it, help develop policies through field-based operational research, and facilitate their translation into practice. Almost all high TB-burden countries have now embarked on PPM DOTS–related interventions to engage all healthcare providers in TB control (25). PPM DOTS has now become an integral part of TB control and features prominently in plans and strategies to achieve TB related targets under the Millennium Development Goals. VII. Public–Private Mix for DOTS and the Millennium Development Goals How can PPM DOTS contribute to meeting the MDGs? Global TB control can help to meet the goal of reducing poverty in a number of ways, such as reducing the costs of being ill, lessening the cost of treatment for illness, limiting the period of reduced productivity due to illness, and reducing the likelihood of livelihoods being lost because of illness.

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PPM DOTS can enhance these effects. Firstly, it can reduce the time between diagnosis and treatment. Secondly, it can reduce the costs of treatment to patients by eliminating or reducing the common practice of ‘‘shopping’’ for care. Thirdly, it can reduce costs to patients by reducing transport costs and ensuring free diagnosis and drugs. The MDG target of reducing prevalence and deaths from TB can be achieved if TB control efforts approach as closely as possible the global goals for case detection and cure rates. Worldwide, cure rates within NTPs are approaching the global goal. However, case finding is still very low in many countries, and considerably below the rate needed to achieve the related MDGs. Increasing case detection, in particular, will depend on involving the private sector in TB control to a much greater extent than at present. Experience from pilot projects suggests that countries with high levels of private sector involvement should aim to increase case detection by 20% to 30% on an average through PPM DOTS. PPM DOTS also has the potential to enhance access to TB control and to improve equity of access to health services. Private sector providers are usually more widespread and decentralized than those in the public sector and, thus, can enhance geographical access to services. Private informal providers in rural areas have been shown to contribute both to case detection and case holding through DOT. PPM DOTS can also improve equity in other ways. Better proximity to services can reduce the time and transport costs for poor people to access TB services. In addition, by providing free diagnosis and drugs, PPM DOTS can reduce the costs of services to those unable to pay (26). The lessons learnt could well be applied to a variety of other health programs. Eventually, it should pave way for identifying and packaging all public health responsibilities of private providers and should lead to the public and private providers jointly achieving major public health goals. Engaging all care providers—public, private, voluntary and corporate—in TB control is an essential and prominent component of WHO’s Stop TB Strategy designed to help meet the TB-related MDG. A guiding document to facilitate the engagement of all health care providers in TB control has recently been developed by WHO (27). References 1. Hanson K, Berman P. Private health care provision in developing countries: a preliminary analysis of levels and composition. Health Policy Plan 1998; 13:195–211. 2. Brugha R, Zwi A. Improving the quality of private sector delivery of public health services: challenges and strategies. Health Policy Plan 1998; 13:107–120. 3. WHO. World Health Report, 2003. Geneva: World Health Organization, 2003. 4. Noor AM, Zurovac D, Hay SI, Ochola SA, Snow RW. Defining equity in physical access to clinical services using geographical information systems as part of malaria planning and monitoring in Kenya. Trop Med Int Health 2003; 8: 917–926.

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5. WHO. Involving Private Practitioners in Tuberculosis Control: Issues, Interventions, and Emerging Policy Framework. WHO/CDS/TB/2001.285. Geneva: WHO, 2001. 6. The Global Alliance for TB drug development. The Economics of TB Drug Development. New York: Global Alliance for TB drug development, 2001. 7. Uplekar M. Involving private health care providers in delivery of TB care: global strategy. Tuberculosis 2003; 83:156–164. 8. Uplekar M, Pathania V, Raviglione M. Private practitioners and public health: weak links in tuberculosis control. Lancet 2001; 358:912–916. 9. WHO. An expanded DOTS framework for effective tuberculosis control. WHO/ CDS/TB/2002.297. Geneva: World Health Organization, 2002. 10. Lo¨nnroth K, Uplekar M, Arora VK, et al. Public-Private Mix for Improved TB Control—what makes it work? Bull WHO 2004; 82:580–586. 11. WHO. Practical tools for involvement of private providers in TB control—a guide for NTP-managers. HO/CDS/TB/2003.325. Geneva: World Health Organization, 2003. 12. Voskens J, Prihatini S, Wuryaningtyas B. Evaluation of the hospital DOTS linkage project in DI Yogyakarta. PERSI, MoH, KNCV, UAB/Gorgas and WHO, 2003. 13. Quy HT, Lo¨nnroth K, Lan NTN, Buu TN. Treatment results among tuberculosis patients treated by private lung specialists involved in a public-private mix project in Vietnam. Int J Tuberc Lung Dis 2003; 7:1139–1146. 14. Mwaniki DL, Kariuki JN, Kamigwi AG, Gathua S, Pathania V, Kutwa A. Investigation towards a strengthened public-private partnership for tuberculosis control in Kenya—the Nairobi case study. Nairobi: KEMRI, KAPTLD, NLTP/MoH, STB/ WHO; 2002. 15. Newell JN, Pande SB, Baral C, Bam DS, Malla P. Control of tuberculosis in an urban setting in Nepal: public-private partnership. Bull WHO 2004; 82:92–98. 16. Murthy KJ, Frieden TR, Yazdani A, Hreshikesh P. Public-private partnership in tuberculosis control: experience in Hyderabad, India. Int J Tuberc Lung Dis 2001; 5:354–359. 17. Arora VK, Sarin R, Lo¨nnroth K. Feasibility and effectiveness of a public-private mix project for improved TB control in Delhi, India. Int J Tuberc Lung Dis 2003; 7:1131–1138. 18. Ambe G, Lo¨nnroth K, Dholakia Y, et al. Every provider counts! Effects of a comprehensive public-private mix approach for TB control in a large metropolitan area in India. Int J Tuberc Lung Dis (accepted). 19. Salim MAH, Uplekar M, Daru P, et al. Turning liabilities into resources: the informal ‘‘village doctors’’ and TB control in Bangladesh. Bull WHO 2006. In Press. 20. Dewan P. An evaluation of a public-private sector collaboration to improve tuberculosis case-detection and treatment, Kannur district, Kerala, India, 2001–2002. Report to Central TB Division, Government of India. Atlanta: Center for Disease Control (in collaboration with Stop TB Division, WHO/SEARO), 2003. 21. Quy HT, Lan NT, Lo¨nnroth K, Buu TN, Dieu TTN, Hai LT. Public-private mix for improved TB control in Ho Chi Minh City, Vietnam: an assessment of impact on case detection. Int J Tuberc Lung Dis 2003; 7(5):464–471. 22. WHO. Cost and cost-effectiveness of Public-Private Mix DOTS: evidence from two pilot projects in India. WHO/HTM/TB/2004.337. 23. Arora VK, Lo¨nnroth K, Sarin R. Improving case detection of tuberculosis through a public-private partnership. Indian J Chest Dis Allied Sci 2004; 46:133–136. 24. Hurtig AK, Pande SB, Baral SC, Newell J, Porter JD, Bam DS. Linking private and public sectors in tuberculosis treatment in Kathmandu Valley, Nepal. Health Policy Plan 2002; 17:78–89. 25. WHO. Global Tuberculosis Control. WHO Report 2005.

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26. Public–Private Mix for DOTS. Global progress. Report of the Second Meeting of the PPM Subgroup for DOTS Expansion. WHO/HTM/TB/2004.338. World Health Organization, 2004. 27. WHO. Engaging all health care providers in TB control-Guidance on implementing public-private mix approaches. WHO/HTM/TB/2006.36. Geneva: World Health Organization, 2006.

40 Controlling Tuberculosis in Large Metropolitan Settings

¨ NNROTH, MATTEO ZIGNOL, and MUKUND UPLEKAR KNUT LO Stop TB Department, World Health Organization, Geneva, Switzerland

I. Introduction It is widely recognized that the burden of tuberculosis (TB) is often greater in urban than in rural settings, both in developing and industrialized countries. There is only a limited amount of documented experience in the use of specific approaches to control TB in large cities and more study is needed to assess their effectiveness and guide future strategies. However, based on available data, anecdotal evidence and best practices in a few cities, a provisional framework for TB control in large cities can be proposed, and is discussed in this chapter. The evolution of the DOTS strategy (see Chapter 27) over the last decade has seen several adaptations in response to changing conditions on the ground. Such adaptations have proved useful in the beginning to address important issues such as community involvement, HIV-associated TB, multidrug-resistant TB, and the role of private health-care providers. Urban areas and especially large cities in poor countries pose distinct challenges that also demand special consideration for effective implementation of the DOTS strategy. Rapid urbanization is taking place in the developing world and a large part of the urban population lives in slums where TB epidemics are fuelled 1005

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by poverty and overcrowding. Barriers to effective TB control in large cities often include a complex mix of poorly coordinated health-care providers, as well as diverse patient groups that require tailored approaches. However, what may be called ‘‘metropolitan TB control’’ has yet to receive the attention and input it deserves from the TB community. This chapter draws attention to the specific challenges facing TB control in large cities. It includes: a brief overview of rapid urbanization in poor countries and the exponential increase in slum settlements; a review of the available information on TB epidemiology in urban areas; a description of the major barriers to TB control in large cities; two case studies on DOTS implementation in major cities (Mumbai and New York); and, for future consideration, a provisional framework for TB control in large cities. II. Rapid Urbanization and Sprawling Slums Today, about half of the world’s population lives in urban areas (1). The urbanization process is most rapid in developing countries. In 1975, 10 of 22 metropolitan cities with more than five million inhabitants were located in developing countries. In 2000, the proportion was 31 of 41 and in 2015 it is expected to be 47 of 59 (2,3). By 2030, it is likely that 80% of the world’s urban dwellers will be living in the developing world (3). The rapid population expansion in urban areas combined with poor planning and lack of resources for infrastructure development has resulted in sprawling slum settlements. In 2001, close to one billion people, or onethird of the world’s total urban population, were living in slums. Here, the definition of a slum dwelling is a household which does not have any of the following features: security of tenure, structural quality/durability of the dwelling, access to safe water, access to sanitation facilities, and sufficient living area (1). The total number of slum dwellers in the world increased by almost 40% during the 1990s, and in the next 30 years it is expected to reach two billion. Slum dwelling is predominantly a developing country phenomenon and the poorer the country, the higher proportion of the population live in slums. In the least developed countries, 78% of the urban population live in slums (1). The poor socioeconomic and environmental conditions that characterize slums facilitate transmission of most communicable diseases, including TB (4,5). Slum dwellers are usually crowded into very small spaces. For example, in Nairobi (Kenya), 60% of the population live in slums, which occupy about 5% of the city area (1). Slums usually lack all basic infrastructures such as water supply, roads, sewers, electricity, and garbage collection and slum areas are often underserved with regard to schools and public health care. Most slum dwellers have very little chance of improving their living conditions and are condemned to live in poor settlements for life. For example, in Kolkata (India), those in more than 41% of slum households have lived in slums for more than 30 years (1).

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III. Urban TB Epidemiology A. Urban TB Burden in Developed Countries

Reviews of notification data in developed countries with relatively wellfunctioning notification systems have shown that TB incidence is often higher in big cities than in other areas. In 29 European cities surveyed during 1999 to 2000, the notification rate was higher than the national average for 27 cities; in eight cities, the notification rate was more than twice the national average (6). A study in Denmark in the 1960s showed that TB incidence in cities was double that found in rural areas (7). In the 1990s, in New York City, TB incidence was four times the national average and in some pockets of the city, like Harlem, it was as high as 20 times the national average. In Toronto, Canada, and in Osaka City, Japan, TB incidence is three times the national average (8). B. Urban TB Burden in Developing Countries

In developing countries, data on urban TB epidemiology are scarce. Official notification data from resource-poor countries rarely reflects either the true incidence or the true rate of case detection. Moreover, notification data disaggregated for urban and rural areas are generally not reported on a routine basis nationally or internationally. However, some secondary data reviewed for selected cities and countries indicate that the notification rate for new smear-positive cases is consistently and often considerably higher in urban than in other areas (Table 1). Few countries have reliable data on the annual risk of TB infection disaggregated by rural and urban settings. However, available data indicate that higher notification rates in cities are due to higher incidence rather than better notification. A national survey conducted in 2003 in India demonstrated that TB prevalence was significantly higher in urban compared to rural areas (Table 2) (11). This is also supported by a small tuberculin survey of children in urban slums in Chennai (12) and in Ahmedabad (13), where the annual risk for TB infection was 3.0% and 5.4%, respectively. In Cambodia, a tuberculin survey in 1995 showed an annual risk of 0.7% and 1% in rural areas and in urban settings (Phnom Penh), respectively (14). Various tuberculin surveys carried out in the 1990s in Vietnam showed that the annual risk was higher in urban areas and that the increase in the 1990s was greater in urban than in rural areas. Ho Chi Minh City, the largest city of the country had the highest annual risk of 3.0% (15). Tuberculin surveys in the Philippines have shown a slightly higher risk in urban areas (2.6%) than the national average (2.3%), whereas among the poor urban population it was very much higher than in both the nonpoor urban and the rural population (5.6%) (16,17). In conclusion, the true incidence is probably higher in large cities than in other areas, whereas the proportion of estimated TB cases that are notified (the so-called case-detection rate) might be considerably lower in cities when compared to the country’s average. The relevance of disaggregating

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Table 1 Notification Rates of New Smear-Positive Patients (per 100,000) in 14 Cities of over One Million Inhabitants Notification rate per 100,000 City, country (reference number) Kinshasa, Democratic Republic of Congo (9) Dakar, Senegal (9) Abidjan, Ivory Coast (9) Phom Phen, Cambodia (10) Ho Chi Minh City, Vietnam (10) Brazzaville, Congo (9) Conakry, Guinea (9) Cotonou, Benin (9) Kathmandu, Nepal (10) Bangkok, Thailand (10) Jakarta, Indonesia (10) Dhaka, Bangladesh (10) Karachi, Pakistan (10) Cairo, Egypt (10)

City

Rest of the country

City/country rate ratio

153

39

3.9

142 138 132 121

41 38 125 67

3.5 3.6 1.1 1.8

105 101 85 82 61 51 34 26 8

65 23 28 54 39 34 32 14 7

1.6 4.4 3.0 1.5 1.6 1.5 1.1 1.9 1.1

notifications and the annual risk of TB infection for understanding urban TB epidemiology is illustrated in Table 3, using notification data from the Maharashtra State (India) (19) and annual risk data for the western zone of India (11). Although use of the national annual risk average misleadingly shows a higher case-detection rate in urban areas, applying the disaggregated data clearly suggests that the case-detection rate is lower in urban areas. C. Driving Forces Behind Urban TB Epidemics

High TB incidence in urban areas can be largely explained by demographic, socioeconomic, and environmental factors. Known risk markers for TB include overcrowding, poor socioeconomic conditions, high HIV prevalence, Table 2 Prevalence of Infection and Annual Risk of Infection in Rural and Urban India in 2003 (NTI 2004)

Rural Urban Total

Prevalence in percentages (95% CI)

Annual risk of infection in percentages (95% CI)

7.0 (5.9–7.5) 11.6 (9.9–13.2) 8.2 (7.4–8.9)

1.3 (1.1–1.4) 2.2 (1.9–2.5) 1.5 (1.4–1.7)

Abbreviation: NTI, National Tuberculosis Institute.

46 61 47

Type of setting

Rural Urban Total

d

80 80 80

57 76 58

Estimated true incidence of new SSþ (b
50)b CDR (per 100,000) (a/c) (%)

c

1.5 2.4 –

Disaggregated ARIc (%)

e

75 120 –

Estimated true incidence of new SSþ (e
50)b (per 100,000)

f

61 51 –

CDR (a/f ) (%)

g

b

RNTCP 2004. From Ref. 11. c From Ref. 18. Abbreviations: ARI, annual risk of infection; SSþ, sputum smear positive; CDR, case-detection rate; RNTCP, Revised National TB Control Program.

a

Old ARIa (%)

New SSþ case notificationa (per 100,000) 1.6 1.6 1.6

b

a

Table 3 Notification Rate, ARI, and CDR in Rural Districts in Maharashtra State and Mumbai City in 2003 Applying the Old and the Recent National ARI, Respectively

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high prevalence of homelessness, and large migrant populations (6,20,21). With over 40% of urban populations in developing countries living in slums, a high urban TB incidence should be expected. For example, in Kampala, the incidence estimated from a prevalence survey in poor periurban communities was nearly five times higher than the estimated incidence for the whole country (22). It is likely that the urban poor are at higher risk than the rural poor due to higher population density and more crowded living conditions. Poverty is also a key factor for the development of TB in low prevalence countries. Two studies carried out in Liverpool (23) and in the Bronx, New York City (24) have demonstrated that the relation between poverty and TB is significant even when adjusting for ethnicity and HIV prevalence. Molecular epidemiology studies using DNA fingerprinting techniques in San Francisco confirmed that active transmission of TB takes place mainly in socioeconomically deprived groups (25). However, a high TB incidence in crowded cities also increases the risk of contracting TB among the nonpoor groups. Immigrants settle more often in urban than rural areas (1) and immigration from regions with high TB incidence can be a major factor behind a high incidence in urban areas. For example, immigrants represent over 50% of the TB cases in the majority of cities with high TB incidence in Europe (6). In developing as well as in developed countries, large cities offer better job opportunities than rural areas and therefore attract a large part of the working population. People in the productive age groups crowd in cities under poor social, economic, and environmental conditions, and therefore have a higher risk of infection and development of clinical disease. Little is known about urban–rural differences in the prevalence of drug-resistant TB. Population-based studies are rare and hospital-based studies do not provide a representative picture. Nevertheless, some data indicate that multidrug-resistant (MDR)-TB prevalence is higher in urban areas (26). Widespread availability of anti-TB drugs, multiple providers offering nonstandardized TB treatment, and weak referral management may be some of the contributing factors. IV. Major Barriers to TB Control in Large Cities Barriers to TB control in large cities may be classified as those related to a multiplicity of health-care providers, those associated with the multiple health authorities, and those linked to different patient populations with diverse characteristics and needs. A. Multiplicity of Health-Care Providers

Globally, the density of formal health-care providers is generally much higher in urban than in rural areas (27–29). The difference is more striking in developing countries. The mix of providers often ranges from nonqualified practitioners in slums through a variety of public, private, corporate, and

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nongovernmental organization (NGO) providers to highly specialized staff in tertiary care hospitals and academic institutions (30). Specialists and tertiary care are almost exclusively concentrated in urban areas. Many of these providers, public as well as private, diagnose and treat TB (30,31). This abundance of health-care providers does not necessarily bring advantages for TB control. Experiences in several National TB Programs (NTP) have shown that it is a great challenge to standardize TB service delivery and create suitable referral chains in settings with large numbers of poorly coordinated health providers (30,31). A large proportion of cases in urban areas are managed by private health-care providers as well as public health-care providers who are not linked to the NTP, such as medical colleges, specialist hospitals, and prison health services. In most metropolitan areas in developing countries these providers do not notify cases to the NTP, nor do they follow DOTS principles for diagnosis, treatment, and management of TB. The lack of alignment to evidence-based TB management leads to over- and under-diagnosis, poor treatment outcomes, development of drug resistance, and poor epidemiological surveillance (30–32). Moreover, lack of coordination and efficient referral chains lead to delayed diagnosis, high health-care costs for patients, drop out during the diagnostic phase, after diagnosis, and during transfer between providers, and poor follow up of treatment results (30–36). B. Multiple Authorities

Urban public health-care providers often operate under a complex mix of authorities, including national ministry of health and health departments under provincial or district administration or a city corporation. Usually, different public providers are funded through and accountable to different authorities. Tertiary care hospitals may belong to the national ministry of health. General public hospitals and health centers may come under the jurisdiction of a city corporation. Public health facilities in suburban areas may come under periurban district health departments. Medical colleges may operate under the stewardship of the ministry of education and prison health services under the ministry of justice, whereas health services under large public corporations, such as a public railway company, may be under the ministry of transport. Private health-care providers are outside the control and influence of health authorities in many developing countries. When control is exercised, several different legislations and authorities are often involved, such as national and local health authorities on different levels and drug regulatory bodies. Coordination among different authorities on district, city, provincial, and national level involves complex interactions of hierarchies and bureaucracies. Generally, the NTP has little influence over the operations of health providers other than those directly under the NTP or those in which the NTP is integrated. Several countries have gone through health sector reforms with decentralization processes leading to greater autonomy of metropolitan administrations. Even when a national ministry of health is strongly

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committed to the DOTS strategy, this is no guarantee that city corporations will follow suit and liaise with the NTP. Expanding DOTS programs to institutions with different affiliations requires commitment of several different authorities at several different levels. NTPs need to develop specific strategies for the coordination of these authorities. In many large urban settings, the management of TB control is carried out by one public health officer working part time on TB. Lack of human resources undermines the quality of the program and prevents any improvement in case finding. Efforts are needed to guarantee appropriate human capacity building. C. Diverse Patient Populations

TB control programs in large cities have to take into consideration the characteristics and needs of the diverse and vulnerable population groups that they serve: slum dwellers, migrants, drug addicts, homeless people, prison inmates, and those with TB–HIV coinfection. Effective case management of these groups often requires adaptation of direct observed treatment as well as improved referral and transfer management. This in turn requires involvement and good coordination between all relevant health providers who are likely to have contact with the various user groups. Some NTPs have adversely addressed the issue by applying criteria to select patients on the basis of their ‘‘adherence characteristics,’’ such as proof of permanent residency. Consequently, TB care has sometimes been denied to a large number of vulnerable people for fear that they would contribute to low cure rates (33,37). Each of the following high-risk groups has distinct and justifiable needs for specific intervention strategies. The challenges for each are outlined in the section below. Floating Population and Migrants

The magnitude of floating populations varies from place to place, but it is certainly a problem for TB control in most large cities. Many of these groups are seasonal workers who move to the city to work for a few months and then return to their villages. Some are commuters, daily or weekly wage earners. Others travel to the city temporarily in search of quality health-care services. The floating population phenomenon has rarely been studied formally. Among seven capital cities in African nations surveyed in 1995, the proportion of notified cases that were permanent residents ranged from 9% to 40% (9). In urban settings, the proportion of migrants may be underestimated because patients may provide false statements about their permanent address for the fear of not receiving treatment in the city (35). Linkages between TB programs in cities and in villages are often weak and consequently a large proportion of the patients are lost during the transfer. In developed as well as in developing countries, foreign immigrants settle in urban areas more often than in rural areas (1). As well as being risk groups for developing TB, they often face social and economic barriers to

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access to health care, TB diagnosis, and TB treatment adherence. In particular, illegal immigrants are reluctant to seek help for fear of revealing their illegal immigrant status (38,39). Slum Dwellers and Homeless People

Slums are not only breeding places for TB epidemics, but they are also often poorly served by the official health-care providers. By not being included in formal city planning, slum areas are often excluded from public health-care planning. Consequently, access to NTP-affiliated facilities may be poor. NTPs, which apply strict criteria of formal residence and proof of address may actively exclude both homeless people and slum dwellers from treatment. Poverty restricts access to health care. Even if care is provided free of charge, indirect costs, such as cost of travel and loss of earnings, may be high. Despite these barriers, many poor people in the slums try to access public and private health care, often spend a substantial proportion of their scarce resources, and become trapped in the viscous disease–poverty circle (30,31,40). The less formal part of the private sector is often an important source of health-care providers in slums in developing countries (30). Local, national, and international NGOs often focus their activities in slums. The quality of TB services provided as well as the extent of coordination between NGOs and NTPs vary greatly within and between settings. Many cities face the problem of a large homeless population. There is a large overlap among the homeless, migrants, and the very poor. Furthermore, among homeless people there is considerable overrepresentation of drug addicts, people with psychiatric conditions and the most socially marginalized (41). These groups, who have often had adverse experiences of contacts with authorities, may be reluctant to approach health services for help. People Living with HIV/AIDS

There is a scarcity of data on urban–rural differences in HIV prevalence. However, demographic and health surveys conducted in Kenya, Zambia, and Mali indicate that urban settings may have higher HIV prevalence than rural areas (42–44). HIV-infected people not only have a dramatically increased risk of developing TB, but also often belong to socially-marginalized groups that have difficulties in accessing health services. Furthermore, the combined stigma of TB and HIV/AIDS make these groups particularly hard to reach with conventional approaches. Although some TB control programs have well-established linkages with HIV/AIDS control programs, there is a need to improve those links as well as to strengthen links between TB, HIV, and social welfare programs in many countries, and especially in urban areas. V. Two Examples of TB Control in Large Cities Experiences of tackling TB control in two large cities, Mumbai and New York City, are presented in the following section. Some of the challenges and how they have been addressed in the two cities are summarized in Table 4.

Poor knowledge about available providers and utilization patterns Poor coordination and standardization of services

Weak political commitment

Challenge Weak support for the involvement of private sector and public providers other than public primary health care Poor knowledge about available private sector providers and TB case load in other than NTP facilities Extremely heterogeneous diagnostic and treatment practices across different providers. High default rate

Situation before action

Action taken

Implementation of common standards according to the DOTS strategy across relevant providers. Strengthened supervision

Mapping of all public and private sector providers and utilization patterns

TB control policy endorsed across relevant ministries and government departments. Additional resources

Mumbai

Poor TB management in several public and private facilities. High default rate. Nosocomial transmission

–

Decline in political interest and resource allocation for TB control

Situation before action

Enforcement of new TB control policy and related guidelines across relevant providers. Strengthened supervision. ‘‘Case managers’’ appointed

–

Additional financial resources and manpower. New TB control policy

Action taken

New York City

Table 4 Main Challenges for TB Control and How They Have Been Tackled in Mumbai and New York City

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Involvement of socially oriented nongovernmental organizations as well as formal and informal private sector facilities in slum areas Notification and Poor notification and No mandatory notifiregistration among monitoring practices cation and poor record patients in major public keeping among other sector institutions and providers than NTP many private facilities facilities

Abbreviation: NTP, National Tuberculosis Program.

Vulnerable and diverse Large slum population. populations Many homeless and migrants with poor access to quality services

Outreach activities. Downsizing of shelters. Housing for homeless. Screening in shelters and prisons. Intensified contact tracing Enforced mandatory notification. Monitoring by ‘‘case managers’’

Epidemic mainly among homeless, the very poor, prisoners, and newly arrived immigrants

Incomplete notification, especially by private providers

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Mumbai (formerly Bombay), with 12 million inhabitants, is one of the largest and most densely populated metropolitan cities in the world. About half of the population lives in slums. Permanent and temporary migration is very common. The government’s Revised National TB Control Program (RNTCP) was fully implemented in Mumbai in 1999. By 2001, the RNTCP facilities in Mumbai had a cure rate of 82.6%. However, the case-detection rate was 42.5 new smear-positive cases per 100,000 population in 2001, which was only 56% of the estimated incidence based on the national annual risk of TB infection (19,45). Numerous problems were encountered in the early stages. One problem was the large number of public and private providers who were not following RNTCP policy on diagnosis, treatment, monitoring, and reporting of TB. It was difficult to standardize practices across the intricate web of health services accountable to a variety of ministries and health authorities on different levels of a complex health-sector bureaucracy. There was a lack of commitment to the RNTCP strategy among health-care staff other than those employed specifically for RNTCP activities. The private health-care sector was totally uncontrolled and provided substandard TB care to a large part of the population (30,32). These problems were underpinned by weak regulation. As in the rest of India, drug regulation was very weak and all anti-TB drugs were available without a prescription in the private retail market. In India, TB is not a notifiable disease by law and cases treated outside RNTCP are therefore not known to health authorities. Another problem was the pressure within the RNTCP to reach the TB control target of 85% cure rate, while facing large numbers of patients from ‘‘difficult patient groups’’ such as slum dwellers, homeless people, migrants, drug addicts, and people with HIV. The standard program infrastructure lacked capacity to provide tailored support for completion of treatment among these vulnerable groups. To ‘‘protect’’ cure rates within RNTCP, many patients from these groups were instead actively excluded from the program (46). In addition, there was a lack of a focused health information strategy, which was difficult to devise because of the lack of real access and ambiguity concerning inclusion criteria for treatment. The RNTCP took a structured approach to try to address these constraints. A number of strategies were put in place in a stepwise manner to adapt the TB control strategy to the health care and epidemiological realities of metropolitan Mumbai. A crucial component was coordination of services and partnership building. The Mumbai District Tuberculosis Control Society (MDTCS), which included a broad representation of stakeholders, served as a steering committee for TB control activities under the RNTCP. Although the MDTCS/RNTCP was responsible for setting standards of care and for overall coordination, supervision, quality control, monitoring, and evaluation, efforts were also made to institute policy changes in all ministries and government departments involved in health-care delivery in the city. Hospitals belonging to the Employees State Insurance Scheme were

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instructed to follow RNTCP guidelines by the Ministry of Labour. Railway hospitals became involved after the Railway Ministry issued directives to implement RNTCP in all its railway hospitals and dispensaries. After initial reluctance, four medical colleges in Mumbai agreed to provide DOTS services according to RNTCP guidelines from 2001. Specific regulatory interventions were applied, such as stopping purchase of anti-TB drugs in several public sector institutions and instead providing drugs through the RNTCP. Partnerships with the private sector were formalized through Memoranda of Understanding with several large and small NGOs. TB care was decentralized to facilities near to patients’ homes or workplaces, using small NGOs and private practitioners as Directly Observed Therapy (DOT) providers in poor neighborhoods and slums, where they also referred TB suspects to the government diagnostic centers. Several NGOs provided social support including nutrition and financial support for poor TB patients. Meetings were arranged for patients where they could express their problems. The RNTCP critically analyzed the case notification pattern in relation to new data on TB epidemiology (see above) in order to move away from a simplistic target-driven TB surveillance toward analysis of underlying causes of high incidence and low case notification (44,45). In 2001, these activities were intensified and the surveillance system was adapted so that the contribution of different providers could be ascertained. All initiatives together, applied at a time when the case notification in the city had levelled out, contributed to improved case notification as shown in Figure 1. Treatment success was above or close to 85% in all facilities that treated TB (47). Although a great deal was achieved, there was still a long way to go for TB control in Mumbai by the end of 2004. Many public and private

Figure 1 New smear-positive case detection under DOTS strategy by provider type in Mumbai, 1999–2003. Abbreviations: NGOs, nongovernmental organizations; PP, private practitioner; RNTCP, Revised National TB Control Program. Source: From Ref. 47.

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health-care providers had not been brought into the RNTCP strategy. Less than 1000 of about 10,000 private individual practitioners had become involved, and none of the large private hospitals and nursing homes. A few medical colleges remained to be targeted as well as some public hospitals and numerous smaller NGOs. Operational research was needed to analyze to what extent the most vulnerable groups were being reached and social support needed to be strengthened further. Referral of TB suspects and cases among the migrating population was still a challenge both between areas and health facilities in the city and between the city and surrounding rural areas. Regulation, particularly with regard to anti-TB drugs, was still weak. B. New York City

After achieving a very low incidence of TB in the 1970s (Fig. 2), the New York City Department of Health and Mental Hygiene (DOHMH) scaled down TB control activities in the 1970s and 1980s. This proved to be untimely because a subsequent resurgence of TB occurred during the 1980s. Notification rates more than doubled between 1980 and 1992. In parts of the city, like Harlem, notification rates exceeded 200/100,000 in the early 1990s, a level on a par with several high TB burden developing countries and similar to New York levels at the beginning of the 20th century. Reasons for the dramatic increase included the HIV epidemic, rising poverty and homelessness, overcrowding, immigration from high prevalence countries, and reduced public health efforts to control TB. Poor TB management played an important role. Cure rates in 1989 were below 50% and many patients defaulted from treatment (49,50). A majority of the TB cases were managed outside New York City Department of Health

Figure 2 Tuberculosis case notification rate in New York City, 1920–2002. Source: From Ref. 48.

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and Mental Hygiene (DOHMH) facilities, mainly in the private sector (51). The performance of these facilities was poor. This situation led to an epidemic of MDR-TB, with the prevalence of drug resistance doubling from 1983 to 1991 (52). A forceful response to these deficiencies, particularly driven by the surge in MDR-TB, was instituted in 1992. This resulted in a prompt reversal of the epidemic curve (Fig. 2) (50). A fundamental component of the TB control reform package was a 10-fold increase in the TB control budget and tripled TB control staff between 1988 and 1994 (50). The TB control strategy was revised and intensified rapidly from 1992 and a number of special units to undertake specific activities were set up.     

Homeless Outreach Unit, which facilitates case finding and DOT in shelters for homeless people Regulatory Affairs Unit, which coordinates enforcement of regulations Immigrants and Refugees Unit, which coordinates with immigration authorities and outreach activities to immigrant communities Quality Management Unit, which has responsibility for ensuring that all involved health providers follow agreed standards Expanded Contact Investigation Unit, which coordinates contact investigation and treatment of latent infections. This unit also includes the Expanded Screening Unit, which undertakes largescale TB screening programs

Operational changes included a range of activities to improve case management and prevention of TB in all relevant health-care facilities in the city. Each patient on treatment was to be supervised by a ‘‘public health assistant’’ (case manager). For MDR-TB cases, an additional layer of supervision was introduced through appointing regional MDR-TB casemanagement supervisors. All health-care providers were instructed to follow guidelines for diagnosis and treatment, including the private sector, which was targeted through educational seminars. By 1997, 70% of TB patients received DOT (48). Free diagnostic and drug susceptibility testing were provided and referral routines were streamlined. A 24-hour hotline service was set up for physicians treating TB. Outreach workers from the DOHMH interviewed all patients who were registered and facilitated treatment through visits to households, workplaces, shelters for the homeless, etc. Outreach workers also supported physicians in providing DOT in their clinics and absentee tracing. These measures rapidly increased the cure rate to around 90%. As the City TB Bureau increased accessibility to treatment services, the proportion of patients treated in private clinics decreased. However, about 30% of all cases were still treated in city or private hospitals in 2002 (48). Legislation to impose diagnostic tests and detention for patients who refused diagnosis or treatment was enforced. However, in most cases less restrictive, nonregulatory measures where very effective, although enforcing

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the legislation may have encouraged adherence in some cases (53). The existing mandatory notification was enforced through intensified monitoring of laboratories and private physicians (50). Other strategies included prevention of transmission in the community through downsizing large shelters and working toward noncongregate housing for homeless people. A number of efforts were put in place to reduce nosocomial infection. There was intensified screening, isolation, and follow up of people in prisons. Contract tracing and preventive treatment were optimized. Furthermore, the program advocated screening for HIV infection. In 2000, the HIV status was known for 66% of registered TB cases (52). Other initiatives included work with communitybased organizations for information and education targeting the general public (48). Until 2002, case notification continued to decrease and drug resistance also declined. In 2003, this declining trend was halted for the first time since 1992. The TB burden was still 2.6 times the national average. The proportion of TB patients born outside the United States had increased while TB incidence among the US-born population decreased. TB among those born outside the United States was a major challenge for the DOHMH (54). There was a need to employ staff with appropriate language skills and cultural understanding and to focus more on improved outreach to immigrant communities, including targeting formal and informal healthcare providers frequently used by immigrant communities. HIV prevalence among TB cases was still high, at 18%. Only about 10% of patients treated in private clinics received DOT and there was a need to further improve case management practices in non-DOHMH facilities and/or to increase the proportion of patients treated in DOHMH facilities. Contact tracing and preventive treatment needed to be strengthened further (48).

VI. A Provisional Framework for TB Control in Large Cities The DOTS strategy (Chapter 27) has been modeled around a typical rural district as the main administrative unit and has usually been implemented mainly through public sector providers. As detailed above, the singlehierarchy model—‘‘district hospital—health centers—subcenters’’—rarely applies to large urban areas where there are parallel public sector hierarchies as well as private providers that fall between the jurisdictions of different health authorities. To control TB efficiently in large cities, the DOTS strategy needs to be adapted to include all of the authorities, providers, and user groups present in large urban settings. On the basis of the five elements of the expanded DOTS framework (55), and available documented experiences of successful metropolitan TB control, the following provisional framework emerges. It takes into account the major issues and challenges of controlling

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TB in urban settings and suggests possible interventions to tackle them. The five components of the proposed framework are as follows: 1. 2. 3. 4. 5.

Ensure political commitment and coordination among health authorities Map providers and health-care utilization patterns Coordinate providers and introduce universal standards Adapt service delivery to the needs of vulnerable segments of the population Establish routines for monitoring and evaluation

A. Ensure Political Commitment and Coordinate Health Authorities

Experiences from successful urban TB initiatives show that it is important that relevant ministries and government departments responsible for different types of health-care providers agree to adapt and enforce policies on TB diagnosis, treatment, recording, and reporting in accordance with core DOTS principles (46,47,49,50). Advocacy and coordination need to start at the most central level of the health-system hierarchies, including ministries and national, state and city level departments of health. Budgetary and legislative issues are likely to be a core component of their discussions. The NTP should take the lead in creating an urban TB control task force with broad representation from relevant stakeholders, e.g., private sector, NGOs, professional organizations, patient organizations, and civil society. Political commitment for urban TB control should be reflected in sufficient staff within the NTP for coordinating stakeholders, including one or several NTP focal points for urban TB control. Authorities may also consider regulatory interventions toward providers such as requiring and enforcing TB notification, prohibiting procurement of anti-TB drugs through sources other than the NTP, limiting prescription rights to certain designated health facilities, and introducing criteria for certification for TB diagnosis and treatment. B. Map Providers and Health-Care Utilization Patterns

In developing countries, there is usually a scarcity of health-systems information, in particular, concerning the nongovernmental health sector. An inventory and mapping of providers are needed to give an overview of the size and composition of different health-provider sectors and to identify who is serving what part of the population. It is particularly important to map which providers are situated in slums and which providers are being used by the poor and marginalized groups. The informal private sector as well as nonhealth NGOs are potentially useful partners in reaching the poor and socially marginalized. Mapping should involve an assessment of current TB diagnosis and treatment practices in order to identify training needs for various DOTS tasks. Mapping of the relevant patient groups involves an overview of the size, location, and health-care utilization patterns.

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Many high-income countries have established chains of care for TB, which involve all relevant primary, secondary, and tertiary health-care institutions in both the public and private sector, backed up by strong infectious disease control legislation and by social health insurance that assures public funding of TB care for all patients, whether treated privately or in public health facilities. Nevertheless, there is need to further standardize TB management practices, agree on roles and responsibilities, and formalize referral routes in many settings. The deterioration and subsequent strengthening of TB control in New York City shows the importance of regularly revisiting the technical, administrative, and regulatory aspects of TB control and instituting efforts to align all relevant stakeholders to the strategy (49,50). To tailor activities to suit the needs of vulnerable groups, coordination often needs to go beyond the health sector to include organizations that support the socially and economically marginalized, such as social services of the public sector and social support–oriented NGOs. In poor countries, the collaborative infrastructure, regulatory capacity, and the possibility to influence service delivery through contracting with third parties, is much weaker than in wealthy countries. Solutions therefore need to be pragmatic and tailored to the local capacities of the NTP, health authorities, and potential partners. Strategies will typically have to rest on principles of partnership rather than on formal mechanisms for contracting, purchasing of services, and regulatory enforcement. It is essential that partners agree on the standards for TB diagnosis, treatment, management, and recording and reporting practices. Achieving this requires considerable time for dialogue between NTP and other stakeholders and opinion leaders (56). In addition, collaboration is needed with HIV/AIDS programs and others involved in care and treatment for PLWHA. The WHO framework for TB–HIV collaborative initiatives (Chapter 38) is useful for planning such initiatives. When involving medical colleges and chest specialist clinics it is important to discuss standardized strategies for the management of drug-resistant TB (Chapter 33). Once the tasks to be performed by different providers and conditions for collaboration between them have been agreed on, practical tools for the collaboration should be developed. These may include tools to improve referral and information systems, such as standardized referral forms, feedback forms, treatment records, laboratory records, and reporting forms (57). Training and information tools are also required. D. Adapt Service Delivery to Needs of Vulnerable Segments of the Population

Economic and social barriers for accessing and adhering to available TB services need to be broken down by systematically applying a patientcentered approach when planning and implementing an urban TB control strategy. So that the poorest sections of the population can benefit from TB services and adhere to treatment, it is important that TB diagnosis is

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provided free of charge or at very low costs and that all anti-TB drugs are free to patients (6,50,56). In addition, the services need to be available at a convenient location and with convenient opening hours. Decentralization of diagnostic and treatment units to urban primary health-care centers, preferably in combination with the involvement of community health workers as supervisors of DOT, increases case detection as well as treatment success (58–61). Principles of involving community volunteers, outlined in Chapter 22, can be applied. Homeless people, drug addicts, and those with psychiatric illness may be reached through the involvement of shelters, social support centers, needle exchange programs, etc. Training of paramedics in the identification of TB suspects or active screening in such facilities may increase case detection. Such initiatives may be facilitated by the introduction of financial or nonfinancial incentives to patients (48,53–65). Provision of a social support package including housing, food, and essential health care may be a strong incentive for these groups to accept TB treatment (66). Contact tracing and active case finding may be particularly relevant in high-risk populations in urban areas (6), at least in developed countries (67). Likewise, specific strategies targeted at immigrants, which is further discussed in Chapter 34, may be particularly relevant in urban areas, where immigrant populations are often concentrated. Involvement of health-care providers and socially oriented NGOs located in slums has a potential to increase case finding and treatment success among high-risk populations. In many poor countries, this may imply involvement of non–medically qualified and unauthorized private practitioners, who often cater for the poorest in slum districts in large urban areas. Involvement of this segment of the private sector is ongoing in several developing countries and the results so far are encouraging (68). Time constraints and inconvenient opening hours of public sector facilities is one of the most important barriers to accessing TB services among the working population both in developed countries (69) and in developing countries (31,33). Arrangement of convenient opening hours as well as the involvement of the corporate sector are potential ways to increase access for the working population. Appropriate health education is important for all patient groups. Provision of sufficient information to patients is particularly needed at the time of referral between health facilities for diagnosis, for initiation of treatment, for DOT, or for transfer to other districts and towns. This needs to be tied to an effective referral system, which ensures correct and timely data transfer and feedback between providers and/or districts for appropriate continuation of management and monitoring of treatment results. E. Monitoring and Evaluation

Most of the experiences of urban TB control, negative as well as positive, are anecdotal. There is a need for more in-depth analysis of the urban health-care provider structure, performance, and coordination among different providers, utilization patterns, and barriers for success. The strategy

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proposed above is based on theory and on anecdotal reporting of successful approaches to urban TB control, but very limited empiric data on the effects of specific urban TB control efforts. Thus, descriptive research on urban TB epidemiology and health-systems constraints as well as careful monitoring and evaluation of new initiatives is needed in order to contribute to the evidence base and future evolution of urban TB control strategies. An essential part of an urban TB control strategy is to ensure that standardized recording and reporting practices are used in all involved health facilities (56). This will enable key TB control indicators to be monitored for quality control and surveillance. By adapting the recording and reporting system to include information about source of referral and place of DOT, specific urban TB control interventions and contributions by different types of providers and can be evaluated. References 1. UN-Habitat. The Challenge of Slums: Global Report on Human Settlements. Nairobi: United Nations Human Settlements Programme (Un-Habitat), 2003. 2. United Nations. World Urbanization Prospects: the 2000 Revision. ESA/P/WP. 165. New York: Population Division, Department of Economic and Social Affairs, 2001. 3. United Nations. World Population Monitoring 2001. New York: Population Division, Department of Economic and Social Affairs, 2001. 4. Khosh-Chashm K. The impact of urbanization on health in the countries of the Eastern Mediterranean Region. Eastern Mediterr Health J 1998; 4:137–148. 5. Harp Ham T, Tanner M. Urban Health in Developing Countries: Progress and Prospects. London: Earth Scan, 1995. 6. Hayward AC, Dalton T, Van-Tam JN, Watson JM, Coker R, Shoebill V. Epidemiology and control of tuberculosis in Western European cities. Int J Tuberc Lung Dis 2003; 7:751–757. 7. Hurwitz O, Knudsen J. A follow-up study of tuberculosis incidence and general mortality in various occupational-social groups of the Danish population. Bull World Health Organ 1961; 24:793–805. 8. IUATLD. Conference on Global Lung Health and the 1996 Annual Meeting of the International Union Against Tuberculosis and Lung Diseases, Paris, France 2–5 October 1996. Tuberc Lung Dis 1996; 77:16, 122–125. 9. IUATLD. Tuberculosis in Large Cities: Proceedings of the seminar held in Gran Bassam, Ivory Coast, 22–23 April 1997. International Union Against Tuberculosis and Lung Diseases, 1997. 10. IUATLD. Special Challenges of TB in Large Cities in Asia and the Middle East: Proceedings of the Workshop Held in Bangkok, Thailand, 5–7 May 2004. International Union Against Tuberculosis and Lung Diseases, 1997. 11. NIT. Annual Risk of Tuberculosis Infection in Different Zones of India. Bangalore: National Tuberculosis Institute, 2004. 12. Chakraborty AK. Tuberculosis in India. Pediatr Today 1999; 1:47–53. 13. Bhagyalaxmi A, Kadri AM, Lala MK, Jivarajani P, Patel T, Patel M. Prevalence of tuberculosis infection among children in slums of Ahmedabad. Indian Pediatr 2003; 40:239–243. 14. Norval PY, Roustit C, San KK. From tuberculin to prevalence survey in Cambodia. Int J Tuberc Lung Dis 2004; 8:299–305.

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55. WHO. An Expanded DOTS Framework for Effective Tuberculosis Control. STOP TB Communicable Diseases. WHO 2002. WHI/CDS/TB/2002.297. Geneva: World Health Organisation, 2002. 56. Lo¨nnroth K, Uplekar M, Arora VK, et al. Public-private mix for improved TB control—what makes it work? Bull WHO 2004; 82:580–586. 57. WHO. Practical Tools for Involvement of Private Providers in TB Control—A Guide for NTP-Managers. WHO/CDS/TB/2003.325. Geneva: World Health Organisation, 2003. 58. Singh AA, Parasher D, Shekhavat GS, Sahu S, Wares DF, Granich R. Effectiveness of urban community volunteers in directly observed treatment of tuberculosis patients: a field report from Haryana, North India. Int J Tuberc Lung Dis 2004; 8:800–802. 59. Bernatas JJ, Ali IM, Ismael HA, Matan AB, Aboubakar IH. Decentralisation of directly observed treatment in a large African city: evaluation of the experience of Djibouti. Int J Tuberc Lung Dis 2003; 7:724–729. 60. LoBue PA, Cass R, Lobo D, Moser K, Catanzaro A. Development of housing programs to aid in the treatment of tuberculosis in homeless individuals: a pilot study. Chest 1999; 115:218–223. 61. WHO. Community Contribution to TB Care: Practice and Policy. WHO/CDS/TB/ 2003.312. Geneva: World Health Organisation, 2003. 62. Tulsky JP, Hahn JA, Long HL, et al. Can the poor adhere? Incentives for adherence to TB prevention in homeless adults. Int J Tuberc Lung Dis 2004; 8:83–91. 63. Rendleman NJ. Mandated tuberculosis screening in a community of homeless people. Am J Prev Med 1999; 17:108–113. 64. Lorvick J, Thompson S, Edlin BR, Kral AH, Lifson AR, Watters JK. Incentives and accessibility: a pilot study to promote adherence to TB prophylaxis in a high-risk community. J Urban Health 1999; 76:461–467. 65. Perlman DC, Friedmann P, Horn L, et al. Impact of monetary incentives on adherence to referral for screening chest x-rays after syringe exchange-based tuberculin skin testing. J Urban Health 2003; 80:428–437. 66. Diez E, Claviera J, Serra T, et al. Evolution of a social health intervention among homeless tuberculosis patients. Tuberc Lung Dis 1996; 77:420–424. 67. Broekmans JF, Migliori GB, Rieder HL, et al. European framework for tuberculosis control and elimination in countries with a low incidence. Recommendations of the World Health Organization, International Union Against Tuberculosis and Lung Disease and Royal Netherlands Tuberculosis Association Working Group. Eur Respir J 2002; 9:765–775. 68. Murthy KJ, Frieden TR, Yazdani A, Hreshikesh P. Public-private partnership in tuberculosis control: experience in Hyderabad, India. Int J Tuberc Lung Dis 2001; 5:354–359. 69. Gupta S, Berg D, de Lott F, Kellner P, Driver C. Directly observed therapy for tuberculosis in New York City: factors associated with refusal. Int J Tuberc Lung Dis 2004; 8:480–485.

41 Health Education and Social Mobilization in Tuberculosis Control

ROBERTO TAPIA-CONYER

ERNESTO JARAMILLO

Subsecretariat of Prevention and Control of Diseases, Mexican Secretariat of Health, Mexico City, Mexico

Stop TB Department, World Health Organization, Geneva, Switzerland

I. Introduction The historical analysis of mortality trends and the models of disease causality indicate that although medical progress is essential, it is not enough to achieve the goal of developing healthy communities (1). Political, economic, and cultural determinants are not only the main driving force of epidemics but they also influence, to a great extent, the actions affecting the biological determinant (2). Although it is necessary to identify means to address health determinants other than the biological, it is also important to intervene on the political, economic, and cultural forces that limit the access of individuals and communities to technologies proven to be efficacious. Public health problems such as the tuberculosis (TB) epidemic, for example, do not escape this analysis (3,4). TB is intimately linked to poverty through reduced personal and family income, malnourishment, crowding, costly and ineffective health care–seeking patterns, limited access to health-care services, limited access to information, stigma and discrimination, etc. Despite major progress achieved in the last 15 years in TB control (5), humanity is still a long way from eliminating this disease. Poverty, social upheaval, and the HIV 1029

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epidemic, for example, all conspire against the progress made by increasing the risk of breakdown in the pool of people already infected. Yet, one of the major threats to sustain and accelerate progress in disease control is the limited access of sick people to appropriate TB care services and the usually unreliable political commitment with effective control strategies. To make matters worse, those who suffer from the disease usually have no means to voice their needs and to influence the public health agenda. In this context, health education has a paramount role to play. An educated community is one that is able to reflect on, and agree upon the meaning and nature of the life it values to live. An educated community mobilizes itself to change social norms, values, policies, and even structures. Governments and societies are not always ready to promote and facilitate supportive environments and spaces for collective analysis, deliberation, and decision making by an educated community. However, in a dialectical way, an educated community can mobilize and press governments to open up and facilitate these spaces. Several experiences in the recent years demonstrate that it is feasible, even in the most adverse circumstances, for affected individuals and communities to participate in all areas related with TB control (6,7). This participation extends from TB patient care to active influence on decision making and setting of local and even global public health agendas. We argue in this chapter that health education and the social mobilization that follow are two essential and interdependent tools that can improve the effectiveness and sustainability of the Stop TB strategy to control TB (7); in support of this argument we focus on the recent experience of the Mexican project ‘‘Mexico Free of Tuberculosis,’’ a work in progress from which several lessons on the role of social mobilization can be learned. The National Tuberculosis Control Program of Mexico is implementing this project, which reduces the priority given to medical care and emphasizes the participation of the community in several aspects related with the World Health Organization (WHO) DOTS strategy (8). Health education and a supportive environment for social mobilization constitute the engine within the community itself, to trigger or increase, for example, the demand for TB control and the actions to combat TB. II. Health Education in TB Control We argue in this manuscript that health education in TB is an activity aimed at the creation of an educated community, that is, individuals and communities able, first, to make informed decisions on TB care at personal and community level and, second, to participate in the political debate for TB control decision-making, and not only in the planning and implementation of program services. Some authors stress that behavior is the main determinant of people’s exposure to TB risk factors, and of their relationship with the health-care system (2). However, by holding a different idea about the determinants of health one may also have a different perception about

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the potential of health education for controlling TB. The issue gets even more complex once the problematic nature of health is taken into account in defining health education. Indeed, different concepts of education and health will result in different notions of health education. We argue that health is the minimum physical and mental condition required to develop enriching social ties, within which the production of services and material goods is a collateral consequence. Thus, health is not only a cause of material welfare but also a result of social development. In this context, the essential aim underlying any health education activity is the promotion of autonomy. That is, the capacity to reflect upon one’s choices and exert self determination. In fact, demand for health-care services, understanding of medical information, acquisition of improved lifestyles, access to social support networks and, even more important, people’s participation in political decisions affecting their health, are activities that require acquisition of knowledge and learning of skills. However, relying only on the provision of knowledge and skills on TB care very easily leads to an individualistic approach that promotes ‘‘patient blaming’’: assuming that provision of TB knowledge and life skills place affected individuals in full control of their treatment outcome means that only they can be blamed in case of default or TB treatment failure. In the real life of TB care services the limited space—in terms of time and quality of communication between health-care workers (HCW) and affected individuals—makes it very difficult to carry out any health educational activity that promotes autonomy. Instead, most of those in the health field demanding TB health education programs do not care too much about autonomy, because what they expect is that education will change the unreliable behavior of some patients who do not follow their advice. This fact explains, to some extent, why most HCWs have a problematic notion of health education within which methodology is what matters and contents are taken for granted. This results in a tendency to define health education in TB merely as efforts to help affected individuals to demand diagnostic services and to comply with treatment. Although triggering the demand for health-care services is a good thing to do in TB control, the potential of health education in TB is wasted if it is restricted to this function. Offering a basic package of information and skills on TB care for treatment compliance is quite often presented as the way for HCWs to ‘‘educate’’ patients on TB (as if open communication, instead of the unidirectional flow of information between HCWs and people with TB, were not the fundamental approach for educating in health). In this scenario, the obvious question is: ‘‘Whose interests are best served by this package of information and skills acquired by the people with TB?’’ Undoubtedly, escaping death and getting cured are priority interests for a person with TB, and these can be very well served by basic health education in TB. While in this case the immediate interests of the person with TB and community are addressed, the wider individual and social interests are not. In fact, limiting TB health education to information and skills that facilitate

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treatment compliance prevents affected individuals and communities from becoming aware about the determinants of TB. The answer to the question ‘‘Why did I get sick at this point in my lifetime while others did not?’’ will say a lot to the people with TB about the large scale political, economic, and cultural forces that give direction to the risk of becoming infected, sick, and dying from TB, and is the first step to enable affected individuals and communities to challenge these forces. Alas, HCWs usually lack the education needed to answer this very valid question. Thus, health education in TB includes more than changing risky behaviors, applying medical preventive measures, and adhering to preventive or curative treatment. Health education in TB should also aim at providing people with the understanding of the determinants of TB and the ways to address such determinants. Ideally, an effective TB health education process in a supportive environment, i.e., one in which free speech is allowed, should result in individuals and communities empowered to voice their needs and rights, and to fight for something more than simply access to diagnosis and treatment. III. Social Mobilization in TB Control Social mobilization has received different definitions and uses depending on who makes the definition and what his or her purposes are. They range from the massive efforts to persuade a population to vote for a political candidate to the rallies of marginalized communities demanding access to basic public services. The most commonly accepted definition is that proposed by McKee, who defines social mobilization as ‘‘the process of bringing together all feasible and practical intersectoral social allies to raise people’s awareness of and demand for a particular development program, to assist in the delivery of resources and services and to strengthen community participation for sustainability and self-reliance’’ (9). Social mobilization, quite often, is not driven by the community as a result of health education. Rather, it is a process in which powerful political actors mobilize the community to perform actions that, despite being in the interest of the community, do not correspond to its free choice. It is therefore always healthy to ask about any social mobilization process, ‘‘who is mobilizing whom?’’ The answer to that question sheds light on the interests at stake and the weight of the political actors involved in the process. Getting people to adopt and maintain healthy behaviors and participate in the public debates on public health policy is a major challenge. Social mobilization in TB control should consist of the actions that empowered groups of the society carry out to ensure that the determinants of the disease are tackled, not only by the government, but also by the joint efforts of the community (Fig. 1). Social mobilization is the expression of social responsibility of individuals and organized groups of the society to tackle the TB epidemic, and represents the most evident sign of civic maturity in the community (10). Social mobilization in TB is a dynamic process comprising several key

Health Education and Social Mobilization in TB Control

Figure 1 zation.

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Empowerment, the bridge between health education and social mobili-

elements (Fig. 2). Educated community is one that understands the determinants of TB and the ways to address such determinants. The community should, at least, be informed that TB is a deadly disease; that its main symptom is cough for more than two weeks; that it is curable and that primary public health-care centers offer free tests and treatment (wherever that is the case). Empowered community is a community health-educated in TB that demands from individuals, society, and government effective actions to tackle, and act on, the determinants of TB. Participating organizations from the civil society refer to the organized members that, within the community, join forces to defend common interests and tackle the determinants of TB. TB Care with community and public health services refer to the joint efforts of community and government to enable access of people with TB to diagnosis and lifesaving treatment, and to address other determinants of the disease. There are three strategic actions for the social mobilization dynamics to effectively operate in TB control. First, continuous communication to ensure that tackling TB becomes a perceived need by the community. For this purpose, it is essential to develop effective communication mechanisms among local authorities, community leaders, voluntary promoters and the community as a whole to facilitate awareness of the TB situation and the respective

Figure 2

The dynamics of social mobilization in tuberculosis.

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actions aimed at controlling the disease (8). The extent of knowledge of the community of existing TB care services constitutes the primary indicator of the degree in which the population and public services are communicating. Second, cohesion between the different social actors for TB control (Fig. 3). This makes particularly difficult the social mobilization to tackle TB determinants other than the biological, as the most powerful social actors may have values and interests that differ from those of groups that are more at risk of developing TB. Third, monitoring the mobilization in order to assess the progress achieved and determine the adjustments needed, and evaluation of the whole process to determine if the goals are being achieved. The purpose is to measure and assess the social impact of the interventions resulting from the ‘‘health education/social mobilization’’ actions.

Figure 3

Social actors involved in the tuberculosis control chain.

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IV. Promoting Social Mobilization: The Experience of the National TB Control Program of Mexico Social mobilization is a fundamental component of the plan ‘‘Mexico Free of Tuberculosis.’’ The most influential strategies to create supportive environment for social mobilization in TB in Mexico are the Bandera Blanca (White Flag) strategy and the National and State Stop TB Committees. One of the best examples of social mobilization in TB in Mexico is the creation of social support networks to support TB care. A. The ‘‘White Flag’’ Strategy

‘‘White Flag’’ is the name of the strategy used in Mexico to provide a supportive technical and political environment for social mobilization. The strategy takes its name from the white flag raised in villages where the community has achieved a set of epidemiological and behavioral targets related to different health problems, including TB. The ‘‘White Flag’’ stimulates people’s and government’s coresponsibility in health by education and promoting community actions on several health care determinants; it promotes a healthy competition between communities, and between local public health authorities. A certified ‘‘White Flag’’ community is one that has adopted a set of healthy lifestyles (mostly related to the timely demand for health-care services) and is committed to maintain health education and social mobilization activities in TB control. The criteria used by the public health authorities to assess the TB component, amongst other public health components, and to determine which community can raise the White Flag are as follows: i.

ii. iii.

Evidence that 100% of the population has received basic information on detection of symptoms, and options for diagnosis and treatment of TB in a DOTS-based program. HCWs and voluntary health promoters are trained in the DOTS strategy and executing joint actions in TB care. Evidence that 100% of TB cases are detected by a functional DOTS-based TB control program.

To be selected as a ‘‘White Flag’’ community, the first two criteria must be met, and the third one is contingent on the existence of TB patients registered in the TB control program. To facilitate the achievement of these criteria, the public health authorities provide training, health education, and technical advice to the local community and the respective local health authorities. Between 2001 and 2004, 2012 communities were approved to raise ‘‘White Flags.’’ The strategy has facilitated the training of 355,995 voluntary health-care promoters. The state of Queretaro, for example, was the first state to achieve 100 White Flag communities. In the 2001– 2004 period, 70% of the 246,200 inhabitants of the state received information in TB control; 6800 voluntary health promoters were trained in TB control and in carrying out TB care actions; and 100% (626) of the people

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notified with TB were diagnosed and treated in health-care facilities using DOTS [90% (594) of them were cured]. An evaluation of the process and impact of the TB component of the ‘‘White Flag’’ strategy is under way. However, preliminary results suggest that the goals proposed by the strategy have been very effective in stimulating social mobilization. B. The ‘‘National Stop-TB Committee’’ Project

The Stop TB Partnership (10a), established in 2000, consists of a network of individuals, countries, and public and private international organizations working together to achieve the goal of eliminating TB (Chapter 25). The Mexican Government has established officially on 7 September 2004 a national Stop TB partnership to catalyze the initiatives of social movements to address TB. It followed the realization that the broad- and long-term actions needed to control TB cannot be achieved without the support of community and organized groups of the civil society, which can join efforts with the government to facilitate the consolidation and sustainability of the DOTS strategy. The mission of the partnership is to assist the Mexican society in ensuring that each person with TB has effective access to diagnosis, treatment, and cure; interrupting the transmission chain, and contributing to reduce the morbidity and mortality associated with TB. The partnership is actively involved in information, education, and advocacy on TB. Important steps are being taken toward the creation of Stop TB committees at state level and the selection of local and international ambassadors who advocate for TB control. By November 2005, 52 organizations were members of the partnership. Members include both public and private organizations, nongovernmental organizations (NGOs), medical and hospital associations and scientific societies, international organizations working in the country, the pharmaceutical industry, and the Ministry of Health. This partnership is not only an expression of a society mobilizing to control TB, but a tool to help educated and empowered communities to mobilize. C. Social Support Networks: Social Mobilization in Action

A remarkable expression of social mobilization in Mexico is the creation of networks to support TB care. The Indigenous Community Bilingual Health Workers Network, the TB Nursing Network, the Prisoners and Volunteer Inmates Network, the Schools of Medicine and Nursing Network, and the Motorcycle Volunteer Promoters Network of Veracruz, for example, are all contributing to facilitate TB care and to meet the goals of the government plan ‘‘Mexico Free of Tuberculosis.’’ The Motorcycle Volunteer Promoters Network of Veracruz is an example of a very effective support network. In 2003, the TB treatment default rate in Veracruz was 11.8% (12/64). Having as background a TB health education process, the community and the TB control program officers discussed the nature of the problem and the

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options to ensure that 100% of people with TB receive directly observed therapy (DOT). After exploring several options, the community established an alliance with a NGO to support a network of volunteers to deliver DOT at the place selected by the person with TB. The NGO donated four motorcycles and supported five drivers with uniforms and traffic protection equipment. The volunteers use the motorcycles to bring treatment closer to the sick when for any reason they cannot attend the DOTS clinic. This initiative has the added value of improving the quality of TB care by reducing the impact of adherence to treatment on the household economy; facilitating the performance of sputum microscopy tests to monitor response to treatment; facilitating the examination of TB contacts who have respiratory symptoms; and, above all, strengthening the social bonding among the members of the community, thereby paving the way for more complex forms of community participation. By 2004, after one year of operation of the network, there was not a single default case among the 67 patients who received treatment; the cure rate increased by 37%, and all contact cases were duly assessed. V. The Impact of Social Mobilization Empowered societies that mobilize can make the difference that TB control programs alone cannot. It has been repeatedly said in different forums and by different bodies that it is utterly unacceptable that people die of a disease like TB, one for which highly cost-effective tools for diagnosis and treatment have been known for many decades. Some social and political insight is necessary to understand why, what many consider morally unacceptable, still occurs. Szreter, drawing on analysis of sociodemographic data, convincingly argues that ‘‘it has been political and ideological forces that have primarily determined when and where human societies have chosen to use or not to use their technical and organizational skills to enhance the health of the majority (11).’’ Thus the new and better diagnostic and treatment tools for TB expected in the coming years will not help much if the society does not devote some time to think and develop the ways to ensure that the current and new tools reach all those who are in need. The public health sector, especially the national TB control programs, have very limited capacity, let alone the mandate, to implement measures to control the biological, social, economical, and political forces that create and perpetuate the TB epidemic. These programs even have limited capacity within the realm of the biological determinant in which they operate. The DOTS strategy, for example, is proving to be efficacious in accelerating the reduction in morbidity and mortality due to TB in those settings that are not badly affected by the HIV epidemic (5). However, the prioritization of the DOTS strategy in the local and global public health agenda, the sustainability of TB control policies, and the implementation of the strategy in adverse conditions, require the involvement of political actors other than the public health bodies (11). It is in this context that health education for

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empowerment of individuals and society and further social mobilization have their place (12). The impact of the dual health education/supportive environment for social mobilization in Mexico has resulted in major progress in TB control: a case detection rate of over 70%, a cure rate of over 80%, and an annual reduction of 5% in mortality have been observed. Creating supportive environments to ensure that the community reach targets in line with TB control policy has been fundamental for expanding and consolidating the DOTS strategy in many communities, and has promoted local solutions to problems that the government alone cannot solve. The success of health education/social mobilization occurs when people informed and educated on the nature of the disease adopt healthy behaviors, provided that they perceive the behaviors recommended as effective and rewarding and the environment is supportive. Indeed, social mobilization follows almost naturally when a health-educated community lives in an environment supportive for expressing the choices and actions the community values. The Stop TB Partnership’s Advocacy, Communication and Social Mobilization (ACSM) Subgroup at Country-Level will publish in 2006 its 10-year strategic plan (http://www.stoptb.org/globalplan/). The implementation of this plan promises to strengthen TB control efforts globally by placing health education and social mobilization high in the agenda at global and country level. Acknowledgments The authors would like to acknowledge the thoughtful contributions of Drs. Oscar Velasquez, Elizabeth Ferreira, and Martin Castellanos, and the suggestions of two anonymous reviewers of this manuscript. References 1. Szreter S. Economic growth, disruption, deprivation, disease and death: on the importance of politics of public health for development. Popul Dev Rep 1997; 23: 693–728. 2. Farmer P. Infections and Inequalities: The Modern Plagues. Berkeley: University of California Press, 1999. 3. Lienhardt C, Ogden JA. Tuberculosis control in resource-poor countries: have we reached the limits of the universal paradigm? Trop Med Int Health 2004; 9(7): 833–841. 4. Jaramillo E. Encompassing prevention with treatment: the path for a lasting control of tuberculosis. Social Sci Med 1999; 49:393–404. 5. Elzinga G, Raviglione MC, Maher D. Scale up: meeting targets in global tuberculosis control. Lancet 2004; 363:814–819. 6. Maher D, Floyd K, Sharma BV, et al. Community Contribution to TB Care: Practice and Policy. Geneva: WHO, 2003. 7. Stop TB Partnership and WHO. Global Plan to Stop TB, 2006–2015. Geneva: World Health Organization, 2006 (WHO/HTM/STB/2006.35). 8. Secretarı´a de Salud Me´xico. 2001–2006 National Health Program. Democratisation of Health in Mexico, Me´xico, 2000.

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9. McKee N. Social Mobilization and Social Marketing in Developing Communities: Lessons for Communicators. Penang, Malaysia: Southbound, 2004. 10. Cortina A. Citizens of the World: Heading Towards a Theory on Citizenship [editorial]. Madrid: Alianza, 1997. 10a.http://www.stoptb.org/. 11. Szreter (Szreter responds). Am J Public Health 2003; 93(7):1033. 12. Klaudt K, WHO. Mobilizing society against tuberculosis: creating and sustaining demand for DOTS in high-burden countries. In: Reichman LB, Hershfield ES, eds. Tuberculosis: A Comprehensive International Approach. New York, NY: Marcel Dekker, 2000:843–864.

42 Workforce Constraints in Tuberculosis Control

GIJS ELZINGA

GILLES DUSSAULT

National Institute of Public Health and the Environment, Bilthoven, Utrecht, The Netherlands

Human Development, World Bank Institute, Washington, D.C., U.S.A.

JOSE´ I. FIGUEROA Public Health Improvement, City and Hackney Primary Care Trust, London, U.K.

I. Introduction In this chapter we discuss why it is imperative to address the health care workforce crisis in order to further improve tuberculosis (TB) control, particularly in high TB burden countries (HBC). Recent data indicate that reaching the TB detection targets, adopted by the international community, will only be achieved if health systems are strengthened and provided with a sufficient, competent, and motivated workforce. Furthermore, workforce problems are multidimensional and complex, and require comprehensive approaches to address them. The potential collaborations between disease-specific programs, such as TB, and the broader health systems are examined with a view to bringing mutual benefits to programs and systems as a whole. How TB programs could also contribute to ameliorating the overall human resource (HR) crisis, while controlling a disease that is both preventable and treatable, is also discussed. II. Global Tuberculosis Control and Health Workforce Constraints In response to global inequities in health and wealth distribution, the international community has recently recognized the need for concerted efforts 1041

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to reduce poverty and tackle preventable/treatable causes of death and disability. This is particularly important in low- and middle-income countries (LMIC). Equity issues have become central to the global cooperation agenda, leading to the adoption of the Millennium Development Goals (MDGs) in 2000. The focus on health issues has generated several new coordination and advocacy partnerships such as Roll Back Malaria (RBM) and Stop TB, or new financial mechanisms such as the Global Alliance for Vaccines and Immunization and the U.S. President’s Emergency Plan For AIDS Relief, or as well as increased financial support from multilateral and bilateral donors, and private foundations including the Bill and Melinda Gates Foundation and the Clinton Foundation, which act directly or indirectly through agencies such as the Global Fund to Fight AIDS, TB, and Malaria (GFATM). These different funding and coordinating initiatives are mainly disease specific, and in support of priority programs such as HIV/AIDS, Malaria, TB, or immunizations. The increased availability of financial resources has generated greater competition between programs for staff. Increased resources for specific programs have placed further demands on the already overburdened workforce. TB programs, which are labor intensive, are strongly affected by this new environment. In sub-Saharan Africa (SSA), the competition for limited staff takes place in a context where the TB and HIV/AIDS epidemics overlap with an overwhelming effect on HRs for health (HRH). The AIDS epidemic has had a devastating effect on health workers morale and availability, either as a direct result of staff becoming ill or having to care for diseased family members or due to the substantial increase in workload. HIV fuels the TB epidemic by increasing numbers of active TB infections, increasing case fatality rates and recurrent disease after completion of anti-TB treatment (1). Low salaries and poor working conditions have led significant numbers of qualified health workers to migrate to more developed economies (often encouraged by active recruitment by the latter, which face important shortages themselves). The attrition of health care staff in LMIC, coupled with the increased workload, has resulted in a demoralized, overworked, underpaid, and insufficient health workforce. Furthermore, stigmatization of health-related occupations, due to a perceived increased risk of HIV infection for health care staff, has reduced recruitment, thereby further contributing to the health-care workforce crisis. III. Human Resources for Health Constraints and Tuberculosis Control Targets Recognition of the burden of the global TB epidemic (2,3) prompted the World Health Assembly (WHA) in 1991 to endorse the TB control targets of detecting 70% of new sputum smear positive TB cases and curing 85% of them by the year 2000 (4). The World Health Organization (WHO) declared TB a global emergency in 1993, and stressed the need to accelerate TB control efforts. In 1998, the first ad-hoc committee on the TB epidemic

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was convened in London, United Kingdom, to identify constraints to achieving the targets and to propose strategies to overcome them (5). The Committee identified neglect of HR as one of the main constraints to global DOTS expansion. It described eight strategic lines for intervention including strengthening HR, management capacity, and health systems. To address the HR problem, the committee proposed to increase training activities, introduce incentives to improve staff retention, and develop leadership capacity. Recommendations concerning strengthening health systems and ‘‘Organization and Management’’ capacity of TB programs were made, arguing for a balance between integration and specificity, and between decentralized and centralized functions to ensure optimal performance of key program functions such as oversight of services, drug procurement, and monitoring and evaluation (M&E). In 2000, the WHA deferred the targets to 2005 (6). The implementation of the ad hoc Committee recommendations resulted in important developments to improve global TB control: the creation of the Stop TB Partnership with its six working groupsa; the organization of a Ministerial Conference in Amsterdam (7) that resulted in enhanced political commitment to TB control; the creation of the Global Drug Facility (GDF) to facilitate access to good quality anti-TB drugs; and the publication of The Global Plan to Stop TB, 2006–2015 (8), signalling a strategic direction to reach the 2005 targets. Although TB programs remained far from achieving the 2000 targets (9), the enhanced political commitment, combined with the Stop TB Partnership, improved advocacy efforts while the establishment of the GFATM in 2001 resulted in a significant increase in funding for TB control. This translated into additional demands on the health workforce to achieve rapid DOTS expansion and improve implementation of TB control. In spite of additional funds and renewed support to TB control efforts, progress to ameliorate the HR constraints has been slow. In 2003, TB program managers from HBC still described the lack of sufficient, competent, and motivated staff as one of the most important barriers to achieving global TB control (10). A second ad-hoc committee on the TB epidemic met in Montreux, Switzerland, in 2003 and recommended that the Stop TB partnership collaborate with national governments and international bodies to promote the development of policies aimed at (a) removing administrative barriers to creating and filling posts, and (b) promoting terms and conditions of service in the health sector that are attractive to employees (11) in order to increase retention of staff and career development. This committee acknowledged

a Three implementation working groups: DOTS Expansion, TB/HIV, and Monitoring and Evaluation working groups, and the Global Alliance for new TB drugs, the TB diagnostics, and the TB vaccines initiatives.

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Table 1 Second Ad-Hoc Committee Recommendations to the Stop Tuberculosis Partnership to Address the Health Workforce Crisis Collaborate with the relevant Ministries (e.g., Health, Planning, Education) to promote the assessment of HR needs in the health sector in general and for TB control in particular. Assist Ministries of Health to address HR needs as part of poverty reduction processes, e.g., poverty reduction strategy papers and debt relief through the Highly Indebted Poor Countries Initiative. Collaborate with governments, financial partners, and technical assistance agencies to support the necessary HR planning and training as identified through the analysis of HR needs. Explore with all stakeholders strategies for further mobilizing HR for TB control from the full range of primary care providers, especially community groups and grassroots NGOs. Urgently explore with all stakeholders specific strategies in countries severely affected by HIV the mobilization of HR to address priority diseases of poverty, including TB. Abbreviations: HR, human resource; NGO, non-governmental organization. Source: From Ref. 11.

the complexities involved in addressing the health workforce crisis and advised policies covering career opportunities, training, work conditions, distribution, incentive schemes and effective prevention, and care services for health workers themselves. The committee also stressed on the importance of addressing HR needs within the country’s health systems and socioeconomic contexts. Other HR recommendations of the committee are shown in Table 1. Although health systems in many countries are severely affected by workforce constraints, reliable quantitative information about the nature and extent of the gap remains limited (10,11). This holds true for general health services as well as for health care staff in priority programs such as TB (1,10), malaria, and HIV-AIDS. Despite the two ad-hoc committee reports and postponing the global TB targets to 2005 and now embracing the MDGs to 2015, the rates of increase of TB incidence in countries in the Former Soviet Union (FSU) and SSA provide strong indirect evidence that TB control must be further strengthened. This can only be achieved by increasing the numbers, availability, quality, and productivity of the health-care workforce (12,13). A. Opportunities

In spite of all public health efforts, differences in health increased globally and within regions and countries during the last century (14). The work of the Joint Learning Initiative (JLI), created by the Rockefeller Foundation to assess whether the existing health workforce (in countries and globally)

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could cope with the health challenges of the 21st century, recognized that health systems face key HR challenges globally. These include the acute shortage of competent staff coupled with poor motivation, maldistribution and migration of staff; skill mix imbalances; negative work environments and a weak knowledge base. The JLI published its final report in November 2004 (15); subsequently, health workforce constraints were addressed by the High Level Forum monitoring the progress toward the health-related MDGs (Abuja, December 2004) and by the G8 summit (Gleneagles, July 2005). Furthermore, one of the JLI working groups (WG5), focused on priority diseases including TB, concluded that programs work within the context of health systems and therefore are as strong as the health system itself. The most promising direction for TB and other priority programs is to contribute strategically to the strengthening of health systems (thereby addressing not only health workforce issues, but other constraints such as limited access to medicines, inadequate infrastructure, weak health information systems, etc.) while preserving the programs’ strengths and attending to their specific needs. Opportunities for synergistic development and collective efforts might be found in the fields such as training (in-service and preservice), oversight, M&E, drug management and procurement capacity, and in the interaction with the general health services. IV. Positioning Tuberculosis Programs Within the Health System A. Program Structure and General Health Services

The degree of integration of TB programs with the general health service varies. In some countries, for instance those of the FSU, due partly to rigid organizational and professional structures and to the need of programs to ensure better control and accountability over limited resources, TB programs still remain organized as parallel structures, in a ‘‘vertical’’ manner, working rather independently of the general health services and even competing for limited HR. However, in the majority of settings, TB programs are partially or fully integrated in health systems and the implementation of TB control activities takes place within the context of primary care in a rather ‘‘horizontal’’ manner. When the integration is complete and dynamic, a stronger health system translates into a stronger TB program and vice versa. In general, the organization of many priority programs consists of three major structural blocks: (i) the development of an intervention strategy and planning of activities; (ii) the implementation of the activities or service delivery (SD); and (iii) the M&E of the implementation processes and outcomes that feed back to the strategy and planning component. The development of the strategy and the planning processes tend to occur centrally and, in general, are specific to each priority program (‘‘vertical’’ component); the M&E, although specific to each program (vertical), can show different degrees of integration between programs and the general

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Figure 1

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Components of tuberculosis programs.

health system. On the other hand, the implementation of disease control activities or SD takes place across the health services often integrated with other programs and services (vertical/horizontal overlap). Figure 1 illustrates the way these three components interact with each other and with the health services (vertical–horizontal interface). An effective control program requires all three components to be in place and functioning adequately. This implies that strategic planning has to be efficient and responsive to the feedback from the M&E processes; these in turn should be effective and based in good reliable data, and the implementation of services should be of standard quality and accessible to all those in need. In terms of numbers, the health workforce is very unevenly distributed over these three components; strategic planning and M&E tend to be centralized functions that require special skills but relatively small numbers of staff. In terms of HR, the implementation of control activities (delivery of services) is by far the largest component and it is directly related to the demand (number of patients). The efficacy of the TB control strategy (DOTS) is well demonstrated and is supported by the fact that overall treatment success rates of patients under DOTS are close to the global target 85% (16). The M&E component of the TB programs is, in general, well developed as indirectly evidenced by the publications of Annual TB Reports since 1997. However, the SD component is seriously hindered, as evidenced by the slow progress in case detection rates (45% in 2005) and the fact that, despite rapid DOTS expansion and increased TB control efforts, there are still increasing trends of TB in SSA and the FSU, as well as somewhat slow declining trends in the rest of the world.

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B. Health-Care Workers vs. Program-Specific Workers

Programs depend on—and are implemented within—health systems. For example, finding 70% of positive sputum smear cases and curing 85% of them implies that TB diagnosis and treatment services need to be close to the patient, preferably at, or close to, the first point of contact between patients and services. In practice, this can only be achieved if the delivery of TB services is an integral part of the larger package of health interventions. To understand the argument, imagine a DOTS center (a center that only serves TB patients) in a particular region with a TB incidence of 200 cases/ 100,000 inhabitants; assume an average of 20 patients are seen each day and the center works 365 days a year; finally, suppose a full course of treatment requires 10 visits per case on an average. With all these assumptions, the catchment population needed for this DOTS center to operate would be of approximately 365,000 people [(20  365)/(10  200)  100,000]; under most circumstances, this is unrealistic. Furthermore, patients do not attend health care centers only with TB; they come with a variety of complaints of which only a proportion happens to be TB related (17). The implementation of interventions of priority programs (delivery of services) occurs within the context of health systems and it is done by health workers who are not program specific but, almost invariably, deal with many more diseases and priority programs. Health-care workers are as a rule part of the general health services; therefore, strengthening the general health workforce would also mean substantial efficiency gains for integrated priority programs. C. Tuberculosis Programs and System Synergies

Thus, apart from countries with specific health system arrangements (such as the TB specialists in Eastern European countries and the FSU or the TB dispensaries still found in some countries like China), most TB patients are served by general health workers at primary care level. These health workers are usually trained and supported at district level by the district TB manager (who has been specifically trained by the TB program). The district TB manager in turn reports to the more central components of the TB program. Support and guidance of health workers at district level focuses mainly on training and supervision; the M&E process follows the opposite direction— up from the TB manager at the district level to the national program manager. However, recent efforts have been made to strengthen peripheral capacity for recording and reporting and for data analysis and interpretation, to encourage the use of local data for self-evaluation and monitoring. TB programs often provide additional support to staff caring for TB patients. Common support includes drug procurement and management training, leadership skills, operational research, practical procurement of anti-TB drugs such as in countries supported by the GDF, and occasionally incentives or rewards to improve retention, motivation, and performance. In many instances working with TB programs may open career perspectives for health workers.

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Strengthening the delivery of DOTS greatly depends on improving HR deficiencies. However, even though SD staff is not a program responsibility, programs can benefit from reliable information on numbers, quality and distribution required for adequate program performance; some of the health workforce characteristics respond to more complex issues. The HIV/AIDS epidemic in many SSA countries increases TB incidence (18) and high TB/ HIV comorbidity; this cripples the relationship between TB case detection and cure rate, on which TB control targets are based. At higher levels of HIV/AIDS prevalence, effective control of both diseases is required in order to curb the TB epidemic. Additionally, ‘‘DOTS coverage’’ is an imperfect measure of patients’ ability to access DOT. The estimates for DOTS coverage (an indirect measure of population access to treatment centers providing DOT) focus almost exclusively on public ministry of health (MoH) facilities, while in many countries patients turn to private providers (for and not-for-profit) or other providers as the main source of care. Health services with sufficient capacity to provide adequate HIV/AIDS prevention and care, as well as TB treatment for all in need, are implausible in many low-income countries. Important deficiencies are observed in the performance of the health workforce, which need to be addressed if SD is to improve. To do so, it is necessary to fully understand the complexities of the processes underlying health workforce strengthening. The most common deficiencies and their causes are  imbalanced distribution of qualified staff in favor of urban and better-off areas and populations (19) results from poor planning and the absence of mechanisms and incentives to recruit and retain staff in remote and poorer regions;  low productivity often results from negative work environments, inadequate skill mix, lack of incentive schemes, absence of adequate supervision and regular training, lack of support, inefficient organization of work (little team work), limited access to working tools and to complementary inputs (Kurowski C, Wyss K, Abdulla S, et al. Human Resources for Health: Requirements and Availability in the Context of Scaling-up Priority Interventions in Low-Income Countries: Case Studies from Tanzania and Chad. London: London School of Hygiene & Tropical Medicine. Submitted for publication), absenteeism (20);  deficient technical quality, illustrated by low proportion of correct diagnosis, poor case management (Millennium Project case studies), is often caused by a weak knowledge base, insufficient or inadequate training, training curricula unrelated to local needs, inadequate skill mix, lack of regular supervision and on the job training, and by organizational inadequacies already mentioned;  service quality, in public services, at such low levels that discourages populations from using the services (21). Various studies

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showing low utilization rates cite poor service quality as a major factor. Impoliteness, rudeness of personnel, verbal and physical violence, lack of attention to patient needs, inadequate opening times, impossibility to be treated by a person of same sex, corruption and nepotism, and informal fees are key causes for the low reputation of publicly provided health services. Low levels of perceived quality thus become a critical constraint to scaling-up priority interventions. V. Strategies and Policies Required The issues related to the health workforce crisis are complex and multifactorial. Therefore, it is crucial to think about HR problems in TB programs in terms of the desired performance of these programs (i.e., achievement of the Global TB control targets—WHA/MDGs). Strategies to address HR bottlenecks should be based firstly on a valid identification of what the problems are, and secondly on an accurate diagnosis of the possible causes involved. For example, a TB manager may observe that the case detection rates are low in a certain part of the country; after a careful situational analysis s/he could identify one or more different causes, for example: insufficient numbers of qualified staff; enough staff numbers but high rates of absenteeism; poor skills of personnel; sub-utilization of available services by the community. The specific identification of the problem/s is essential because the strategies required to address each example are quite different. A. Health Workforce Strengthening: Systems Perspective

In most cases, it is likely that problems faced by TB programs have their roots in weak health care delivery systems, and are not specific to TB services. This is why a systemic approach is recommended. For example, shortages of staff in remote or deprived areas are usually caused by the difficulty to attract/retain staff, precisely because the area is remote and deprived (inverse care law). Specific incentives need to be in place to convince personnel to move to such areas. These obviously include better remuneration, but also professional and family incentives, such as access to continuing education, accelerated promotion, housing, transport, support to education of children, or employment of the spouse. The selection of specific strategies is a matter of feasibility, including: affordability (incentives cost money and what will be offered to health staff will be demanded by staff in other sectors, e.g., teachers; on the other hand, incentives need to be sustainable because once introduced it is highly detrimental to withdraw them); acceptability (for example, assigning people to an area by decree may be less acceptable than attracting them with an incentive package), and political feasibility. The latter is often difficult to achieve; governments are critical for workforce development because they set policies, secure financing, support education, and operate the public sector while regulating the private sector. A robust policy framework for

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strengthening the position of health workers and making working in the health system more attractive, starts first and foremost at this level. Advocacy requires a minimal consensus among the numerous stakeholders, who in the case of HR, belong to various sectors beyond health, such as education, civil service, planning, and finance. HR development (HRD) for health is a long-term investment issue. Information and analysis may reveal that in a given setting, the additional numbers and skills of health workers needed to meet the health system requirements cannot be produced within a short time frame. In such a case, a step-by-step health workforce strengthening process over a longer period may be called for. The Need for a Human Resource Development Plan

HRD is a strategic function of health systems. Addressing multidimensional and complex problems such as HR deficiencies requires multiple and well coordinated strategies and interventions, and these need to be context specific. Furthermore, countries need to have a national HRD plan which is developed locally, taking account of the country’s socioeconomic situation and the development and needs of the health system. The national HRD plan should mobilize the support of all stakeholders, including donor agencies, which play a critical role in the implementation of TB programs. The plan should consider middle and long-term workforce requirements (HR planning); local workforce production capacity; quality of preservice training (adequacy of training curricula); issues affecting staff distribution, retention, and motivation; how to maintain quality and motivation (performance), and current and future threats (such as HIV/AIDS). Given the complexity of HR issues, strategies to address HR bottlenecks for TB control need to be crafted on the basis of careful analysis of local challenges and according to the country context. The degree of integration of TB programs with the general health service—the vertical/ horizontal interface—is very much country specific. Organization and development of health systems, and priority programs, differ from country to country. Health workforce problems are highly context specific; the choice of which health facility and personnel will deliver DOTS depends on prevailing availability of staff, qualifications, workload, infrastructure, more than on specialized or not specialized staff and institutions. Even the cadre of health workers undertaking specific tasks—or allowed to undertake certain tasks—varies between countries. This specificity is pivotal because one strategy for dealing with limited numbers of health workers is to assign tasks to the lowest cadre of personnel that can handle them adequately (task shifting). Quoting a WHO TB expert:b ‘‘ . . . there is no dogma, the structural and human context is the driving force. What counts ultimately is to reach patients.’’

b

Le´opold Blanc (WHO), personal communication, September 13, 2004.

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Figure 2 Factors affecting the health workforce in terms of quantity, quality, and distribution.

The Need for Country Specificity

The country specificity of health workforce strengthening strategies becomes even clearer when looking at the different factors affecting the quantity, quality, and distribution of the health workforce (Fig. 2). The complexity of this network of interrelated determinants makes clear that strengthening the health workforce requires a comprehensive plan at national (or even state) level. Such a plan requires the support of the Ministry of Health but also of other stakeholders such as the Ministries of Finance, Education, and Planning; as already stated, political feasibility is often the most difficult determinant to achieve. The health workforce is central to the health service system. Countries can achieve much, with limited resources. The following are successful examples of innovative interventions to improve SD in several countries in different regions of the world; some of these interventions are already being used to improve access to DOT. None of these countries is rich; what they share is a commitment to better the health of their population using their available health workforce. They have also designed their own strategies, adapted to their specific needs and circumstances. In Brazil, Community Health Agents (CHA), introduced by the Ministry of Health to address the primary health care (PHC) needs of marginalized populations, care for 93 million people across the country (22). Each CHA covers 150 families in rural areas or 250 families in urban settings. Instructors or supervisors—most often nurses—are responsible

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for coaching and providing technical support for CHA. The CHA program has stimulated municipal health services organization and shaped new referral systems, enabled communities to participate in planning and performance evaluations and strengthened linkages between local communities, local health services, state and federal actors. More recently, Brazil has started tackling the problem of access to qualified health services in rural areas through helping municipalities to recruit ‘‘family health teams,’’ which now are present in 84% of its 5560 municipalities, covering 38% of the population, mostly outside the major urban concentrations (23). Both family health teams and CHA are involved in DOT administration and patient support in DOTS performing areas. Two other Latin American countries have developed HRH policies, which have helped them achieve health results comparable to those of developed economies. Cuba intentionally produces enough health workforce, in quantity and quality, to attend to the needs of its population and to ‘‘lend’’ personnel to other low-income countries. Cuba’s policy of training and deploying doctors and nurses for PHC has enabled the country to achieve health outcomes comparable to those of the richest countries, e.g., infant mortality rate of 6.2/00 in 2001, versus 6.9/00 in the United States (24); and it is now working on its TB elimination strategy. Costa Rica, in a different political environment, has achieved excellent health care access by laying the foundations for universal health insurance as early as 1941, and by adopting public health policies emphasizing access to primary care (25), including a rural health program started in 1971. In less than two decades, Iran was able to close and ultimately eliminate its rural–urban child and maternal mortality gap by adopting a management strategy which linked paid community workers (‘‘behvarze’’) and female community volunteers to ‘‘rural health houses’’ dispersed equitably throughout the country (26). In Sri Lanka, traditional ayurvedic medicine has been incorporated in the health care system and access to services is free of charge; although it remains one of Asia’s poorest countries its health indicators rank fifth in the region; infant mortality is 12/00, maternal mortality is among the lowest in poor countries (most deliveries are assisted by qualified staff, and more than two-thirds in hospital), and life expectancy is 73 years. On the other hand, Thailand has used innovative strategies over the last 30 years to deploy and keep health personnel in its more isolated areas; it offers an example of continuing commitment to improving access to services and also of flexibility in adjusting strategies to do so (27). The Need for Donors Awareness and Technical Assistance

Many LMIC have developed their health workforce policies in reaction to incentives from the global community, reflecting global health system trends and the program preferences of the donors. Since the 1990s, global efforts to improve health in developing countries have substantially boosted priority programs. This, however, seems to have had very little benefit in the health care workforce, in terms of regular budget for personnel, retention

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schemes, etc. On the contrary, the pressure to achieve the targets set for priority programs (such as those for HIV/AIDS, malaria, TB, immunisations, etc.), has increased competition for limited health care staff and threatened to overburden the already stretched health workforce. The availability and performance of health workers depends very much on the environment in which they have to work, i.e., the organization, management, and infrastructure. In SSA countries, HIV/AIDS and migration are dominant health workforce erosion factors; supply, through education and training, is essential but needs to match the demand, i.e., sufficient production of adequately qualified staff and sufficiently attractive vacancies for new health workers. To improve the health of the population, demand has to mirror the need. National policies, backed by global support, have to be in place to achieve the right balance between supply, demand, and need. There is no component in the support from donors to add workers to the general workforce in order to cope with additional tasks or targets. Donors and programs need to be aware of their responsibility to strengthen the general health services they depend on for the delivery of specific program interventions. The recent change in the global community’s perception of health systems needs to be translated into increased technical assistance to countries for building capacity for HRD and HR planning within programs to strengthen health systems and achieve the health-related MDGs. The technical assistance provided must be country specific, taking into consideration the impact of the factors described in Figure 2 country’s HR constraints and possible solutions within the specific country setting. B. Health Workforce Strengthening: Program Contributions Collective Efforts of Programs

One of the JLI recommendations for addressing the health workforce crisis was to mobilize, retain and train health workers to combat HIV/AIDS and other priority problems while steadily building PHC systems (15). This recommendation underlines the fact that programs are not independent of each other or the health system. It calls for profiting from opportunities/synergies between priority programs and the health system by identifying strategies that benefit program/s implementation while also strengthening health systems. TB programs simply cannot be managed in isolation, without taking account of the participants in other programs, the health system and in other related sectors. On the contrary, TB programs need to devise their strategies within the context of health systems, with a broader picture in mind, and realizing the importance of influencing policies outside their own specialized area of intervention. These will ensure that they benefit from stronger and better performing health systems. DOTS delivery close to the patient is only possible in combination with other services. The kind of services will in part depend on the organization of health services and on the local epidemiology (disease burden). In SSA for instance, the main services required could be a combination of

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Figure 3

Priority programs health system strengthening framework.

interventions targeting HIV/AIDS, treatment of opportunistic diseases, which would be fully compliant with the TB/HIV recommended collaborative interventions (28). If the two programs are integrated within the health system, strengthening one of them will have a positive impact in both programs and the system as a whole. In Bangladesh, BRAC delivers TB services through female community health volunteers who are trained to manage a few common illnesses including diarrhoea, dysentery, common cold, scabies, anaemia, gastric ulcer, and worm infections (29). What a Program for Tuberculosis Can Do

In many SSA countries, HIV/AIDS, malaria, TB, and maternal and child health issues, constitute approximately 80%c of all PHC consultations (Fig. 3). If the priority programs are strengthened to adequately respond to a large fraction of PHC consultations, this would not only have an impact on the priority programs themselves but will also strengthen the health system, have a positive impact on the population’s health and promote sustainability. However, to ensure adequate utilization of services, these should be available, affordable, acceptable, and accessible to the population. Furthermore, services provided at PHC have to be defined in relation to those at referral level (including laboratory facilities). This relation will vary from place to place but should always be considered. In addition, services provided at PHC should also consider what private providers (both for-profit and non-for-profit) and the community could contribute.

c Varying with location and season one out of five care seekers, aged five years and over, present respiratory problems that might be caused by tuberculosis (WHO/HTM/TB/ 2004.333).

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TB programs have already taken a leading role in working with other programs. Some of the progress in the management of TB HIV coinfection is the result of the excellent cooperation between TB and HIV/AIDS programs. This collaboration, however, needs to go beyond two diseases one patient; it needs to identify synergies, possibilities for collaboration or areas of cost-effective partnership with other programs, always within the context of strengthening health systems. Collaboration between the programs shown in Figure 3 in areas such as advocacy, HRD, drug procurement and management, infrastructure (including laboratory services), M&E and health information systems, all offer possibilities for improving program specific implementation while steadily strengthening health systems; the WG5 of the JLI proposed different areas for priority programs cooperation in strengthening health systems, as summarized in Table 2. The degree of leadership and the type of actions needed to strengthen health systems from the primary care perspective will depend on the level of the intervention. For example, at ministerial level (Ministries of Health, Finances, or Planning) the key activity is advocacy. TB program managers could collaborate with other priority programs to assess HR requirements in order to ensure adequate availability, accessibility and affordability at PHC level and to advocate for consideration of these needs within the government HRD and planning agenda (note that this needs to include planning for laboratory facilities and referral centers). Advocacy at central level is also important to ensure appropriate budgeting and adequate preservice training (numbers and content) as well as the infrastructure required for program delivery. At district level, district TB officers could take the lead among other program officers for joint development of implementation plans including HR strengthening activities. Working together could assure cost-effective coordination/collaboration/integration of activities such as in-service training, supervision, M&E visits, building program management capacity, and even incentive schemes for intervention delivery in difficult areas, increased staff motivation, and retention. Staff at health facility level should be adequately supported to be able to implement services of the priority programs that respond to the needs of the local community and ensure they maintain the skill mix required for appropriate SD. Similarly, support is needed to ensure that health facilities are adequate for the delivery of services and that staff are equipped with the necessary tools and medicines to undertake their tasks. VI. Conclusions In conclusion, there are different ways in which priority programs and health systems can contribute to ameliorate health workforce constraints. However, health workforce issues are complex and multifactorial and it will take considerable efforts of all the different actors involved to overcome the

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Table 2 Five Core Strategies to Strengthen Human Resources for Health for Intervention Delivery 1.

Strategy and planning design



2.

Service delivery



3.



Integrate human resource consequences of agreed targets of priority programs in medium and long-term sector planning Integrate priority programs in sector-wide approaches developed by donor agencies for funding the health sector

Stewardship and management

 

5.

Determine synergies based on task analysis (in what combination similar services, for different priority programs, can be delivered most effectively)

Identifying the need for health workers



4.

Adapt as far as possible the strategies, planning of implementation and service delivery to the country’s available skills and resources

Assure that priority programs contribute to institutional development in key areas within the health sector (based on agreed targets) Compare the working conditions and financial incentives in general health care and in priority programs and take care that such differences are adequately balanced

Supply of health workers



Strengthen preservice training through effective cooperation between priority programs and the Ministries of Health and Education

health workforce crisis faced by programs such as Stop TB. Collaboration at country level is essential. Critical conditions for the success of these efforts include the mobilization of all the numerous stakeholders involved, starting with the health workers themselves. Involvement of the health sector, including all health care providers, is important; however, participation of other partners beyond the health sector is as important, if not more so. The Ministry of Finance, which determines the resources and policies available for employing and compensating health staff d, the Civil Service, which d

Whether it is staff employed by the public services, or contracted from the private sector, or paid by public insurance schemes.

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defines the working conditions, or the Ministry of Education, which regulates and manages the training of qualified personnel, are also decisive partners. The other prerequisite for success is that decision-makers, at the various levels of involvement in the design and implementation of a national HRD plan, need to be supportive and to remain permanently committed. References 1. Harries AD, Zachariah R, Bergstrom K, et al. Human resources for control of tuberculosis and HIV-associated tuberculosis. Int J Tuberc Lung Dis 2005; 9(2):128–137. 2. Murray CJ, Styblo K, Rouillon A. Tuberculosis in developing countries: burden intervention, and cost. Bull Int Union Tuberc Lung Dis 1990; 65:6–24. 3. Kochi A. The global tuberculosis situation and the new control strategy of the World Health Organization. Tubercle 1991; 72:1–6. 4. Resolution WHA44.8. Tuberculosis control programme. In: Handbook of Resolutions and Decisions of the World Health Assembly and the Executive Board. Vol. 3. 3rd ed. (1985–1992). Geneva: World Health Organization, 1993; WHA44/1991/REC/1. 5. Report of the Ad Hoc Committee on the Tuberculosis Epidemic, London 17–19 March 1998. World Health Organization, Geneva, 1998; WHO/TB/98.245:1–14. 6. Stop Tuberculosis Initiative. Report by the Director General. Fifty-third World Health Assembly, Geneva, 15–20 May 2000; A53/5. Available at: http:/ www.who.int/gb/ebwha/pdf_files/WHA53/ea5.pdf. 7. Stop TB Initiative. Amsterdam 22–24 March 2000—Tuberculosis and Sustainable Development. Report of a Conference. World Health Organization, Geneva, 2000; WHO/CDS/STB/2000.6. 8. The Global Plan to Stop Tuberculosis. Stop TB Partnership. World Health Organization, Geneva, 2002; WHO/CDS/STB/2001.16. 9. Global Tuberculosis Control, Surveillance, Planning, Financing. WHO Report 2002. Geneva: World Health Organization, 2002; WHO/CDS/TB/2002.295:1–227. 10. Figueroa-Mun˜oz J, Palmer K, Dal Poz MR, et al. The health workforce crisis in TB control: a report from high-burden countries. Human Resour Health 2005; 3:2. 11. Report on the Meeting of the Second Ad Hoc Committee on the TB Epidemic, Montreux, 18–19 September 2003. World Health Organization, Geneva, 2004; WHO/ HTM/STB/2004.28:1–17. 12. Liese B, Dussault G. The State of the Health Workforce in Sub-Saharan Africa: Evidence of Crisis and Analysis of Contributing Factors. Washington: World Bank, Africa Region Human Development Working Papers Series 2004, No. 75, p43. 13. TB Emergency Declaration. Maputo, Mozambique: WHO Regional Office for Africa, 2005. http://www.who.int/tb/features_archive/tb_emergency_declaration/ en/print.html. 14. Ruxin J, Paluzzi JE, Wilson PA, et al. Emerging consensus in HIV/AIDS, malaria, tuberculosis, and access to essential medicines. Lancet 2005; 365:618–621. 15. Chen L, Evans T, Anand S, et al. Human resources for health: overcoming the crisis. Lancet 2004; 364:1984–1990. 16. Global Tuberculosis Control, Surveillance, Planning, Financing. World Health Report 2004. Geneva: World Health Organization, 2004; WHO/HTM/TB/2004.331:1–218. 17. Ottmani S-E, Scherpbier R, Chaulet P, et al. Respiratory Care in Primary Care Services—A Survey in 9 Countries. Geneva: World Health Organization, 2004; WHO/HTM/TB/2004.333:1–107. 18. Elzinga G, Raviglione MC, Maher D. Scale up: meeting targets in global tuberculosis control. Lancet 2004; 363:814–819.

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19. Dussault G, Franceschini MC. Not Enough Here, Too Many There: Understanding Geographical Imbalances in the Distribution of Health Personnel. World Bank Institute, 2003, Discussion paper. 20. Chaudhury N, Hammer JS. Ghost Doctors: Absenteeism in Bangladeshi Health Facilities. World Bank Policy Research Working Paper 3065, 2003. http:// econ.worldbank.org/files/27031_wps3065.pdf. (accessed May 2003). 21. Jaffre Y. Prolegomena to reform of healthcare services: from identification of problems to development of effective tools. Med Trop 2003; 64(6):527–532. 22. http://portal.saude.gov.br/saude/arquivos/pdf/psfinfo21.pdf (accessed on 03–01–05). 23. http://portal.saude.gov.br/saude/visao.cfm?id_area=149 (accessed on 05–10–04). 24. Erikson D, Lord A, Wolf P. Cuba’s social services: a review of education, health and sanitation. Background paper to the World Development Report 2004. World Bank, Washington, DC, January 2002. http://econ.worldbank.org/files/30599_3_pdf. 25. Lisulo A. Costa Rica: health policies. Background paper to the World Development Report 2004. World Bank, Washington, DC, September 2003. http:// econ.worldbank.org/files/32811_35Angela_Lisulo_Costa_Rica_Health_Policies.pdf. 26. Mehryar A. Primary health care and the rural poor in the Islamic Republic of Iran. Paper prepared for the Scaling up Poverty Reduction: A Global Learning Process and Conference Shanghai, May 25–27, 2004. http://www.worldbank.org/wbi/reducingpoverty/ docs/FullCases/MENA%20PDF/Iran%20Primary%20Health%20Care.pdf. 27. Wibulpolprasert S, Pengpaibon P. Integrated strategies to tackle inequitable distribution of doctors in Thailand: four decades of experience. Human Resour Health 2003; 1(1):12. 28. Guidelines for implementing collaborative TB and HIV programme activities. World Health Organization, Geneva, 2003; WHO/CDS/TB/2003.319, WHO/HIV/ 3002.01. 29. Chowdhury M. Health workforce for TB control by DOTS: The BRAC case. Joint Learning Initiative on Human Resources for Health, 2003. http:// www.globalhealthtrust.org/doc/abstracts/WG5/ChowdhuryFINAL.pdf.

43 The Practical Approach to Lung Health Strategy for Integrated Respiratory Care

SALAH-EDDINE OTTMANI

JAOUAD MAHJOUR

Stop TB Department, World Health Organization, Geneva, Switzerland

Directorate of Epidemiology and Disease Control, Ministry of Health, Rabat, Morocco

I. Introduction To improve the detection of tuberculosis (TB) cases and the quality of TB diagnosis as well as the quality of care of respiratory patients in general, the World Health Organization (WHO) has developed a strategy called the Practical Approach to Lung Health (PAL). This strategy focuses on addressing the quality of the management of patients with respiratory conditions, among whom TB cases should be identified. It also defines how the process of this management should be adapted to the health resources and infrastructure. This is why PAL aims at improving: (i) the quality of respiratory care in primary health-care (PHC) settings and (ii) the efficiency of respiratory service delivery within health systems, with a focus on the district health system. PAL is a component of the global strategy to control TB (1). This chapter describes the rationale behind the development of the PAL strategy, highlights its objectives, explains its components and why it should be adapted to the specific country health environment, specifies the successive steps needed to develop and implement PAL, reports the first country experiences in PAL development and implementation, and 1059

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outlines its potential impacts on TB control, respiratory care, and general health services. II. Burden of Respiratory Illnesses in Populations Respiratory illnesses, both acute and chronic, are among the most common diseases worldwide. They occur in all populations irrespective of their level of affluence, and are common in all age and social groups. In 2002, more than 11 million deaths were attributed to respiratory conditions, accounting for 20% of total deaths worldwide and 15.7% of disability-adjusted life years (2). Acute respiratory infections (ARIs), TB, asthma, chronic obstructive pulmonary diseases (COPD), and cancer of the respiratory tract are the leading causes of respiratory morbidity and mortality. ARIs are very common in populations and include various respiratory conditions ranging from simple common cold to severe, potentially fatal pneumonia. Lower respiratory tract infections ranked third among the leading causes of death in 1990; it is expected they will still be ranked fourth by 2020 (3). ARIs account for 25% of mortality from communicable diseases in developing countries and 66% in developed countries (4). Most of the deaths attributed to ARIs are due to pneumonia mainly in children under the age of five years in developing countries, and in children and the elderly in developed countries. It is estimated that 8.8 million new patients developed TB (140 per 100,000 population) worldwide in 2004; among them 3.9 million were smear positive (62 per 100,000 population) and 1.7 million died from TB (5). The data of the global TB surveillance system of WHO suggests that the incidence, prevalence, and death rates of TB have fallen since 1990 in five WHO regions but risen in Africa, and more particularly in African countries with a high human immunodeficiency virus (HIV) burden (5). Approximately 9% of TB cases in the 15- to 49-year age group are associated with HIV infection (6). Asthma has increased over recent decades in both children and adults of both sexes; its prevalence significantly varies between world regions. Asthma seems to be more frequent in industrialized countries than in non-industrialized countries and more frequent in urban than in rural areas (7–10). COPD is a major cause of morbidity and mortality at the global level. Its frequency has increased over time and is, in general, higher in men than in women (11). In terms of lost disability-adjusted life years, COPD ranked 12th in 1990 and will rank 5th by 2020 (12). COPD is a public health problem in developed countries and also in many developing countries. Tobacco smoking, chiefly cigarette smoking, is a major risk factor for COPD. Cancer of the respiratory tract is the leading cancer in adult males. Its frequency has increased with tobacco smoking throughout the world, particularly in developing countries. It was ranked 10th among the leading causes of death in 1990; it is expected to be ranked 5th in 2020 (3).

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III. Demand of Care for and Management of TB and Other Respiratory Illnesses in PHC Settings The usual process of TB diagnosis in PHC settings relies on: (i) the identification of TB suspects, through the utilization of a standard definition, among patients who visit health-care facilities for respiratory symptoms, and then (ii) the identification of TB cases among TB suspects through sputum-smear examinations and other diagnostic tools, as needed. Once the diagnosis of TB is established, the patient is managed in a well-defined and standardized manner in line with DOTS: registration, treatment, monitoring, and follow-up of TB cases (13). Except for ARI in children younger than five years of age, in most developing countries, there is no clearly defined approach to manage the respiratory patients who are not identified as TB cases. At PHC level, the quality of diagnosis of respiratory diseases is often poor, the treatment prescriptions are often inappropriate and unnecessarily costly, there are no clearly defined criteria for referral of respiratory cases, and there is no established mechanism to monitor and follow patients with chronic respiratory conditions within the district health system. Respiratory conditions account for a significant part of the demand for care in PHC facilities. Indeed, data from countries show that among patients aged five years and over, who visit PHC facilities for any reason, up to one-third seek care for respiratory symptoms. This proportion is usually higher in males than in females and decreases with age (Fig. 1). Surveys carried out by WHO in 54 PHC facilities with medical officers and 22 with nurses only, in nine developing countries located in three different continents (14), showed that acute upper respiratory infections and acute lower respiratory infections together accounted for more than 80% of all respiratory conditions in many countries (Table 1). The proportion of pulmonary TB cases was low among respiratory patients in all study countries and in both health-care levels; the overall proportion of TB cases was 1.5%. Also, these surveys showed that medication was prescribed for the majority of respiratory patients and antibiotics were prescribed for more than 50% of them; for instance, more than 75% of respiratory patients were prescribed antibiotics in Guinea and Morocco (14). It is clear that respiratory conditions are very common and TB accounts for a very small proportion among them in most countries. Furthermore, clinical symptoms presented by pulmonary TB patients are in general similar to the symptoms developed by many nontuberculous respiratory patients, particularly those with persistent symptoms. Also, health workers in PHC settings manage patients, including those with respiratory symptoms, on the basis of symptoms without any clear indications and directives in the majority of countries. This results in a nonstandardized, anarchic, and costly management. The development and implementation of a comprehensive, standardized, and integrated symptom-based strategy to manage patients with

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Five provinces, Morocco, February 2000

Percent

80 70 60 50 40 30 20 10 0 0–4yrs

5–14yrs

15–49yrs

Age

Males

Females

50+yrs

Overall

Lima, Peru, 2000 and 2001 60

Percent

50 40 30 20 10 0

5–9yrs

10–14yrs

15–19yrs 20–49yrs Age Year 2000

50–64yrs

>=65yrs

Year 2001va

Jordan, 2001 60

Percent

50 40 30 20 10 0

0–1yr

1–4yrs

5–14yrs Age

Females

15–44yrs

Males

>44yrs

Both

Percent

Bishkek, Kyrgyzstan, November 2003 90 80 70 60 50 40 30 20 10 0

0–4yrs

5–14yrs Females

Age

15–49yrs Males

50+yrs

Overall

Figure 1 Respiratory cases among patients attending primary health-care settings in Jordan, Kyrgyzstan, Morocco, and Peru.

2.8 77.4 5.0 6.9 4.6 0.8 2.4 100.0

1274 1756 1186 214 620 25,585

%

722 19,813

Number

0.0–18.3 1.5–18.1 0.8–22.8 0.0–4.6 0.0–21.1

0.4–8.9 41.7–89.0

Range

b

4.3 3.6 2.3 1.6

89 61

88.1

165 137

3362

%

0.3–9.9 0.0–10.7

0.0–17.2 0.0–12.5

49.6–96.2

Range

PHC facilities with nurses (5 countries)b Number

Argentina, Chile, Coˆte d’Ivoire, Guinea, Kyrgyzstan, Morocco (2 surveys), Nepal, Peru, and Thailand. Coˆte d’Ivoire, Guinea, Kyrgyzstan, Nepal, and Thailand. Abbreviations: PHC, primary health care; COPD, chronic obstructive pulmonary disease. Source: From Ref. 14.

a

Acute respiratory infections Cases of pneumonia Cases of nonpneumonia Chronic respiratory diseases Tuberculosis suspects Asthma Chronic bronchitis/COPD Other chronic cases Other respiratory diseases Total

Respiratory disease

PHC facilities with doctors (9 countries)a

Table 1 Overall Distribution of Respiratory Disease Cases in Primary Health Facilities with Medical Officers and in Those with Nurses

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respiratory conditions in PHC settings is likely to improve the quality of respiratory care and, subsequently, create conditions resulting in increasing TB case detection. These principles are the key elements in the development of PAL. IV. Objectives of the PAL Strategy PAL is a PHC strategy, based on a syndromic approach, for the integrated management of respiratory conditions, in patients aged five years and over. It has a major emphasis on TB, ARIs, and chronic respiratory diseases (CRDs), with a focus on asthma and COPD in developing countries. The PAL strategy has four groups of objectives. A. Managerial Objectives

These objectives focus on increasing the efficiency of the operations to plan and implement PAL activities through: (i) setting criteria for the request of laboratory tests, thorax radiography, and other complementary tests, (ii) standardizing the drug treatment of respiratory diseases, (iii) promoting the essential drug list of countries, (iv) establishing clear criteria for referral and counter-referral to facilitate the management and/or follow-up of respiratory patients within district health systems, (v) defining the role of each health worker category in respiratory care management according to the health-care level, (vi) identifying the essential equipment needed for diagnosis and treatment of respiratory conditions, (vii) defining planning parameters and contributing to rationalizing the management of the available health resources, and (viii) monitoring and evaluating the impact and performance of the health service delivery through the utilization of the existing health management information system (HMIS) and TB control information system. B. Clinical Objectives

The improvement of the quality of respiratory care is a major target in PAL. Indeed, PAL strategy aims at: (i) improving the diagnosis of TB in patients with sputum smear–negative microscopy, particularly in those who are HIV positive, (ii) enhancing the quality of care for TB patients, (iii) ensuring a high rate of TB treatment success, (iv) standardizing the management of ARIs, in particular pneumonia, (v) contributing to identifying HIV suspect patients, (vi) improving the management of respiratory infections in HIVpositive patients, (vii) upgrading the quality of treatment of asthma attacks and COPD exacerbations, and (viii) organizing and monitoring, within district health system, the long-term management of patients with CRDs. C. Economic Objectives

These are intended to decrease the cost of management procedures and to promote cost-effective health-care interventions for respiratory conditions by: (i) reducing the managerial cost per respiratory patient while improving her/his quality of life, (ii) reducing the absenteeism associated with asthma

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and COPD, (iii) reducing the attendance at emergency room and intensive care unit by patients with CRD, and (iv) increasing the number of respiratory patients managed in PHC settings while reducing hospital morbidity associated with respiratory illnesses. D. Epidemiological Objectives

These are intended to reduce the morbidity and mortality burden of respiratory diseases through: (i) the reduction of TB morbidity, mortality, and risk of transmission of TB infection, (ii) the decrease of case fatality from pneumonia, particularly in high HIV burden settings, (iii) the prevention of complications from bacterial respiratory infections, and (iv) the increase of time interval between exacerbations of CRDs, particularly asthma and COPD. V. Components of the PAL Strategy Focusing on the improvement of the quality of respiratory case management and of the efficiency of health-care services for respiratory illnesses, PAL includes two major components: standardization and coordination. A. Standardization of Clinical Care

Clinical practice guidelines are an appropriate vehicle to achieve standardization and integration of case management of priority respiratory illnesses at each level of district health system. The clinical guideline for first-level health facilities should be symptom-based while that for referral levels should deal with the respiratory conditions encountered at or referred to this level. The two guidelines should have well-established connections. Two models for case management guidelines at first-level health facilities are available. A semialgorithmic model has been developed by WHO and adapted in Nepal, Peru, Tunisia, and South Africa. A nonalgorithmic model was constructed in Algeria, Bolivia, Guinea, Jordan, Kyrgyzstan, Morocco, and Syria. Both models are based on the same guiding principles of using a minimum number of key signs that lead to diagnostic classification, determination of and degree of severity, and decision making. Experience has shown that PAL guidelines should be consistent with: (i) the rules on drug prescription, particularly antibiotic prescribing (15), (ii) the international recommendations on the management of lower ARIs and pneumonia (16–18), (iii) TB management as formulated in DOTS, and (iv) the management of asthma and COPD as, respectively, defined by the Global Initiative for Asthma (19) and the Global Initiative for Chronic Obstructive Lung Disease (11). In country settings, PAL guidelines should also be developed in line with the existing national guidelines such as the National TB Program (NTP) guideline, HIV/AIDS guideline, the integrated management of adolescent and adult illness (IMAI) guidelines, or other clinical guidelines. Only drugs that feature on WHO’s Essential Drug List (20) are recommended in

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the PAL guidelines. Special care should be taken to include the cheapest option when several equally effective alternatives exist. Respiratory cases referred from first-level health facilities to upper health-care level also need to be managed in a standardized way through the development of clinical guidelines. Guidelines for referral level have been developed in Bolivia, Guinea, Morocco, Peru, and Syria. These guidelines are formatted according to how services are institutionally provided: emergency and outpatient care, inpatient care, discharge, follow-up, counter-referral, and special care. To strengthen long-term treatment adherence and promote safe behavior, the PAL guidelines include a component dealing with health education for patients. This should focus on: (i) ensuring that TB patients cooperate with directly supervised treatment and contacts are screened for TB, (ii) ensuring that asthma and COPD patients adhere well to self-medication and learn how to perform inhalation procedures correctly and when to seek care, (iii) helping asthma patients to avoid asthma attack–triggering factors, (iv) advising all respiratory patients who smoke to stop smoking, and (v) promoting prevention of tobacco use among respiratory patients who attend district health services. B. Coordination

Coordination in the PAL strategy refers to the identification and involvement of the key components of the health system in the organization and the efficiency of health-care service delivery for respiratory illnesses. Country experience showed that these components are many and may vary among countries. In a well-established PHC system, coordination within the health sector implies organized collaboration among health workers at the same and different levels of the health system, as well as within and among the various categories of health workers. To be successful, coordination also needs to clearly define the involvement, in respiratory case management, of each health-care provider category and of each health-care level. This results in coordination between first-level health facilities and referral facilities contributing, subsequently, to full integration of respiratory case management within the health system, particularly at the district level. The development and implementation of the PAL strategy also requires coordination with: (i) national health resource planning, (ii) NTP, HIV/AIDS program, IMAI projects, PHC services, and the management of general health services for training, supervision, logistics, and communication, (iii) HMIS for monitoring and evaluation of PAL activities, and (iv) the essential drugs program to make drugs available and affordable for respiratory patients. VI. Adaptation of the PAL Strategy PAL strategy should be adapted not only to the specific epidemiological and socioeconomic circumstances of countries but also to their prevailing

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health policies and national health priorities. The resources available at first-level health facilities as well as at referral levels widely differ among countries. These differences are related to various factors such as: (i) the number of health-care levels, (ii) the educational and training level of health staff, (iii) the accessibility to laboratory facilities, (iv) the availability of equipment, whether basic (e.g., functioning weighing scales and thermometers), diagnostic (e.g., stethoscope, sphygmomanometer, peak flow meter, spirometer, and X-ray), or therapeutic (nebulizers, sources of oxygen), (v) the availability of a national essential drug list, (vi) the existence of a scheme of health-care cost coverage, (vii) the accessibility to and affordability of certain drugs such as medications for use by inhalation, (viii) the accessibility to hospitalization, or (ix) the coverage of the health system by HMIS and TB control information system. For instance, comparison of Tables 2A and 2B highlights the differences between Bolivia and Jordan regarding the health resources available in their health-care facility categories. Furthermore, national health priorities are likely to differ among countries in function of the epidemiological transition level and the burden of HIV infection in population (Table 3). In pretransition countries and in high HIV prevalence settings, the control of TB and ARIs are likely to have preference over the need to improve case management for CRDs, while in transitional or posttransition settings, CRDs are likely to be considered as important health priorities. VII. Steps to Introduce the PAL Strategy in Countries Experiences in promoting and supporting PAL projects under various epidemiological, economic, and sociocultural circumstances in recent years have shown that the introduction of the PAL strategy in countries should follow a stepwise process in order to ensure the sustainability and efficiency of the activities. Approximately 10 steps are needed to adapt, develop, and implement PAL strategy in countries (22). A. Promotion of the PAL Health Strategy Within Country

To stimulate the political commitment of the national health authorities for PAL and encourage the involvement of the potential stakeholders in the future PAL activities, one document or more on PAL should be prepared and distributed; the organization of advocacy meetings will also help promote PAL strategy in-country. This/these document(s) should include the main background data that help to understand the foundations of PAL strategy, its objectives, components, and perspectives; the WHO recommendations on PAL (4,14,22–24) and the ongoing PAL experiences in countries should be highlighted as well. They can be also used as working documents for advocating PAL strategy in national seminars, workshops, or conferences. The meetings are important forums for groups of interested professionals and key stakeholders to reach

Nurse GP

þ


þþþ þþþ

þ

þ

þ

þ

Spirometry Nebulizer

þ þ

þ

Peak flow


þ

þþ

þ

Chest X-ray

Consulation register

þ

TB lab

Hospital accessibility

þþþ

Chest specialist

Equipment

Abbreviations: GP, general practitioner; O2, oxygen; CS, corticosteroids; IB, ipratropium bromide.

Peripheral health post Primary health-care center Comprehensive health center Chest disease center

Peripheral þþþ
health post þþ þþþ Primary health-care center Comprehensive þþ þþ health center Chest disease þ
center

Health facilities

Health worker

Table 2A Health Resources in Health-Care Facilities in Jordan, December 2002

þ

þ

þ




O2

þ

þ

þ

þþþ








TB information system

þ

þ

þ

Inhaled b2 Inhaled agonist CS

þ

þ




IB

Access to inhaled medications

1068 Ottmani and Mahjour

þ




þþþ þþ þþþ

Nurse GP

þþþ

Chest specialist

þ

þ


þ

O2

þ þ þ




Spirometry Nebulizer


þ þþþ

þ

Peak flow

Consulation register

þþ

Chest X-ray

Hospital accessibility

þ

þþþ

TB lab

Equipment




IB

þ þ þ

TB information system




Inhaled b2 Inhaled agonist CS

Access to inhaled medications

Abbreviations: OPD, outpatient department; GP, general practitioner; O2, oxygen; CS, corticosteroids; IB, ipratropium bromide.

Health post Primary health-care center Municipality hospital OPD

Health post Primary healthcare center Municipality hospital OPD

Health facilities

Health worker

Table 2B Health Resources in Health-Care Facilities in Bolivia, July 2003

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Table 3 Distribution, in Percentage of Disability Adjusted Life Years (DALYs), of Respiratory Disease Burden in the Population over 15 Years of Age by Epidemiological Profile and Socioeconomic Status of Countries in 2000 Respiratory conditions

High HIV prevalence countries (%)

Low-income countries (%)

Middle-income countries (%)

High-income countries (%)

70.8

59.4

32.4

12.8

16.0

30.6

58.0

73.5

13.2

10.0

9.6

13.7

100.0

100.0

100.0

100.0

Acute respiratory diseases Chronic respiratory diseases Other respiratory diseases Overall Source: From Ref. 21.

a common understanding of concepts including PAL, as well as of its advantages and implications for strengthening TB control programs and PHC services. Participants to these meetings may make recommendations to the ministry of health and/or other health institutions of the country to initiate the process of PAL adaptation and development. B. Political Commitment

As a second step, the ministry of health should prepare and issue an official statement announcing that PAL adaptation and development should be explored in pilot sites, and its perspectives of implementation and impact should be assessed. A focal point within the ministry of health should be designated to coordinate the introduction of PAL. At this stage, the national health authorities may request WHO for technical collaboration or assistance to initiate the process of PAL adaptation and development in country. The National health authorities should circulate its official statement among all the relevant programs and department within the ministry of health, together with a memorandum requesting their collaboration and support in the initiation phase of PAL strategy. To fulfil the political commitment, a National Working Group (NWG) on PAL should be officially established. C. National Working Group on PAL

The establishment of a NWG on PAL is crucial in the initial phase of PAL introduction and provides essential leadership for the subsequent steps. The role of the NWG is not only to guide and support the initial PAL activities, but also to ensure the involvement of all the relevant stakeholders in adapting, developing, planning, implementing, and funding PAL strategy.

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The NWG should include members who represent various entities such as NTP, PHC services, HIV/AIDS program, IMAI projects, essential drug program, drug procurement policy department, HMIS department, health-care service planning, the department in charge of the health sector reform, chest specialists from university departments, physicians and nurses practicing in PHC settings and at referral levels, health insurance funds, nongovernmental organizations in community-based interventions, cooperation agencies, and others. The terms of reference of the NWG are to: (i) adapt and develop the national PAL guidelines, (ii) develop the training material specifically adapted to implement the national PAL guidelines, (iii) test the guidelines as well as the training material in pilot sites, (iv) evaluate the potential impact of PAL implementation from the pilot site experience, (v) develop a national plan for PAL implementation, and (vi) submit the plan of PAL implementation to the national health authorities. D. Assessment of Health Environment for PAL Adaptation and Development

This assessment is usually carried out by an external consultant along with the PAL focal point and the NWG members. However, it can be undertaken by a core group from the NWG. The assessment findings are crucial to identify the respiratory conditions to be considered in the national development of PAL strategy, adapt the guidelines to the existing health infrastructure and resources, and identify the health-care levels where PAL guidelines will be implemented. Moreover, the assessment should aim at identifying any existing funding or institutional mechanism that can facilitate PAL implementation in the future, as well as any further resource that can support the NWG work and the adaptation and development of PAL. This assessment should be based on various elements such as: (i) the public health sector policies in relation to program and budget priorities, integration of programs, management of health-care services, planning and financial procedures, essential package of health services, and contribution of external financial aid to the health sector, (ii) the process of decentralization and health sector reform, (iii) the managerial organization of the ministry of health at central, regional, and district levels, (iv) the managerial activities to implement interventions such as training and supervision, (v) the level of demographic and epidemiologic transitions, as well as the burden of respiratory illnesses within the national health system, (vi) the situations of TB and TB control as well as the level of HIV burden in the general population and risk groups, (vii) populations covered by health-care services, particularly PHC, and by a health insurance system, (viii) resources available within the health system to manage respiratory conditions, (ix) the organizations of the referral system and of HMIS, (x) the organization of respiratory disease management such as the existence of management guidelines for TB, pneumonia, asthma, COPD, or any respiratory condition, or the existence of organized referral system for CRDs, and (xi) others.

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The findings of this assessment should be discussed with and among the NWG members; this will help establish a work agenda for the NWG for the future steps in PAL adaptation and development. E. PAL Guideline Adaptation and Development

PAL guidelines should be adapted and developed by the NWG. The contribution and assistance of an external consultant may be solicited by the country for this step. The existing country guidelines and/or WHO guideline can help in developing PAL guidelines for the specific country (25,26). Other documents can be used, such as the international consultation reports on PAL (4,27) and the international recommendations on the managements of lower ARIs/pneumonia, asthma, COPD, and TB (11,13,16–19), as well as on smoking cessation (28). The guideline for first-level health facilities should be symptom based with a clear connection with the guideline for referral level. The simplification and the standardization of case management for respiratory conditions include disease classification and treatment decision making. The guidelines should: (i) refer to the respiratory illnesses considered as health priorities in the country, (ii) clearly specify the equipment and the essential drugs needed to manage the respiratory conditions targeted, as well as the role of each health worker category in this management, (iii) clarify the process for referral, specifying which respiratory conditions should be referred from first-level health facilities to upper health-care level facilities and conversely which respiratory illnesses need to be counter-referred from the referral level to the first-level health facilities for management, monitoring, and follow-up, and (iv) include the standardized information system needed for collecting data on routine basis; this information system should rely as much as possible on the existing HMIS and involve the recording and reporting system of the NTP. F. Training Material Development for PAL

The development of the training material is one of the key tasks of the NWG. It should be developed after the finalization of PAL guidelines. The training material should target the implementation and the appropriate utilization of PAL guidelines by health-care workers in their daily tasks. The training material includes: (i) the PAL guidelines, (ii) a simplified document explaining the basic concepts and rationale of the PAL strategy, (iii) case studies that cover all the content of the guidelines, including the information system, (iv) a document explaining the usefulness of the information system for PAL activities, and (v) documents on how to use, clean, and maintain equipment such as peak flow meter, inhalation chamber, nebulizer, spirometry, and oxygen supply. G. Feasibility Test

The feasibility test is undertaken after the preparation of the guidelines and the training material. The objectives of the test are to assess the impact, in the short term, of the implementation of PAL guidelines on the knowledge of

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the health-care workers and on health care delivery to patients with respiratory symptoms in PHC settings. The test is carried out in three phases in selected pilot sites, preferably during the cold season. It should involve 80 to 100 health care workers practicing in PHC facilities that are easy to supervise. In the first phase of the test, the management of respiratory patients by the PHC workers is assessed according to a standard study protocol, described elsewhere (22). This assessment is carried out for five consecutive days before any training on PAL and provides baseline data. The second phase starts three weeks after the first phase and consists of the training on the PAL guideline of the same PHC workers involved in the baseline assessment. The training usually lasts three to four days and relies on: (i) the utilization of the training material developed, (ii) practical sessions on the utilization of peak flow meter, nebulizer, and other equipment, if specified in the guideline, and (iii) practical sessions in PHC facilities with real respiratory patients. Then, the trained PHC workers use the PAL guideline for the following week in their daily work. The third phase immediately follows the week of utilization of the PAL guideline by the PHC workers. In this phase, the management of respiratory patients by the trained PHC workers is reassessed for five consecutive days in the same conditions as the baseline study. This second study evaluates the impact of the training on PAL. The baseline and impact studies should involve the same PHC workers, the same study supervisors, and the same PHC facilities; also, they should be undertaken within an interval of six to seven weeks and carried out within the same season. The findings of the baseline and impact studies are compared and analyzed to show whether the health care services for respiratory patients in PHC settings are more rationalized by the use of the PAL strategy. H. Development of PAL Implementation Plan

The plan of PAL implementation can be developed for specific regions, in a first phase, or for the whole country. It should be multiyear and stepwise. Also, it needs to be elaborated in close coordination with the NTP and the national PHC department and discussed with the other relevant stakeholders. The plan should formulate the equipment needed for each healthcare level in line with the directives included in the national guidelines on PAL. In Kyrgyzstan, peak flow meters and nebulizers were planned for the first-level health facilities and, in addition, spirometers and oxygen concentrators for the referral level. In Morocco, the PAL implementation plan has scheduled peak flow meters and inhalation chambers for the first-level health centers and, in addition, spirometers for the TB and chest clinics. The plan should also establish a training agenda for first health-care level and referral level, including emergency room, while taking into account the number of health professionals to be trained for each health-care level.

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However, the plan focuses specifically on first-level health facilities. For instance, in Chile, where not all PHC workers are trained, a team including a physician, a nurse, and a physiotherapist is trained in each PHC center where PAL is implemented. The plan should clearly identify the entity that will be responsible for the training. In Kyrgyzstan, the Kyrgyz State Medical Institute of PostGraduate and Continuation Education was designated to carry out the national training agenda on PAL. In Chile and Morocco, a core of national trainers from NTPs, PHC services, and medical schools was constituted; this core group is in charge of the implementation of the training program on PAL through a network of trainers at the regional level. Finally, the plan should estimate the cost of implementation by year and health-care level. The potential sources of funding from government, regional administration, health sector reform funds, or donors should be proposed in the plan. I. Mobilization of Funds for PAL Health Implementation

After the NWG has developed the national PAL guidelines and the training material, shown the potential impact of PAL through the feasibility test, and formulated the plan of implementation, the national health authorities should explore the potential sources of funding to carry out the implementation plan. The Government may provide funds for all the components of the plan or financially support specific parts of the plan. In some circumstances, funds can be mobilized through the process of the health sector reform. In Chile, the ongoing plan of PAL implementation is fully financed by the Chilean government in the orient work of the health sector reform. In Kyrgyzstan, training is financially supported through the ongoing health sector reform but the equipment is funded by the Ministry of Foreign Affairs of Finland. In Morocco, WHO mobilized funds to support the training, but the equipment procurement was financed by the Ministry of Health. Sources of funding should also be explored through bilateral and multilateral cooperation with donors involved in the development of health care services within countries. J. PAL Health Implementation

PAL implementation should be under the leadership of a clearly identified coordination unit within the ministry of health. This unit can be under the responsibility of the NTP or PHC department; in both cases, PAL activities should be implemented in close collaboration with the TB control and PHC services. In Chile, PAL implementation is under the responsibility of the PHC Department, whereas in Morocco it is under the responsibility of the NTP. Once funds are available, the PAL unit should proceed to their budgeting to procure equipment and organize the training sessions.

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When PAL activities are carried out within district health system, the PAL coordination unit should, in collaboration with NTP, PHC services, and HMIS, implement the monitoring and supervision system and collect information on a routine basis to evaluate the quality and the performance of these activities. VIII. Preliminary Results from Country Experiences Countries involved in implementing PAL activities include Chile, Morocco, Kyrgyzstan, and South Africa, whereas others including Algeria, Bolivia, El Salvador, Estonia, Guinea, Jordan, Lithuania, Nepal, Peru, Republic of Korea, Syria, Tunisia, and Uganda are developing PAL projects. The available data are still preliminary. In many countries, the process of data collection for the feasibility test is still ongoing, and the analysis of the data set constituted in the two-operation research country sites (Nepal and South Africa) are being finalized. The routine information system for PAL activities established in countries where PAL implementation is ongoing has provided, so far, very few data and these will need appropriate analysis. However, preliminary results suggest that the PAL strategy has an impact on respiratory case management. Some aspects of this impact are reproducible across country settings. A. Integration of Respiratory Case Management in PHC Setting

The feasibility test carried out in pilot sites in Bishkek, Kyrgyzstan, showed that the proportion of respiratory patients referred from first-level health facilities to referral level either for hospitalization or for further clinical investigation decreased by one-third after training of PHC workers on PAL. Similar results have been recently reported from the feasibility test carried out in three cities in Jordan. This finding suggests that PAL strategy is likely to facilitate the integration of respiratory case management within PHC services. B. TB Control

Results showing an impact on TB detection are not yet widely available. A randomly controlled trial carried out in the Free State Province, South Africa, showed that the probability of detecting TB among patients with respiratory symptoms increased by 72% in PHC centers with nurses trained on PAL in comparison to PHC centers with nurses who had not received this training (29). The feasibility tests carried out so far in few countries have failed to yield such results on TB detection. This approach of feasibility test is probably not the appropriate method to show such impact given that the study populations involved are often too small to detect small proportions of TB cases among respiratory patients. However, data from the feasibility test carried out in Tunis, Tunisia, suggests that PAL improves the quality of the process of establishing the diagnosis of TB among respiratory patients in PHC setting.

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PAL implementation is well advanced only in Chile and Morocco. PAL impact on TB detection is not visible in these two countries because both of them had a high TB case detection rate ( > 80%) before PAL implementation. However, this impact is likely to be significant in countries with a low TB detection rate. In countries with high detection rate, PAL may improve the quality of TB diagnosis. Indeed, in Morocco, the information system on TB control showed, in the provinces where PAL was implemented, an increase in the bacteriological confirmation of pulmonary TB: from 83% in 2001 before PAL to 85.1% in 2003 after PAL implementation. C. Drug Prescription and Cost of Drugs Prescribed

The feasibility tests carried out in Kyrgyzstan and Morocco (Table 4) showed that the number of drugs prescribed per respiratory patient and the proportion of respiratory patients who were prescribed antibiotics significantly decreased with PAL. Moreover, the average cost of drugs prescribed per patient was reduced by 18% and 32% in Morocco and Kyrgyzstan, respectively, after training of PHC workers on PAL. The data collected in the feasibility tests carried out in Jordan and Tunisia show results similar to those of Morocco and Kyrgyzstan. Data from the Kyrgyzstan feasibility test show a significant decrease in prescription of any bronchodilator and any corticosteroid after training on PAL; but, among patients who received bronchodilator or corticosteroid prescription, the proportion of those who were prescribed inhalers was significantly higher after training on PAL. The feasibility test data of Jordan and Tunisia have yielded similar outcomes. Data from Morocco highlight this outcome by showing a higher prescription of b2-antagonists for inhalation use with PAL guideline. The randomly controlled trial carried out in the Free State Province, South Africa, showed a significant increase in the prescription of corticosteroids for inhalation use in PHC centers with nurses trained on PAL (29). Routine data collected in Chile suggest an increase in inhaled corticosteroid prescription in asthma patients after PAL implementation (30). The feasibility tests carried out in Kyrgyzstan, Morocco, and Tunisia also highlight a significant reduction in the prescription of antitussives, expectorants, and vitamins after training on PAL. D. Quality of Life

Beside the cost reduction on drug prescription, PAL is expected to improve patients’ symptoms and quality of life. A sample selected from the data collected on routine basis in the PAL sites in Chile shows that after one year of follow-up of 250 asthma patients, the number of hospitalizations and emergency room visits, as well as sleep disturbance and daily life limitations in these patients, has significantly decreased after PAL implementation (30). E. Monitoring and Information System

In Chile and Morocco, monitoring system for CRD patients was established. These patients are followed within the district health system either

3352 90.9 1.7 53.7 Dirhams 59.0

93.8 2.0 71.7 Dirhams 72.0

With PAL

1520

Before PAL

95.2 2.6 57.5 Coms 148.6

–15.0a –25.1a –18.1a

893

Before PAL

–3.1a

Variation (%)

Note: Dirhams and Coms are the national currencies of Morocco and Kyrgyzstan, respectively. a p < 0.001. b p < 0.01. Abbreviation: PAL, practical approach to lung health. Source: From Ref. 23.

Sample size: number of respiratory patients Any drug prescription: % of patients Number of drugs per prescription Antibiotics prescribed: % of patients Average cost of drug prescription per respiratory patient

Indicators

Morocco, 2002

Coms 100.6

44.1

2.3

97.7

992

With PAL

Kyrgyzstan, 2003

Table 4 Impact of the Practical Approach to Lung Health on Drug Prescription in Morocco and Kyrgyzstan

–32.4a

–23.3a

–11.3a

þ2.6b

Variation (%)

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as asthma, COPD, or other CRD cases, but they are also assumed to be controlled for their TB status through a regular screening. Moreover, this system of monitoring and follow-up of CRD patients is likely to encourage the other CRD patients who are not under any monitoring process to use PAL services within the district health system. The PAL information system can provide, on routine basis, quantitative and qualitative information on respiratory disease demand in the PHC network, which is presently not available in most country settings. For instance, six months after the implementation of PAL in Casablanca, Morocco, approximately 48,000 patients visited PHC centers for respiratory symptoms; among them, 11% were identified and followed as CRDs. IX. Perspectives of the PAL Strategy PAL designed on the basis of TB control managerial principles represents a natural evolution toward the standardization of case management of respiratory diseases. PAL should be envisaged in areas where DOTS strategy has been implemented, PHC structures are available and there is a formal political commitment to adapt, develop, and implement this approach. Millions of patients suffer from respiratory diseases because of a poor access to appropriate diagnosis and treatment. Many episodes of respiratory conditions are treatable with effective and affordable medications. It is the purpose of PAL to reinforce TB control, improve the access to appropriate care for all respiratory patients in PHC setting, contribute to promoting respiratory health, and strengthen the management of the district health system. A. PAL Strategy and TB Control

PAL is likely to contribute to improving TB case detection and the quality of TB diagnosis, particularly in high HIV prevalence settings, as well as the quality of care of TB patients. Preliminary findings suggest that the PAL strategy reduces referral from first-level health facilities. Therefore, this strategy is likely to facilitate the integration of TB control activities within PHC services, particularly in countries where TB control programs are essentially vertical. Given the major focus of PAL on TB, its development and implementation should logically keep this disease high among health priorities in country settings with ongoing health sector reform, as well as secure and empower TB control in epidemiological transition settings, particularly when the TB burden tends to decrease. B. PAL Strategy and Respiratory Care Services

PAL provides an essential and integrated health care package to address the challenging burden of respiratory illnesses in PHC setting. This strategy is likely to increase the attendance of patients with respiratory disorders in PHC facilities while standardizing and optimizing the referral system for respiratory conditions. Country experience shows that PAL enables the health system to provide on routine basis information on respiratory

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illnesses, as well as establishes mechanisms of monitoring and follow-up for patients with CRDs. C. PAL Strategy and District Health System Management

PAL is likely to facilitate planning of health resources within the district health system, because standard case management should clearly define the training needs, equipment, drugs, and other supplies for the first-level health facilities and the referral level. PAL is also likely to help district health authorities to cope with the process of decentralization and health sector reform. Country experience suggests that HMIS can be improved through PAL implementation and used for managerial purposes. Data from countries clearly indicate that PAL is likely to improve drug prescription while decreasing drug costs. Country experience also suggests that PAL upgrades the skills of PHC workers. PAL is therefore likely to strengthen PHC services and increase their utilization by meeting the needs of patients with respiratory symptoms. This can contribute to reinforcing the confidence of the population in PHC services. Given the various components of PAL, this strategy should normally help strengthen the links between the technical and managerial tasks at the different levels of the district health system. Moreover, the PAL strategy can be the first building block for the integrated management of adolescent and adult illnesses at district level. X. Conclusion PAL is an integrated strategy to manage respiratory patients in PHC settings with a focus on priority respiratory diseases, particularly TB, ARIs, and CRDs (asthma and COPD). Its objectives are to improve the quality of respiratory case management and the efficiency of the health system for respiratory conditions. It relies on two pillars: (i) standardization of the management of respiratory conditions and (ii) coordination among the relevant components dealing with respiratory care management within the health system. PAL should be adapted to the health environment of country; to be successful, its adaptation, development, and implementation in country need to follow a well-defined stepwise process. However, further issues need to be addressed in order to fully promote PAL: (i) price reduction schemes to increase drug access for chronic respiratory illnesses should be set in motion for developing countries; indeed, medications for inhalation use, such as inhaled corticosteroid and ipratropium bromide, are still not available or financially accessible for the majority of asthma and COPD patients in many low- and middleincome countries, (ii) standards for reliable, affordable, low-technology, least consumable-dependent diagnostic equipment should be defined and developed, and (iii) support for the clinical interventions should be extended beyond the health facilities to the community level, through the development of public health interventions to promote respiratory health.

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PAL is still at the early stage of promotion and development at the global and regional level. Although the available data suggest that PAL improves drug prescription and the quality of care, chiefly in CRD patients, the impact of PAL on increasing TB detection needs to be better documented. By defining and standardizing the management of nontuberculous pulmonary illnesses, PAL can be expected to improve the quality of pulmonary TB diagnosis by reducing false TB cases, particularly false smearnegative TB cases. By implementing a monitoring and follow-up system for the CRD patients enrolled in the orient of PAL activities, PAL strategy is likely to increase TB case detection. The improvement of respiratory care for respiratory illnesses, in general, at PHC level and the systematic monitoring and follow-up of CRDs are likely to increase the attendance of PHC facilities by respiratory patients. This will, therefore, contribute to identifying more TB cases among patients with respiratory symptoms. The existing country experiences should be monitored, analyzed, and documented to create a momentum to promote PAL strategy at global, regional, and country levels. References 1. Ve´ron LJ, Blanc LJ, Suchi M, et al. DOTS expansion: will we reach the 2005 targets? Int J Tuberc Lung Dis 2004; 8(1):139–146. 2. The World Health Report, 2003. Shaping the Future. WHO: Geneva, 2003. 3. Murray CJL, Lopez AD. The Global Burden of Disease. A Comprehensive Assessment of Mortality and Disability from Diseases, Injuries and Risk Factors in 1990 and Projected to 2020. Vol. 1. Boston: Harvard University Press, 1996. 4. Scherpbier R, Hanson C, Raviglione M. Report: Adult Lung Health Initiative—Basis for the Development of Algorithms for Assessment, Classification and Treatment of Respiratory Illness in School-Age Children, Youths and Adults in Developing Countries—Recommendations of the Consultation, Geneva 4–15 May 1998. Geneva: WHO, 1998 (WHO/TB/98.257). 5. World Health Organization. WHO Report 2006: Global Tuberculosis Control— Surveillance, Planning, Financing. WHO: Geneva, 2006 (WHO/HTM/TB/2006.362). 6. 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. 7. Seaton A, Godden DJ, Brown K. Increase in asthma: a more toxic environment or a more susceptible population? Thorax 1994; 49(2):171–174. 8. The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee. Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjonctivitis, and atopic eczema: ISAAC. Lancet 1998; 351(9111):1225–1232. 9. Faniran AO, Peat JK, Woolcock AJ. Prevalence of atopy, asthma symptoms and diagnosis, and the management of asthma: comparison of an affluent and nonaffluent country. Thorax 1999; 54(7):606–610. 10. Becklake MR. International union against tuberculosis and lung disease (IUATLD): initiatives in non-tuberculous lung disease. Tuberc Lung Dis 1995; 76(6):493–504. 11. Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary

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17.

18.

19.

20. 21.

22. 23.

24. 25. 26. 27.

28. 29.

30.

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Disease-NHLBI/WHO Workshop Report. Bethesda, Maryland: National Institutes of Health, April 2001. Murray CL, Lopez AD. The Global Burden of Disease. Geneva: World Health Organization and World Bank, 1996. World Health Organization. Treatment of Tuberculosis—Guidelines for National Programmes. 3rd ed. Geneva: WHO, 2003 (WHO/CDS/TB 2003.313). Ottmani S, Scherpbier R, Chaulet P, et al. Respiratory Care in Primary Care Services—A Survey in 9 Countries. Geneva: WHO, 2004 (WHO/HTM/TB/2004.333). World Health Organization. Guide to Good Prescribing. Geneva: WHO, 1994 (WHO/DAP/94.11). Mandell LA, Marrie TJ, Grossman RF, et al. Canadian guidelines for the initial management of community-acquired pneumonia: an evidence-based update by the Canadian Infectious Diseases Society and the Canadian Thoracic Society. Clin Infect Dis 2000; 31(2):383–421. European Study on Community Acquired Pneumonia (ESOCAP) Committee Chairmen: Huchon G, Woodhead M. Guidelines for management of adult communityacquired lower respiratory tract infections. Eur Respir J 1998; 8(4):391–426. Bartlett JG, Breiman RF, Mandell LA, et al. Guidelines from the Infectious Diseases Society of America. Community-acquired pneumonia in adults: guidelines for management. Clin Infect Dis 1998; 26(4):811–838. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention—NHLBI/WHO Workshop Report. Bethesda, Maryland: National Institutes of Health, 1996. http://www.who.int/medicines/organization/par/edl/expertcomm13.shtml (accessed November 2004). http://www3.who.int/whosis/menu.cfm?path¼evidence,burden,burden_estimates, burden_estimates_2000,burden_estimates_2000_V3,burden_estimates_200_V3_Subregion&language¼English. World Health Organization. Practical Approach to Lung Health Handbook. Geneva: WHO, 2005 (in stage of finalization). World Health Organization. Practical Approach to Lung Health: A Primary Health Care Strategy for Integrated Care Management of Respiratory Conditions. Geneva: WHO, 2005 (WHO/HTM/TB/2005.351; WHO/NMH/CHP/CPM/CRA/05.3). World Health Organization. PAL: Practical Approach to Lung Health. Information Brochure. Geneva: WHO, 2003. http://whqlibdoc.who.int/hq/2002/WHO_CDS_TB_2002.298a.pdf (accessed November 2004). World Health Organization. Practical Approach to Lung Health—Guidelines for First Level Facility Health Workers. Geneva: Stop TB, WHO, 2002. World Health Organization. Report of the First International Review Meeting— Practical Approach to Lung Health Strategy, Rabat, Morocco September 4–6, 2002. Geneva: WHO, 2003 (WHO/CDS/TB/2003.324). World Health Organization. Policy Recommendations for Smoking Cessation and Treatment of Tobacco Dependence—Tools for Public Health. Geneva: WHO, 2003. Fairall LR, Zwarenstein M, Bateman ED, et al. Effect of educational outreach to nurses on tuberculosis case detection and primary care of respiratory illness: pragmatic cluster randomised controlled trial. BMJ 2005; 331:750–754. Sepulveda R. Emergency and Continuing Care for Asthma in Latin America. Symposium: ‘‘Emergency and Continuing Care in Asthma.’’ 35th IUATLD World Conference on Lung Health, Paris, France, October 28–November 1, 2004. Paris: International Union Against Tuberculosis and Lung Disease, 2004.

44 The Responsibilities of Medical and Nursing Schools in Tuberculosis Care and Control in Countries with Medium and High Tuberculosis Incidence

PIERRE CHAULET and NOUREDDINE ZIDOUNI Faculty of Medicine, University of Algiers, Algiers, Algeria

I. Introduction Although the World Health Organization (WHO) tuberculosis (TB) control strategy has been widely accepted for the past 10 years, it is far from meeting the targets set internationally, in particular, those regarding the detection of contagious cases. The reasons for this shortfall include the lack of qualified personnel, deficient laboratory services, poorly decentralized activities, and the inability of National Tuberculosis Programs (NTPs) to bring on board all health-care providers at both the public and private levels (1). Nevertheless, since 1996, the global TB program recommended that ‘‘training materials, including the medical school curriculum and nursing school teaching materials, incorporate TB control and the DOTS strategy’’ (2). Since 1993, TB treatment has become significantly more successful, thanks to the widespread application of standard short-course chemotherapy and better information for health-care personnel already directly involved in TB control. TB case detection, however, has yet to be fully incorporated into primary health-care services and patient care has not been sufficiently decentralized.

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Now more than ever, medical and nursing schools have a pivotal role to play, particularly in countries with high TB prevalence where the human and financial resources dedicated to health are limited. As a matter of priority, an extra effort must be made in these countries to enhance the training of health-care personnel in TB control. II. The Social Responsibility of Training Institutes In all countries, these institutes aim to train health-care workers so that they may respond as best as possible to the health needs of the population by delivering appropriate health services and implementing priority public health programs, including the NTPs. The all-too-frequent lack of coordination among the health ministry and medical schools or public and private paramedical training centers bars the development of overall plans to develop human resources in the health sector as well as the comprehensive training of all health-care workers in TB control. Either there is no coordination for institutional or intersectoral reasons, or in cases where there is some measure of coordination, it tends to be rather haphazard and is more often the result of personal relations between the directors of national programs and faculty members than a political decision materialized by an institutional mechanism. As they are not held accountable or bound to provide any justification to the political decision-makers about the social and health-related impact of their activities, training centers undertake self-evaluation exercises based on the total numbers of qualified trainees. They give little or no thought to the relevance of the training they provide and are not subject to any external inspection by the health authorities, practicing health-care personnel or health-care service users (3). As a result, TB control training programs often do not correspond to the epidemiological and economic realities of the country and training institutes find that they are not included in enhancing TB control. III. Limitations of the Traditional Approach to the Teaching of TB The main deficit in TB training is the failure to link with the national program and its needs. Furthermore, the traditional teaching approach in the area of TB focuses more on theory than practical training in countries where TB is a major problem. Following are the most common constraints: 1.

2.

Large numbers of students attend the small number of theoretical courses, which are delivered in overcrowded lecture halls; there is a tendency to eliminate practical training courses or to consider them optional. The majority of teachers who lecture on TB as part of the curriculum are unfamiliar with recent data on TB control.

Responsibilities of Medical and Nursing Schools 3.

4.

5.

6.

7.

8.

9.

10.

1085

Acquisition of theoretical knowledge on TB (bacteriology, immunology, pathological anatomy, clinical aspects of pulmonary and extrapulmonary TB in adults and children, treatment, epidemiology, and public health) is piecemeal over years of study. Methods of diagnosing and treating TB can vary from teacher to teacher and may be contradictory. There are established global standards for TB diagnosis, and these should be taught systematically. Whereas the majority of TB patients are seen in outpatient settings such as dispensaries, the optional practical training course usually takes place in a specialized hospital unit, rarely in a dispensary. The objectives to which the training course and examinations are directed are often not determined in advance, and consequently there is no objective evaluation of the skills acquired during the course. The number of teaching hours dedicated to TB and TB control is not determined on the basis of teaching objectives. It depends more often on the influence of faculty members on academic boards than on the needs of the public. Teaching materials (textbooks, handbooks, photocopies, audiovisual aids, and CD-ROMs) are inadequate. Materials developed by university lecturers to meet the needs of countries in the North often tend to be ill adapted to the working conditions of healthcare professionals in countries in the South. Training institutes are incapable of guaranteeing that trained personnel are capable of participating in implementation of the NTP because of lack of evaluation of theoretical knowledge, attitudes and practical skills acquired in the area of TB control through continuous assessment and/or final examinations which are compulsory in order to obtain a qualification. Teaching of TB control is often considered by faculty as a domain reserved for clinical or public health TB specialists, and unrelated to teaching on the diagnosis and treatment of other respiratory diseases (severe respiratory infections and chronic respiratory diseases) that are much more common than TB.

IV. Introducing Innovative Teaching Techniques in TB Control In training institutes that have already been influenced by the teaching renaissance of the 1970s and 1980s, progress has been made with a view to better preparing future health-care workers to discharge their professional duties (4). Yet too often, particularly in countries with high TB prevalence,

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inflexible teaching structures and faculty habits bar the way to any change. Notwithstanding this situation, the publicly acknowledged magnitude of the TB problem paves the way for introducing novel teaching methods in the area of TB control and provides training institutes with the opportunity to demonstrate their usefulness to society. To implement innovative techniques of this kind, various measures have been proposed, namely: Committee of faculty and NTP staff: Establish within each training institute a teaching coordination committee for TB and TB control, comprising all relevant faculty members and a representative of the NTP. The role of this committee is to define, on the basis of the various functions and tasks of each professional category, the teaching objectives of the training course, develop theoretical and practical training modules and tools for evaluating the skills acquired (5). Block of TB teaching: Incorporate all TB care and control training activities into a specific period (or module) of between two and four weeks as part of the curriculum depending on the profiles of the professionals involved (5). Evaluation: Inform students from the outset of the objectives of the module: acquisition of knowledge, attitudes, and practical skills on which they will be evaluated. Methods: Limit to a minimum academic lectures and opt for selflearning as a learning tool (reading of handbooks, instructions, photocopies, diskettes, and CD-ROMs beforehand), reinforced by group discussions. Practical training: Organize students into small groups of 8 to 12 students under the guidance of a tutor (resident or assisting physician) to discuss clinical cases, therapeutic or community health problems based on concrete, actual or simulated cases or role playing. Planning: Identify the objectives of the practical training course, the places where the training course will take place (in hospital at the patient’s bedside, in dispensaries, or in laboratories) and provide guidance by a tutor (senior nurse, laboratory technician, doctor). Ensure at the end of each practical exercise that the objective has been reached. TB module: Develop a training program that gradually incorporates the acquisition of theoretical knowledge and practical activities during the part of the module dedicated exclusively to the study of TB. Combine, if possible, the training module on TB with the training module on respiratory diseases (severe respiratory infections, chronic respiratory diseases), thereby rendering clinical training and training in reading chest X-rays easier for future physicians. All health-care workers should be exposed to the combined approach of learning about TB and the most common respiratory diseases (6). HIV links: In countries with a high prevalence of HIV/AIDS infection, the TB module should be supplemented by training in TB/HIV co-infection (7). Evaluation: In the final evaluation of knowledge, attitudes and practical skills acquired by the student, the score for the period where the module

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focused on TB control, which should be based on individual assessment and should be a compulsory component for which a pass is required to obtain an overall pass in countries where TB is a major problem. Local adaptation: The measures proposed are based on general teaching principles applied to health-care personnel (8,9). They should be adapted to each national context on the basis of epidemiological data, available financial resources, and the organization of health services. There is no single module for training health-care staff in TB control. The training program cannot be the same for a country where primary health-care workers see several patients suspected of having TB and another where the healthcare staff may see one TB case per year. V. Basic Training for Health-Care Workers Three categories of health-care workers are of paramount importance in the process of integrating TB control activities into local health services, irrespective of the conditions in which they practice, namely physicians, nurses, and laboratory technicians. A. Training of General Practitioners

In medical schools, training in TB control should be incorporated in the curriculum designed for general practitioners (GPs). It should have a dedicated slot in the module of between 10 and 15 days and should combine practical know-how and the acquisition of theoretical knowledge. By dividing the class into small groups, rotation guarantees all students a place in lecture halls and the practical training course in equal learning conditions. Several teaching seminars organized by WHO have sought to identify the objectives of such training (10–14). There are documents to facilitate this type of training (15–17). The objectives of theoretical training are summarized in Table 1. The objectives of learning attitudes and practical skills throughout the practical training course or special training sessions are summarized in Table 2. Although these objectives usually translate for patients and faculty into the skills acquired by students, actual fulfillment of these objectives is too rarely evaluated. The adoption by the medical school teaching coordination board of both lists of objectives cited (to be completed or adapted where necessary) is a first step in the process of teaching innovation. The board should develop a training and activities program that would allow students to attain those objectives, and above all, evaluate all students on completion of the training module to ensure that they have attained the objectives. The latter is more difficult to implement (14). B. Training of TB District Coordinators

Medical schools, bearing in mind the needs expressed by the department within the Ministry of Health in charge of the NTP, can be given the

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Table 1 What Future General Practitioners Should Learn About TB and TB Control Compare the scale of the TB problem in their country with other countries Explain the modes of transmission of TB bacille within a community and the stages of progression from infection to disease Describe the biological characteristics of TB bacille, the methods of staining them for microscope examination and of laboratory culture Select TB suspects from among patients presenting respiratory symptoms and collect sputum samples for laboratory examination List the criteria for diagnosing TB (pulmonary and extrapulmonary) and classify cases depending on their site, bacteriological status, and existence or absence of previous TB treatment Prescribe the standard short-course chemotherapy regimen suitable for the category of treatment provided for in the NTP, identify methods of monitoring the patient throughout the treatment and criteria of success or failure of the treatment Adapt the chemotherapy prescription to special situations such as: Pregnancy, comorbidity, and drug dependence, coinfection with HIV Chronic cases and cases of multidrug-resistant TB TB complications and side effects of chemotherapy Ensure appropriate follow up of contacts, at least in the household. Cite instances when the BCG vaccine and preventive chemotherapy are indicated, such as those provided for in the national program List the objectives of the national program and allocate responsibilities and tasks for its implementation: quarterly reports on screening and treatment and standard individual patient case file Abbreviations: NTP, National Tuberculosis Program; BCG, bacille Calmette–Gue´rin.

responsibility for organizing training sessions targeting future TB district coordinators. These GPs, who would have already received basic training, will receive further training before taking up their new duties. This complementary training will take the form of a workshop lasting between 10 and 15 days which will allow the trainees to attain the objectives summarized in Table 3 (10,11,13) using WHO-edited training modules (18–20). C. Training of Nurses

Training nurses to implement NTP relies on the acquisition of basic knowledge necessary to perform specific tasks under the direct supervision of a qualified public health teacher. Theoretical training is limited to general knowledge about TB, its magnitude at the country level, its contagious and communicable nature and the existence of means of prevention and cure. Practical training should be developed gradually to allow future nurses to discharge the professional duties described in Table 4 (18,20,21).

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Table 2 Behavioral Patterns and Practical Qualifications Future General Practitioners Must Acquire During Their Training in Tuberculosis Control Examine TB patients, identify all their medical and social problems, and advise the patients (and the families) of measures to be taken (further testing, treatment plan, monitoring deadlines) Identify abnormalities on a series of chest X-rays that are consistent with the diagnosis of active TB Administer an intradermal injection of tuberculin, read and interpret the results Collect sputum samples in compliance with safety norms, prepare sputum smears, stain them and examine them under the microscope, and record the quantitative results in the laboratory register Take a pleural and cold abscess tap (from a lymph node or bone) Carefully fill in the columns of the health unit’s TB register and keep individual patient files up to date Notify on a quarterly basis the TB district coordinators of detected cases of TB and the results of TB treatment Keep a calendar of dates for the distribution of medical supplies to patients and/or their TB treatment supervisor as well as dates for checkups Supervise the activities of the nurse in charge of detecting TB suspects and administering treatment and the activities of the microscopist. Correct, if need be, any omissions or faults and explain their consequences

D. Training of Laboratory Technicians

TB laboratory technicians can be trained in a range of establishments that vary from country to country. They include: paramedical training schools, public health institutes, and the national public health laboratory. The purpose of theoretical training, albeit limited, is to inform future laboratory technicians about the key role they play in TB control in terms of diagnosing contagious cases, monitoring patients during treatment and confirming that they are cured. The practical training program varies for microscopists and higher level qualified laboratory technicians. For microscopists, training lasts between 5 and 10 days depending on their initial level. It can be combined with training in the microscopy-aided diagnosis of other important infectious or parasitic diseases. In fact, technicians who work in multifunctional peripheral laboratories that serve between 20,000 and 50,000 people do not work on TB cases full-time. The objectives of the practical training course on TB microscopy are summarized in Table 5 (22–24). For laboratory technicians who work in intermediary laboratories serving 50,000 to 100,000 inhabitants, the training course lasts from three weeks to two months depending on their experience and initial professional qualifications. The training course is part of the curriculum for laboratory technicians. The skills they should acquire are summarized in Table 6.

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Table 3 Proposed Objectives for Training Workshops on TB Control Intended for TB District Coordinators Organize, equip, and monitor the network of laboratories within their district (peripheral microscopy, culture at the district level) Manage the regular supply of essential anti-TB drugs and laboratory supplies Train and supervise health staff in charge of selecting suspected TB patients and treating confirmed peripheral TB cases and workers responsible for microscopy and for keeping TB and laboratory registers at the district level Implement an information system centered on primary care: a log of treatment consultations, a list or register of suspected TB patients, a form for requesting bacteriological examinations, a TB register, a laboratory register, a stock letter for patient transfers and quarterly reports Complete quarterly reports on the screening of cases detected during the previous quarter and on the results of treatment for cases admitted to treatment during the same period for the previous year (by breaking down treatment of new cases and failures, relapses, treatment after interruption for patients who received a standard treatment) and verify them before forwarding them to the provincial or national authorities Develop professional relationships with specialists from referral centers for complicated TB cases or cases of extrapulmonary TB that are difficult to diagnose, chronic cases and cases of multidrug-resistant TB Broaden collaboration with primary health-care programs (to implant the PAL), the national AIDS program (to manage TB cases coinfected with HIV) Analyze the main indicators of TB control in their district (health service coverage, detection rate, quality of diagnosis, treatment outcomes, epidemiological trends) with a view to overcoming shortfalls Ensure feedback on program performance to all district dispensaries Abbreviation: PAL, practical approach to lung health.

VI. Training of Trainers Training the staff who will subsequently provide instruction for others is one of the core tasks of training centers for health-care staff who must meet the needs of the new generation and keep abreast of new expertise and techniques. A. Who Are the Trainers Who Need to Be Trained?

 In medical and public health schools, they are the future specialists (postgraduate students in infectious diseases, pneumology, or community medicine) who will be managing the NTP at the central and intermediary levels, public health consultants or medical school faculty (5,19,25).  In nursing schools they are the teaching staff responsible for guiding students during their initial training in TB (18,21).

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Table 4 The Professional Duties Related to Tuberculosis Control for Which Nurses Require Training Administer a BCG vaccine to newborns Do a tuberculin test (by intradermal route) and read the results Select persons suspected of carrying TB from among persons seeking medical care Collect sputum samples necessary for diagnosis and monitoring of treatment, send them to the laboratory in accordance with safety norms, and register patients on the log of suspected TB cases Administer under DOT anti-TB drugs in keeping with the chemotherapy and dosage regimens provided for in the program’s technical directives Explain to the patients (or families) and their TB treatment supporter about the importance of regular treatment Gradually complete the individual patient treatment file Refer the patient to a physician in case of complications, prolonged interruption of treatment or transfer to another establishment (at the patient’s request). Note the patient’s contact information (family address, place of employment or study, neighbors and list the persons living under the same roof Contact persons who have come into contact with the patient and invite them to come in for an examination. Prescribe preventive chemotherapy to children under 4 yr of age who have come into contact with the patient regardless of their vaccination status Bring back defaulters by paying them a house call and making enquiries with the TB treatment supervisor Manage the supply of anti-TB drugs to avoid any interruption of ongoing treatment Conduct information sessions on TB control for target groups (mothers, primary school students, and factory workers) Abbreviations: BCG, bacille Calmette–Gue´rin; DOT, directly observed therapy.



For the departments responsible for training laboratory technicians, they are the higher-level qualified laboratory technicians who have already acquired work experience and teaching skills and who collaborate with, or work in, the national mycobacteria reference laboratory (22,26,27).

B. What Should Be the Course Content?





Acquisition of teaching skills, which are too often neglected before the appointment as instructors and even while on the job. This could be done initially through teaching workshops prior to appointment and subsequently by way of continuous training (8,9). Ongoing update of knowledge, TB diagnosis and treatment methods, and management of the NTP with a view to producing instructors capable of choosing the most suitable and most effective methods and techniques in the actual conditions of program implementation (25,28,29).

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Table 5 The Areas in Which Tuberculosis Control Microscopists in Peripheral Laboratories Should Be Competent Organize the transport, collection, and storage of sputum samples Prepare a smear, stain it, and read the results under a microscope equipped with an immersion objective Record the results in the laboratory register and convey the results to the establishments requesting the tests Take charge of microscope maintenance Manage the supply of laboratory supplies and reagents Observe safety measures when handling samples and examining them under the microscope Store positive and negative slides separately with a view to external quality control Disinfect and destroy contaminated materials Observe the normal procedures for sending samples to an intermediary laboratory (for culture and drug susceptibility testing) Identify any problems encountered and inform the supervisor of them

 Participation in multidisciplinary research programs applied to the NTP. Such programs could be organized by training centers for health-care personnel or research institutes in order to meet the demands of those in charge of the national program: enhanced selection of suspected TB patients, case detection and diagnosis, treatment methods and results, supervision of activities within the districts, and epidemiological surveillance of TB (27,30,31).

Table 6 The Skills in Tuberculosis Control that Laboratory Technicians in Intermediary Laboratories Should Acquire Technical skills Master staining techniques (Ziehl–Neelsen, auranime) and (simple or fluorescence) microscope reading Prepare reagents Prepare seeding of culture media and follow procedures up to the reading and recording of results Management skills Train and supervise microscopists in peripheral laboratories Ensure quality control of peripheral microscope examinations Organize the transport of sputum samples within districts and from districts to intermediary laboratories Estimate needs in terms of equipment, reagents, and supplies for the laboratory network to prepare the program budget

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VII. Participation in Continuous Training Continuous training (or on-the-job training) is divided into two components, namely  

retraining: refresher courses on knowledge and best practices and proficiency: acquiring new knowledge or skills.

By supervising TB control activities at the district and provincial levels (intermediary level), training needs can be identified and quantified. The central TB control authority relays its program needs to training institutes and in conjunction with them develops the program of seminars, meetings, symposia, or retraining courses; preferably this program of activities should be decentralized (25). The continuous training of health-care personnel in TB as a whole is sometimes organized by scientific agencies, professional associations, or nongovernmental organizations. The role of instructors is to address these meetings so as to explain the choices made by the national program in TB detection methods, standard chemotherapy regimens, activity supervision, and patient monitoring.

VIII. Building Partnerships to Assess the Impact of Training on the Performance of National Programs During the workshops organized by WHO since 1997, there has been a noticeable lack of coordination between those in charge of the NTP and the administration of training centers. This is, therefore, the first partnership to build and institutionalize. On the basis of that collaboration, the deficits and shortcomings of training programs can be brought to the forefront and solutions to address them can be proposed (15). Above and beyond that fundamental partnership, the question remains: Who should be instrumental in introducing innovative teaching practices in training centers? To that end, other alliances could be forged: 

 

With professional associations such as the medical association, the nurses association, or the laboratory technicians association with a view to involving them in the external evaluation of training centers by way of surveys on the relevance of the training received by the various categories of health personnel; With institutions or international nongovernmental organizations to obtain information on experimentation with teaching techniques in other countries; Finally, with pharmaceutical firms with the aim of becoming involved in all national initiatives geared toward enhancing the quality of training offered to health-care personnel and promoting the rational use of anti-TB drugs as provided for in the national program.

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In the context of globalization of trade and of the health-care worker labor market, it is paradoxical that countries with a high TB prevalence rate desire both to enhance the quality of training offered to their health-care personnel and at the same time to discourage them from migrating in search of better living and working conditions. This is the challenge facing Asian, African, and Latin American countries whose training institutes often tend to stray from their initial objectives, thereby preparing physicians and nurses to work in other countries (32). Training centers in countries in the South are also responsible for attracting the attention of national decision-makers to this situation and for proposing concrete measures to staunch the health-care worker brain drain by organizing career development for health workers through training schemes, improved working conditions (33,34), and strengthening technical, administrative and financial support for public health activities, among which TB control is a priority. References 1. World Health Organization. Global tuberculosis control: surveillance, planning, financing. WHO report, Geneva, 2004, WHO/HTM/TB/2004.331. 2. World Health Organization/Global tuberculosis Programme. Recommendation 6th meeting of the coordination advisory and review group, 6 November 1996. 3. World Health Organization. Doctors for health: a WHO global strategy for changing medical education and medical practice for health for all. Geneva, 1996, WHO/ HRH/96.1. 4. World Health Organization. Increasing the relevance of education for health professionals. Report of a WHO study group on problem solving education for the health professionals. WHO Tech. Rep. Series, n 838, Geneva, 1997. 5. World Health Organization. Tuberculosis control and medical schools. Geneva, 1998, WHO/TB/98.236. 6. World Health Organization. An expanded DOTS framework for effective tuberculosis control. Geneva, 2002, WHO/CDS/TB/2002.297. 7. World Health Organization. TB/HIV: a clinical manual. 2nd ed. Geneva, 2004, WHO/HTM/TB/2004.329. 8. Guilbert JJ. Educational Handbook for Health Personnel. 6th ed. Geneva: World Health Organization, 1992: Offset publication n 35. 9. Abbat FR. Teaching for Better Learning: A Guide for Teachers of Primary Health Care Staff. 2nd ed. Geneva: World Health Organization, 1992. 10. World Health Organization. Regional Office for Africa. Teaching of tuberculosis control in French speaking countries in Africa. Workshop report, Dakar, July 1998. 11. World Health Organization. Regional Office for Africa. Teaching of tuberculosis control in medical schools in English speaking countries in Africa. Workshop report, Lusaka, July 1999. 12. World Health Organization. Regional Office for Eastern Mediterranean. Report on the inter-country meeting on tuberculosis and medical schools, Amman, September 2000, WHO/EM/TUB 227.EL.2001. 13. World Health Organization. Inter-regional workshop report. Medical schools and tuberculosis control in countries of the Maghreb. Tunis, September 2001.

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14. World Health Organization. Regional Office for Africa. Evaluation of teaching of tuberculosis control in medical schools in French speaking countries in Africa. Workshop report, Bamako, May 2003. 15. A€
t Khaled N, Enarson DA. Tuberculosis: a manual for medical students. WHO/ IUATLD, Geneva/Paris, 2003, WHO/CDS/TB/99.272. 16. World Health Organization. Treatment of tuberculosis: guidelines for national programmes. Geneva, 2003, WHO/CDS/TB/2003.313. 17. Crofton J, Horne N, Miller F. Clinical Tuberculosis. In: IUATLD/TALC. 2nd ed. London: Macmillan Education Ltd., 1999. 18. World Health Organization. Management of tuberculosis: training for health facility staff. WHO, Geneva, 2003, WHO/CDS/TB/2003.314. 19. World Health Organization. Management of tuberculosis: training for TB district coordinators. WHO, Geneva, 2004. 20. World Health Organization. A guide for tuberculosis treatment supporters. WHO, Geneva, 2002, WHO/CDS/TB/2002.300. 21. Pan-American Health Organization. Tuberculosis Control: A Manual in the Methods and Procedures for Integrated Programs. Washington: PAHO, Scientific Publication n 498, 1986. 22. World Health Organization/Global tuberculosis programme. Laboratory services in tuberculosis control. Part I: Organization and management. Part II: Microscopy. Part III: Culture. WHO, Geneva, 1998, WHO/TB/98.258. 23. International Union Against Tuberculosis and Lung Disease. The Public Health Service National Tuberculosis Reference Laboratory and the National Laboratory Network. Paris, IUATLD, 1998. 24. Fujiki A. TB Microscopy. In: The Research Institute of Tuberculosis. Tokyo: Japan Antituberculosis Association, 1998. 25. Pio A, Chaulet P. Tuberculosis Handbook. Geneva: World Health Organization, 1998, WHO/TB/98.253. 26. Abdelaziz M, Ba F, Becx-Bleumink M, et al. External Quality Control of Direct Microscopy Examination of Sputum for Acid-Alcohol Fast Bacilli. Washington: Association of Public Health Laboratories, 2004. 27. WHO/IUATLD. Global project on antituberculosis drug resistance surveillance. Guidelines for surveillance of drug resistance in tuberculosis. World Health Organization, Geneva, 2003, WHO/CDS/TB/2003.320. 28. Rieder H. Interventions for Tuberculosis Control and Elimination. International Union Against Tuberculosis and Lung Disease, Paris: 2002. 29. Toman’s tuberculosis. Case detection, treatment and monitoring. Questions and answers. 2nd ed. by T. Frieden. World Health Organization, Geneva, 2004, WHO/ HTM/2004.334. 30. Enarson DA, Kennedy SM, Miller DL. Bakka Research Methods for Promotion of Lung Health. A Guide to Protocol Development for How Income Countries. Paris: International Union Against Tuberculosis and Lung Diseases, 2001. 31. Jindani A, Nunn A, Enarson DA. Controlled Clinical Trials in Tuberculosis: A Guide for Multicentre Trials in High-Burden Countries. Paris: International Union Against Tuberculosis and Lung Diseases, 2004. 32. World Health Organization. Training for better TB control: human resource development for TB control. A strategic approach within country support. Geneva, 2002, WHO/CDS/TB/2002.30. 33. Stilwell B, Diallo K, Zurn P, Vujicic M, Adams O, Dal Poz M. Migration of health care workers from developing countries: strategic approaches to its management. Bull WHO 2004; 82:595–600. 34. Saravia NG, Miranda JF. Plumbing the brain drain. Bull WHO 2004; 82:608–615.

45 Tuberculosis in the Poverty Alleviation Agenda

CHRISTY L. HANSON Division of Infectious Disease, Bureau for Global Health, U.S. Agency for International Development, Washington, D.C., U.S.A.

DIANA E. C. WEIL and KATHERINE FLOYD Stop TB Department, World Health Organization, Geneva, Switzerland

I. Introduction ‘‘[To understand TB] demands that the impact of social and economic factors on the individual be considered as much as the mechanisms by which tubercle bacille cause damage to the human body.’’

Dubos R. and Dubos J. (1) Historically and today, tuberculosis (TB) has been associated with economic hardship, urbanization, and other socioeconomic factors linked to deprivation (1–5). Poverty and economic crises have been cited among the causes of the reemergence of TB in established market economies as well as its worsening in the developing world (6). The World Health Organization (WHO) estimates that 95% of the deaths due to TB occur in developing countries (7). Although case detection is improving, only 54% of all estimated infectious TB patients were registered in DOTSbased treatment programs in 2004. Coverage has accelerated but at too

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slow a pace to meet the global 2005 TB control targets. It is hypothesized that problems associated with poverty contribute to deficiencies in patient access to, and the impact of, TB services. The HIV/AIDS pandemic and the rapid increase in HIV-associated TB is a further cause for concern, especially as HIV’s impact on poor, highly vulnerable and/or marginalized populations is well-documented. Poverty alleviation has reemerged as a core priority within development efforts. Starting in the late 1990s, many developing countries have worked with their development partners to prepare Poverty Reduction Strategy Papers (PRSPs) and, in turn, to design and implement multisectoral plans to strengthen their response to poverty. Increasing coordination among health authorities, financing agencies and researchers to explore health and equity emerged at the end of the 1990s (8,9). Addressing health as a human right and TB control in this context also took on force in the last decade (10). At the United Nations’ Millennium Summit in September 2000, all 189 Member States adopted Millennium Development Goals (MDGs) that highlight poverty reduction and human development aims, including the control of communicable diseases. In 2001, the Commission on Macroeconomics and Health called for further investment in interventions targeting the poor (11). The theme for World TB Day 2002 was ‘‘Stop TB, fight poverty’’ and the Partnership has sponsored a sub–working group on TB and poverty since 2004 (Chapter 25). In 2006, TB and poverty were featured during G8 summit conferences. In 2004, the World Bank’s World Development Report examined how to get services to the poor (12), and its 2006 report tackles the challenges of attaining equity as part of development (13). WHO has also established a Commission on the Social Determinants of Health, which will further explore many of the issues noted above, and the importance of the relationship between TB and poverty has been highlighted recently in the editorial of a leading journal (14). The Stop TB Partnership, now representing over 450 partners, including governments and other organizations, the goal of which is to reverse the worsening TB epidemic, includes the following among its objectives: (i) to ensure every TB patient access to effective diagnosis, treatment, and cure and (ii) to reduce the inequitable social and economic toll of TB (15). The first part of this chapter considers evidence on the association between poverty and TB incidence, the relationship between proxy indicators of poverty and TB infection and disease, the impoverishing effects of TB, and the association between poverty and access to and utilization of TB services. Although not attempting to provide an exhaustive review of this literature, it highlights the major findings from published studies. The second part of the chapter discusses how pro-poor and poverty-reduction efforts can be promoted within the context of the new Stop TB Strategy, a strategy that is designed to guide TB control efforts over the decade 2006 to 2015 (Chapter 50).

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II. Associations Between TB and Poverty A. Definitions of Poverty

In considering the association between TB and poverty, the following definitions of poverty were considered. Individual country definitions of poverty are usually related to absolute income levels. Measures of absolute poverty consider an individual or group’s income in relation to a standardized and quantitative cutoff point. The World Bank’s economic definition of absolute poverty is living on US $1 per day or less. Measures of relative poverty consider an individual or group’s income in relation to other individuals within the same or comparison population. Recently, the World Bank proposed a broader definition of poverty that considers not only the lack of income but also deprivation in terms of food, housing, knowledge, power, or access to infrastructure and social services (16). The chapter considers both absolute and relative measures of poverty as well as the broader societal definition. B. Poverty and TB Incidence, Prevalence, and Mortality

Of the 22 countries that accounted for 80% of the world’s TB burden in 2003 (17), 15 (68%) had an annual gross national income (GNI) per capita of US $825 or less, which was the criterion used by the World Bank for classification as a low-income country in 2004 (13). None of the highest TB burden countries are high-income countries. Regionally, the incidence of TB and per capita GNI are inversely related (Fig. 1). In 2003, ever 2.6 million new cases occurred among people who lived on less than $2 per day, in the highest burden countries (Table 1). The strength of the association between macroeconomic conditions and TB can also be illustrated by examining longitudinal data from countries that have experienced periods of relative wealth as well as periods of economic hardship. Historical reviews have demonstrated that increased TB incidence may be associated with constrained macroeconomic conditions and periods of economic transition. In Switzerland and the Netherlands, TB mortality increased during the Second World War—a period of economic hardship, population disruption, and food shortages (18). More recently, a period of economic and social transition following the breakup of the Soviet Union was accompanied by a dramatic increase in TB incidence in the affected countries during the 1990s, including the Russian Federation (19). The Republic of Korea provides another longitudinal example. TB deaths were highest during the Korean War in the 1950s, a period of economic and social instability for the country. Per capita gross national product increased steadily from the mid-1960s through the mid-1990s, while TB case notifications and TB deaths decreased at almost the same rate. It is important to note that this progress in TB control was also related to the introduction of a national TB program in the mid-1960s. Income disparities within countries have also been shown to be associated with differences in TB incidence, prevalence, and mortality,

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Figure 1 Estimated incidence of smear-positive tuberculosis and per capita gross national income (purchasing power parity) by region. Source: From Refs. 13,17.

with higher rates generally found among poorer subpopulations. Studies conducted from 1910 to 1920 in Norway, Germany, and Vietnam found important socioeconomic variance in the age-specific prevalence of TB, with the poorer segments of the population having consistently and substantially higher prevalence rates (20). In New York City, neighborhood poverty was associated with higher rates of TB disease. A 10% increase in the proportion of people in a neighborhood living below the U.S. federal poverty line was associated with a 33% increase in the incidence of TB (21). In Manila, the prevalence of TB among the urban poor was 1.5 times higher than among the urban nonpoor population (22). A prevalence survey conducted in China in 2000 found that the prevalence of TB disease was greater in areas with poor geographical access to health services. The prevalence rate of smear-positive TB in cities averaged around 73/100,000, while in townships the average was almost 110/100,000, and in villages, it was 131/100,000 (23). In Mexico, the TB mortality rate was twice as high in Chiapas, a state with high poverty levels, as the national level (24). Income disparities have also been associated with differences in epidemiological trends among different population groups. A study of TB trends in England and Wales noted that between 1988 and 1992 TB notificationsa increased by 35% among the poorest 10% of the population, 13% among the next poorest 20%, and did not increase at all among a

Number of cases notified.

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Table 1 Estimated TB Incidence Among the Poor in the 22 Highest TB Burden Countries

Country

Estimated Percentage number of TB of casesa not Estimated estimated Percentage a detected under of incidence: TB cases Population all forms (in detected population DOTS that are under living on poorc (<$2/day) (in millions, thousands, DOTS <$2/day (in thousands) 2003) 2003)

Afghanistan Bangladesh Brazil Cambodia China DR Congo Ethiopia India Indonesia Kenya Mozambique Myanmar Nigeria Pakistan Philippines Russian Federation South Africa Tanzania Thailand Uganda Vietnam Zimbabwe

24 147 178 14 1304 53 71 1065 220 32 19 49 124 154 80 143

80 361 110 72 1334 195 252 1788 627 195 86 85 363 278 237 161

17.5 24.4 15.5 38.9 41.5 43.6 46.4 46.8 28.4 47.2 33.7 89.4 12.1 26.3 56.5 13.0

73.6b 82.8 22.4 77.7 46.7 84b 77.8 80.6 52.4 58.3 78.4 82.8b 92.4 73.6 47.5 7.5

49 226 21 34 364 92 105 767 235 60 45 7 295 151 49 11

45 37 63 26 81 13

242 137 89 106 145 85

93.8 45.3 61.8 39.6 64.1 62.4

34.1 72.5 32.5 58.3b 82.8b 83

5 54 11 37 43 27

Total

3942

7027

41.5

60.3

2688

a

All new and relapse cases. Estimates. (No data available. Myanmar and Vietnam considered at poverty level of Bangladesh; Afghanistan given the level in Pakistan; DR Congo given the level in Central African Republic; Uganda given the level of Kenya.) c Based on estimated proportional share of population living in poverty for the given country. Source: From Refs. 13,17. b

the wealthiest 70% of the population (25). The authors reported that the case-detection rate remained at around 85% across the study period, indicating that the increase in notifications reflected a real increase in disease prevalence rather than a change in health service delivery. TB among newly arriving immigrants accounted for less than half of the overall increase,

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leading the authors to conclude that the evidence indicated a ‘‘major role for socioeconomic factors in the increase in TB’’ (25). The available evidence is less conclusive when evaluating the association between poverty and an individual’s risk of TB infection or disease. In South Africa, individual TB patients and non-TB patients living in the same community were compared in terms of socioeconomic factors. These factors, including household assets and living conditions, were not found to be significantly associated with TB disease (26). Preliminary analysis from a facility-based survey in Thailand also suggested that the socioeconomic characteristics of TB patients who accessed care did not differ significantly from those of the general populationb (Sawert H, Kamolratanakul P, Payanandana V, et al. Socio-economic profile of tuberculosis patients in Thailand, unpublished). However, a study in Malawi found that socioeconomic factors among TB patients who accessed care were significantly worse than those of the general population (Nhlema B, et al. A systematic analysis of TB and poverty. Geneva, World Health Organization, 2003, unpublished document available from the Stop TB Partnership Secretariat). A national retrospective study conducted in the United States using individual data found that the relative risk of developing TB was 2.3 among the poorest 25% of the population, compared to the baseline of 1 for the wealthiest 25% of the population (27). C. Proxy Measures of Poverty and Their Relationship to TB

Proxy measures of poverty, based on the broad definition of poverty explained above, include ethnic minority status, female gender, malnutrition, and overcrowding. Ethnic Minority Status

Ethnic minority status is often used as a proxy for poverty or marginalization, although the association is complex. Some of the studies cited above found that income poverty measures were more strongly associated with increased TB disease than were indicators of ethnic minority status. However, other studies have found ethnicity to be more important. A study in London, United Kingdom, found that ethnicity explained more of the variance in TB than did the Jarman index of social deprivation, although both were statistically significant (28). Another study from the United Kingdom found that poverty in Birmingham was significantly associated with TB among the white population but that this association did not exist among the Asian population (29). In the United States, a high proportion of incident cases occur among the foreign born, while a study in San Francisco found that the transmission index was higher among the U.S.-born population (30). This suggests high levels of infection originating in the home country and may also reflect increased vulnerability to the breakdown of b

WHO estimates that Thailand detected 40% of its infectious cases in 1999 (World Health Organization, 2001).

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disease as a result of the socioeconomic stresses associated with immigration. A study from two prisons in the United States found that black inmates had twice the relative risk of becoming infected with TB while in prison when compared to white inmates (31). The authors noted that it was not clear whether there were underlying biological factors or socioeconomic variables associated with this disparity. Female Gender

Women account for 70% of all poor individuals (32). Female gender is therefore sometimes considered to be a proxy for poverty or vulnerability. Globally, there are 1.7 times as many male pulmonary TB cases reported annually as female cases (17). A review of existing surveys of prevalence of TB disease suggested that the male to female ratio was similar between prevalent cases and notified cases (33). However, other population-based studies have found underdetection of female cases where prevalence was similar among men and women. In the Bavi district in Vietnam, for example, case detection among females was estimated at 12%, compared to 39% among men (34). A review of the literature on gender and TB published during 1999 and 2000 found evidence that pulmonary TB was diagnosed later in women than in men and that among patients with cough, men were given sputum examinations more often than women (35). Although the prevalence of disease overall may tend to be higher among men, women may still be at higher risk of developing the disease following infection. A review of gender and TB reported that women between 15 and 40 years of age are almost twice as likely as their male counterparts to progress from TB infection to disease (37). The disparity in the development of disease may be explained by the later age at which women are infected and the fact that new infections are more likely to progress to disease (35). This may suggest that women with TB infection may face higher collective risks of poverty and TB disease than men. Therefore, differentials in reported TB rates between men and women may result from underlying epidemiological differences (e.g., biological factors affecting risk of infection or development of disease, and/or differences in risk of exposure), and from inequities in access to care (36). Malnutrition

An association between nutritional status and the defense capacity of the immune system has been documented (38). Malnutrition has been shown to increase the probability of breakdown from TB infection to disease (18), and vitamin D deficiency in particular has been linked to an almost 10-fold increase in the risk of TB diseasec (39). Increased TB c

Vitamin D deficiency is also associated with overcrowding, a lack of sun exposure, and poverty. Therefore, there is likely some interaction in its effect and that of poverty on the risk of TB disease.

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incidence during the First and Second World Wars in Germany and the Netherlands, respectively, was associated with increased rates of malnutrition (40). We were not able to identify any recent studies investigating the relationship between poverty, malnutrition, and TB disease in low- and middle-income countries. Overcrowded Housing Conditions

The infectious nature of TB makes overcrowding an obvious risk factor for increased transmission. There is evidence of an association between overcrowding and increased TB case rates as well as death rates (1,41,42). It is surprising how little has been published since urbanization has taken off in the developing world in the last decades on how the emergence of marginalized urban communities may be contributing to worsening of TB transmission and the specific challenges for these communities. Some information as noted above is available from recent prevalence surveys in Asia, which have examined disease prevalence in rural, urban poor, and urban nonpoor populations, but more is needed. D. Impoverishing Effects of TB Economic Poverty Caused by TB

The economic impact of TB on individuals and households, as well as its impact at a macroeconomic (national) level, is discussed in detail in Chapter 24. The evidence is therefore considered only briefly here. The available data clearly show that TB can worsen the socioeconomic status of individuals and households by causing expenditures and wage losses that are large in relation to income. The results suggest that in low-income countries, patient costs generally range from around US $50 to $300 during treatment, and that costs prior to diagnosis can be even greater. Relative to individual and household incomes, these costs are high. At the national level, the main recent study concerns India. It was estimated that the value (in 1993–1994) of current and future benefits due to DOTS implementation was US $8 billion, equivalent to 4% of gross domestic product at that time. It was argued that the current and future costs of DOTS implementation were likely to be less than US $8 billion, and therefore that TB control using the DOTS strategy would contribute to economic growth (5). A more recent study assessed the impact of TB on economic growth using macroeconomic data, but the results were inconclusive. There are two major ways in which the existing data about the effect of TB on economic poverty could be improved. The first would be to demonstrate whether and to what extent TB causes poverty (i.e., the extent to which people who were above the poverty line prior to developing TB fall below that line as a consequence of developing TB) by collecting data on the socioeconomic status before and after the completion of treatment. The second would be to produce more robust data about the impact of TB at the national level, whether this is expressed in terms of the economic losses caused by TB each

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year or as the impact of TB on national economic growth rates. A study of the economic impact of TB in Africa, recently commissioned by the World Bank and due to be completed in late 2006, may produce such data. Noneconomic Forms of Poverty Caused by TB

TB can also cause noneconomic forms of impoverishment, which are relevant when a broad definition of poverty is used. The stigma associated with TB can impoverish individuals in terms of social position and power. Studies from India and Vietnam suggest that women fear the social ramifications of TB, such as isolation and rejection, while men fear the economic impact of the disease (43–45). Other studies in South Asia suggest that stigma linked to having, or having had, TB can result in women being unable to marry, thereby creating economic and social insecurity. This mirrors similar social impacts when TB was a major killer in Europe and the United States in the 19th century and early 20th century, due to the stigma linked to TB’s association with inherited ‘‘weaknesses’’ and poverty (1,46). The stigma of HIV–TB coinfection and disease may be creating new economic and social burdens for those affected, and further studies are needed to explore this possibility, particularly in Africa where TB incidence among women is growing most rapidly. E. Poverty and TB Treatment: Access and Adherence Access

The burden that diagnosis and treatment imposes on individuals, especially in low-income settings, has been well documented. It includes expenditures on transport and diagnostic services, the opportunity cost of time away from work or home, limited decision-making power about where and from whom to seek care, and fear of discrimination during treatment (47–49). Lack of access to health care can be an important indicator of poverty at both the individual and population level. The people who were interviewed for the World Bank’s ‘‘Voices of the Poor’’ series highlighted impoverishment in terms of limited access to infrastructure, including the health care network (16). Income poverty and several proxy indicators of poverty, particularly female gender, are often associated with delays in care seeking, diagnostic delays, and constraints in accessing health care in general and TB services in specific (45,49–52). The 2000 prevalence survey in China found that 37.3% of the patients who delayed treatment seeking noted that this was due to financial constraints as a barrier to access (23). In Manila, 20% of patients reported that they had symptoms for at least three months before seeking treatment. Of these, 22% noted that a lack of money contributed to this delay (50). Chronic barriers to access among the poor may result in increasing prevalence of disease in some subpopulations. Treatment Adherence

People who are impoverished may abandon TB treatment before they are cured, owing to economic, social, health system, and geographic barriers,

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as well as a lack of knowledge of appropriate care practices by providers and patients (53,54). Numerous studies have shown an association between unemployment and poor treatment adherence, in both hospitalized settings (55) and ambulatory settings (56). Studies examining gender differences in treatment adherence rates have found the association between gender and adherence to be highly country or region specific, with some showing lower adherence among female patients [e.g., in Cambodia (57)], whereas others showed higher rates [e.g., in India (58)]. For a fuller review of the association between poverty-related barriers and adherence to TB treatment and related outcomes, see Refs. (53,54).

III. TB Control and the Poverty-Reduction Agenda Given the relationships between TB and poverty documented above, this section of the chapter suggests how future efforts in scaling up TB control can contribute to as well as benefit from wider efforts to alleviate poverty. As noted above, global support for efforts to reduce poverty and address infectious disease threats have never been stronger, and so the opportunities for coherent action on both fronts need to be seized. A. Poverty-Reduction Strategy Papers

Governments in many low- and middle-income countries are elaborating PRSPs, for strengthening their systemic response to poverty. For highly indebted poor countries, the PRSP is the foundation on which debt relief is granted. In addition, PRSPs represent a broad development framework supported by many donors and other financial partners and they have been used by several low- and middle-income countries that do not qualify for debt relief. Multilateral lending institutions are also providing financing through Poverty Reduction Strategy Credits. Of the 22 high TB burden countries, 11 have developed, or are in the process of developing, PRSPs.d Unfortunately, TB is not well covered in most existing PRSPs despite the fact that TB is recognized as a burden among poor populations (Pande A, Adeyi O, Weil D. Putting tuberculosis control in the mainstream of development: how responsive are poverty reduction strategies? Washington, DC, World Bank, Health, Nutrition and Development, Human Development Department, unpublished discussion note). This is partly because more countries need to document the differential burden that TB places on the poor, as well as the extent to which TB control services can reach the poor and how new initiatives in TB control can benefit poor populations. Various efforts are now under way to increase the priority given to TB control in PRSPs. d

Cambodia, DR Congo, Ethiopia, Indonesia, Kenya, Mozambique, Nigeria, Pakistan, Tanzania, Uganda, and Vietnam.

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B. Poverty Mapping and Intensified Efforts to Improve Services in Poor Areas

There is a body of literature on mapping of poor areas and poor populations for the targeting of interventions and intensified support (59–61). Poverty mapping is being used in some countries, such as China, as an integral part of national priority setting for public health service delivery, including TB control. In the implementation of its multiyear plan, which began in 2002, the national TB program is targeting the poorest provinces in China, and providing extra financing for TB control in these areas. In Brazil, mapping has been used to target areas where intensified TB control efforts are needed. Areas were mapped according to a social deprivation index and TB incidence, and used to produce a ‘‘TB risk’’ score. Similar approaches could be used to target poor areas in other countries and thereby ensure that these areas are among the first rather than the last to benefit from the availability of new resources to fight disease and innovative service-delivery strategies. C. The New Stop TB Strategy

During 2005, the WHO developed the new Stop TB Strategy with substantial input from a wide range of stakeholders. The strategy builds on the successes of the DOTS strategy while also addressing unmet needs, including the many challenges associated with ensuring that the poor have access to high-quality TB diagnostic and treatment services. It relies on the lessons learnt from innovations and adaptations in the application of DOTS over the last decade, and also gives prominence to the need for expanded operational research as well as the development and roll out of new diagnostics, new drugs, and new vaccines. One of the four objectives of the strategy is ‘‘to reduce the human suffering and socioeconomic burden associated with TB, and to protect poor and vulnerable populations from TB, TB/HIV, and multidrug-resistant TB.’’ The strategy is described fully in Chapter 50. Here, in Table 2, we highlight the components of the strategy that have particular relevance to poverty alleviation. The strategy makes explicit the objectives of reducing suffering associated with the disease and serving the needs of poor and vulnerable populations. Most of the interventions promoted in the Stop TB Strategy have been pilot tested and scaled up already in numerous settings. Interventions such as the Practical Approach to Lung Health (62), Public–Private Mix models in TB care (63), social support and enablers in TB control (64), expanded laboratory networks (65), and community-based care (66,67) are all proving to expand access to and/or the quality of services delivered. Many of the intervention strategies are benefiting poor and vulnerable individuals in very poor communities (3,68,69) and are being implemented in some of the lowest-income countries, such as Bangladesh, Uganda, Malawi, Haiti, and Cambodia. Still, as these approaches are more widely applied, further work is needed to better document to what extent the very poor are being reached or missed.

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Table 2 Potential Contributions of the Stop TB Strategy to Poverty Reduction and Reaching the Poor Stop TB Strategy components Pursue high-quality DOTS expansion and enhancement

Address TB/HIV, MDR-TB, and other challenges

Contribute to health system strengthening

Potential contributions Further emphasis on political commitment expressed through sustained financing for TB control, via mechanisms including poverty reduction strategies Expanding diagnostic capacity through culture (and roll out of newer diagnostics as they become available) to increase early diagnosis of all persons ill with TB; this is especially important in settings where the prevalence of HIV is high, and relevant to reducing the costs of undiagnosed disease Increased focus on patient-centered care, including treatment supervision at home or close to home and support, treatment enablers, and special needs of vulnerable groups Drug supply systems that ensure availability of quality-assured drugs for the full course of treatment, free of charge to patients Enhanced monitoring and evaluation systems that include measurement of impact and documentation of who is being reached and who may be missed Rapid roll out of approaches to identify and serve those most affected by HIV-associated TB and multidrug-resistant TB, including collaboration across programs to ensure service access and crossreferral Development and/or implementation of policies to best serve other populations at high risk of disease or poor outcomes, including prisoners, refugees, ethnic minorities, etc. Active participation of national TB programs in national and global system strengthening efforts that aim to increase sustained financing, harmonize approaches, and progress toward universal access to quality and affordable services in line with MDGs Share innovations from TB control that increase access and quality of services, such as public–private mix approaches and integrated respiratory care Collaborate to build on innovations from other fields such as in community engagement and social mobilization (Continued )

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Table 2 Potential Contributions of the Stop TB Strategy to Poverty Reduction and Reaching the Poor (Continued ) Stop TB Strategy components Engage all care providers

Empower people with TB and communities

Enable and promote research

Potential contributions Scale-up approaches that utilize all available partners in service delivery, especially those that reach the poor and vulnerable, within the public and private sectors Apply International Standards of TB Care and associated provision of resources, training, and incentives to enable quality care and eliminate dangerous practices Dramatically increase information, education, and communications on TB to increase demand for, participation in, and successful use of services, particularly by those for whom access is most limited Increase awareness and application of the Patients’ Charter for Tuberculosis Care Expand social mobilization to advance TB control, especially in high-risk communities, as well as community TB care approaches that overcome barriers to effective care Promote operational research done by programs and partners, which documents the socioeconomic characteristics of people with TB, as well as the extent to which services reach the poor Expand research and development that will facilitate the rapid roll out of affordable new tools that increase prevention, early detection, and/or treatment for TB, with special attention to serving the needs of poor countries, communities, and vulnerable groups

Abbreviations: MDR-TB, multidrug-resistant tuberculosis; MDGs, Millennium Development Goals.

D. Monitoring and Evaluation of Those Reached by the TB Programs and Partners

To demonstrate the impact of the Stop TB Strategy on poverty alleviation and on poor individuals, it is essential to monitor and evaluate its effect on health status, access to services, and service utilization among poor and vulnerable populations. The Stop TB Strategy calls for impact measurement, and The Global Plan to Stop TB, 2006–2015 (launched in January

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2006) includes targets for expanding monitoring and evaluation of whether the poor are being reached. To assess who is benefiting from TB control services, and the extent to which the poor in particular are being reached, both population- and facility-based data are needed. There are two possible approaches to the collection of population-based data that require minimal additional investments in surveillance. The first is to include questions related to TB symptoms or known TB disease in household health and expenditure surveys, such as the Demographic and Health Surveys and Living Standards Measurement Surveys. The second is to include questions about socioeconomic status in national TB prevalence surveys. At the health care facility level, data on the socioeconomic status of TB patients should be assessed. Comparison of such facility- and population-based data would allow assessment of the extent to which TB affects the poor and the extent to which services reach the poor. During times of political or economic unrest or health sector reforms, such monitoring would also enable the health system to rapidly detect and respond to worsening inequities. IV. Conclusions TB has been associated with poverty and vulnerability for centuries. The disease disproportionately affects poor countries and can disproportionately affect poor and marginalized subpopulations within countries With the 21st century movement to place poverty reduction again at the center of the development agenda, and to advance related goals, including combating epidemics and advancing health, there are unique opportunities now to control TB and reduce poverty in a concerted manner. There are strong associations between TB and poverty with some data demonstrating causal relationships between poverty (and/or proxy variables for poverty) and TB exposure, infection, incidence, and prevalence. Economic and social burdens associated with TB and with help-seeking behavior in the face of the disease have been documented in many settings. Approaches to reach the poor with adequate TB care and to limit the impoverishing effects of TB are justified on epidemiological, economic, and equity grounds. In 10 years, the DOTS strategy has enabled expansion of TB diagnosis and treatment to half of those falling ill each year. Still, extending access to the vast majority of those affected will take further expansion of innovative approaches, political support, and new tools as well as an intensified approach to measuring who is being reached and who is being missed. The Stop TB Strategy and the Global Plan to Stop TB, 2006–2015, provide the framework for these advances. If larger efforts to address the social determinants of ill health, strengthen equitable access to services, and advance poverty reduction are combined with these TB-focused actions, the future for the communities most at risk today could be dramatically different.

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SECTION VI: BUILDING THE FUTURE

46 New Diagnostics for Tuberculosis: An Essential Element for Global Control and Elimination

MARK D. PERKINS and RICHARD J. O’BRIEN Foundation for Innovative New Diagnostics, Geneva, Switzerland

I. Introduction During the past decade, while the importance of tuberculosis (TB) as a continuing major public health problem was increasingly recognized and the DOTS control strategy was successfully implemented, diagnostic tests for TB were virtually ignored. In large part, this stemmed from the dogma that TB treatment services should be strengthened before increasing case finding, in order to avoid the creation of a large pool of poorly treated, potentially drug-resistant cases. Moreover, the most widely available diagnostic tool, acid-fast bacillus (AFB) microscopy, when properly applied, appeared to be sufficient for the diagnosis of the most infectious cases, which often were also the most ill and in need of treatment. Thus, the diagnostic focus of the DOTS strategy was appropriately on improving the quality of smear microscopy through training and quality assurance programs. However, as DOTS has been successfully implemented, its limitations in two important areas have become apparent. Both have important diagnostic implications. The growing problem of multidrug-resistant (MDR) TB in Eastern Europe, China, and India requires urgent attention. Widespread

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implementation of the MDR TB treatment strategy developed by World Health Organization (WHO) and its partners, known as DOTS-Plus, is seriously limited by the lack of facilities for mycobacterial culture and drug susceptibility testing (DST). In countries in sub-Saharan Africa, HIV infection has continued to fuel the TB epidemic, overwhelming the TB control programs. In contrast to HIV-negative patients, many, if not most, of HIV-infected patients with pulmonary TB are AFB smear-negative (1). The diagnostic algorithms for smear-negative TB that were developed prior to the widespread TB/HIV epidemic appear to lack sensitivity and specificity, especially in HIV-infected patients. Although calls for expansion of these laboratory facilities to facilitate the diagnosis of both MDR TB and HIV-associated TB are now being made, the magnitude of the challenge to develop, equip, and supply the technicians needed to enable laboratories to perform culture is enormous. Thus, the need to both expand the use of currently available TB diagnostic technologies and to develop less costly, more efficient, and more easily implemented diagnostic tools has never been more apparent. Advocates from the HIV/AIDS community have raised the visibility of the need for new TB diagnostics. Fortunately, this need has been highlighted at a time when more resources are flowing into TB control programs, and increased funding is becoming available to support research and development to produce the diagnostic technologies they need. In this chapter, we will outline in more detail the need for new diagnostics, list the impediments to progress in this area, describe the characteristics of needed tools, review the current developmental pipeline of new diagnostics, and propose a structure and process that we believe will pave way for diagnostics that can radically change our approach to TB control and make possible TB elimination by the mid-century. II. The Need for Improved Diagnostics As noted above, the primary TB diagnostic technology promoted in the DOTS strategy, sputum AFB smear microscopy, addresses the limited need to identify and treat the most infectious TB cases. However, this technology requires well-maintained equipment and trained technicians who should spend up to 15 minutes examining a single sputum smear before recording it as negative. The DOTS diagnostic strategy calls for a patient with suspected pulmonary TB to provide three sputum specimens over two days and return on a third day to receive results. In an average developing country setting, 10 patients with suspected TB are screened to identify a single case. Thus, under optimal conditions one technician would spend an entire day examining AFB smears to diagnose a single patient with AFB smearpositive TB. However, such human resources are seldom available; thus that the quality of smear-microscopy is usually inadequate. This process is burdensome for the patients as well, and in some settings the dropout rate even from this limited diagnostic process is significant (2).

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By definition, microscopy cannot identify patients with paucibacillary pulmonary TB, which may constitute half or more of those with pulmonary disease. Patients whose sputum smears are negative often undergo additional diagnostic procedures, including chest radiograph and a trial of broad-spectrum antibiotics. Facilities for mycobacterial culture, the cornerstone of TB diagnosis in industrialized countries, are generally not available. Thus, during this cumbersome diagnostic process, many patients drop out or are misdiagnosed, resulting in both under- and overtreatment. Diagnosis of other forms of paucibacillary TB, notably extrapulmonary disease and childhood TB, is at least as difficult. There has been a significant increase in the incidence of AFB smearnegative pulmonary TB in countries where both TB and HIV are prevalent. This increase in smear-negative cases strains already overloaded laboratories, while also eroding the predictive value of microscopy. For a number of reasons, HIV-positive, smear-negative pulmonary TB patients have inferior treatment outcomes, including higher mortality rates, compared to HIV-positive, smear-positive pulmonary TB patients and HIV-negative TB patients (3). In the absence of an easily applied diagnostic test that is more sensitive than AFB smear microscopy, diagnostic algorithms that include a trial of broad-spectrum antibiotics have been recommended. However, these algorithms lack sensitivity and specificity, and it is believed that during the evaluation process, which may take up to one month under routine program conditions, many HIV-infected patients die before TB treatment is started. In fact, autopsy studies have found disseminated TB in 40% to 60% of HIV-infected people in TB endemic countries, many of whom were undiagnosed prior to death (4,5). The emergence of drug resistant strains of Mycobacterium tuberculosis is proving to be one of the most formidable obstacles faced by national TB programs (NTPs). Random mutations in the bacterial DNA that occur at low but predictable rates confer resistance to individual anti-TB drugs. The growth of such mutants can be controlled by other drugs used in recommended treatment (DOTS). Improper or inadequate treatment permits these mutants to grow unchecked, resulting in treatment failure with the emergence of drug-resistant TB and the subsequent transmission of these resistant strains. Amplification of resistance (i.e., resistance to additional drug or drugs) may occur with further ineffective treatment. This has led to the worldwide development and spread of MDR TB. This form of TB is significantly more difficult to treat than drug-susceptible TB, in large part because the necessary second-line drugs are more expensive, must be administered for a longer period of time, are less effective, and are often associated with more severe side effects than the standard first line anti-TB drugs. In response to the emergence of MDR-TB, WHO adopted the DOTSPlus strategy for MDR-TB in 1998. Despite the recommendation of this strategy and the establishment of the Green Light Committee, that grants programs access to discounted second-line anti-TB drugs, the management

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of MDR TB cases and controlling the spread of resistance remain serious public health concerns throughout the world. In fact, drug-resistant TB was identified in 96% of areas surveyed globally between 1999 and 2002 (6). Although well-functioning DOTS and DOTS-Plus programs are critical for the control of MDR TB, these strategies are hindered by the difficulty and length of time required to diagnose drug-resistant TB. Conventional DST is a slow process, requiring culture of mycobacteria from clinical specimens, followed by a comparative growth evaluation after exposure to drug in solid media such as Lo¨wenstein–Jensen (LJ). This process can take two to six months, during which time patients with drug-resistant infections are often treated inappropriately for drug-susceptible TB. The resultant delay in proper treatment may adversely affect treatment outcome and contribute to the transmission of drug-resistant TB. Thus, it is imperative that concerted efforts are made to develop and implement rapid methods for the diagnosis of both paucibacillary and drug-resistant forms of TB. Although of less relevance to developing countries, improved tests for the diagnosis of latent TB infection (LTBI) are needed in settings where the incidence of active disease is low and identification and treatment of patients with LTBI is an important control strategy. The limitations of the tuberculin skin test (TST) are well known. Recently, two tests based on release of interferon-gamma from sensitized lymphocytes have been developed and are being marketed in industrialized countries (7,8). It is expected that these tests will gradually come to replace the TST in these settings. However, the role and optimal use of these tests in low-income countries has yet to be defined (Chapter 9). III. Obstacles to TB Diagnostic Development A number of new TB diagnostic tools, as reviewed below, have recently been developed. Most of these, especially molecular tests and automated culture systems, were developed for markets in industrialized countries and are not readily implemented in resource-constrained settings. Given the compelling need for better TB diagnostics for use in settings of endemic disease, it is relevant to ask why they are not already available. As outlined below, there are a number of obstacles, technical, financial, and political, to the development of the technologies needed to support patient care and disease control in high-burden countries. The technical challenges to development of TB diagnostic tests are manifold. The organism is often present in low numbers in clinical specimens; it grows slowly, poses a biohazard, has a thick, waxy cell wall that is difficult to lyse, and yields DNA with a high guanine–cytosine content. Perhaps most importantly, the most common specimen submitted for TB detection is sputum, which is a difficult, complex, and variable sample type requiring complex processing in most test systems. Financial obstacles to TB test development are equally evident. Private companies, the source of most modern technologies, develop and

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manufacture products in order to make profits. For many companies, the profitable market in TB diagnostics is not readily apparent, especially because rates of TB have declined in the established market economies (EME). Markets in EME are relatively fully penetrated with automated culture systems, and even nucleic acid amplification tests (NAATs), with their clear advantage of speed, have not been implemented to the degree that was predicted by marketing studies a decade ago. Not surprisingly, companies are wary of committing to new test development when the risk of inadequate return on investment appears high. The fact that TB cases are concentrated in developing countries has three important effects on business thinking. First, it mandates a highvolume, low-profit business model, which is not attractive. Second, it places rigid limits on test complexity, increasing the technical difficulty of test development. Detection of bacteria present at low concentrations, for example, usually requires a concentration or amplification step that would customarily result in a test too complex for use in most TB diagnostic settings in developing countries. Third, it places test sales in markets that are often wholly unfamiliar to biotechnology companies. The size and character of developing world diagnostics markets, their future trends, and how they can be accessed, have all been relatively obscure. The recently completed Diagnostics for Tuberculosis: Global Demand and Market Potential, by the UNICEF/UNDP/World Bank/WHO Special Programme on Research and Training in Tropical Diseases (TDR) and the Foundation for Innovative New Diagnostics (FIND), attempts to address this knowledge gap. Beyond clear-cut technical and financial hurdles, companies wishing to develop new diagnostics face philosophical obstacles as well. National Tuberculosis Programs (NTPs), which tend to be some of the best organized of the public sector disease-control programs, have been relatively rigid in their approach to diagnostic technologies. Under well-reasoned advice from international technical agencies such as WHO and the International Union Against Tuberculosis and Lung Disease (IUATLD), countries have focused their efforts on the implementation of smear microscopy, leaving little room for the introduction or even the evaluation of alternative technologies. The introduction of novel methods is always disruptive, and international health communities have been traditionally wary of such disruptions to often fragile disease-control efforts (9). Additional costs associated with such changes may also result in funds being diverted from other worthy health projects. Finally, diagnostics, of all the health technologies, tend to be undervalued. The curative power of medications and the preventive impact of vaccines are easy concepts to appreciate. The importance of diagnostics, which may be more often applied to people who do not have a given disease than to people who do, is more difficult for the public to value. Fortunately, each of the obstacles described above can be overcome and advances are being made in all of these areas. The need for improved case-finding to meet disease-control targets is now recognized as a priority

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at all levels in the TB control community, and there is a move toward greater flexibility in the diagnostic approaches used within the DOTS strategy. Furthermore, through the Global Fund for AIDS, TB and Malaria, countries now have access to new resources to improve diagnostic capacity with culture and other methods, and to implement other interventions that were not previously possible. The possibility of large public sector tender markets, with high volume annual purchase of tests by national governments, presents an important mechanism to facilitate the development of new tools. Lastly, advances in technology have also increased the feasibility of developing better diagnostic tools for developing countries, with simplified amplification methods, robust detection systems and engineered point-of-care solutions becoming available. These advances are spurred in part by large investments in biodefense as well as by a shift toward delivery of point-of-care diagnostic services in industrialized countries. They can be leveraged by appropriately resourced public sector diagnostic development programs to develop highly effective and sophisticated but simple to use diagnostic technologies suitable for use in developing countries. IV. TB Diagnostic Priorities As TB is detected in clinical settings that vary widely, multiple types of diagnostics are needed. Which tests are needed most? For the public sector, the priority diagnostics are those that would have the greatest impact on casefinding, on interruption of transmission, and on decrease in morbidity and mortality from TB. The diagnostic priorities for TB control are summarized in Table 1. The order of these priorities is based on: (i) the number of individuals that Table 1 Tuberculosis Diagnostic Priorities Purpose Case detection

Drug susceptibility testing LTBI

Test indications

Target population size

Detect pulmonary TB with high bacterial load (sputum smear– positive) Detect pulmonary TB with low bacterial load (sputum smear– negative, culture-positive) Detect extrapulmonary and pediatric TB

100–200 million

Detect MDR TB for treatment

10 million

Detect MDR TB for surveillance

100,000

Detect LTBI for surveillance Detect LTBI for treatment

Unknown Test-dependent

Abbreviations: LTBI, latent TB infection; MDR, multidrug resistant.

100–200 million

5–50 million

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would directly benefit by an improved tool, (ii) the importance of specific populations (such as smear-positive patients) to disease-control efforts, and (iii) the degree of medical benefit that new technologies could offer over existing tests. Detection of active TB is the highest priority, and requires differentiating the nearly nine million new cases of TB from over 10 times as many individuals who have other similar symptoms due to other conditions (10). For simplicity, these calculations are generally based on the annual number of incident cases, and not the number of prevalent cases, though clinics will obviously see a mixture of both. The number of prevalent cases, which includes those already diagnosed and currently on therapy, those with chronic untreatable disease, and those with undetected disease, may be twice as large as the number of incident cases. Extrapulmonary and pediatric TB, though less common, are both lethal and especially difficult to diagnose using the technologies currently available in disease-endemic countries. The need for improved DST methods that could be used to direct drug therapy (using more expensive and more toxic second-line drugs for multidrug-resistant cases), is ranked above the need for DST surveillance tools, not because the latter use is not important, but because existing DST technologies, although slow, are generally adequate for this purpose. The need for new diagnostic tests for LTBI is of less relevance for global TB control efforts for the short term. However, new tests may facilitate surveys to determine the annual risk of infection that currently rely on TST. In addition, improved diagnostics for LTBI in HIV-infected persons may become more important as HIV/AIDS care programs expand. As for most health interventions, patient access will be at least as important as specific performance characteristics in determining the overall impact of a given diagnostic test. Tests that are so complex that they can only be used at referral laboratories will have a much lower impact than those that are widely accessible at lower levels of the health system such as a local health clinic. The vast majority of TB patients first seek care at peripheral health clinics where microscopy services are often not available. Thus, tests that could replace microscopy, especially if they were simple enough to be used at the local clinics, would reach the greatest number of patients. Such tests would also have the greatest impact by providing rapid access to correct treatment and thus reducing both morbidity and transmission of TB. In an idealized health system such as represented in Figure 1, the types of TB testing carried out at each level would match the services intended to be provided there. The national reference laboratories would support the laboratory network through appropriate supervision and the provision of reference methods necessary for both quality control and quality assurance. District or regional referral laboratories would work to resolve complex cases or detect those that could not be detected with the diagnostics available more peripherally. The bulk of diagnostic work would be carried out in the local health-care facilities. In many health systems, diagnostic services at peripheral health centers are scarce, and much of

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Figure 1

Diagnostic needs at levels of the health system.

the microbiologic confirmation of disease today occurs at district laboratories. This is largely due to the complexity of the current diagnostic tools. Simplifying these technologies would allow testing at more appropriate local level, and significantly facilitate the diagnostic process. V. Characteristics of Needed Tests How does this schematic translate into a specific set of goals for test development? The diagnostic industry begins the development process with a definition of what is required by the end user. This customer requirement document lays out the clinical performance targets as well as other required features, such as ease of use and robustness, for a given use indication. A customer requirement document for a tool to replace microscopy is shown in Table 2. VI. TB Diagnostics Currently in the Development Pipeline While waiting for new diagnostic tests that will revolutionize TB control, significant advances may be made both by improving available technologies and by more widely implementing existing tests that until now have had only restricted use in low-income countries. Improvement in the yield of AFB smear-microscopy is possible by digesting and concentrating the sputum prior to staining and examination. (Text continues on page 1126.)

<10 min None None

No need for biosafety cabinet, no special disposal needs

Time-to-result

Instrumentation

Additional equipment required

Biosafety

Comments

(Continued )

Determined in an adult population of symptomatic individuals with and without HIV or parasitic coinfection

Sputum, skin, breath, blood, Should work with at least one of serum, urine mentioned sample types Simple 5–10 step procedure <15 min per sample <1 wk, if performance equal Incl. sample prep and readout to culture Replaceable or maintenance-free device Only robust equipment with minimal maintenance ( >6 mo between maintenance). No balance, HEPA filter, temperature control, etc., needed No need for biosafety cabinet

Minimum

>95% of smear-positive patients >90% smear-positive cases (if and >75% of culture-positive significantly easier than patients microscopy) and >40% smearnegative cases detected

None

Sample preparation

Performance Diagnostic sensitivity

Sputum, skin, breath, urine

Desired

Workflow Sample Sample type

Feature

Table 2 Customer Requirement Document TB Case Detection: Microscopy Level

New Diagnostics for Tuberculosis 1123

Reconstituted reagents stability

Product design Stability/storage requirements Kit stability

Diagnostic specificity

Feature >97% overall, with some falsepositives in clinically important NTM infections

Minimum

Determined in TB suspects confirmed not to have TB by negative microscopy and culture (X2) AND either improvement without TB treatment or confirmation of an alternate cause of symptoms. Must not require exclusion of patients with prior BCG-vaccination, TB exposure, NTM infection, cured TB, or HIV infection

Comments

12 mo storage at 35 C, 70% 24 mo storage at 4 C and 7 days at humidity, incl. transport stress 35 C incl. transport stress (48 hr (48 hr at 50 C) at 50 C) Ready-to-use reagents, no 8 hr at 4 C Cannot require packaging reconstitution configuration mandating high unit manufacturing costs

>98%, with no NTM crossreactivity

Desired

Table 2 Customer Requirement Document TB Case Detection: Microscopy Level (Continued )

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No 115/220 V AC operates at 35 C

Yes Option for battery operation (if electricity required). Instrument can be used also for testing of other infections <1 hr, nurse level <2 days high school diploma or equivalent

Opened package lasts 2 wk at 4 C

Ready-to-use units, no reconstitution

Fixed cutoff No more than 1 calibrator Full-process positive control and Positive control, negative control negative control Full-process positive must shall include lysis process where appropriate

Note: Tuberculosis diagnostic test: peripheral clinic level. Intended use: Detection of active infection with Mycobacterium tuberculosis. This is presently accomplished via smear, which is relatively insensitive even for pulmonary disease, by clinical examination and X-ray, which are relatively nonspecific, or (more rarely) by culture, which takes four to six weeks. The primary goal is to provide a test system with sensitivity and specificity equal or better than that of microscopy, but at much faster time-to-result. Must work properly in HIV-infected patients from target population (‘‘high endemic countries for TB’’ as defined by the World Health Organization). Abbreviations: NTM, nontuberculosis mycobacterial; BCG, bacille Calmette-Gue´rin; HEPA, high efficiency particulate air.

Training and education needs

Determinations per ‘‘reconstituted reagent unit’’ Result capturing and documentation Instrument design

Calibrators Controls

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A variety of sputum digestion methods are available. The method of greatest interest involves the use of household bleach (sodium hypochlorite) that both liquefies sputum and kills mycobacteria, thereby decreasing the possibility that laboratory technicians would become infected through exposure to infectious sputum (11). Centrifugation is generally used in combination with bleach to concentrate sputum specimens, increasing the yield on microscopy by 15% to 50% in a number of studies. However, the low-cost centrifuges available in most developing country laboratories cannot achieve the speed required for efficient sputum concentration. Moreover, it is not likely that resources, both financial and human, would be available in the near future to provide efficient centrifuges in peripheral laboratories in developing countries. Therefore, bleach processing followed by overnight sedimentation may be a feasible method that requires validation studies to determine its usefulness (12). Fluorescence microscopy is another method that both increases yield over light microscopy and significantly reduces the time needed to examine a sputum smear. However, the cost of fluorescence microscopes and the requirement for frequent bulb replacement has restricted widespread application of this technology. Prototype lower-cost microscopes using light-emitting diodes that allow battery operation and obviate the need for frequent bulb changes have been developed (13), but their performance for TB detection needs to be evaluated and the impact of their implementation needs to be demonstrated. Microbiologic isolation and identification of M. tuberculosis from a diagnostic specimen remains the reference standard for the diagnosis of TB. However, in many developing countries culture capability is limited to a single reference laboratory that supports periodic surveys, e.g., drug resistance surveys and research studies. Many of those laboratories are poorly equipped and staffed and do not participate in quality assurance programs. It is estimated that the cost of establishing a culture-capable laboratory with adequate biosafety standards may be as high as US $250,000. However, with more resources flowing into TB control and the pressing need, expansion of culture facilities in support of case finding is being considered. Besides fiscal impediments, the lack of highly trained laboratory technicians is a serious concern. Because culture facilities are being upgraded and expanded, opportunities exist to assess new culture systems that are more rapid than traditional culture on solid media. These include liquid culture systems (14–16) and solid culture media with a colorimetric readout (17). Although somewhat more costly than conventional egg-based media such as LJ, the increased speed of detection (and for the liquid systems) the increased sensitivity, may provide personal and public health benefits that offset the greater cost. Alternative noncommercial methods to speed culture-based detection have been proposed, including microscopic observation of mycobacterial growth in solid (18) or liquid culture (19), but these involve additional work for laboratory technicians and they have not been widely used.

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Several groups have exploited the capacity of mycobacteriophages to infect and replicate in tubercle bacilli as biologic amplification systems to detect TB, and one such test has been commercialized (20,21). Although requiring the same facilities and involving more specimen manipulation as those needed for mycobacterial culture, the assays provide results in only a few days. Particularly interesting are those phage-based assays that provide accurate and rapid information on drug susceptibility as well as confirming the presence of mycobacteria (see below) (22). Molecular methods, in particular NAATs, have demonstrated high specificity and sensitivity approaching that of culture for the diagnosis of pulmonary TB (23–25) Results from these assays are available within one day, compared with four to six weeks for culture results on solid media. However, the cost and moderate complexity of NAATs have limited their widespread use, even in industrialized countries. Studies of NAAT use in developing countries have produced mixed results, with widely variable performance (26). There are data, however, suggesting that such assays might be more cost-effective than AFB smear examination when patient costs are included (27). It may be possible to dramatically simplify NAAT technology by using isothermal amplification methods with visual readout (28), and by engineering the sputum processing steps to provide a relatively inexpensive, hand-held device. Such systems are presently under development. Serologic tests based on the detection of circulating antibody to mycobacterial antigens have been of interest for over 100 years (29–34). Tests that utilized crude mycobacterial proteins [e.g., purified protein derivative (PPD)] lacked specificity because of cross-reactions. During the past several decades, work in this area has focused on the use of specific antigens, including several that are present uniquely in the M. tuberculosis complex. A number of such tests, using purified or recombinant antigens and formatted as ‘‘lateral flow’’ test strips with visual reading, are being marketed in low-income countries. However, when these tests were evaluated in carefully designed, independent studies, their performance characteristics were poor, so that the tests could not be recommended for use (35). This is especially true in immunosuppressed patients (36,37). Nonetheless, work in this area is continuing. The most promising of such work focuses on evaluation of the entire proteome of M. tuberculosis to determine whether there are any antigens, or combination of antigens, that can detect an antibody response that could be diagnostic for active TB. One of the most exciting areas for new test development is the detection of small molecules produced or excreted by tubercle bacilli during active replication. These include mycobacterial antigens and DNA fragments, which can be detected in blood or urine (38–41). If tests for such mycobacterial products can be made to be sufficiently sensitive, it may be possible to incorporate them in simple, point-of-care kits requiring no equipment and little spesialized training for use. Similar work continues on the detection of volatile mycobacterial products through sophisticated sensing systems (i.e., ‘‘electronic noses’’) for diagnosing TB (42,43).

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The presently available culture systems are also used for the detection of drug resistance. However, under optimal conditions with liquid culture and DST, up to four weeks are required for results. Direct DST (i.e., inoculation of smear-positive sputum specimens onto drug-containing medium) on solid medium can produce more rapid results but is not widely used. A novel method for determining rifampicin resistance based on phage replication produces reliable results in only two days for patients with sputum smear–positive pulmonary disease (44). Even more rapid are molecular tests based on determination of mutations in the genome that confirm drug resistance, e.g., rpoB for rifampicin and katG for isoniazid. Although rapid and accurate, such tests are presently too costly and complex for use in most settings where drug resistance is problematic. However, simplified NAATs that might be developed for diagnosis of active TB could also allow screening for drug resistance. As noted above, two interferon-gamma release assays (IGRAs) assays have been commercialized and are undergoing further development to make the application more feasible in field settings. These assays use the proteins ESAT-6 and CPF-10 from a section of the mycobacterial genome nominated RD1 for being a ‘‘region of deletion’’ from M. bovis BCG. Such RD1 genes are also absent from most strains of nontuberculous mycobacteria. Thus, the specificity of these tests compared to that of the TST using PPD is high. Limited data suggest that these assays may maintain better sensitivity than TST in HIV-infected populations (45). As mentioned above, the sensitivity and utility of such tests in countries with a high burden of TB is not yet clear (46), although there is some suggestion that they might be used as a sensitive marker for TB in children (47). Early attempts to use these and other specific antigens as skin test reagents, while showing some promise in animal models, have not succeeded in human studies. While there is still interest in the potential of skin tests that have better performance characteristics than the current TST, it has been tempered with the advent of the IGRAs. VII. Public–Private Partnerships and a Development Strategy Public funding for TB research, such as that from the U.S. National Institutes of Health, is providing for significant advance in our understanding of the pathogenesis of TB infection and disease. Such advances may provide insights into novel approaches to TB diagnosis. Funding is also generally available for initial evaluation of these concepts to advance to the ‘‘proofof-principle’’ stage, indicating that a concept can be shown to work in a highly controlled setting. However, at this point further advances often cease for lack of additional funding. The creation of FIND has provided a mechanism to move promising diagnostic technologies that may be stalled because of lack of funding through the development pipeline. Using limited resources to undertake

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laboratory-based validation studies, FIND has been able to secure intellectual property rights to ensure that, if successful, the technology will be available for use in the public sector in low-income countries at the lowest possible price. Beginning at the post–proof-of-principle stage, support is provided for the additional laboratory-based work to refine test performance and package it in a format that can then be used in clinical trials. Technologies that perform well in laboratory-based studies are then more rigorously evaluated in well-controlled clinical settings analogous to Phase III clinical trials of a new drug or drug regimen. In the past, these studies have been undertaken without regard to the standards that are well accepted for clinical therapy trials. Problems that have plagued these studies include failure to include representative patients with and without TB, inappropriate choice of the reference standard for diagnosis, observational biases because of failure to blind the readers to both clinical and laboratory results, and absence of valid statistical methods to analyze study results. This lack of rigor in part explains the discrepancies between the results of studies conducted by test manufacturers and those by independent scientists. Fortunately, a recent initiative to bring rigor to studies of diagnostic tests and their evaluation has gained widespread acceptance, especially among editors of bio, edical research journals (48). The requirement for adherence to the Standards for Reporting of Diagnostic Accuracy initiative for consideration for publication of diagnostic trials should lead to a much higher quality of diagnostic test research reported in the medical literature. A Diagnostics Evaluation Expert Panel, convened jointly by FIND and TDR, is working to further set methodologic standards for the design and execution of trials to evaluate diagnostic tests for infectious diseases. Studies of new tests for active TB are best evaluated in the population of intended use, i.e., in patients with signs and symptoms of TB. These studies would include mycobacterial culture on solid and liquid media and careful assessment, with clinical and microbiologic follow-up, of culturenegative patients who may have paucibacillary TB. Test sensitivity should be based on a gold standard that includes patients with culture-negative disease and test specificity on those patients with signs and symptoms of TB who are found not to have the disease after careful assessment and follow-up. A critical component of FIND’s strategy is large-scale demonstration projects of technologies that have been proven to perform well in carefully controlled studies. In these projects, newly proven tests are incorporated into routine laboratory and program settings to assess their ease of implementation, acceptance, and impact on such factors as morbidity, mortality, and disease transmission, and, importantly, cost. Data from these studies can be used by internationally recognized technical bodies such as WHO and the IUATLD to guide policy on test use, and by Ministries of Health and Finance and nongovernmental organizations working in TB to make decisions about test purchase and implementation. Finally, guaranteeing access to new tests by those most in need can be facilitated by distribution networks

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such as the Global Drug Facility that have been established to assist NTPs in access to high-quality TB drugs. Without concurrently and significantly strengthening laboratory TB diagnostic services in the developing word, promising new tools may flounder because the infrastructure to support their use does not exist. Thus, the activities being championed by the Stop TB Partnership’s Working Group on Laboratory Capacity Strengthening require urgent support. This work includes: standardization of laboratory methods and guidelines; development of programs for external quality assurance similar to that for smear microscopy; provision of technical assistance to countries in the form of technical consultation and training courses and materials; a significant increase in funding for TB diagnostic services at all levels to include provision of adequate, well trained staff; and careful monitoring and evaluation of progress to upgrade diagnostic capacity.

VIII. Conclusion Global TB control is at a crossroad. A decade and a half after the introduction of the WHO DOTS strategy, its successes and limitations have never been more apparent. The basic elements of sound TB control are largely in place throughout the world. However, further advancement to meet the challenges posed by the HIV epidemic and the widespread emergence of MDR-TB will not be possible without the expansion of diagnostic capabilities beyond AFB microscopy and the implementation of new diagnostic technologies. These needs, and the opportunities for significant progress to meet them, have been captured in the Stop TB Partnership’s Global Plan to Stop TB, 2006–2015. The network to implement the elements of the plan related to diagnostics led by FIND and its partners is in place. It is now up to the world at large to see that this plan is implemented with adequate support. If it is, 10 years from now we will be able to plan for global elimination of human TB. If not, we will likely be mired in an expanding, out-of-control epidemic in which breathing becomes a high-risk behavior. The choice is ours. References 1. Burman WJ, Jones BE. Clinical and radiographic features of HIV-related tuberculosis. Semin Respir Infect 2003; 18:263–271. 2. Squire SB, Belaye AK, Kashoti A, et al. ‘Lost’ smear-positive pulmonary tuberculosis cases: where are they and why did we lose them? Int J Tuberc Lung Dis 2005; 9: 25–31. 3. Hargreaves NJ, Kadzakumanja O, Whitty CJ, et al. ‘Smear-negative’pulmonary tuberculosis in a DOTS programme: poor outcomes in an area of high HIV seroprevalence. Int J Tuberc Lung Dis 2001; 5:847–854. 4. Pronyk PM, Kahn K, Hargreaves JR, et al. Undiagnosed pulmonary tuberculosis deaths in rural South Africa. Int J Tuberc Lung Dis 2004; 8:796–799.

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5. Gutierrez EB, Zanetta DM, Saldiva PH, et al. Autopsy-proven determinants of death in HIV-infected patients treated for pulmonary tuberculosis in Sao Paulo, Brazil. Pathol Res Pract 2002; 198:339–346. 6. Anti-tuberculosis drug resistance in the world. Third global report. WHO/IUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 1999–2002. World Health Organization, 2004. 7. 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; 361:1168–1173. 8. Ferrara G, Losi M, Meacci M, et al. Routine hospital use of a new commercial whole blood interferon-gamma assay for the diagnosis of tuberculosis infection. Am J Respir Crit Care Med 2005; 172:631–635. 9. Tuberculosis Division International Union Against Tuberculosis and Lung Disease. Tuberculosis bacteriology—priorities and indications in high prevalence countries: position of the technical staff of the Tuberculosis Division of the International Union Against Tuberculosis and Lung Disease. Int J Tuberc Lung Dis 2005; 9: 355–361. 10. World Health Organization. Global Tuberculosis Report 2004. 11. Angeby KA, Hoffner SE, Diwan VK. Should the ‘bleach microscopy method’ be recommended for improved case detection of tuberculosis? Literature review and key person analysis. Int J Tuberc Lung Dis 2004; 8:806–815. 12. Miorner H, Ganlov G, Yohannes Z, et al. Improved sensitivity of direct microscopy for acid-fast bacilli: sedimentation as an alternative to centrifugation for concentration of tubercle bacilli. J Clin Microbiol 1996; 34:3206–3207. 13. Herman P, Maliwal BP, Lin HJ, et al. Frequency-domain fluorescence microscopy with the LED as a light source. J Microsc 2001; 203:176–181. 14. Morgan MA, Horstmeier CD, DeYoung DR, et al. Comparison of a radiometric method (BACTEC) and conventional culture media for recovery of mycobacteria from smear-negative specimens. J Clin Microbiol 1983; 18:384–388. 15. Somoskovi A, Kodmon C, Lantos A, et al. Comparison of recoveries of mycobacterium tuberculosis using the automated BACTEC MGIT 960 system, the BACTEC 460 TB system, and Lowenstein-Jensen medium. J Clin Microbiol 2000; 38:2395–2397. 16. Angeby KA, Werngren J, Toro JC, et al. Evaluation of the BacT/ALERT 3D system for recovery and drug susceptibility testing of Mycobacterium tuberculosis. Clin Microbiol Infect 2003; 9:1148–1152. 17. Baylan O, Kisa O, Albay A, et al. Evaluation of a new automated, rapid, colorimetric culture system using solid medium for laboratory diagnosis of tuberculosis and determination of anti-tuberculosis drug susceptibility. Int J Tuberc Lung Dis 2004; 8:772– 777. 18. Mejia GI, Castrillon L, Trujillo H, et al. Microcolony detection in 7H11 thin layer culture is an alternative for rapid diagnosis of Mycobacterium tuberculosis infection. Int J Tuberc Lung Dis 1999; 3:138–142. 19. Moore DA, Mendoza D, Gilman RH, et al. Microscopic observation drug susceptibility assay, a rapid, reliable diagnostic test for multidrug-resistant tuberculosis suitable for use in resource-poor settings. J Clin Microbiol 2004; 42:4432–4437. 20. Alcaide F, Gali N, Dominguez J, et al. Usefulness of a new mycobacteriophage-based technique for rapid diagnosis of pulmonary tuberculosis. J Clin Microbiol 2003; 41:2867–2871. 21. Kalantri S, Pai M, Pascopella L, et al. Bacteriophage-based tests for the detection of Mycobacterium tuberculosis in clinical specimens: a systematic review and metaanalysis. BMC Infect Dis 2005; 5:59.

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22. Pai M, Kalantri S, Pascopella L, et al. Bacteriophage-based assays for the rapid detection of rifampicin resistance in Mycobacterium tuberculosis: a meta-analysis. J Infect 2005; 51:175–187. 23. Shamputa IC, Rigouts L, Portaels F. Molecular genetic methods for diagnosis and antibiotic resistance detection of mycobacteria from clinical specimens. APMIS 2004; 112:728–752. 24. Huggett JF, McHugh TD, Zumla A. Tuberculosis: amplification-based clinical diagnostic techniques. Int J Biochem Cell Biol 2003; 35:1407–1412. 25. Woods GL. Molecular techniques in mycobacterial detection. Arch Pathol Lab Med 2001; 125:122–126. 26. Suffys P, Palomino JC, Cardoso Leao S, et al. Evaluation of the polymerase chain reaction for the detection of Mycobacterium tuberculosis. Int J Tuberc Lung Dis 2000; 4:179–183. 27. van Cleeff M, Kivihya-Ndugga L, Githui W, et al. Cost-effectiveness of polymerase chain reaction versus Ziehl-Neelsen smear microscopy for diagnosis of tuberculosis in Kenya. Int J Tuberc Lung Dis 2005; 9:877–883. 28. Iwamoto T, Sonobe T, Hayashi K. Loop-mediated isothermal amplification for direct detection of Mycobacterium tuberculosis complex, M. avium, and M. intracellulare in sputum samples. J Clin Microbiol 2003; 41:2616–2622. 29. Daniel TM. Antibody and antigen detection for the immunodiagnosis of tuberculosis: why not? What more is needed? Where do we stand today? J Infect Dis 1988; 158:678–680. 30. Gennaro ML. Immunologic diagnosis of tuberculosis. Clin Infect Dis 2000; 30(suppl 3):S243–S246. 31. Samanich K, Belisle JT, Laal S. Homogeneity of antibody responses in tuberculosis patients. Infect Immun 2001; 69:4600–4609. 32. Weldingh K, Rosenkrands I, Okkels LM, et al. Assessing the serodiagnostic potential of 35 Mycobacterium tuberculosis proteins and identification of four novel serological antigens. J Clin Microbiol 2005; 43:57–65. 33. Houghton RL, Lodes MJ, Dillon DC, et al. Use of multiepitope polyproteins in serodiagnosis of active tuberculosis. Clin Diagn Lab Immunol 2002; 9:883–891. 34. Perkins MD, Conde MB, Martins M, et al. Serologic diagnosis of tuberculosis using a simple commercial multiantigen assay. Chest 2003; 123:107–112. 35. Pottumarthy S, Wells VC, Morris AJ. A comparison of seven tests for serological diagnosis of tuberculosis. J Clin Microbiol 2000; 38:2227–2231. 36. Somi GR, O’Brien RJ, Mfinanga GS, et al. Evaluation of the MycoDot test in patients with suspected tuberculosis in a field setting in Tanzania. Int J Tuberc Lung Dis 1999; 3:231–238. 37. Talbot EA, Hay Burgess DC, Hone NM, et al. Tuberculosis serodiagnosis in a predominantly HIV-infected population of hospitalized patients with cough, Botswana, 2002. Clin Infect Dis 2004; 39:e1–e7. 38. Sada E, Aguilar D, Torres M, et al. Detection of lipoarabinomannan as a diagnostic test for tuberculosis. J Clin Microbiol 1992; 30:2415–2418. 39. Tessema TA, Hamasur B, Bjun G, et al. Diagnostic evaluation of urinary lipoarabinomannan at an Ethiopian tuberculosis centre. Scand J Infect Dis 2001; 33: 279–284. 40. Bentley-Hibbert SI, Quan X, Newman T, et al. Pathophysiology of antigen 85 in patients with active tuberculosis: antigen 85 circulates as complexes with fibronectin and immunoglobulin G. Infect Immun 1999; 67:581–588. 41. Wallis RS et al. Induction of the antigen 85 complex of Mycobacterium tuberculosis in sputum: a determinant of outcome in pulmonary tuberculosis treatment. J Infect Dis 1998; 178:1115–1121.

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42. Pavlou AK, Magan N, Jones JM, et al. Detection of Mycobacterium tuberculosis (TB) in vitro and in situ using an electronic nose in combination with a neural network system. Biosens Bioelectron 2004; 20:538–544. 43. Fend R, Geddes R, Lesellier S, et al. Use of an electronic nose to diagnose Mycobacterium bovis infection in badgers and cattle. J Clin Microbiol 2005; 43:1745–1751. 44. Albert H, Trollip A, Seaman T, et al. RJ. Simple, phage-based (FASTPplaque) technology to determine rifampicin resistance of Mycobacterium tuberculosis directly from sputum. Int J Tuberc Lung Dis 2004; 8:1114–1119. 45. Dheda K, Lalvani A, Miller RF, et al. Performance of a T-cell-based diagnostic test for tuberculosis infection in HIV-infected individuals is independent of CD4 cell count. AIDS 2005; 19:2038–2041. 46. 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; 38:966–973. 47. Liebeschuetz S, Bamber S, Ewer K, et al. Diagnosis of tuberculosis in South African children with a T-cell-based assay: a prospective cohort study. Lancet 2004; 364:2196–2203. 48. Bosssuyt PM, Reitsma JB, Bruns DE, et al. Towards complete and accurate reporting of studies of diagnostic accuracy: The STARD Initiative. Clin Chem 2003; 49:1–6.

47 New Drugs for Tuberculosis

ANN GINSBERG

MELVIN SPIGELMAN

Clinical Department, Global Alliance for TB Drug Development, New York, New York, U.S.A.

Research and Development, Global Alliance for TB Drug Development, New York, New York, U.S.A.

I. Introduction Although treatment of active, drug-sensitive, pulmonary tuberculosis (TB) is potentially 95% to 98% effective (1), there are cogent arguments for developing new TB drugs. These arguments include the need to: (i) shorten and simplify current treatment regimens for active, drug-sensitive disease; (ii) provide safer, more effective, lower-cost treatment alternatives for multidrug-resistant (MDR) TB; (iii) remove obstacles to effective treatment of TB in HIV-positive individuals; and (iv) shorten treatment of latent TB infection (LTBI). The following sections examine each of these rationales. II. Treatment of Active Tuberculosis Current recommended treatment regimens for active pulmonary TB are lengthy, lasting a minimum of six months, and complex, typically requiring administration of four drugs daily during the first two months and two drugs during the remaining four months (2). The World Health Organization (WHO) TB treatment strategy, DOTS, has at its core the direct observation by trained personnel of patients taking their TB medications to ensure compliance and prevent development of drug-resistance. These features, 1135

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although key to treatment success, render TB therapy burdensome and labor-intensive to deliver effectively, as well as difficult for patients to adhere to (current TB treatment is more fully treated in Chapter 8). As a result, many patients do not receive adequate treatment, inhibiting control of the global TB epidemic and enabling the development and spread of MDR strains of Mycobacterium tuberculosis. Components of the current regimens (primarily, the rifamycins) have the added disadvantage of interacting with antiretroviral therapy (ART) [protease inhibitors (PIs); see below and Chapter 13, section VII], a significant problem given the high incidence and prevalence of HIV/M. tuberculosis coinfection. The primary goal in improving treatment of active TB is to deliver to patients more efficacious and safer agents and regimens that will shorten and simplify the therapeutic course, thereby decreasing the burdensome nature of the treatment regimen for both patients and health care systems and increasing rates of successful treatment completion while lowering rates of treatment default and loss to follow-up. III. Treatment for MDR-TB MDR-TB is a man-made scourge resulting from inappropriate or incomplete treatment of patients with active disease. Factors contributing to the development of MDR-TB include inadequate treatment programs, drug shortages, and lack of adherence to prescribed regimens, creating conditions that select for M. tuberculosis strains resistant to first-line drugs. Streptomycin, the first anti-TB drug identified, was introduced for use in 1944; by 1948, cases of streptomycin-resistant TB had been reported (3). To be classified as MDR-TB, a strain must be resistant to at least isoniazid and rifampicin. In the latest WHO/International Union Against Tuberculosis and Lung Disease (IUATLD)-sponsored global surveillance of drug resistance (4), a global median of 1.1% of newly diagnosed cases were found to be MDR-TB. Treatment of MDR-TB must rely on drugs that are less effective and more toxic than first-line therapy, as well as up to 110-fold more expensive overall (5–7). To significantly improve treatment of MDR-TB, novel drugs that are affordable as well as safe and effective against these strains must be developed. To contain the spread of MDR-TB, a combination of appropriate and effective treatment of drug-sensitive cases with careful introduction of second-line drugs for treatment of MDR cases must be instituted (8). Prospective, randomized, controlled trials of novel MDR-TB treatment regimens will pose significant challenges; no such trials have been reported to date. Rather, current MDR-TB treatment regimens are based on anecdotal evidence and retrospective cohort studies. As can be seen in the descriptions below, except for the rifamycins, all classes and agents in the current pipeline of compounds being developed for treatment of active TB have novel mechanisms of action relative to current first-line TB drugs and therefore have the potential to be effective against MDR-TB.

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IV. Treatment of Active TB in Individuals Infected with HIV In 2000, 9% of all new TB cases in adults aged 15 to 49 years were attributable to HIV infection; in the WHO Africa Region, 31% of TB cases were HIVpositive and in the United States, 26%. Twelve percent of the estimated 1.8 million TB deaths in 2000 were attributable to HIV, and TB was identified as the cause of 11% of all adult AIDS deaths (9). WHO estimates that onethird of the 40 million people currently infected with HIV are coinfected with M. tuberculosis. Up to half of people living with HIV/AIDS develop active TB, and TB speeds HIV progression, so effective therapy of TB in these individuals is crucial. Unfortunately, rifampicin induces certain cytochrome P450 enzymes, which metabolize some of the PIs and nonnucleoside reverse transcriptase inhibitors (NNRTIs) used in ART. Therefore, concomitant use of rifampicin with ART can lead to decreased serum levels of these drugs. PIs and NNRTIs can also affect the P450 system, thereby altering serum levels of rifampicin. These drug–drug interactions seriously complicate the treatment of TB in persons with HIV/AIDS. In addition, both isoniazid and nucleoside reverse transcriptase inhibitors can cause peripheral neuropathy, leading to enhanced toxicity if these are used together. Therefore, a priority for treatment of these patients is to develop novel drugs for TB treatment with an enhanced safety profile, and in particular, without cytochrome P450 interactions. V. Treatment of Latent TB Based primarily on the results of tuberculin skin test surveys, an estimated 2 billion people globally are infected with M. tuberculosis (10). Current recommended treatment of LTBI to prevent later reactivation consists of nine months of isoniazid in HIV-positive persons. Due to the long duration of therapy and potential for hepatic toxicity, nonadherence with the regimen is a significant problem. There are also significant operational barriers to implementing such a regimen on a scale widespread enough to eradicate this enormous reservoir of future disease. Shorter and more intermittent regimens have been tested and are used under some conditions, but have demonstrated significant rates of adverse effects, including hepatic toxicity and joint pain, and those that contain rifamycin pose difficulties for administration in HIV-positive persons taking antiretroviral medications (11,12). New drugs are needed to shorten the treatment course while maintaining efficacy and ensuring tolerability, as well as suitability for HIV-positive individuals. One major hurdle in the search for new drugs for the improved treatment of LTBI is the lack of understanding of the underlying mechanisms of chronic, asymptomatic (latent) infection. VI. The Global Alliance for TB Drug Development In 2000, because the public health need for improved TB drugs was far outstripping the global effort devoted to developing these drugs, the Rockefeller

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Foundation convened a meeting in Cape Town, South Africa, hosted by the South African Medical Research Council, to address means for stimulating TB drug development. Over 120 organizations including governments, academic institutions, large pharmaceutical companies, biotech companies, international NGOs, patient advocacy groups, foundations, and others attended the meeting and concluded by recommending the formation of a public–private partnership whose mission would be to develop improved treatments for TB and ensure access to these treatments by those patients who need them. An initial grant from the Rockefeller Foundation established the Global Alliance for TB Drug Development (TB Alliance), a 501(c) (3) not-for-profit foundation, with substantial additional funding soon following primarily from the Bill and Melinda Gates Foundation. The TB Alliance functions as a virtual pharmaceutical company to establish and develop a robust pipeline of compounds and ultimately ensure their equitable access for all patients, using the expertise of private industry, among others, to meet this public health goal. Collaborations and partnerships of various types have been and will continue to be forged by the TB Alliance with pharmaceutical and biotech companies, as well as academic and governmental organizations, to move promising compounds and projects through the drug development process. These arrangements include, as examples, in-licensing of compounds, sponsored projects, contracts for outsourcing of various stages of development, codevelopment, and other forms of partnerships. VII. The Drug Development Process The process of drug development is frequently described as advancing compounds through a ‘‘pipeline’’ which begins with Discovery, proceeds through Preclinical or Nonclinical Development (including in vitro and in vivo animal testing), to Clinical Development (human testing; typically divided into phases I, II, and III).a If the clinical data warrant, compounds are then registered with regulatory agencies for the desired indication. Registration is generally followed by ‘‘post-marketing’’ trials known as phase IV studies, to investigate further how a drug is functioning in terms of safety and/or efficacy in the marketplace, and potentially to explore a

The phases I, II, and III are typically defined as follows (see for example, http://www. clinicaltrials.gov/ct/info/): phase I trials: Initial studies to determine the pharmacokinetics, metabolism, and pharmacologic actions of drugs in humans, the side effects associated with increasing doses, and to gain early evidence of efficacy; may include healthy participants and/or patients. Phase II trials: Controlled clinical studies conducted to evaluate the efficacy of the drug for a particular indication or indications in patients with the disease or condition under study and to determine the common short-term side effects and risks. Phase III trials: Expanded controlled and uncontrolled trials after preliminary evidence suggesting efficacy of the drug has been obtained, and are intended to gather additional information to evaluate the overall benefit-risk relationship of the drug and provide an adequate basis for physician labeling.

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new indications or combinations. In reality, drug development is a highly iterative process. Results from one stage of development most often inform additional studies still being designed and executed in an ‘‘earlier’’ stage, either for that compound or for a ‘‘next generation’’ compound in the same chemical class for the same or a similar indication. VIII. The Emerging Global Tuberculosis Drug Portfolio For the first time in decades, there is a pipeline of new drugs being explored specifically for their potential utility in the treatment of TB. While a small number of these drugs belong to classes that have already been approved for TB therapy, such as the rifamycins, most belong to chemical classes that have never been approved for a TB indication. These classes include the nitroimidazoles, pyrroles, diarylquinolines, fluoroquinolones, oxazolidinones, macrolides and diamines, and several compounds in development appear to have completely novel mechanisms of action. A. Nitroimidazoles

Two compounds within the nitroimidazole class are currently under investigation as potential anti-TB drugs. These are the nitroimidazo-oxazine, PA-824, being developed by the TB Alliance, and the dihydroimidazooxazole, OPC-67683, being developed by Otsuka Pharmaceutical Company. Each of these compounds can trace its history back to at least the 1970s, when Ciba-Geigy studied a series of nitroimidazoles for their potential as radiosensitizing drugs. These compounds were subsequently discovered to have antimicrobial activity, including activity against M. tuberculosis. However, when the lead compound (CGI-17341) was found to be mutagenic in the Ames assay, Ciba-Geigy stopped development of the class. PA-824

In the 1990s, PathoGenesis, a small biotech company, modified the ring structure of the nitroimidazoles that Ciba-Geigy had developed, and thereby discovered the nitroimidazo-oxazines (also referred to in earlier literature as nitroimidazopyrans). From more than 700 novel compounds tested, PA-824 (2-nitro-6,7-dihydro-5H-imidazo[2,1-b](1,3)oxazine) was found to be both nonmutagenic and the most active against M. tuberculosis in a murineinfection model (13). The development of PA-824 was, however, stopped when Chiron purchased PathoGenesis in 2000. Soon thereafter, the TB Alliance and Chiron signed an exclusive license agreement granting the TB Alliance worldwide rights to PA-824 and the other nitroimidazole derivatives that had been discovered by PathoGenesis. Since this agreement, the TB Alliance has been developing PA-824. The preclinical evaluation of PA-824 revealed in vitro and in vivo activity against M. tuberculosis. In vitro studies showed that the minimum inhibitory concentration (MIC) of PA-824 against a variety of drugsensitive TB isolates is in the range of 0.015 to 0.25 mg/mL. The activity

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is highly selective, with potent activity only against bacille Calmette– Gue´rin (BCG) and M. tuberculosis of the mycobacterial species tested, and without significant activity against a broad range of gram-positive and gram-negative bacteria (with the exception of Helicobacter pylori and some anaerobes). Perhaps of even greater significance is the finding in anaerobic culture that PA-824 has activity against non-replicating bacille, indicating its potential for activity against persisting organisms and shortening treatment duration. PA-824 is also active against strains of M. tuberculosis with known resistance to standard TB therapies, indicating a novel mechanism of action (13). The in vivo activity of PA-824 is also fairly pronounced. Pathogenesis tested PA-824 in a mouse model of TB, employing an M. tuberculosis reporter strain expressing firefly luciferase. At oral doses of 25, 50, and 100 mg/kg daily in mice for 10 days, PA-824 significantly reduced M. tuberculosis levels in both spleen and lung compared to controls and demonstrated a linear dose response. Longer-term mouse studies with PA-824 at 50 mg/kg/day demonstrated reductions in bacillary lung burden similar to isoniazid at 25 mg/kg/day, with all mice treated with PA-824 surviving while all untreated control animals died by day 35. In a guinea pig aerosol infection model, daily oral administration of PA-824 at 37 mg/kg/day for 35 days also produced reductions of M. tuberculosis counts in lungs and spleens comparable to those produced by isoniazid (13). More recent murine studies by Grosset et al. have shown that the minimum effective dose of PA-824 (defined as the minimum dose that prevents the development of gross lung lesions and splenomegaly) is 12.5 mg/kg/day, and that the minimum bactericidal dose of PA-824 (defined as the minimum dose that reduces the lung colony forming unit counts by 99%) is 100 mg/kg/day (14). Although as noted above, PA-824 appears to have a novel mechanism of action, the exact target is not known. The compound appears to inhibit both protein and lipid synthesis but does not affect nucleic acid synthesis. There is a resultant accumulation of hydroxymycolic acid with a concomitant reduction in ketomycolic acids, suggesting inhibition of an enzyme responsible for the oxidation of hydroxymycolate to ketomycolate (13). Interestingly, PA-824 is a prodrug that undergoes activation via an F420-dependent mechanism. Mutations in the gene encoding the F420 enzyme ( fgd) are responsible for some instances of PA-824 resistance identified in vitro (13). One hypothesis is that PA-824 undergoes nitro-reduction, producing highly reactive intermediates, which interact with multiple intracellular targets. Several other drugs used in TB treatment are also prodrugs, including isoniazid, pyrazinamide, and ethionamide (a second-line TB drug). When tested in the Ames assay, both with and without S9 activation, PA-824, unlike the Ciba-Geigy lead compound, CGI-17341, has shown no evidence of mutagenicity. Furthermore, chromosomal aberration, mouse micronucleus, and mouse lymphoma tests have all been negative, confirming no evidence of genotoxic potential for the compound. Of importance also are the in vitro findings that PA-824 neither inhibits nor is metabolized

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by major P450 enzyme isoforms, indicating a low potential for drug–drug interactions with the presently used AIDS antiretrovirals (Global Alliance for TB Drug Development, personal communication). Pharmacokinetic studies of PA-824 in the rat indicate excellent tissue penetration. Following a single 100 mg/kg oral dose of PA-824, the time to reach maximal concentrations of PA-824 in heart, liver, kidney, spleen, and lung is approximately four hours as compared to six hours in plasma. Total exposure in these tissues as measured by area under the (time-concentration) curve (AUC) is three- to eightfold higher than exposure in plasma. There is, however, no evidence of accumulation in either the rat or the monkey (Global Alliance for TB Drug Development, personal communication). OPC-67683

The dihydroimidazo-oxazole, OPC-67683, is a newly synthesized nitroimidazole under development by Otsuka Pharmaceutical Company for the treatment of TB. Currently in phase I of clinical development in normal volunteers (Otsuka Pharmaceutical Company, personal communication), Otsuka reports the compound has extremely potent in vitro antimicrobial activity against M. tuberculosis. MICs against multiple clinically isolated TB strains range from 0.006 to 0.024 mg/mL. As with PA-824, OPC-67683 shows no cross-resistance with any of the currently used first-line TB drugs, thereby also indicating most likely a novel mechanism of action. Based on their relatively similar chemical structure, it is likely that the mechanisms of action of PA-824 and OPC-67683 will prove to be the same. In a chronic infection mouse model, the efficacy of OPC-67683 is superior to that of the currently used TB drugs. In these experiments, the effective plasma concentration was 0.100 mg/mL, which was achieved with an oral dose of 0.625 mg/kg, confirming the remarkable in vivo potency of OPC-67683. In nonclinical in vitro and in vivo studies, OPC-67683 in combination with various first-line TB drugs shows either synergistic, additive, or no appreciable interaction, but no evidence of any antagonistic activity. B. Diarylquinolines

Another novel, potent class of compounds, the diarylquinolines, are being investigated by Johnson and Johnson for their utility in TB therapy (15). The lead compound, TMC207 (previously known as R207910), is active in vitro against both drug-sensitive and drug-resistant strains of M. tuberculosis (MIC 0.06 mg/mL). Strains tested include those resistant to a wide variety of commonly used drugs including isoniazid, rifampicin, streptomycin, ethambutol, pyrazinamide, and the fluoroquinolones. Although TMC207 is active in vitro against other mycobacteria, including Mycobacterium smegmatis, M. kansasii, M. bovis, M. avium, and M. fortuitum, the compound is not active against a variety of gram-positive and gramnegative organisms such as Nocardia asteroides, Escherichia coli, Streptococcus aureus, Enterococcus faecium, or Haemophilus influenzae. Of note, two resistant

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M. smegmatis isolates were not cross-resistant to a wide range of antibiotics, including the fluoroquinolones. Based on gene sequences of drug-resistant mutants, the mechanism of action of TMC207 has been postulated to be inhibition of the proton pump of adenosine triphosphate (ATP) synthase. Point mutations that conferred resistance to TMC207 were identified in both M. tuberculosis and M. smegmatis. In three independent mutants, the only gene commonly affected encoded atpE, a part of the F0 subunit of ATP synthase. Two point mutations were identified, one in M. smegmatis and one in M. tuberculosis. Further transformation studies confirmed the importance of the atpE gene in the mechanistic pathway of TMC207. Pharmacokinetic studies in mice have shown rapid absorption with extensive tissue distribution in at least liver, kidney, heart, spleen, and lung. Of note, half-lives ranged from 28.1 to 92 hours in tissues and from 43.7 to 64 hours in plasma. One contribution to the relatively long half-life appears to be slow redistribution from the tissue compartments. TMC207 has also demonstrated significant in vivo activity in mouse models of both established and nonestablished disease. In the nonestablished disease model, mice were treated for four weeks starting the day after inoculation. In this setting, a once-weekly dose of 12.5 mg/kg was almost as efficacious as 6.5 mg/kg given five times per week. At 12.5 and 25 mg/kg, TMC207 was more efficacious than isoniazid at 25 mg/kg. In the established disease model, treatment was begun 12 to 14 days after inoculation. In combination studies, the substitution of TMC207 for any of the three commonly used drugs (isoniazid, rifampicin, and pyrazinamide) had greater efficacy than the standard regimen of isoniazid, rifampicin, and pyrazinamide. The combination of either TMC207, isoniazid and pyrazinamide, or TMC207, rifampicin and pyrazinamide, resulted in negative spleen and lung cultures after eight weeks of therapy. Animals were not apparently observed after cessation of therapy for relapse and more definitive evidence of cure. TMC207 has also been tested in phase I pharmacokinetic and safety studies in healthy volunteers. Single oral administration of TMC207 at doses ranging from 10 to 700 mg revealed the drug to be well absorbed with peak serum concentrations at about five hours. The pharmacokinetics were dose proportional over the range studied. A multiple ascending dose study (once daily doses of TMC207 at 50, 150, and 400 mg/day for 14 days) was then performed in healthy volunteers. Accumulation was observed with a doubling of the AUC on the 14th day compared to day 1. Of note, the average observed AUCs were greater than those that achieved optimal activity in the established infection in the mouse. Safety evaluations revealed only mild or moderate adverse events with the majority considered only possibly related to the study drug. C. Pyrroles

Another promising class of compounds for TB therapy is the pyrroles. First described in 1998 by Diedda et al. (16) as having fairly good

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antimycobacterial activities, the most potent compound was designated BM212. MICs for BM212 ranged between 0.7 and 1.5 mg/mL against several strains of M. tuberculosis. The MICs for strains resistant to the commonly used antitubercular drugs were similar to those for sensitive strains, indicating most likely a novel mechanism of action. However, no mechanism of action has yet been elucidated for this class of compounds. Some non-TB mycobacterial strains also appeared to be sensitive to BM212, albeit with MICs higher than for M. tuberculosis. A novel pyrrole compound, LL3858, discovered by Lupin Limited, is currently beginning clinical development for TB (17). This compound has been reported by Lupin to have submicromolar MICs and significant efficacy in a mouse model of TB: in combination with currently used antiTB drugs, LL3858 reportedly sterilized lungs and spleens of infected animals in a shorter timeframe than conventional therapy. The compound has completed preclinical development and been approved for start of phase I study in human volunteers in India. D. Macrolides

The macrolides, potent inhibitors of protein synthesis, bind to the 50S ribosomal subunit of bacteria at the peptidyl transferase center formed with 23S rRNA; they may also block formation of the 50S subunit in growing cells. Macrolides could therefore add a novel mechanism of action to TB combination therapy, and thereby also hold out the promise of being equally effective against MDR-TB and drug-sensitive TB. The macrolides, known to be orally active, have also proven to be safe and well-tolerated when used for non-TB indications. Key for TB treatment, they also tend to exhibit high levels of intracellular activity and extensive distribution into the lungs. This class of antibiotics is currently being evaluated as potential TB therapy at the Institute for Tuberculosis Research at the University of Illinois at Chicago, in conjunction with the TB Alliance. Macrolides have already proven to be clinically useful in treatment of other mycobacterial diseases including M. avium complex (MAC) and leprosy. Erythromycin, a natural product isolated from Streptomyces erythreus in the 1950s, represents the first-generation macrolides. It has proven effective in treatment of infections caused by gram-positive bacteria, but its use is hampered by its short serum half life and by side effects on gastric motility. This latter characteristic, due to marked acid lability, causes gastrointestinal discomfort. Second-generation macrolides, including azithromycin, clarithromycin, and roxithromycin, were successfully developed by blocking the acid degradation pathway of erythromycin. Although they have little activity against M. tuberculosis, many of the second-generation antibiotics have proven to be potent against M. avium and M. leprae. Second-generation macrolides also demonstrate good potency against other mycobacterial pathogens, including M. kansasii, M. xenopi, and M. marinum. Unfortunately, gram-positive cocci have developed significant levels of resistance to the second-generation macrolides, primarily via two

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mechanisms: efflux pathways (encoded by mef genes) and ribosome modification (due to activity of methyl transferases encoded by erm genes). Third-generation macrolides, represented primarily by members of the ketolide class, have been developed to overcome this resistance. Telithromycin, the first commercially available third-generation macrolide, is more potent than clarithromycin against mycobacteria, including M. tuberculosis, M. bovis, BCG, M. avium, M. ulcerans, M. paratuberculosis, M. africanum, and M. simiae (18). The current work at the University of Illinois at Chicago to develop even more potent macrolides for the treatment of TB is based on modifying various substituents on the macrolide scaffold to enhance potency while maintaining low toxicity and avoiding key resistance mechanisms and drug–drug interactions. E. Diamines

SQ109, an adamantan-ethane-diamine, has been under development by Sequella, Inc. for its potential use in the treatment of TB. Although originally conceived as a second-generation improvement of the first-line TB drug, ethambutol, its structural dissimilarity to ethambutol and potential differences in its intracellular target(s) suggest that it may be a truly novel antimycobacterial agent, and not simply an ethambutol analog. A diverse combinatorial library of compounds with the 1,2-diamine pharmacophore of ethambutol was synthesized and tested for activity against M. tuberculosis (19). After a series of sequential in vitro and in vivo tests, SQ109 was ultimately identified as the most potent compound in the series and was subjected to pharmacokinetic (PK)/pharmacodynamic (PD) testing. In vitro studies of SQ109 revealed an MIC against M. tuberculosis in the range of 0.1 to 0.63 mg/mL with 99% inhibition of M. tuberculosis growth in macrophages at its MIC. The compound is also active against MDR strains of M. tuberculosis in vitro, and M. tuberculosis demonstrates a relatively low mutational frequency for developing resistance to SQ109 (2.18  10 9). In vivo mouse studies showed a reduction of 2 to 2.5 log in colony-forming units (CFU) counts in lung and spleen with enhanced antimycobacterial activity when used in combination with rifampicin and isoniazid (rapidmouse model and chronic-infection model). Although the mechanism of action of SQ109 appears to be that of a cell wall inhibitor because it induces, like other cell wall targeting antibiotics (ethambutol, isoniazid, ethionamide, and thiacetazone), the Rv0341 promoter, the specific target of SQ109 is not yet clearly defined (20). The pharmacokinetic profile of SQ109 (21) is interesting in that the oral bioavailability of the drug in mice is only 4%. However, SQ109 distributes into lungs and spleen at concentrations exceeding the MIC, and therefore the relatively low overall oral bioavailability of this drug may not represent a hindrance to the drug’s use. Cytochrome P450 reaction phenotyping suggests exclusive involvement of CYP2D6 and CYP2C19 in SQ109 metabolism. Incubation of SQ109 with human, mouse, dog, and

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rat microsomes suggests similar metabolism of the drug in all tested species. Based on results of formal preclinical toxicology studies, SQ109 is poised to enter phase I studies in human volunteers. F. Oxazolidinones

The oxazolidinones, a relatively new class of antimicrobial agents, exert their antimicrobial effect by inhibiting protein synthesis through binding to the 70S ribosomal initiation complex (22,23). They have a relatively broad spectrum of activity, including anaerobic and Gram-positive aerobic bacteria as well as mycobacteria (24,25). The class was initially discovered by scientists at DuPont in the 1970s (26,27). The first and thus far only oxazolidinone to be approved is linezolid. Although not approved for use in TB, linezolid has in vitro activity against M. tuberculosis. Of the oxazolidinones that have been evaluated for their activity in in vivo systems, the most active appears to be PNU-100480, with efficacy similar to that of isoniazid or rifampicin (25). Because of the clinical availability of linezolid, it has been used sporadically in patients with MDR-TB and demonstrates biologic activity as evidenced by sputum-culture conversion (28). However, with relatively long-term use in MDR-TB patients, there are emerging reports of peripheral and optic neuropathy (29). Even though the oxazolidinones appear to have the potential to become a welcome addition to the armamentarium of anti-TB drugs, there has never been a truly concerted effort to optimize their activity against M. tuberculosis. In the meantime, linezolid’s neuropathic side effects, emerging with its long-term use, will require careful monitoring as linezolid becomes more commonly used in the treatment of MDR-TB. G. Long-Acting Rifamycins

Rifampin has probably had the greatest impact of any drug on shortening the duration of therapy for active TB disease. However, even rifampicinbased regimens must be given for at least six months for optimal effectiveness, usually daily for the first two months of therapy and then from three to five days a week for the ensuing four months. Regimens based on more intermittently delivered dosing have proven to be less efficacious and have demonstrated higher rates of acquired rifampicin resistance in HIVinfected patients. Therefore several other rifamycin derivatives with significantly longer serum half-lives than rifampicin’s (two to four hours) have been evaluated in intermittent regimens. Rifabutin, with a terminal half-life of 36 hours, was the first to enter clinical testing (30). The initial trials tested its potential role in prophylaxis for MAC infection in HIV-positive individuals (31). Rifabutin was approved for MAC prophylaxis in the United States and for the treatment of TB in several other countries, but it is now utilized primarily as a rifampicin substitute in patients for whom rifampicin-based drug–drug interactions are problematic (32). It is not recommended for use as part of intermittent regimens in patients with

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advanced immunosuppression due to associated high rates of acquired rifamycin resistance in these individuals (33). Rifalazil, a second long-acting rifamycin derivative, has an even longer half-life than rifabutin (approximately 60 hours), demonstrates relatively high potency against M. tuberculosis in animal-infection models (34), and has a relatively low potential for drug–drug interactions (33). In phase I tolerability studies, however, rifalazil (50 mg single dose) was associated with unacceptably high rates of a ‘‘flu-like’’ syndrome (35). This dose-limiting side effect may be due to cytokine release, as it is associated with increased interleukin-6 serum levels. Once-weekly rifalazil did not demonstrate significant anti-mycobacterial activity in an Early Bactericidal Activity (EBA) study (at relatively low doses: 10 and 25 mg) when administered with isoniazid for two weeks (36). There is the potential that rifalazil analogs could be identified with a better tolerability profile and low potential for enzyme induction, but there are no currently active programs investigating such compounds for TB treatment. The best studied of the long-acting rifamycins has been rifapentine, a cyclopentyl-substituted rifampicin with a half-life of 14 to 18 hours in normal adults. Following a 600-mg dose, serum levels in excess of the MIC persist beyond 72 hours, suggesting the potential for intermittent administration. Grosset et al. reported that in mice, a once-weekly continuation phase of rifapentine and isoniazid for four months following a standard two-month induction phase with daily isoniazid, rifampicin, and pyrazinamide was as effective as standard therapy given daily for six months (37). This work stimulated the large phase III trial that was begun by U.S. Centers for Disease Control and Prevention (CDC) in 1995 [known as TB Trials Consortium (TBTC) Study 22]. Study 22 randomized adults with newly diagnosed, drug-susceptible pulmonary TB to a four-month (16-week) continuation phase regimen of either once-weekly rifapentine–isoniazid or twice-weekly rifampicin–isoniazid following a standard two-month induction phase (38). Early in the trial, however, a high rate of relapse with acquired rifampicin-monoresistance was found among HIV-positive patients assigned to the rifapentine arm and enrollment of HIV-positive patients was stopped (39). The results of this study, along with other rifapentine data, led to approval of rifapentine for the treatment of TB in the United States and to a recommendation for the use of a once-weekly rifapentine–isoniazid continuation phase regimen for HIV-negative adults with drug-susceptible, non-cavitary TB and negative acid-fast bacilli (AFB) smears at two months (40). However, rifapentine-based treatment is not recommended either for those with cavitary disease or concomitant HIV infection. Experimental studies have also suggested that weekly rifapentine and isoniazid for as short a period as three months may provide effective treatment for LTBI (41). Therefore, the CDC has embarked on an ambitious study, intended to randomize 8000 patients with LTBI to either weekly rifapentine/isoniazid for 12 weeks or daily isoniazid for nine months. This study is due to complete after 2008.

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H. Fluoroquinolones

Like the rifamycins, fluoroquinolones are in relatively advanced clinical testing for the treatment of active TB. Although there are few clinical data to support their use other than anecdotal reports, during the past decade fluoroquinolone antibiotics have become a key class of ‘‘second-line’’ drugs for treating patients infected with MDR strains of M. tuberculosis. Only recently, however, have these drugs begun to be actively considered for the treatment of drug-susceptible disease. In part, this is because the few randomized, controlled trials of fluoroquinolones for drug-susceptible TB that have been conducted have not demonstrated a benefit. The recent publication by the Tuberculosis Research Center in Chennai, India, of a clinical trial with ofloxacin-containing regimens, however, has restimulated interest. This trial unfortunately did not include a standard control group, but rather randomized patients with newly diagnosed pulmonary TB to one of four ofloxacin-containing regimens (42). Rates of sputum-culture conversion to negativity at two months, an endpoint that correlates well under appropriate conditions with relapse rates following TB treatment (43), ranged from 92% to 98%. This compares to an expected rate of approximately 80% with standard four-drug treatment (41). In patients randomized to three months of daily isoniazid, rifampicin, pyrazinamide, and ofloxacin, or three months of daily isoniazid, rifampicin, pyrazinamide, and ofloxacin followed by twice-weekly isoniazid and rifampicin for one or two months, relapse rates during the two years following completion of treatment were 8%, 2%, and 4%, respectively. These results suggest that fluoroquinolones have the potential to shorten the duration of TB treatment regimens. Recent murine data also indicate that fluoroquinolones may be able to significantly shorten treatment regimens for active TB. Of the more recently developed fluoroquinolones, the two most potent against M. tuberculosis in vitro and in animal models are moxifloxacin and gatifloxacin. A recent evaluation of fluoroquinolones in an in vitro model of persistent M. tuberculosis infection also found that moxifloxacin had the greatest sterilizing activity (44). Jacques Grosset and colleagues at Johns Hopkins University have recently conducted a series of studies of moxifloxacin in mouse models of acute M. tuberculosis infection, which have also contributed to interest in this drug. The initial study, in which infected mice were treated for one month with one of several fluoroquinolones, found that moxifloxacin had the greatest bactericidal activity, comparable to that of isoniazid, the most potent bactericidal drug in EBA studies. A second study suggested that moxifloxacin also had potent sterilizing activity and might substantially improve the efficacy of once-weekly rifapentine treatment (45). The most recent study surprisingly demonstrated that a combination of rifampicin, pyrazinamide, and moxifloxacin had substantially greater sterilizing activity not only than the standard regimen, but also than the standard regimen plus moxifloxacin (46). The results of two small EBA studies have demonstrated that moxifloxacin has bactericidal activity superior to that of rifampicin and perhaps comparable to that of isoniazid (47,48).

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Moxifloxacin is about to enter and gatifloxacin is currently in phase III trials. These two fluoroquinolones are being tested in combination regimens in which they replace ethambutol in the initial two-month phase of therapy. Moxifloxacin will also be tested in the setting of replacing isoniazid during the initial two months of therapy. In the moxifloxacin trials, the primary endpoint is rate of sputum-culture conversion at two months (49). Studies of gatifloxacin are being conducted by a product development team supported by the United Nations Children’s Fund (UNICEF)/United Nations Development Program (UNDP)/World Bank/WHO Special Program for Research and Training in Tropical Diseases and the European Commission. The phase II study randomizes newly diagnosed patients to one of three fluoroquinolone-containing regimens (ofloxacin, moxifloxacin, or gatifloxacin) in combination with isoniazid, rifampicin, and pyrazinamide during the first two months of treatment. Depending on the results of these phase II trials, the fluoroquinolones, moxifloxacin, and gatifloxacin, have probably the greatest potential to move into definitive phase III programs. These programs could lead to the first truly novel approved drug for the treatment of TB in over 30 years. IX. Future Prospects in TB Drug Development As noted above, current WHO recommended TB treatment regimens for drug-sensitive active disease consist of a two-month intensive phase of daily dosing with four drugs, followed by a four-month continuation phase with two drugs given three to five times a week. In the relatively short term, it should be feasible to develop a two- to three-month treatment regimen with once-weekly dosing of three to four drugs. This would in effect shorten and simplify treatment from 26 weeks to 8 to 12 weeks’ duration, and from approximately 120 treatments to 10. Making this dramatic an improvement will likely require a completely new combination of drugs. If new drugs developed for active TB are based on novel mechanisms of action relative to current TB therapy, and are screened early to avoid compounds with undesirable drug–drug interactions, successful drugs should also prove to be equally effective for drug-sensitive and MDR-TB, and for treatment of HIV-negative and HIV-positive patients. Time-efficient clinical testing of new compounds will require simultaneous rather than strictly sequential testing of multiple compounds, an approach that has already seen some interest in areas such as the development of new anti-retroviral treatments. Longer-term, it would be desirable to shorten TB treatment regimens to a 10-day or two-week course of antibiotics, comparable to present treatments for acute respiratory infections. Accomplishing this will likely require much greater fundamental understanding of the mechanisms of persistent infection in TB, which likely underlie the current need for prolonged antibiotic therapy. Finally, diagnostics and surrogate markers that could identify patients as soon as they are cured, or those individuals who will ultimately relapse post-therapy, or those latently infected at high risk for reactivation,

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would significantly speed clinical development of effective new compounds for active disease and latent infection. Development of appropriate surrogate markers, however, will require more research and ultimately field testing for their validation. Five years ago, the pipeline of novel TB drugs was virtually nonexistent. Now it is reinvigorated and growing, with up to seven drugs expected to be in clinical testing by the end of 2006, indicating that low-cost, simplified, safe, and effective treatments for drug-sensitive and MDR-TB, in both HIV-positive and HIV-negative patients, are challenging but attainable goals. References 1. 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. 2. Treatment of tuberculosis: guidelines for national programme, 3rd ed. WHO/CDS/ TB/2003.313; Am J Respir Crit Care Med 2003; 167:603–662. 3. Crofton J, Mitchison DA. Streptomycin resistance in pulmonary tuberculosis. Br Med J 1948; 2:1009–1015. 4. Anti-tuberculosis drug resistance in the world, report no. 3: prevalence and trends. WHO/HTM/TB/2004:343. 5. Moore-Gillon J. Multidrug-resistant tuberculosis: this is the cost. Ann NY Acad Sci 2001; 953:233–240. 6. Dye C, Williams BG, Espinal MA, et al. Erasing the world’s slow stain: strategies to beat multidrug-resistant tuberculosis. Science 2002; 295:2042–2046. 7. Costa JG, Santos AC, Rodrigues LC, et al. Tuberculosis in Salvador, Brazil: costs to health system and families. Rev Saude Publica 2005; 39(1):1–7. 8. Espinal MA. The global situation of MDR-TB. Tuberculosis 2003; 83:44–51. 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. WHO Tuberculosis Fact Sheet No. 104, revised March 2004; see also Chapter 9 [S14]. 11. 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(suppl):S221–S247. 12. Gordin F, Chaisson RE, Matts JP, et al. Rifampin and pyrazinamide vs isoniazid for prevention of tuberculosis in HIV-infected persons: an international randomized trial. JAMA 2000; 283:1445–1450. 13. Stover CK, Warrener P, VanDevanter DR, et al. A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis. Nature 2000; 405:962–966. 14. Grosset J, Nuermberger E, Yoshimatsu T, Tyagi S, Williams K, Bishai WR. The nitroimidazopyran PA-824 has promising activity in the mouse model of TB. Am J Respir Crit Care Med 2004; 169(suppl):A260. 15. Andries K, Verhasselt P, Guillemont H, et al. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science 2005; 307:223–227. 16. Diedda D, Lampis G, Fioravanti R, et al. Bactericidal activities of the pyrrole derivative BM212 against multidrug-resistant and intramacrophagic M. tuberculosis strains. Antimicrob Agents Chemother 1998; 42:3035–3037. 17. Arora SK, Sinha N, Sinha RK, et al. Synthesis and in vitro anti-mycobacterial activity of a novel anti-TB composition LL4858 [abstract F-1115–2004]. 44th

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34. Klemens SP, Cynamon MH. Activity of KRM-1648 in combination with isoniazid against Mycobacterium tuberculosis in a murine model. Antimicrob Agents Chemother 1996; 40:298–301. 35. Rose L, Vasiljev KM, Adams P, Mizuno V, Wells C, Montgomery AB. Safety and pharmacokinetics of PA-1648, a new rifamycin in normal volunteers. Am J Respir Crit Care Med 1999; 159(suppl):A495. 36. Dietze R, Teixeira L, Rocha LM, et al. Safety and bactericidal activity of rifalazil in patients with pulmonary tuberculosis. Antimicrob Agents Chemother 2001; 45:1972– 1976. 37. Daniel N, Lounis N, Ji B, et al. Antituberculosis activity of once-weekly rifapentinecontaining regimens in mice. Long-term effectiveness with 6- and 8-month treatment regimens. Am J Respir Crit Care Med 2000; 161:1572–1577. 38. Tuberculosis Trials Consortium. Rifapentine and isoniazid once a week versus rifampin and isoniazid twice a week for treatment of drug-susceptible pulmonary tuberculosis in HIV-negative patients: a randomised clinical trial. Lancet 2002; 360:528–534. 39. 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. Lancet 1999; 353:1843–1847. 40. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America. Treatment of tuberculosis. Am J Respir Crit Care Med 2003; 167:603–662. 41. Chapuis L, Ji B, Truffot-Pernot C, O’Brien RJ, Raviglione MC, Grosset JH. Preventive therapy of tuberculosis with rifapentine in immunocompetent and nude mice. Am J Respir Crit Care Med 1994; 150:1355–1362. 42. Tuberculosis Research Centre. Shortening short course chemotherapy: a randomized clinical trial for treatment of smear positive pulmonary tuberculosis with regimens using ofloxacin in the intensive phase. Ind J Tuberc 2002; 49:27–38. 43. Mitchison DA. Assessment of new sterilizing drugs for treating pulmonary tuberculosis by culture at 2 months. Am Rev Respir Dis 1993; 147:1062–1063. 44. Hu Y, Coates AR, Mitchison DA. Sterilizing activities of fluoroquinolones against rifampin-tolerant populations of Mycobacterium tuberculosis. Antimicrob Agents Chemother 2003; 47:653–657. 45. Lounis N, Bentoucha A, Truffot-Pernot C, et al. Effectiveness of once-weekly rifapentine and moxifloxacin regimens against Mycobacterium tuberculosis in mice. Antimicrob Agents Chemother 2001; 45:3482–3486. 46. Nuermberger EL, Yoshimatsu T, Tyagi S, et al. Moxifloxacin-containing regimen greatly reduces time to culture conversion in murine tuberculosis. Am J Respir Crit Care Med 2004; 169:334–335. 47. Gosling RD, Uiso LO, Sam NE, et al. The bactericidal activity of moxifloxacin in patients with pulmonary tuberculosis. Am J Respir Crit Care Med 2003; 168: 1342–1345. 48. Pletz MW, De Roux A, Roth A, Neumann KH, Mauch H, Lode H. Early bactericidal activity of moxifloxacin in treatment of pulmonary tuberculosis: a prospective, randomized study. Antimicrob Agents Chemother 2004; 48:780–782. 49. Global Alliance for TB Drug Development. Scientific blueprint for tuberculosis drug development. Tuberculosis (Edinb) 2001; 81(suppl 1):1–52.

48 The Future of Tuberculosis Vaccinology

RUTH GRIFFIN and DOUGLAS YOUNG CMMI, Department of Infectious Diseases and Microbiology, Imperial College London, London, U.K.

I. The TB Vaccine Challenge: To Improve on Bacille Calmette–Gue´rin The outcome of infection with Mycobacterium tuberculosis is crucially dependent on the immune response of the host. Most individuals mount a response that is sufficient to prevent progression to disease but may allow persistence of viable bacteria in the form of a latent infection. Around 10% of individuals exposed to M. tuberculosis develop clinical tuberculosis (TB), either as a result of failure to control the initial infection or due to reinfection or reactivation of latent infection (1). This secondary disease pathway highlights a major challenge for TB vaccines. The hallmark of the adaptive immune system is its ability to learn from an initial infection how to mount a rapid and effective response when reexposed to the same pathogen. Classically, vaccination mimics the learning process associated with natural infection. Development of secondary disease in individuals who had contained a primary infection with M. tuberculosis shows that the robust learning process seen for a disease like smallpox does not always occur for TB (1). Similarly, individuals who have been cured of TB remain susceptible to reinfection and further disease (2). 1153

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The BCG vaccine follows the classical paradigm of attempting to reproduce the immunogenicity of natural infection in the absence of pathological sequelae. Evidence from a range of experimental animal models demonstrates that it is able to accomplish this goal. Vaccinated animals mount an accelerated immune response that restricts multiplication of M. tuberculosis in the early phase of infection, reduces pathology, and prolongs survival. From these experimental results, it would be predicted that BCG would have a protective effect at least against progression to primary TB in humans. Support for this is provided by clinical trials of neonatal BCG vaccination, which demonstrate a reduction of around two-thirds in the incidence of severe forms of childhood TB, particularly meningitis (3–5). However, vaccination has proved less effective in older age groups. Although trials in U.K. school children demonstrated 80% protection against primary TB, the efficacy of this vaccine varies from 0% to 80% in different countries with a consistently low efficacy in many tropical regions of the world where the vaccine is most needed (6–10). A range of hypotheses have been put forward to account for the disparity in BCG effectiveness, including the methodology of administration and age at vaccination (11), variations in the efficacy of BCG substrains (12), variations in the pathogenesis of different strains of M. tuberculosis (13), and an influence of environmental non-TB mycobacteria on immunity (7,8). Exposure to environmental mycobacteria could limit the impact of BCG vaccination by inducing immunity that masks the effect of subsequent BCG vaccination (14,15), or by having a direct antagonistic influence on subsequent BCG vaccination (16,17). Alternatively, environmental mycobacteria may inhibit BCG multiplication and thereby curtail the vaccine-induced immune response before it is fully developed (18,19). Whatever is the underlying mechanism, it is clear that BCG vaccination has failed to limit the incidence of the infectious forms of adult pulmonary TB in countries where TB is highly prevalent. Despite its limitations, BCG represents an essential benchmark for scientists generating novel vaccines. Its efficacy against childhood disease makes BCG a key component of the Expanded Program on Immunization vaccination regimen; it has proven efficacy against the related mycobacterial disease of leprosy (20); and there is some evidence of a general benefit on infant mortality (21). Although limited evidence from U.K. trials suggest that the impact of BCG vaccination wanes over a period of 10 to 15 years, a 50-year follow-up of American Indians and Alaska natives who participated in a placebo-controlled BCG vaccine trial shows that it has lifelong benefit in some settings (22). It is anticipated that the next generation of TB vaccines will be delivered as some form of supplementation to BCG, augmenting responses to particular antigens or priming additional T-cell subsets. The goal is to produce a vaccination protocol that protects against pulmonary TB in adults in addition to disseminated disease in young children.

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II. The Genome and New Vaccine Candidates Production of new TB vaccine candidates has been greatly facilitated by advances in mycobacterial genomics over the last decade (23). It is now possible to clone antigen-encoding genes from M. tuberculosis for use in DNA or protein production for subunit vaccines or for expression in a range of vaccine delivery systems. Novel genes can be introduced and expressed in BCG, and conversely individual genes can be modified or deleted in BCG or in M. tuberculosis itself. Several hundred new candidates have been generated and tested in experimental animal models, predominantly using standard protocols in central testing facilities supported by the U.S. National Institutes of Health and the European Union (24,25). Strategies for generating candidates have been based on engineering of live mycobacteria to produce attenuated variants of M. tuberculosis or recombinant BCG, or on targeting selected antigen subunits for delivery as DNA or proteins in adjuvant or as components of recombinant live vaccine vectors. In this section, we will focus particularly on analysis of the different hypotheses underpinning the development of new vaccine candidates. A. Live Mycobacterial Vaccines Vaccines with Greater Resemblance to Mycobacterium tuberculosis

BCG is an attenuated variant of Mycobacterium bovis, and immunological differences between the vaccine and the pathogen may limit its efficacy. Thus attempts have been made to attenuate M. tuberculosis while maintaining its immunogenic properties. The deletion of virulence associated genes such as lysA, panCD, and RD1 have successfully led to the attenuation of M. tuberculosis. These vaccine candidates are currently in the preclinical stage of being tested (Table 1). Similarly, a series of auxotrophic mutants of M. tuberculosis have been generated that are unable to cause disease in normal or severe combined immunodeficient (SCID) mice (39,40). They vary in their protective efficacy, with some matching BCG in protection, while surpassing BCG in terms of safety (40). This offers the hope of a vaccine that could safely be used in areas such as equatorial Africa where HIV and M. tuberculosis coinfection are common (41). Vaccines with Prolonged Persistence

Vaccines that persist for prolonged periods within the host are particularly effective in inducing immune memory. Mutant strains of M. tuberculosis that persist in the host without causing disease, such as the mutant with phoP deleted (Table 1) (28) are attractive vaccine candidates. A caveat with this hypothesis is that an immune response, which is insufficient to clear an attenuated strain, may be insufficient to control latent infection with the wild-type pathogen. Because M. tuberculosis as a vaccine vector is potentially hazardous, such candidates must contain at least two different mutations to reduce the risk of reversion and thus meet the safety regulatory requirements for such delivery systems.

Construction

Stage of development

Preclinical development candidates being tested to meet regulatory requirements Evaluating safety BCG:RD1 BCG Pasteur expressing RD1 locus of M. tuberculosis M. tuberculosis M. tuberculosis with GMP production PhoP phoP gene deleted GMP production M. tuberculosis M. tuberculosis with mc2 6020 lysA and panCD deleted M. tuberculosis GMP production M. tuberculosis with mc2 6030 RD1 and panCD deleted DureChlyþrBCG GMP production BCG Pasteur expressing Application to Listeriolysin of Listeria regulatory bodies for monocytogenes and use. Aim to enter with urease gene Phase I trials in 2005 deleted BCG perfringolysin BCG expressing GMP production AgA, B, Y perfringolysin and Scheduled for clinical antigens A, B and Y trials in 2006 AdVac85A, B, Y Adenovirus expressing GMP production Ag85A Due to enter Phase I trials at start of 2006 Ag85B/ESAT-6 Fusion protein Due to enter Phase I trials mid-2005

Vaccine

Table 1 Examples of Vaccines Being Tested

Institut Pasteur/Eurovac

Martin C and Gicquel B (28) Jacobs WR Jr

Andersen P

Max Plank Institute for Infection Biology/ Valzine Projekt Management

Kaufmann SH (29,30)

Statens Serum Institut SSI

Crucell/Aeras

Aeras

Albert Einstein College of Medicine

Jacobs WR Jr

Albert Einstein College of Medicine

Institut Pasteur/Eurovac

Institute

Cole ST (26,27)

Researchers (Refs.)

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Vaccinia virus expressing Ag85A

MVA85A

Phase III trial completed in March 1996. The vaccine showed no benefit to chemotherapy

Phase I trials started in United States in 2004; results pending. Phase I/ II trials are nearing completion in Europe Phase I trials started early 2004 in United States; results pending. Similar trial planned for S. Africa Phase I trials completed in United Kingdom in 2004 and in The Gambia in 2005. Phase II trials in United Kingdom started in February, 2005 and due to start in Cape Town in July, 2005

Abbreviations: SSI, Statens Serum Institut; BCG, bacille Calmette–Gue´rin.

Candidates tested in Phase III trials M. vaccae Heat-killed bacteria administered with chemotherapy

BCG tice expressing Ag85A

rBCG30

Candidates being tested in Phase I or II trials Mtb72f Fusion protein of two M. tuberculosis antigens, Mtb32 and Mtb39

Oxford University, U.K.

Hill AV and McShane H (36,37)

King George V Hospital, Durban, S. Africa. Stanford Rook Holdings Ltd (U.K.), South African MRC

University of California, Los Angeles (UCLA)

Horwitz MA (34,35)

Rook GA (38)

Corixa, GlaxoSmithKline Biologicals, Infectious Disease Research Institute

Reed SG and Skeiky YA (31,33)

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Griffin and Young Enhancing the Immunogenicity of BCG

Genome sequence comparisons have enabled us to precisely determine the genetic differences between BCG and M. tuberculosis. The first region of deletion to be discovered in BCG, called RDI, comprises genes encoding two important antigens ESAT6 and CFP10 (23,42). The restoration of RD1 in recombinant BCG improved the protective efficacy of this organism (Table 1) (26,27). Safety criteria regarding the potentially enhanced virulence of BCG:RD1 is currently being tested. Another recombinant strain of BCG has been engineered to overexpress Ag85B (rBCG30, Table 1) and was found to have improved protective efficacy in a guinea pig model (34,35). Several attempts have been made to enhance the immunogenicity of BCG by engineering expression of mammalian cytokines by recombinant BCG, particularly, to augment the protective Th1 response associated with macrophage activation (43). An alternative approach has been to enhance the ability of BCG to trigger CD8 T-cells. Experiments in mice demonstrate an important role for these cells in protection against M. tuberculosis (44); the existing BCG vaccine has very little ability to prime a CD8 response (45). To achieve this, BCG was genetically modified to express listeriolysin, a hydrolytic enzyme that damages the phagosomal membrane that encloses BCG within cells, making mycobacterial antigens more accessible for presentation to CD8 T-cells (29). This strain was further engineered to eliminate mycobacterial urease activity, optimizing the pH for listeriolysin activity. The resultant strain, DureChlyþrBCG promoted improved cross priming, culminating in improved T-cell–mediated protection against M. tuberculosis (Table 1) (30). Aeras have successfully expressed perfringolysin in BCG, which has the advantage of functioning at a higher pH to listeriolysin negating the need for the elimination of urease activity. Aeras are using this recombinant strain to overexpress selected antigens, such as A, B, and Y (Table 1). Quashing the Immunosuppressive Effects of M. tuberculosis

The success of M. tuberculosis as a pathogen is dependent on its ability to survive host immune responses and it is likely that this has been accompanied by selection of factors that subvert immunity. In contrast to the conventional vaccine paradigm, therefore, the natural immune response to M. tuberculosis may be suboptimal, and the route to a more effective vaccine may be to remove these immunomodulatory components that suppress innate immune interactions and subsequent adaptive responses. An example of a potent M. tuberculosis inhibitor of innate immunity is superoxide dismutase (SOD). Diminished SOD production in a mutant of M. tuberculosis was associated with both increased early mononuclear infiltration and apoptosis at the infection site, leading to attenuation greater than that of BCG in the mouse model of M. tuberculosis infection (46). More recently, it has been demonstrated that subtle differences in the pattern of glycans

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and lipids present on the mycobacterial surface promote different innate, and subsequent adaptive, responses (47). Optimizing the orchestration of innate immune signaling could provide an important strategy for the development of improved vaccines. Bill Jacobs and coworkers at the Albert Einstein School of Medicine have adopted this approach of preventing the expression of mycobacterial components that suppress the immune system (presented at the Berlin Vaccine Symposium, 2005). B. Subunit Vaccines

Development of subunit vaccines involves selection of candidate antigens and appropriate delivery systems. Increasingly, the latter step is being viewed in the context of prime-boost systems using BCG either as primer or booster. Three hypotheses have been pursued for antigen selection. Secreted Antigens

The protective efficacy of BCG depends on it being viable, and one of the characteristic features of viability is the ability to secrete antigens. It can be anticipated that antigens that are secreted from live mycobacteria will be immediately available for immune recognition well before intracellular antigens are released from lysed organisms, and may therefore be more appropriate targets for an early immune response (48). Andersen et al. have pursued this hypothesis in an exhaustive screen of M. tuberculosis antigens that are released from bacteria growing in a defined culture medium (49). Based on a systematic evaluation of a large number of antigens, they have identified members of two protein families as showing encouraging potential for subunit vaccines. Firstly, the family comprising Ag85A and Ag85B, which are the most abundant protein components in culture filtrates and encode mycolyl transferase enzymes that are involved in formation of the mycobacterial cell wall (50). Secondly, the family comprising the low molecular weight proteins, ESAT6 and CFP10, which are encoded by adjacent genes in RDI (hence deleted from BCG) (51), and form dimmers (31,52). An Ag85B/ESAT6 fusion protein subunit vaccine is due to enter Phase I clinical trials in mid-2005 (Table 1). Antigens Expressed In Vivo

A limitation of the culture filtrate screen is that it only detects antigens expressed by the bacteria in vitro. It may be that an optimal vaccine should be customized to the antigen repertoire expressed in vivo. One possible candidate antigen is a member of the alpha-crystallin family of chaperone proteins that is expressed at high levels under hypoxic conditions (32). Antigens Recognized by the Natural Immune Response

A strategy that circumvents potential differences between in vitro and in vivo expression is based on the hypothesis that the optimal antigens for subunit vaccines will be those that are recognized by T-cells from tuberculinpositive individuals who have been exposed to infection but show no sign of clinical disease. The most extensive systematic screen based on this hypothesis was carried out by Reed and colleagues. They identified

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predominantly intracellular proteins such as Mtb32 and Mtb39, which were combined to generate a fusion protein Mtb72f, that is now being tested in Phase I and II trials (Table 1) (33,53). Adjuvanted Proteins

Delivery of purified proteins in appropriate adjuvants provides a simple and effective strategy for vaccine production. Experiments in mouse and guinea pig models demonstrated that by selecting appropriate adjuvants it is possible to generate protective efficacy comparable to BCG using culture filtrate proteins and, in some cases, defined individual antigens or fusions. However, progress has been limited by the fact that few of the adjuvants approved for human use are effective in inducing T-cell responses, but promising data have been generated using Mtb72f with AS02A (Table 1) (54). C. Expanding the T-Cell Response for Improved Protection

Current adjuvant formulations predominantly induce CD4 T-cell responses. Although a CD4 T-cell response is the classic protective lymphocytic response against TB (55,56), there is mounting evidence that CD8 responses may be required in addition for optimal vaccine efficacy (57–61). A series of studies have shown that delivery of purified DNA encoding mycobacterial antigens primes CD8 responses and confers a level of protection at least comparable to that obtained with adjuvanted protein vaccines in mice (36,62,63). One group has shown that DNA vaccination can induce a protective response capable of promoting bacterial clearance in mice that already have an established M. tuberculosis infection (37). However, this approach has not progressed to human trials as a result of the poor immunogenicity of current DNA vectors, the lack or reproducibility in different animal models, and concerns about the potential for induction of immunopathological responses. An alternative strategy to induce CD8 T-cells involves delivery of antigens as components of recombinant viral vectors. This approach has been pursued using a recombinant smallpox vaccine system based on Modified Vaccinia Ankara expressing M. tuberculosis Ag85A (MVA85A) (Table 1) (64). The MVA construct confers protection comparable to BCG in mice and better than BCG in a guinea pig model (64,65). Interestingly, in spite of the rationale for choosing a viral vector, protection appears to be mediated by CD4 rather than CD8 T-cells. As discussed below, this candidate has progressed into Phase II trials, showing excellent immunogenicity and safety (Table 1). Recombinant adenoviral vectors are also being used as delivery systems for candidate antigens such as Ag85A (Table 1). Adenoviruses have advantages over MVA in the logistics of large-scale production and have shown considerable promise as HIV vaccines (66). In addition to conventional CD4 and CD8 T-cells, several other T-cell subsets have been implicated in the immune response to mycobacterial infection. These include T-cells expressing a cd receptor, and CD1restricted T-cells capable of recognizing non-protein antigen (67,68). The

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extent to which these T-cells are required for priming memory responses following vaccination, and contributing to protection following challenge, is not known. One possibility is that they play a role in the interface between innate and adaptive responses, and that their modulation could provide a useful adjunct during conventional vaccination. D. Enhancing the Efficacy of BCG in Prime-Boost Regimens

Although some of the candidates described above have performed better than BCG in particular animal models, it is their use in combination with BCG that holds the most promise. Prime-boost regimes—in which an immune response to an antigen is established by delivery in one vaccine vector and then augmented by delivery in an alternative vector—have shown considerable promise in HIV and malaria vaccinology. The TB subunit candidates entering into clinical trials are all anticipated to be used in prime-boost combinations with BCG. III. Clinical Trials The vaccine candidates discussed above were generated as part of a very extensive program of research in experimental animal models during the 1990s. It was then time that TB vaccine research moved into human trials, but there were limitations in experience and infrastructure to take this forward. The only trials previously carried out were focused on assessing heat-killed Mycobacterium vaccae as an adjunct to chemotherapy (Table 1) (38,69–72). The need to develop vaccine trial expertise was recognized by the Sequella Foundation, who obtained funding from the Bill and Melinda Gates Foundation to set up a comparative trial of different delivery systems for BCG at a site near Cape Town. For the Global Plan for 2000 to 2005, the New Vaccines Working Group of the Stop TB Partnership set the goal of obtaining and testing five novel vaccines candidate in Phase I clinical trials (Fig. 1). Three candidates are currently being tested and two more are scheduled to be tested by the end of 2005 (Table 1). The goal set by the

Figure 1

Projected timeline for tuberculosis vaccine development.

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working group for the second global plan initiative is to have a safe, effective, and licensed vaccine available at reasonable cost by 2015 (Fig. 1). An extensive network of clinical trials will be required to meet this goal. A. Phase I Trials

The first stage of moving a candidate from preclinical development to clinical trials is to produce the vaccine to Good Manufacturing Practice with detailed toxicology and tissue distribution studies performed in small animals. MVA85A was the first candidate TB subunit vaccine to enter human trials since BCG over 80 years ago (Table 1). McShane et al. began testing their vaccine in September 2002, and demonstrated that it provoked an overwhelming CD4 T-cell response—the strongest T-cell response ever witnessed following vaccination in a clinical trial against an infectious agent (64,65). These workers showed that BCG prime followed by an MVA85A boost to be the most effective at raising an immune response compared to MVA85A or BCG alone. Encouraging safety and immunogenicity results have been seen in clinical trials in both the United Kingdom and in the Gambia (in a TB endemic area). The two other candidates that have entered Phase I trials are rBCG30 (34,35) and Mtb72F in AS02A formulation (Table 1) (53,54,73). Careful assessment in a systematic series of Phase I trials is essential to establish vaccine safety. In addition to safety in uninfected healthy individuals, it is crucial to evaluate stringently the safety of the vaccine in individuals with latent TB infection and, particularly for live vaccines, that it is safe in HIV-immunocompromised subjects. For vaccines intended for neonates, safety is evaluated initially in adults, followed by age de-escalating trials until safety is demonstrated in the target group. On average, it is anticipated that Phase I trials will involve around six permutations with approximately 30 individuals in each arm of the study. B. Phase II Trials

Having defined initial safety, the vaccine is tested in larger groups with around 300 individuals per arm. Phase II trials provide more extensive safety data and an opportunity to collect significant information about immunogenicity. Again, trials will incorporate different permutations. Investigation of immunogenicity in groups with varying exposure to environmental mycobacteria represents one important factor highlighted by previous BCG trials. Immunogenicity Markers

It would be enormously beneficial to assess vaccine efficacy by some simple immunological measurement. Considerable effort has been invested in discerning those immune responses that could be considered as ‘‘correlates’’ of protection (i.e., responses that are associated with protective immunity even though they may not have a direct causal link with protection), or as ‘‘surrogates’’ of protection (i.e., responses that are directly involved in protective mechanisms). At present we do not have any validated correlates or

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surrogates. To truly validate such a biomarker it is necessary to reliably identify distinct protected and unprotected populations, and it can be argued that having a vaccine with proven optimal efficacy will be a prerequisite for such validation. Tuberculin status is not a reliable predictor of disease susceptibility (74). Measuring T-cell repertoire also has limitations. While it is known that a vaccine is unlikely to confer protection if it fails to induce a population of T-cells that produce interferon-c (IFNc) in response to mycobacterial antigens (30,75) simple measurement of the magnitude of the IFNc response does not correlate with efficacy (76). In fact, the magnitude of the IFNc response following infection provides a correlate of disease progression (77,78). A potential method for evaluating vaccine efficacy in the context of T-cell activity is assaying for T-cell homing to the lung. This technology was originally developed for testing the efficacy of HIV vaccines where T-cell homing to the gut (the main infection site in primates) is measured as a correlate of immune protection. Alternatively, surface markers on antigenspecific cells (particularly those associated with memory phenotypes) may prove informative, and assays that directly assess functional antimycobacterial activity may also have a role. In the absence of established correlate or surrogate measures for TB vaccines, it will be important to maximize identification of immunological markers during Phase II studies. C. Phase III Trials

Ultimately, the efficacy of new TB vaccines will have to be assessed by measuring their ability to protect against disease in Phase III trials. Progression from Phase II to Phase III trials represents a major commitment of funding and human resources, with cohorts expanding from around 300 to around 30,000 individuals to obtain a statistically robust trial size. However, too much effort, time, and money on obtaining such statistically robust figures on vaccine efficacy may impede progress in vaccine development. An alternative strategy is to have an escalating Phase IIb study, in which the vaccine is delivered to an increasingly expanded cohort, with immunogenicity and disease incidence measures used as ‘‘Go/NoGo’’ criteria for moving toward a final statistically robust trial size. Two different scenarios can be proposed for Phase III trials. In the first, the new candidate would be delivered to a neonatal cohort together with, or shortly after, routine BCG vaccination. Incident disease would be monitored over the next three to four years. Such a trial could be added on to the current Cape Town trial of BCG delivery systems. This trial would test the ability of the new vaccine to improve on BCG-induced protection against primary TB in children; a prolonged follow-up would be required in order to determine whether improved efficacy at this stage was associated with reduced incidence of disease in later life. In the second trial design, the new vaccine would be delivered to a teenage cohort who had received BCG vaccination at birth. It would be anticipated that this population would include individuals for whom BCG

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was their only mycobacterial exposure, as well as individuals whose immune system had already been primed by M. tuberculosis and who may be harboring latent infection. The two groups could be distinguished by immunological tests (e.g., using RD1 antigens) and a decision could be made whether to employ universal vaccination or to select the M. tuberculosis-na€
ve subgroup (as was done for BCG trials). If the trial is conducted in a high-incidence area, the na€
ve subgroup may represent only a small portion of the population. Again, incident cases would be monitored over a three- to four-year period, corresponding to the peak incidence of young adult TB. This scenario has the attraction of directly targeting adult pulmonary TB. The vaccine would, however, have to be successful in redirecting an immune response in individuals already primed by previous exposure to mycobacteria. In South Africa, already studies on the vaccination of over 8000 adolescents with previous exposure to M. tuberculosis, are under way (sponsored by Aeras) to evaluate efficacy against acquisition of new infection and reactivation from latent infection. A similar scale study is due to commence in India, which will further aid in determining sample sizes required for the evaluation of vaccine efficacy. D. Phase IV Trials

These trials are post-licensure studies, which use the infrastructure of the country in which the vaccine is being administered to monitor safety and determine the efficacy of the vaccine in epidemiological studies. E. Timelines and Logistics

Given the uncertainties surrounding mechanisms of immunity and protection it is important that multiple vaccine candidates are evaluated and in parallel to successfully achieve the goal of a licensed vaccine by 2015 (Fig. 1). A realistic plan is to bring 20 candidates into Phase I trials over this period, with the assumption that around half will progress to Phase II, leading to four full Phase III trials. Candidates currently entered into clinical trials are expected to complete Phase I and II by 2009, with the first Phase III trials completed by 2013 (Table 1; Fig. 1). Although vaccine development can be represented as a simple linear pipeline, the reality is more likely to involve an iterative learning process, in which early candidates may fail while nonetheless providing crucial immunological insights that feed back into refinement of subsequent generations of improved candidates. This is an ambitious but feasible program. It will require substantial funding, estimated at around US $1 billion in additional resources. However, the payoff would be a truly powerful new tool that would allow not only disease control but also potential elimination of TB by 2050. References 1. Smith PG, Ross AR. Epidemiology of tuberculosis. In: Bloom BR, ed. Tuberculosis: Pathogenesis, Protection, and Control. Washington, D.C.: American Society of Microbiology, 1994.

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2. van Rie A, Warren R, et al. Exogenous reinfection as a cause of recurrent tuberculosis after curative treatment. N Engl J Med 1999; 341(16):1174–1179. 3. al-Kassimi FA, al-Hajjaj MS, al-Orainey IO, et al. Does the protective effect of neonatal BCG correlate with vaccine-induced tuberculin reaction? Am J Respir Crit Care Med 1995; 152(5 Pt 1):1575–1578. 4. Colditz GA, Berkey CS, Mosteller F, et al. The efficacy of bacillus Calmette–Guerin vaccination of newborns and infants in the prevention of tuberculosis: metaanalyses of the published literature. Pediatrics 1995; 96(1 Pt 1):29–35. 5. Miceli I, de Kantor IN, Colaiacova D, et al. Evaluation of the effectiveness of BCG vaccination using the case-control method in Buenos Aires, Argentina. Int J Epidemiol 1988; 17(3):629–634. 6. Bloom BR, Fine PEM. The BCG experience: implications for future vaccines against tuberculosis. Washington, D.C.: American Society for Microbiology, 1994. 7. Fine PE. The BCG story: lessons from the past and implications for the future. Rev Infect Dis 1989; 11(suppl 2):S353–S359. 8. Fine PE. Variation in protection by BCG: implications of and for heterologous immunity. Lancet 1995; 346(8986):1339–1345. 9. Smith DW, Wiegeshaus EH, Edwards ML. The Protective Effects of BCG Vaccination Against Tuberculosis. In: Bendinelli M and Friedman H, eds. Mycobacterium tuberculosis. Plenum Publishing Corporation, New York, 1988:341–370. 10. ten Dam HG. Research on BCG vaccination. Adv Tuberc Res 1984; 21:79–106. 11. Tripathy SP. The case for BCG. Ann Natl Acad Med Sci 1983; 19(1):11–21. 12. Lagranderie MR, Balazuc AM, Deriaud E, et al. Comparison of immune responses of mice immunized with five different Mycobacterium bovis BCG vaccine strains. Infect Immun 1996; 64(1):1–9. 13. Chan J, Kaufmann SHE. In: Bloom, ed. Immune Mechanisms of Protection, Pathogenesis and Control. Washington, D.C.: B. R. American Society of Microbiology, 1994. 14. Palmer CE, Long MW. Effects of infection with atypical mycobacteria on BCG vaccination and tuberculosis. Am Rev Respir Dis 1966; 94(4):553–568. 15. Weiszfeiler JG, Karasseva V. Mixed mycobacterial infections. Rev Infect Dis 1981; 3(5):1081–1083. 16. Rook GA, Bahr GM, Stanford JL. The effect of two distinct forms of cell-mediated response to mycobacteria on the protective efficacy of BCG. Tubercle 1981; 62(1):63–68. 17. Stanford JL, Shield MJ, Rook GA. How environmental mycobacteria may predetermine the protective efficacy of BCG. Tubercle 1981; 62(1):55–62. 18. Brandt L, Feino Cunha J, Weinreich Olsen A, et al. Failure of the Mycobacterium bovis BCG vaccine: some species of environmental mycobacteria block multiplication of BCG and induction of protective immunity to tuberculosis. Infect Immun 2002; 70(2):672–678. 19. Fine PE, Vynnycky E. The effect of heterologous immunity upon the apparent efficacy of (e.g. BCG) vaccines. Vaccine 1998; 16(20):1923–1928. 20. Fine PE, Rodrigues LC. Modern vaccines. Mycobacterial diseases. Lancet 1990; 335(8696):1016–1020. 21. Kristensen I, Aaby P, Jensen H. Routine vaccinations and child survival: follow up study in Guinea Bissau, West Africa. Br Med J 2000; 321(7274):1435–1438. 22. Aronson NE, Santosham M, Comstock GW, et al. Long-term efficacy of BCG vaccine in American Indians and Alaska Natives: A 60-year follow-up study. JAMA 2004, 291(17):2127–2128. 23. Cole ST, Brosch R, Parkhill J, et al. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 1998; 393(6685): 537–544.

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24. Izzo A, Brandt L, Lasco T, et al. NIH pre-clinical screening program: overview and current status. Tuberculosis (Edinb) 2005; 85(1–2):25–28. 25. Williams A, James BW, Bacon J, et al. An assay to compare the infectivity of Mycobacterium tuberculosis isolates based on aerosol infection of guinea pigs and assessment of bacteriology. Tuberculosis (Edinb) 2005; 85(3):177–184. 26. Demangel C, Brodin P, et al. Cell envelope protein PPE68 contributes to Mycobacterium tuberculosis RD1 immunogenicity independently of a 10-kilodalton culture filtrate protein and ESAT-6. Infect Immun 2004; 72(4):2170–2176. 27. Pym AS, Brodin P, et al. Recombinant BCG exporting ESAT-6 confers enhanced protection against tuberculosis. Nat Med 2003; 9(5):533–539. 28. Perez E, Samper S, Bordas Y, et al. An essential role for phoP in Mycobacterium tuberculosis virulence. Mol Microbiol 2001; 41(1):179–187. 29. Hess J, Miko D, Catic A, et al. Mycobacterium bovis Bacille Calmette-Guerin strains secreting listeriolysin of Listeria monocytogenes. Proc Natl Acad Sci USA 1998; 95(9):5299–5304. 30. Grode L, Seiler P, Baumann S, et al. Increased vaccine efficacy against tuberculosis of recombinant Mycobacterium bovis bacille Calmette–Guerin mutants that secrete listeriolysin. J Clin Inv 2005; 115(9):2472–2479. 31. Louise R, Skjot V, Agger EM, et al. Antigen discovery and tuberculosis vaccine development in the post-genomic era. Scand J Infect Dis 2001; 33(9):643–647. 32. Sherman DR, Voskuil M, Schnappinger D, et al. Regulation of the Mycobacterium tuberculosis hypoxic response gene encoding alpha-crystallin. Proc Natl Acad Sci USA 2001; 98(13):7534–7539. 33. Dillon DC, Alderson MR, Day CH, et al. Molecular characterisation and human T-cell responses to a member of a novel Mycobacterium tuberculosis mtb39 gene family. Infect Immun 1999; 67(6):2941–2950. 34. Horwitz MA, Harth G. A new vaccine against tuberculosis affords greater survival after challenge than the current vaccine in the guinea pig model of pulmonary tuberculosis. Infect Immun 2003; 71(4):1672–1679. 35. Horwitz MA, Harth G, et al. Recombinant bacillus Calmette–Guerin (BCG) vaccines expressing the Mycobacterium tuberculosis 30-kDa major secretory protein induce greater protective immunity against tuberculosis than conventional BCG vaccines in a highly susceptible animal model. Proc Natl Acad Sci USA 2000; 97(25):13853–13858. 36. Fonseca DP, Benaissa-Trouw B, van Engelen M, et al. Induction of cell-mediated immunity against Mycobacterium tuberculosis using DNA vaccines encoding cytotoxic and helper T-cell epitopes of the 38-kilodalton protein. Infect Immun 2001; 69(8):4839–4845. 37. Lowrie DB, Tascon RE, Bonato VL, et al. Therapy of tuberculosis in mice by DNA vaccination. Nature 1999; 400(6741):269–271. 38. Stanford JL, De las Aguas J, Turres P, et al. Studies on the effects of a potential immunotherapeutic agent in leprosy patients. Health Coop Pap 1987; 7:201–206. 39. Hondalus MK, Bardarov S, et al. Attenuation of and protection induced by a leucine auxotroph of Mycobacterium tuberculosis. Infect Immun 2000; 68(5): 2888–2898. 40. Smith DA, Parish T, et al. Characterization of auxotrophic mutants of Mycobacterium tuberculosis and their potential as vaccine candidates. Infect Immun 2001; 69(2):1142–1150. 41. Campos JM, Simonetti JP, et al. Disseminated Bacillus Calmette–Guerin infection in HIV-infected children: case report and review. Pediatr AIDS HIV Infect 1996; 7(6):429–432.

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42. Brosch R, Gordon SV, et al. A new evolutionary scenario for the Mycobacterium tuberculosis complex. Proc Natl Acad Sci USA 2002; 99(6):3684–3689. 43. Murray PJ, Aldovini A, Young RA. Manipulation and potentiation of antimycobacterial immunity using recombinant Bacille Calmette–Guerin strains that secrete cytokines. Proc Natl Acad Sci USA 1996; 93(2):934–939. 44. Sousa AO, Mazzaccaro RJ, Russell RG, et al. Relative contributions of distinct MHC class I-dependent cell populations in protection to tuberculosis infection in mice. Proc Natl Acad Sci USA 2000; 97(8):4204–4208. 45. Flynn JL, Goldstein MM, Triebold KJ, et al. Major histocompatibility complex class I-restricted T cells are required for resistance to Mycobacterium tuberculosis infection. Proc Natl Acad Sci USA 1992; 89(24):12013–12017. 46. Edwards KM, Cynamon MH, Voladri RKR. Iron-cofactored superoxide dismutase inhibits host responses to Mycobacterium tuberculosis. Am J Respir Crit Care Med 2001; 164:2213–2219. 47. Reed MB, Domenech P, Manca C, et al. A glycolipid of hypervirulent tuberculosis strains that inhibits the innate immune response. Nature 2004; 431d(7004): 84–87. 48. Andersen P. Effective vaccination of mice against Mycobacterium tuberculosis infection with a soluble mixture of secreted mycobacterial proteins. Infect Immun 1994; 62(6):2536–2544. 49. Andersen P, Askgaard D, Ljungqvist L, et al. Proteins released from Mycobacterium tuberculosis during growth. Infect Immun 1991; 59(6):1905–1910. 50. Content J, de la Cuvellerie A, de Wit L, et al. The genes coding for the antigen 85 complexes of Mycobacterium tuberculosis and Mycobacterium bovis BCG are members of a gene family: cloning, sequence determination, and genomic organization of the gene coding for antigen 85-C of M. tuberculosis. Infect Immun 1991; 59(9):3205–3212. 51. Berthet FX, Rasmussen PB, Rosenkrands I, et al. A Mycobacterium tuberculosis operon encoding ESAT-6 and a novel low-molecular-mass culture filtrate protein (CFP-10). Microbiology 1998; 144(Pt 11):3195–3203. 52. Alderson MR, Bement T, Day CH, et al. Expression cloning of an immunodominant family of Mycobacterium tuberculosis antigens using human CD4(þ) T cells. J Exp Med 2000; 191(3):551–560. 53. Skeiky YA, Alderson MR, Ovendale PJ, et al. Differential immune responses and protective efficacy induced by components of a tuberculosis polyprotein vaccine, Mtb72F, delivered as naked DNA or recombinant protein. J Immunol 2004; 172(12):7618–7628. 54. Reed SG, Alderson MR, Dalemans W, et al. Prospects for a better vaccine against tuberculosis [Review]. Tuberculosis (Edinb) 2003; 83(1–3):213–219. 55. Munk ME, Emoto M. Functions of T-cell subsets and cytokines in mycobacterial infections. Eur Respir J Suppl 1995; 20:668s–675s. 56. Chackerian AA, Perera TV, Behar SM. Gamma interferon-producing CD4þ T lymphocytes in the lung correlate with resistance to infection with Mycobacterium tuberculosis. Infect Immun 2001; 69(4):2666–2674. 57. van Pinxteren LA, Cassidy JP, Smedegaard BH, et al. Control of latent Mycobacterium tuberculosis infection is dependent on CD8 T cells. Eur J Immunol 2000; 30(12):3689–3698. 58. Canaday DH, Wilkinson RJ, Li Q. CD4(þ) and CD8(þ) T cells kill intracellular Mycobacterium tuberculosis by a perforin and Fas/Fas ligand-independent mechanism. J Immunol 2001; 167(5):2734–2742. 59. Serbina NV, Flynn JL. CD8(þ) T cells participate in the memory immune response to Mycobacterium tuberculosis. Infect Immun 2001; 69(7):4320–4328.

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60. Stenger S. Cytolytic T cells in the immune response to mycobacterium tuberculosis. Scand J Infect Dis 2001; 33(7):483–487. 61. Turner J, D’Souza CD, Pearl JE, et al. CD8- and CD95/95L-dependent mechanisms of resistance in mice with chronic pulmonary tuberculosis. Am J Respir Cell Mol Biol 2001; 24(2):203–209. 62. Vordermeier HM, Zhu X, Harris DP. Induction of CD8þ CTL recognizing mycobacterial peptides. Scand J Immunol 1997; 45(5):521–526. 63. Zhu X, Venkataprasad N, Thangaraj HS, et al. Functions and specificity of T cells following nucleic acid vaccination of mice against Mycobacterium tuberculosis infection. J Immunol 1997; 158(12):5921–5926. 64. McShane H, Pathan AA, Sander CR. Recombinant modified vaccinia virus Ankara expressing antigen 85A boosts BCG-primed and naturally acquired antimycobacterial immunity in humans. Nat Med 2004; 10(11):1240–1244. 65. McShane H, Pathan AA, Sander CR, et al. Boosting BCG with MVA85A: the first candidate subunit vaccine for tuberculosis in clinical trials. Tuberculosis (Edinb) 2005; 85(1–2):47–52. 66. Kaufmann SH, McMichael AJ. Annulling a dangerous liaison: vaccination strategies against AIDS and tuberculosis. Nat Med 2005; 11(4):S33–S44. 67. Kaufmann SH. Gamma/delta and other unconventional T lymphocytes: what do they see and what do they do? Proc Natl Acad Sci USA 1996; 93(6):2272–2279. 68. Moody DB, Ulrichs T, Muhlecker W, et al. CD1c-mediated T-cell recognition of isoprenoid glycolipids in Mycobacterium tuberculosis infection. Nature 2000; 404(6780):884–888. 69. Poziak A, Stanford JL, Johnson NMcl, et al. Preliminary studies of immunotherapy of tuberculosis in man. Proceedings of the International Tuberculosis Congress, Singapore. Bull IUALD 1987; 62:39–40. 70. Bahr GM, Shaaban MA, Gabriel M, et al. Improved immunotherapy for pulmonary tuberculosis with improved Mycobacterium vaccae. Tubercle 1990; 71:259–266. 71. Stanford JL, Bahr GM, Bypass O, et al. A modern approach to the immunotherapy of tuberculosis. Bull IUTLD 1990; 65:27–29. 72. Durban Immunotherapy Trial Group. Immunotherapy with Mycobacterium vaccae in patients with newly diganosed pulmonary tuberculosis: a randomised controlled trial. Lancet 1999; 354:116–119. 73. Orme IM. Mouse and guinea pig models for testing new tuberculosis vaccines. Tuberculosis 2005; 85:13–17. 74. Fine PE, Sterne JA, Ponnighaus JM, et al. Delayed-type hypersensitivity, mycobacterial vaccines and protective immunity. Lancet 1994; 344(8932):1245–1249. 75. Cooper AM, Dalton DK, Stewart TA, et al. Disseminated tuberculosis in interferon gamma gene-disrupted mice. J Exp Med 1993; 178(6):2243–2247. 76. Agger EM, Andersen P. Tuberculosis subunit vaccine development: on the role of interferon-gamma. Vaccine 2001; 19(17–19):2298–2302. 77. Vordermeier HM, Chambers MA, Cockle PJ, et al. Correlation of ESAT-6-specific gamma interferon production with pathology in cattle following Mycobacterium bovis BCG vaccination against experimental bovine tuberculosis. Infect Immun 2002; 70(6):3026–3032. 78. McMurray DN. A coordinated strategy for evaluating new vaccines for human and animal tuberculosis. Tuberculosis (Edinb) 2001; 81(1–2):141–146.

49 Research Priorities in Tuberculosis

PHILIP ONYEBUJOH

WILLIAM RODRIGUEZ

Implementation Research and Methods, UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR), Geneva, Switzerland

Harvard Medical School Division of AIDS, The Landmark Center, Boston, Massachusetts, U.S.A.

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.

I. Background and Introduction Tuberculosis (TB) continues to be a major global public health problem (1–5). Approximately two billion people worldwide are infected with Mycobacterium tuberculosis (MTb). The global incidence of active TB is estimated to be 8.8 million new cases per year—25,000 new cases each day (2). In developing countries—home to 95% of TB cases and 98% of TB deaths—TB causes 25% of the burden of preventable diseases. In 1991, the World Health Assembly adopted targets of detecting 70% of all infectious TB cases and curing at least 85% of detected cases by 2005 (2). Despite intensified efforts, these targets have not yet been met (3). At the end of 2003, 82% of TB cases were successfully treated, but only 45% of infectious TB cases were detected (4). Detection and cure rates are especially low in sub-Saharan Africa and other high–HIV-prevalence settings (5). Several questions regarding the TB epidemic remain unanswered today. 1169

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How can the research community contribute to achieving the targets set by the World Health Assembly, The Stop TB Partnership, and other public health officials? What is the role of research in addressing an emerging global health crisis? The new Stop TB Strategy of the World Health Organization (WHO), announced in early 2006 (see also Chapter 50), and underpinning the Global Plan to Stop TB, 2006–2015 of the Stop TB Partnership, has six elements, the sixth of which is ‘‘enabling and promoting research for new tools and program performance’’ (Table 1) (3). Although knowledge of the epidemiology, immunobiology, and disease control of TB is accumulating, achieving the detection and treatment goals will require generation and implementation of new knowledge through focused and targeted research in several areas.

Table 1 Six Components of the World Health Organization’s New Stop TB Strategy and Implementation Approaches, 2006–2015 1. Pursue quality DOTS expansion and enhancement Political commitment with increased and sustained financing Case detection through quality-assured bacteriology Standardized treatment, through supervision and patient support Effective drug supply and management system Monitoring and evaluation system, and impact measurement system 2. Address TB/HIV coinfection, MDR-TB, and other challenges TB/HIV collaborative activities Prevention and control of MDR-resistant TB Addressing prisoners, refugees, and other risk groups and special situations 3. Contribute to health-system strengthening Active participation in efforts to improve system-wide policy, human resources, financing, management, service delivery, and information systems Sharing innovations that strengthen systems, including the Practical Approach to Lung Health Adapting innovations from other fields 4. Engage all care providers Public–public and public–private mix approaches International standards for TB care 5. Empower people with TB, and communities Advocacy, communication, and social mobilization Community participation in TB care Patients’ charter for TB care 6. Enable and promote research Program-based operational research Research to develop new diagnostics, drugs, and vaccines Abbreviation: MDR-TB, multidrug-resistant TB. Source: From Ref. 3.

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The Global Plan to Stop TB, 2006–2015 targets are linked to Millennium Development Goals (MDGs) (6) and endorsed by the Stop TB Partnership’s targets.





By 2015, to detect at least 70% of new smear-positive cases and cure successfully at least 85% of these cases To have halted and begun to reverse incidence of TB by 2015 (MDG 6, target 8) (6) To halve TB prevalence and death rates in 2015 compared to 1990 levels To eliminate TB as a public health problem by 2050

The sixth element of the new Stop TB Strategy of WHO (Table 1) validates the importance of research in optimizing control efforts by suggesting two general areas where the attention of the research enterprise is most urgently needed. Current UNDP/UNICEF/World Bank/WHO Special Programme in Research and Training, Scientific Working Group (SWG) recommendations (7) for priority research into TB are grouped into seven areas (Table 2). These include the following: 1. 2. 3. 4. 5. 6. 7.

Improved diagnostics for TB Improved clinical management for TB by new drug development and more effective and shortened treatment regimens Social, economic, and behavioral research Operational and implementation research Immunopathogenesis and new vaccine studies Improved program performance and capacity building Improved epidemiological research in national TB programs

First, research on program performance is essential (7). Up to 60% of TB cases can be detected with existing diagnostic tools, and nearly all can be cured using existing regimens. The current shortfalls in case detection and treatment success rates suggest inadequate knowledge on how to implement proven approaches. In fact, implementation research has been previously identified as a priority in TB control efforts (7). One of the most persistent challenges in TB management in developing countries has been the lack of a specific, sensitive, inexpensive, and rapid method for the diagnosis of TB. This has been addressed in part by the new Global Plan to Stop TB, 2006– 2015 by ensuring that case detection is expanded to include ‘‘strengthening of laboratory networks to facilitate detection of all forms of TB including smear-negative TB.’’ How else can case detection be improved? Research into the social and behavioral factors limiting case detection will be necessary, as well as evaluations of new case-detection strategies. Key factors to study include transportation, user fees, hunger, work and gender discrimination, and other barriers to accessing care. Better clinical diagnostic algorithms and case definitions are required for diagnosing TB in HIV-infected

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Table 2 Tuberculosis Research Priorities Priority area Improved diagnostics for TB

Improved clinical management of TB in HIV-positive and HIV-negative individuals

Social, economic, and behavioral research and the global TB agenda

Operational and implementation research

Immunopathogenesis and vaccine studies

Specific activities Improving and evaluating existing tools Developing and evaluating new tools Developing tools for monitoring disease activity, cure, and relapse Strengthening research capacity and operational research Establishing and maintaining research resources Facilitating new TB drug research and development Enhancing clinical trials site capacity Building evidence base for country adoption of new, more effective, and shortened drug treatment regimens Optimizing existing treatment strategies for different categories of TB (special populations of TB patients: HIV-infected TB, MDR-TB, pediatric, pregnancy) Developing and validating surrogate end points and biomarkers to shorten clinical trials Evaluating the potential of simulation mathematical models for efficacy and costs of new interventions to better inform clinical trials of investigational new drugs Identifying determinants and reduction of risk and vulnerability to TB Addressing impact of poverty on health-seeking behavior Determining effects of gender inequality on disease severity and case detection Identifying impact of community factors on health services and DOTS programs Developing practical solutions to common and critical issues in implementation of TB related interventions by the following: Building a close collaboration between researchers, national TB control programs, Ministry of Health, and others. Improving organization and management Engaging all health-care providers Empowering patients and communities Generating political will and commitment Improving human resources Promoting (demand for) research Evaluating adherence support strategies Defining the macro- and micro-TB epidemiology Identifying immune correlates of protection to facilitate vaccine studies Investigating and utilizing new information on the immunopathogenesis of MTb infection (latency, (Continued )

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Table 2 Tuberculosis Research Priorities (Continued ) Priority area

Improved program performance and capacity building

Epidemiological research in national TB programs

Cross-cutting issues

Specific activities dormancy, and reactivation) to inform new interventions for improved TB control Evaluating the use of adjunctive immunotherapy to facilitate treatment shortening Developing approaches to detect and manage IRIS and ARV–TB drugs interactions Investigating and documenting geographic diversity of pre-existing immune status of the vaccine target population through target-country vaccine-preparatory studies Individual and institutional capacity building in the least-developed countries including improving NTP management Linking research with national TB programs and coordination of TB/HIV research Inclusion of basic social, economic, and behavioral research in national programs Development and evaluation of alternative TB care–delivery strategies Integration of TB and HIV/AIDS treatment strategies Improved case finding in vulnerable populations and access to care Focusing on partnership with local, regional, and international organizations Impact of early diagnosis to have an impact on TB transmission Duration of occurrence of TB disease after HIV infection Development of systems to disaggregate NTP data for use in studying locally and hard-to-reach populations Development of new diagnostic tools for identifying latent TB infection and conducting TB prevalence surveys Determinants of risk, poverty, gender, and community factors Pediatric TB (new diagnostics and revised diagnostic algorithms) MDR-TB (management and cost-effectiveness) Regulatory issues (product registration) Biological banks (creation and monitoring) Ethics of research in developing countries

Abbreviations: NTP, National TB Program; ARV-TB, antiretroviral-tuberculosis; MDR-TB, multidrug-resistant TB; IRIS, immune reconstitution inflammatory response; MTb, Mycobacterium tuberculosis. Source: From Ref. 7.

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individuals and children. Different diagnostic strategies—sputum concentration methods, fluorescence microscopy, and improved mycobacterial culture system—also need to be evaluated for their impact on case detection. Diagnostic algorithms, including the use of empiric antibiotic trials to exclude TB, need to be carefully reassessed and improved. Implementation research can also assess the potential of integrating health service at district and health center levels as a means of overcoming infrastructural and manpower impediments to operationalizing case-detection services. How can current treatment outcomes be optimized? Most critically, treatment adherence support strategies (such as directly-observed therapy) need to be assessed and optimized. The use of new anti-TB and immunomodulatory drugs needs to be carefully reviewed—meta-analyses of prior trials and new trials based on reasonable expectations of benefit and well-defined end points. Finally, the growing importance of HIV–MTb coinfection on TB treatment outcomes and implementation research focused on HIV–TB care need to be addressed. WHO’s Interim Policy on Collaborative TB/HIV program activities provides guidance to develop mechanisms for collaboration between TB and HIV/AIDS programs, decrease the burden of TB in HIV-positive persons, and decrease the burden of HIV in TB patients (8). Implementation research is urgently required to investigate different models of collaboration between programs within health systems in disease-endemic settings. Second, it is well established that the research community must generate new tools for TB diagnosis, treatment, and prevention. As many as 3 million cases of TB each year present as sputum smear-negative pulmonary disease and extrapulmonary disease, for which sputum smear microscopy is inadequate; pediatric and multidrug-resistant TB (MDR-TB) pose additional diagnostic challenges not addressed by sputum-smear microscopy. The currently available short-course chemotherapy (SCC) still requires six months of drug adherence with suboptimal toxicity profiles; drug interactions between antimycobacterial drugs and antiretroviral drugs for HIV treatment represent a major new challenge, and there is no proven, simple regimen for simultaneous treatment. Thus, better diagnostics and drug regimens will improve case-detection rates, improve treatment outcomes, simplify program implementation, and thus accelerate TB control efforts. Diagnostics need to be driven by the reality of health systems infrastructure; well-engineered, simplified tests are needed at the point-of-care, at district hospital laboratories, and at central laboratories (7). An effective vaccine will be necessary for TB control, and its development will require new insights into the immunopathogenesis of TB and the advances in TB genomics and proteomics, and a better understanding of the deficiencies of bacille Calmette–Gue´rin (BCG). The development of new drugs is also important. The challenges of HIV coinfection, poor case detection, poor adherence, and a reduced capacity of the health systems’ to cope with the increasing burden of TB, necessitate new drugs with novel modes of action. The strategic treatment goals include shortening and simplification of TB

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treatment regimens, improved treatment for MDR-TB, and management of TB/HIV coinfection with drugs that can be safely coadministered with antiretroviral drugs. The 30-year lull in investments in TB drug development is now changing. In the long term, the sequencing of the genome of MTb and refined techniques for elucidating metabolic pathways are opening up exciting new avenues of research. In a shorter time, there are interesting prospects with six new drug candidates for TB currently in clinical phases, with five other additional compounds in preclinical development (9). Much of this progress has been possible through new public–private collaborations. The not-for-profit organization Global Alliance for TB Drug Development, supported by the Bill and Melinda Gates Foundation and the Rockefeller Foundation, has brought a new focus on and leadership for TB drug development. Many of the new treatments have a broad therapeutic scope: the fluoroquinolones and the new diarylquinoline (R207910) hold promise for the management of TB and MDR-TB, and their safe coadministration with antiretroviral agents (10,11). Finally, research programs cannot be divorced from the strength and capacity of the health systems within the resource-limited, high-burden countries most affected by the TB pandemic. Thus, the TB research agenda assumes availability of resources to strengthen the health system’s capacity to cope with the anticipated increased burden of cases, and to participate in research. Appropriate research for TB control cannot be conducted without concomitantly developing the relevant research capacity locally; ultimately, the relevant research skills belong in TB endemic countries. Research capacity should not be built at the detriment of control programs, but rather to strengthen and compliment control. For implementation research studies to be appropriately designed and conducted, national TB control programs, ministries of health, and other relevant public and private agencies must take an active role in research. This will require new funding and new forms of collaboration between the research community (including social and implementation research) and public officials. For diagnostic, drug, and vaccine development to succeed, a series of enabling factors must be in place. Studies must conform to international standards of quality. Pivotal trials will require well-resourced clinical trials infrastructure, including adequately trained staff; current clinical trial capabilities are insufficient to absorb all of the products currently in preclinical and clinical phases of development. This points to the need for strengthening research capacities in high-burden countries. Accelerated and fast-track mechanisms for regulatory approval of investigational new drug application will have to match the urgent demand for the new interventions. Once proven and approved, innovative approaches to implementation will be critical to expedite the rate at which the available evidence is translated into guideline development and clinical use. With tens of thousands of new TB infections each day, and nearly 7000 TB deaths each day, there are great needs, but also an occasion to innovate and generate new knowledge that can be directly applied to the growing epidemic.

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Three of the major seven areas of priority TB research listed in Table 2 (Improved Diagnostics for TB; New Drugs for TB; and Vaccine Development) are detailed in Chapters 48, 49 and 50. However, all seven priorities will be dealt with in this chapter so that an overall view of research priorities in TB is presented. All of the research priorities listed in Table 2 are discussed in this chapter and are largely based on recent literature on the subject matter, and it summarizes the core material arising from the TB/HIV expert consultation to define operational research priorities in TB and TDR’s SWG meeting to identify TB research priorities held in Geneva, in February and October 2005, respectively (7,12). A. Improved Diagnostics for TB

The lack of accurate, robust, and rapid diagnostics is a critical impediment to TB patient management and disease control (13). For individual patients, the cost, complexity, and potential toxicity of six months of standard TB treatment demands certainty in diagnosis. For communities, the risk of transmission from undetected cases requires widespread access to diagnostic services and early detection. Unfortunately, current diagnostic services in most TB endemic settings fail both the individual and the community. Patients are commonly diagnosed after weeks to months of waiting, at a substantial cost to themselves, and at huge costs to society as TB goes unchecked. Many patients are missed altogether, and contribute to the astonishing number of annual deaths from TB worldwide. Some of this failure could be corrected by better implementation of existing standards of clinical and laboratory practice. To their credit, the WHO and its member states have made great gains in the expansion of the DOTS strategy to control TB, with a gratifying rise in the rates of cure. Improving case-detection rates has proven more difficult, in large part because of limitations of existing diagnostic technologies, something that in the 21st century we should be able to correct. The core diagnostic technology enshrined in the DOTS strategy is sputum microscopy, a methodology essentially unchanged from when it was developed in the 1880s. Microscopy is an attractive technology for public health programs. It requires a single piece of equipment, can be used for more than one purpose, provides visual evidence not only of TB disease, but also of bacterial burden, and in most cases is specific enough that no confirmatory testing is needed. The limits to microscopy have become just as obvious. Only tiny amounts of material are examined, as little as 0.2 mL even when viewing more than 100 microscopic fields, so bacteria must be present in high concentrations to be visible—typically over 10,000 acid fast bacille (AFB)/mL sputum. The low sensitivity of the technology, which is only capable of detecting roughly half of all active TB cases when properly used, is compounded by its complexity. Although routinely described as a simple test, it is highly dependent on

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the training and diligence of the microscopist, requires multiple examinations, and in programmatic conditions takes days rather than hours to complete, so that many patients drop out during the diagnostic process. As an indicator of the difficulty of implementing quality microscopy services, fewer than 45% of predicted incident smear-positive cases of TB are currently detected and notified. By definition, microscopy cannot detect MTb in patients with smearnegative disease. Although not prioritized for detection under conventional DOTS because of their lower transmission potential, these patients, many of whom later become smear-positive, contribute importantly to global TB morbidity and mortality. In areas struck by epidemic HIV, smearnegative disease is disproportionately common. Reduced bacterial burden and less obvious chest X-ray findings make TB more difficult to diagnose in these populations, but not less fatal. In a carefully done study in Malawi, the eight-month mortality in a group of patients with a diagnosis of smearnegative TB was 40% (14). Pediatric TB is also difficult to detect with microscopy; TB has become an important killer disease of children in sub-Saharan Africa and a large proportion of childhood TB remains undiagnosed and untreated. Thus, precisely in the areas of the world where TB microscopy has the poorest performance, the need for early detection is the greatest. Indeed the MDGs for reductions in TB incidence and mortality are not likely to be reached in Africa and Eastern Europe unless improved tools become available. More than one type of test is needed. International workshops on TB diagnostics have highlighted the need to: (i) replace or improve microscopy with a simpler technology to detect smear-positive TB, (ii) develop a faster alternative to culture to detect smear-negative TB, (iii) improve antibiotic susceptibility testing, and (iv) develop tests for detecting latent infection at risk for relapse. The diagnostic priorities for TB are listed in the table below, in roughly rank order of importance to global TB control. An industry survey performed in the late 1990s identified over 50 companies (mostly small) with an interest in TB diagnostics. It was assumed that this commercial interest, armed with the significant recent technical advances in diagnostics and mycobacteriology, would lead to the development of a series of new tools to meet the stated needs. To facilitate the relevant commercial activity, WHO, and later its Special Programme for Research and Training in Tropical Diseases (WHO-TDR), established an enabling infrastructure for industry, which included banks of reference materials, diagnostic trial sites, and market research. Unfortunately, this work alone could not ensure that new tools would get developed, or, once developed, that they would meet the needs of disease-endemic countries or be affordable. To overcome this, Foundation for Innovative New Diagnostics (FIND), an independent nonprofit foundation, was established to work in contractual partnership with industry and academic groups, acting as an engine to drive the development of new diagnostic technologies. Launched

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Table 3 Priorities for Tuberculosis Diagnostics Development Type of diagnostic tool Case detection

Drug susceptibility testing Latent TB infection

Disease to be detected Pulmonary TB with high bacterial load Pulmonary TB with low bacterial load Extrapulmonary and pediatric TB MDR-TB for treatment MDR-TB for surveillance Latent TB for treatment Latent TB for surveillance

Abbreviation: MDR-TB, multidrug-resistant TB. Source: From Ref. 7.

at the World Health Assembly in 2003 with initial funding from the Bill and Melinda Gates Foundation, FIND works closely with WHO-TDR and other public sector agencies to fulfill its mission to accelerate the development, evaluation, and appropriate use of high-quality yet affordable diagnostic tools for infectious diseases in developing countries (Table 3). FIND is working to develop technologies that are appropriate for the level of the health system at which they would be used, prioritizing tests that can be used at the most peripheral level, where the majority of patients first seek care. The technologies targeted for each level of the health system are intended to match the human resources available there, and the degree of complexity of the diagnostic question. Table 4 provides a simplified illustration of the levels of a hypothetical health system, indicating the proportion of patients seeking care at each level, the diagnostic needs, the problems with the currently available tests, and the types of technologies that might be available to overcome them. A number of potential replacement technologies listed in Table 4 are now at various stages in the developmental pipeline. It is likely that some of the tests completing development first will be bridging technologies that may be replaced by later or second-generation assays. More detailed information about the emerging technologies is available on the FIND Web site (15). Following the completion of test development, high-quality laboratory and clinical evaluations in populations of intended use are necessary to ensure that performance characteristics are well understood, with narrow confidence intervals. Such data are often lacking, even for marketed products, and results from trials of TB serology tests demonstrate the degree to which performance data provided by the manufacturer can be misleading. A Diagnostics Evaluation Expert Panel, convened by WHO-TDR and FIND, is developing guidelines for the performance of diagnostic trials for TB and other diseases, which are intended to establish quality standards for clinical testing.

30

60

Microscopy center

Health post

Detect smear-negative TB Detect MDR Test for TB in suspects with inconclusive screening result Screen for latent TB infection Screen for TB in suspects

Diagnostic need

Difficult to implement Insensitive Poorly predictive of future TB Clinical exam nonspecific

Microscopy

Tuberculin skin testing None

Slow

b

Problem with current test

Culture and drugsusceptibility testing

Existing test

More sensitive microscopy using fluorescence or processing additives such as NaOCl. ICT—immunochromatographic test (dipstick). Abbreviations: MDR, multidrug resistance; IFN, interferon; NAAT, nucleic acid amplification test. Source: From Ref. 3.

a

10

Percent access

Referral laboratory

Health system level

Table 4 Current and Potential Alternative Tuberculosis Diagnostic Tests

IFN-c release assay Breath test ICT antigen detectionb ICT antibody detectionb

Phage assay Rapid culture Simplified NAAT Simplified NAAT Improved microscopya

Potential alternatives

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Lastly, good performance under trial conditions does not always translate into effectiveness after implementation. Demonstration projects are needed to evaluate the feasibility, impact, and cost-effectiveness of new diagnostic interventions after scale-up in national control programs. The outcome of these projects, which are a critical feature of FIND’s diagnostics development activities, should provide evidence for policy, so that useful technologies can be rapidly adopted, and impractical or ineffective technologies improved or dropped. Remarkable progress has been made over the past decade in upgrading the speed and quality of mycobacteriology services in industrialized countries using new culture systems and molecular methods (16), but for most of the developing world where TB is a major killer, these gains have not been realized. The array of promising technologies now available, and the capacity for FIND and other groups to speed their development and evaluation, has created a vital mood of optimism in the global scientific community. Donor agencies and research institutions should make investment in TB diagnostics development a priority. Sputum-Smear Microscopy

The microscopic evaluation of a sputum smear, first used in the diagnosis of TB in 1882, is still at the heart of TB diagnosis. Sputum-smear microscopy alone, however, is inadequate for diagnosis of the majority of the 9,000,000 cases of active TB annually. There are three main reasons for this. First, a significant percentage of active pulmonary TB cases have negative sputum smears (reflecting both the biology of TB and the technical limitations of the assay) (17). Diagnosing sputum smear–negative cases requires slower, more complex, and more expensive methods, including chest X-ray and mycobacterial culture. Second, roughly one in three cases of active TB is extrapulmonary disease. In these cases, sputum smears are obviously of little use. Diagnosis necessarily depends on biopsy, with pathologic examination and/or culture. The proportion of both sputum smear–negative pulmonary disease and extrapulmonary disease is substantially higher in HIV coinfected patients, exacerbating the problem with diagnosis in high-prevalence HIV settings. Finally, even in the 4 million annual cases of diagnosable sputum smear–positive pulmonary disease, sputum-smear microscopy has proven to be surprisingly difficult to implement. The performance specifications of traditional sputum-smear microscopy—low throughput and high technical skill—are suboptimal. Overall, sputum-smear microscopy has a sensitivity of only 40% to 60% in high-burden countries, and even lower sensitivity in HIV coinfection. Other Methods of Diagnosis

Mycobacterial culture remains the gold standard for the definitive diagnosis of active disease. Few TB programs in low-income settings, however, are

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able to support the use of existing culture methods at a primary care level, and the delay of several weeks before interpretable results can be obtained limits the utility of culture as a diagnostic tool (1). Currently available serologic tests for TB lack sensitivity and specificity for active disease. Chest radiography (18), in addition to technical and cost concerns, can also be misleading, because diseases related to HIV (including Pneumocystis carinii/jiroveci pneumonia, heart failure, and bacterial pneumonia) may be misdiagnosed as TB. The use of responsiveness to an empiric trial of antimicrobials as a diagnostic decision point is fraught with concerns about antimicrobial resistance, partial treatment of TB (when fluoroquinolones are used), and delay in diagnosis. None of these diagnostic approaches can be used reliably to diagnose extrapulmonary and pediatric TB in a timely fashion (19). Thus, particularly within the 22 high-burden countries that encompass 80% of the global TB burden, the absence of a simple and reliable diagnostic test for active TB has created difficult choices for TB control programs: the use of mycobacterial culture systems for diagnosis of active pulmonary disease; the use of chest radiography, biopsy, and/or diagnostic algorithms focused on symptoms; or, worse, persistent underdiagnosis and misdiagnosis. In addition to the need for better diagnosis of active pulmonary and extrapulmonary disease in adults, there is also a need for improved diagnostics in special populations. There is a particular need to improve pediatric TB diagnosis and to improve drug-susceptibility testing (DST) for the diagnosis of MDR-TB. Given the limited advances in TB diagnostics for more than a century, the development of new diagnostics has become a central part of the TB research agenda in recent years. Many organizations have acknowledged the urgent need for improved TB diagnostics, and have advocated for additional research (1). Recommendations stemming from these groups have been incorporated into TDR’s strategic plan for TB diagnostics research, and a targeted diagnostics research agenda is reflected in the Stop TB Partnership’s Second Global Plan to Stop TB, 2006–2015 (3). Several promising TB diagnostic tests that vary in the level of the health system in which they could be introduced are currently in development. Unfortunately, tests that would have the greatest impact on TB control—point-of-care tests—are in early development. New diagnostics that increase the sensitivity or simplicity of diagnosing active disease are in later development. These diagnostics would only be implemented at district or central referral laboratories; nonetheless, they are expected to have a measurable impact on TB control. Rapid implementation of proven new technologies will also be critical to meet the urgent public health need and TB control targets. Improved Diagnostics for TB Incidence and Prevalence Studies

Over the past years, the quality of information on TB micro- and macroepidemiology has increased substantially. There is, however, consensus

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on the need for more and better TB prevalence surveys. Tuberculin skin testing is still the method in use, despite its shortcomings. Novel diagnostic methods for use in TB epidemiological studies are highly desirable. Optimization of Existing Tools

Sputum-Smear Microscopy. Existing tools should be optimized to diagnose specific categories of TB disease in specific settings. Despite the shortcomings of sputum-smear microscopy, several areas of research could lead to better sensitivity and improved use in field conditions.
Sample processing techniques to improve the yield of standard sputum smears, including better methods of sputum collection, sputum transport, and sputum concentration should be investigated.
The optimal use of fluorescence microscopy should be defined through implementation research studies. Mycobacterial Culture Methods. Existing culture methods need improvement to allow adoption by TB programs in low-income settings and timely results. Simplified or speeded cultures are a priority for shortterm TB diagnostic improvement, before the availability of new tests that might replace point of care culture (Table 5). Colorimetric solid media are among the promising strategies demanding evaluation. Diagnosis of TB in Patients with M. tuberculosis and HIV Coinfection

There are special challenges in the diagnosis of TB in MTb/HIV coinfected patients, in particular, the need for the development of new tools and algorithms to improve diagnosis of smear-negative TB in adults and children. Additional elements for evaluation include the optimal algorithm to exclude active TB in asymptomatic individuals with HIV infection; diagnostic tests for detection of latent TB infection in persons with HIV infection; the accuracy and utility of novel markers of disease activity (such as T-cell–based interferon assays and cytokines) in individuals with HIV infection; as well as, the optimal approach to diagnosing HIV infection in patients presenting with active TB. Rapid Diagnosis of Multidrug-Resistant Tuberculosis

Delays in diagnosing MDR-TB result in increased morbidity, the selection of drug-resistant populations of bacteria, and the continued transmission of MDR-TB. Improved resistance testing and surveillance is a fundamental element in tackling MDR-TB. New rapid and accurate tests for drug resistance are urgently needed. Further, there is a need to define the optimal diagnostic algorithm for persons with suspected MDR-TB. Accelerate efforts and streamlined evaluation are necessary. More detailed discussion of TB diagnostics is outlined in Chapters 6, 8, and 13.

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Table 5 Research Topics in Tuberculosis Diagnostics Research topic Diagnostics in support of epidemiologic research 1. Development of new diagnostic tools for identifying latent TB infection and conducting TB prevalence surveys 2. Can interferon-c assays be used in surveys on prevalence and annual risk of TB infection studies? Diagnostics in support of case finding 3. What are the implications of changing symptom-based and laboratory-based diagnostic algorithms for case finding? 4. What is the sensitivity and specificity of various thresholds for chronic cough (e.g., 2 vs. 3 weeks) as screening tests for tuberculosis? 5. What is the role of culture-based detection methods on case finding? Optimization of existing tools: smear microscopy 6. What is the value and role of sputum processing and concentration (e.g., bleach, centrifugation, sedimentation, and combinations) in improving the accuracy and yield of smear microscopy? 7. What are the role, feasibility, and applicability of fluorescent microscopy in routine field conditions? Is fluorescence microscopy more sensitive in HIV-infected populations as compared to conventional microscopy? 8. What is the clinical and public health significance of a ‘‘scanty smear,’’ particularly in HIV-positive patients? 9. What is the optimal cutoff point for declaring a smear examination positive? Is one of three positive smears adequate for initiation of anti-TB treatment? 10. What is the impact of introducing the two-smear strategy in high-burden settings? Optimization of existing tools: mycobacterial culture methods 11. What is the optimal use of mycobacterial culture systems, including automated systems, in TB diagnosis in resource-limited settings? Evaluation of diagnostic algorithms 12. What is the existing evidence base for the current diagnostic algorithms for TB diagnosis? 13. What is the optimal diagnostic algorithm for establishing a diagnosis in smear-negative patients, including patients with HIV coinfection? 14. What is the optimal diagnostic algorithm for persons with suspected extrapulmonary TB? 15. What is the role of therapeutic antimicrobial trials in the diagnostic algorithms for smear-negative tuberculosis? 16. What is the impact of widespread use of fluoroquinolones on the utility of therapeutic antimicrobial trials in the workup of smear-negative tuberculosis? Development and evaluation of new diagnostics 17. What are the specifications of new diagnostics that can be used to increase case detection at each level of the health system? (Continued )

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Table 5 Research Topics in Tuberculosis Diagnostics (Continued ) Research topic 18. Program to independently evaluate new diagnostics in field trials, including nucleic acid amplification, and antigen and antibody detection methods Diagnosis of TB in HIV coinfection 19. What is the optimum algorithm to exclude active TB in asymptomatic individuals with HIV infection? 20. What is the optimal diagnostic test for detection of latent TB infection in persons with HIV infection? What is the accuracy and utility of novel markers of disease activity (e.g., T-cell–based interferon-c assays, cytokines, etc.) in individuals with HIV infection? 21. What is the optimal approach to diagnosing HIV infection in patients presenting with active TB? Diagnosis of pediatric TB infection 22. What is the optimal diagnostic algorithm for children with suspected tuberculosis? Can NAA, gamma interferon, and urine DNA PCR tests be utilized together to improve the diagnostic sensitivity for MTb? Diagnosis of MDR-TB 23. What is the optimal diagnostic algorithm for persons with suspected MDR-TB? 24. Evaluation of rapid tests for drug resistance 25. What is the role of rapid rifampicin resistance tests in the management and control of MDR-TB? Implementation research: health systems and operations 26. How can the uptake of proven new diagnostic tests be accelerated in both public and private settings? 27. What measures will be helpful in shortening the duration of TB workup (diagnostic pathway) and the number of consultation visits before a diagnosis is made? 28. How can laboratory workload be reduced in high-burden countries? Abbreviations: NAA, nucleic acid amplification; PCR, polymerase chain reaction; MTb, Mycobacterium tuberculosis; MDR-TB, multidrug-resistance TB. Source: From Ref. 7.

B. Research Priorities to Improve Clinical Management of TB in HIV-Negative and HIV-Positive Individuals

The current efforts at developing new anti-MTb drugs are discussed in Chapter 49. Research and Development of Anti-tuberculosis Drugs

Waksman’s discovery of streptomycin in the 1940s heralded the modern era of anti-TB chemotherapy, followed by the later discovery of a fungus, Streptomyces mediterranei (in 1959), which produced a new antibiotic, Rifamycin B. Further research led to the development of a new anti-TB medication of remarkable potency, rifampicin. Two more TB drugs, pyrazinamide and ethambutol, followed shortly thereafter, in 1963 and 1967,

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respectively, enabling simplified, effective, multidrug treatment for TB (20,21). Following the successful application of multidrug therapy, the death rate from TB dropped rapidly in settings where diagnosis and treatment were available. TB sanitoria closed. Despite early success, treatment costs, treatment duration, and poor implementation prevented TB infected people living in conditions of widespread poverty from benefiting from multidrug treatment. Moreover, research into drugs, diagnostics, and vaccines for TB stagnated; no new classes of drugs for TB have been developed in the past 40 years. The only available TB vaccine, BCG, was developed at the beginning of the 20th century and has been in use since 1921, and is largely ineffective in most countries. The main diagnostic technique—sputum-smear microscopy—dates to the 1880s, yet remains the mainstay of TB diagnosis without improvement in more than a century of use. With the rate of the current TB epidemic expected to climb over the next few years, it is clear that meeting the MDGs for TB control and the elimination of TB as a global public health issue by 2050 will require new tools—new drugs, diagnostics, and vaccines. This is hardly a new refrain in TB research. The momentum for new drugs, diagnostics, and vaccines has been building for more than decade: working groups on new diagnostics, new drugs, and new vaccines have been convened by the Stop TB Partnership and have set out strategies to develop new, improved tools for the detection, treatment, and prevention of TB disease, drug resistance, and latent infection. Research supported by a number of organizations worldwide has led to the discovery of new compounds and new immune markers of disease, and several promising drugs, diagnostics, and vaccines are currently in the developmental pipeline for the first time in 40 years. Strategies for the optimized implementation of new products— and to ensure delivery of existing drugs, diagnostics, and vaccines to areas of need—have also been established. These achievements are the result of fruitful collaborations between public and private partners, which have leveraged the scientific and clinical knowledge of industry, public health, and academic laboratories worldwide. Surrogate Markers of Disease

There are no accurate clinical, biochemical, immunological, or molecular markers of TB disease activity, TB cure, or TB relapse. A major challenge to drug (and vaccine) development is the length of time for assessment of efficacy through dependence on long-term clinical outcomes. New biomarkers of treatment success would provide useful surrogates in drug regimen trials (and vaccine studies), reducing costs, and decreasing the long development timeline. Particularly important are surrogate biomarkers that can reduce the two-year follow-up currently used to monitor relapse. Research in this area is required urgently. Impact of HIV on Tuberculosis

The increasing number of new TB cases each year—especially those propelled by the 10% annual increase in TB incidence in sub-Saharan

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Africa—is attributable largely to HIV infection. Coinfection rates in TB infected patients in some countries are as high as 70% (1). The HIV epidemic is not merely increasing TB but also driving a significant increase in the proportion of TB cases that are smear-negative pulmonary and extrapulmonary disease; these presentations of TB pose considerable challenges to currently available diagnostic methods and to clinical management. Even when diagnosed, HIV-positive, smear-negative pulmonary TB patients have inferior treatment outcomes, including excessive early mortality (22). The HIV epidemic is now of such magnitude that meeting initial TB control targets for sub-Saharan Africa would only result in a marginal decline of the annual rise in incidence in the region—from 10% to 7% per year (5). To counter the HIV-driven TB epidemic, WHO and the Stop TB Partnership advocate a TB control strategy of expanded scope (23). These expanded efforts will be central to decreasing the burden of TB in HIV-positive persons, and to reversing the alarming rise in African (and global) incidence rates (8). It is now widely recognized that collaboration between TB and HIV/AIDS disease programs to provide patient-centered, integrated care and services will be essential to controlling the TB epidemic (1). In responding to the challenge of the synergistic HIV/TB pandemic, a key strategic objective of the Second Global Plan to Stop TB, 2006–2015 is to scale-up implementation of collaborative TB/HIV activities in all countries with a high burden of TB/HIV. WHO’s Interim Policy on Collaborative TB/HIV Activities (8), the core essential guidance document to assist countries in implementing and monitoring collaborative TB/HIV activities, suggested specific activities to address the dual epidemic, including: (i) the establishment of mechanisms for collaboration; (ii) decreasing of the burden of TB among people living with HIV/AIDS—through earlier detection of active TB through intensified case-finding, provision of isoniazid preventive therapy (IPT) for coinfected patients, and ensuring TB infection control in health-care and congregate settings; (iii) decreasing of the burden of HIV among TB patients—through provision of voluntary counseling and testing for people at risk of HIV, introducing HIV prevention methods and co-trimoxazole preventive therapy, ensuring HIV/AIDS care and support, and introducing antiretroviral therapy (ARV); and, finally, (iv) improvement of the care of people who are infected with both TB and HIV—through cross training and collaborative care initiatives. In February 2005, an Expert Consultation Meeting was held to define the TB/HIV research priorities in resource-limited settings (12). The discussion of the SWG for tuberculosis affirmed the WHO HIV/TB Working Group and Expert Consultation recommendations. There was emphasis on the promotion and support of operational research to establish evidence for global policy on collaborative TB/HIV activities. It was recommended that operations research be encouraged at the national level to shape TB/HIV collaborative activities to the country’s needs and to develop national research capacity. The SWG highlighted the need for close collaboration with Drugs, Diagnostics, and Vaccines WGs of the Stop TB Partnership

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to rapidly test and implement new diagnostics, treatments, and vaccines as they are developed. Notably, an investigational agenda was proposed for addressing the following major research areas: preventive therapy for TB; research in co-trimoxazole prophylaxis, including interactions with antiretroviral treatment and delivery strategies; determination of efficacy of and optimal time for initiation of prophylaxis among people living with HIV/AIDS and TB; timing of initiation of ARV and definition of immune reconstitution syndrome, research to operationalize intensive case finding; and the development of new tools and algorithms to improve diagnosis of smear-negative TB in adults and children. The principles of DOTS were first developed in the national TB program in Tanzania, and subsequently expanded to a further six countries in Africa and to Nicaragua, with the assistance of the International Union Against Tuberculosis, later to become the International Union Against Tuberculosis and Lung Disease (IUATLD) (24). The principles were adapted and promoted by WHO as DOTS, and adopted in programs around the world (25). By the early 1990s, when asked to describe the optimal approach to TB treatment, most TB control professionals would produce a long list of interventions, including passive case finding, SCC, patient compliance with treatment, adequate drug supply, and sound reporting and recording systems. Thus, the basic principles of the strategy were not new. The crucial innovation was the addition of the human element—health-care workers or volunteers forming a close bond with patients to help them successfully complete treatment. In the United States, this approach was known as DOT. The brand name ‘‘DOTS’’ was born in 1994, with the modification of the commonly used DOT acronym to include another key element of the strategy—the short-course treatment regimen (25). DOTS has been evolving since its creation, and countries have adapted DOTS to suit local circumstances. New strategies that address some of the major barriers for TB control are all built on the core foundations of DOTS. A new essential element in current TB clinical management is the integration of HIV and TB care. The global HIV epidemic is fuelling an unprecedented increase in TB cases, and in the number of patients coinfected with both diseases. Management of TB/HIV coinfected patients is often fragmented, with little coordination of care between TB and HIV treatment programs in many areas and at many levels. As referred to earlier, care is further hampered by limitations of current TB diagnostic methods, limited access to and underutilization of HIV counselling and testing services, drug interactions between first-line TB and HIV regimens, and a paucity of data regarding optimal regimens and optimal timing of initiation of ARV (11,26). Collaboration between TB and HIV programs and integration of services especially at service delivery levels is strongly advocated (25). Collaboration is, however, hindered by a history of independent structures and functions in established national TB programs and newly

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established HIV programs, by the differential funding and by inadequacies of primary care and general health system on which to build integrated care in many countries. Treatment Simplification

Poor compliance, especially among HIV-infected TB cases, is primarily due to an increased rate of adverse drug events, the length of treatment, and the pill burden in TB treatment. Two important research streams explore the feasibility of shortening TB treatment from six to four months through the use of gatifloxacin or moxifloxacin (27,28), and in addition assess the efficacy and safety of fixed-dose combinations of anti-TB medications versus ‘‘loose’’ anti-TB medications in improving treatment compliance. The expected outcomes of the work are not only to gather evidence on the efficacy and safety of gatifloxacin or moxifloxacin for shortening of TB treatment—thus reducing the pill burden, compliance, and TB treatment outcomes—but also establish, through a blinded, randomized controlled trial, the efficacy and safety of the currently recommended four fixed-dose combination therapies versus ‘‘loose’’ TB drugs among HIV-negative and HIV-infected TB cases. In addition, the work builds institutional and research capacity within National Control Programs for TB clinical trials in the conduct of such research. Patient Support for Standardized Treatment

Adherence to therapy remains a central issue in determining therapeutic effectiveness of TB treatment. There is a well-recognized need to evaluate ways to broaden DOT to include more effective strategies for providing adherence support. Examples include evaluation of the following:
Patient ‘‘treatment literacy’’ preparation before initiation of therapy
Adherence support provision by health-care workers and/or community or family members
The most effective frequency and intensity of adherence support
Combinations of these interventions
The most effective method of supporting adherence in HIVþ TB patients receiving antiretroviral therapy (ARV). Does the coadministration of TB and HIV therapies require different or expanded adherence support strategies compared to TB or HIV alone? For these studies, outcome measures should include both standardized and validated measures of adherence as well as biologic and clinical measures for TB (sputum conversion, treatment completion, case holding, relapse, resistance, etc.) as well as adherence and biologic and clinical outcomes for HIV (adherence assessment through standardized measures, viral load, clinical disease progression, mortality, etc.).

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Preventive Therapy for Tuberculosis

The following research priorities, which distinguish between the population and individual levels, were suggested by the WHO-2005 February meeting (12). At population level: 1.

2.

3.

4.

5.

Identifying macrolevel barriers to implementing IPT and mechanisms to overcome these barriers: Although policy on providing preventive therapy is permissive, uptake of this intervention is still insufficient. It was felt that acceptance of preventive therapy programs is low at the health ministry level. Fear that drug resistance will emerge and concerns about the short duration of efficacy have been discussed as potential impediments to implementation. Ways to better promote implementation of preventive therapy programs should be identified. Evaluating the outcomes of a national IPT program in Botswana: Lessons learned—Botswana is the only country so far that has widely implemented a preventive therapy program. Evaluation of the program is instrumental in extrapolating the lessons learned relevant to international policy. Establishing the effectiveness in special populations and regions with elevated isoniazid resistance: Limited data are available on how IPT programs affect the emergence of drug resistance. This lack of information represents a problem in the context of emerging global drug resistance. Participants agreed to follow current recommendations and to evaluate the efficacy of IPT in settings with MDR-TB. Guidelines should then be revised accordingly. At individual level: Developing the optimum algorithm to exclude TB disease: Recent evidence shows that a screening chest radiograph is not required to exclude active TB (pulmonary and pleural only) in asymptomatic people. However, the results from these studies should be validated in routine conditions. New diagnostic tools for screening TB are welcome and should be included. Determining the added benefit of IPT among people receiving ARV: One study supported by the Consortium to Respond Effectively to the AIDS/TB Epidemic (CREATE) in Brazil is already specifically looking at the added benefit of IPT among people receiving ARV. Coadministering isoniazid with the protease inhibitors and non-nucleoside reverse transcriptase inhibitors may result in increased hepatotoxicity and risk of rash, especially when isoniazid is given alone to treat latent TB infection in people living with HIV/AIDS, receiving these types of ARV. This has important clinical implications and should be studied.

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7.

Determining whether there are subgroups of people who are likely to benefit: Evidence is growing that the incidence of TB is higher among people living with HIV/AIDS who have a low CD4 count. Would introducing a CD4 count threshold as a criterion for entering a preventive therapy program provide public health benefits? As a subset of this question, would the threshold jeopardize the implementation of preventive therapy programs? Determining effectiveness among infants and children: Improved methods need to be developed for excluding active TB and for assessing the effectiveness of preventive therapy programs in children.

Co-trimoxazole Prophylaxis for Opportunistic Infections

The routine use of co-trimoxazole in developing countries, especially subSaharan Africa, has been minimal despite provisional recommendations from WHO and UNAIDS that co-trimoxazole be given to everyone in Africa with HIV/AIDS, including those who have TB. The interim policy on collaborative TB/HIV activities promotes co-trimoxazole use among people living with HIV/AIDS who have TB. Four topics were identified as priority areas for research at the WHO2005 February meeting (12): 1.

2.

3.

4.

Determining the role of co-trimoxazole in the context of ARV: Studies are needed to better determine the added efficacy of cotrimoxazole among people receiving ARV. In particular, better guidance is needed on other criteria (clinical or arbitrary time period) other than CD4 cell count, which might guide the decision to stop providing co-trimoxazole whether people are receiving ARV or not. Among people living with HIV/AIDS and TB, when is the optimal time to start co-trimoxazole (with and without ARV): If most deaths during the first months of TB treatment are due to TB, considering initiating ARV during this period is reasonable. Establishing the determinants that influence efficacy: More observational data are needed on co-trimoxazole efficacy in Asia. The relationship between the level of background drug resistance and efficacy should also be determined. What are the best delivery strategies to improve the uptake of cotrimoxazole prophylaxis: Various delivery strategies should be developed to ensure that co-trimoxazole is offered at healthcare entry points, including TB diagnostic centers, voluntary counseling and testing, ARV clinics, and clinics preventing mother-to-child transmission. Collaboration with HIV programs is essential.

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ARV for People Living with HIV/AIDS Who Have TB or Develop TB

TB/HIV treatment is far from being a reality for people living with HIV/ AIDS, who have TB or develop TB while on ARV. Clear recommendations on the best-informed practice are needed. Given that limited data are available, there is a need to move from evidence-based individual clinical interventions to a public health approach that will be informed by emerging evidence. 1.

2.

3.

Validating the optimal time to start ARV among people living with HIV/AIDS who have active TB (to improve efficacy and decrease toxicitiy): The frequent coexistence of TB and HIV, varying from about 35% to 70% in sub-Saharan Africa, implies the need to manage both diseases simultaneously. Managing TB alone in the absence of HIV treatment is associated with an increase in mortality during the treatment duration for TB. No prospective controlled study has examined the optimal timing of ARV after TB treatment is initiated. The decision about when to initiate ARV among people living with HIV/AIDS and TB must balance the risk of HIV disease progression, morbidity, and mortality with the potential risk of drug toxicity and adverse events, including immune reconstitution inflammatory syndrome stratified by the stage of HIV disease. The feasibility and effect of concomitant and early use of antiretroviral drugs and TB medications on TB treatment outcomes and survival (through pharmacokinetic studies) will establish the impact of drug–drug interactions on plasma levels of highly active antiretroviral therapy (HAART) and anti-TB drugs. What are the best ARV regimens, with dose adjustment when required, to use with TB treatment regimens? Some evidence is available on the pharmacokinetics of efavirenz and nevirapine when coadministered with rifampicin containing regimens. Additional studies are needed to determine the clinical efficacy and safety profiles of regimens containing efavirenz and nevirapine. In addition, more information is needed on the requisite doses for coadministration of efavirenz in the presence of rifampicin, including the best methods for monitoring the adequacy of the recommended dose. Determining the efficacy and safety profile of alternative ARV regimens: Drug development should be an area of focus for research on effectively treating people living with HIV/AIDS who have TB in resource-constrained settings. In particular, the development of fixed-dosed combinations of antiretroviral drugs (mainly efavirenz-containing fixed-dosed combinations) for people with TB should also be pursued. Replacing rifampicin with rifabutin should also be considered. If this is the case, studies

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4.

5. 6. 7.

are needed to determine the feasibility and cost-effectiveness of rifabutin-containing TB treatment regimens for people living with HIV/AIDS who are receiving ARV. Developing the best clinical definition for immune reconstitution inflammatory syndrome for use in resource-constrained settings (validation studies): Clinical data available are based on different definitions of immune reconstitution inflammatory syndrome. There is an urgent need to standardize the definition and to identify the risk factors and predictors for immune reconstitution inflammatory syndrome. Clear and standardized guidance on how to prevent and/or treat an episode of immune reconstitution inflammatory syndrome is essential. What is the cost-effectiveness of different regimens and strategies? What are the minimal requirements for clinical and laboratory monitoring for outcomes related to efficacy and safety? What are the best strategies (including DOTS) for measuring and enhancing adherence for people receiving tuberculosis therapy and ARV?

For all these questions, consideration of special populations, including their comorbidity and unique characteristics, is encouraged.

Use of Immunomodulators

Immunomodulators—including corticosteroids, therapeutic vaccines, and other drugs and biologics—have the potential to shorten TB treatment, by modulating the host response and helping the immune system eliminate persistent organisms. Immunotherapy is a novel approach to treatment shortening. Strategies studied to date in mouse models have been found to reduce the Th2 inhibitory effect on the protective Th1 response—either by inhibiting interleukin-4 production, or by downregulating the Th2 response. In animal models, impressive treatment shortening times have been observed, and further human testing under appropriate study designs are warranted. In addition to treatment shortening, immunomodulation might improve treatment outcomes, using existing treatment protocols. The current understanding of severe TB is that the host inflammatory response induces pathology that contributes to mortality. The use of novel immunomodulators or adjunctive corticosteroids could downregulate this response. Adjunctive corticosteroids are widely used and have been shown to be beneficial in selected severe forms of TB. The level of evidence is incomplete in other forms of TB (29), and is limited for HIV coinfected patients. Additional studies are warranted. Several claims have been made of immunomodulators that could shift Th2 responses to Th1. When subject to scrutiny through testing under randomized clinical trials, the mistletoe extract, the South African potato, and a killed preparation of M. vaccae, did not do better than the placebo.

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Treatment Needs of Multiorganism-Infected Patients (Across Neglected Diseases)

Scant attention has been paid to the treatment needs of patients with multiple organismal diseases, including malaria, TB, and HIV infection. Institutions such as TDR would be specially positioned to address the specific research questions related to exposure to multiple diseases (notably, malaria/HIV/ TB) and associated treatments. Recommendations of the SWG on TB research underlined this activity as a high priority and a leadership-filling role for TDR. Specifically, it was considered important to evaluate the pharmacokinetics, drug–drug interactions, and safety/toxicity issues, and the defining of optimal treatment regimens in multiply-infected patients. An often neglected area of evaluation within TB research is pediatric TB. All elements demanding evaluation in the adult population would require attention among children. Children rarely have sputum smear–positive TB, and diagnosing TB in children is difficult. Studies are urgently needed to develop and validate adapted diagnostic algorithms in children, utilizing newer diagnostic tests. In addition, it is essential to evaluate the optimal models to integrate revised algorithms into WHO Practical Approach to Lung Health (PAL) and Integrated Management of Adult and Adolescent Illness (IMAI). There is a need for evaluation of efficacy/safety of drug formulations in use, and a need for information on pediatric pharmacokinetics in different epidemiological contexts, co-trimoxazole treatment efficacy, incidence of side effects, and how to manage complications in children. Pharmacovigilance Activities

There is a need to conceptualize research strategies of relevance to disease control and implement them from an end-user perspective. Pharmacovigilance activities in disease-endemic countries fall in this special category at the transition from drug research and development to implementation. As a high priority, the following are recommended:




Engaging the local TB and National AIDs Control Program (NACP) control programs Devising systems to generate, process, and use pharmacovigilance data at both the local and global scale Strengthening the capacity to conduct pharmacovigilance studies, and to analyse, report, and make decisions based on data

Immune Reconstitution Inflammatory Syndrome Induced by Antiretroviral Treatment

HAART in HIV-infected patients restores protective immune responses against a wide variety of pathogens and dramatically decreases mortality (30). In a subset of patients receiving HAART, immune reconstitution is associated with a pathological inflammatory response leading to substantial short-term morbidity and even mortality. Some patients with HIV/TB coinfection who are on anti-TB treatment and HAART will also develop an exacerbation of symptoms, signs, or radiological manifestations of TB that

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are not due to relapse or recurrence of their TB. The etiology of these immune reconstitution inflammatory syndrome (IRIS) reactions is unknown, but it is presumed that they occur, at least in part, as a consequence of HAART-related reconstitution of immunity. The past several years have seen marked advances in our clinical understanding of the IRIS (31), but many questions remain. A consistent finding from multiple groups is that IRIS develops in a substantial percentage of HIV-infected patients who have an underlying opportunistic infection and receive HAART. As the use of HAART stands to markedly increase over the next several years, optimal care of patients receiving HAART will need to incorporate monitoring for and treating complications of IRIS. This was identified as a priority research area by the WHO/TB/HIV Research Priorities in Resource Limited Settings (12). Key areas would be to develop a case definition, to identify an immunological signature and develop effective management strategies. Research Priorities

Tables 6 and 7 list the research priorities for improving the clinical management of TB. C. Social, Economic, and Behavioral Research

Social science research for TB control refers to the contributions of the basic and applied social sciences to addressing fundamental social, Table 6 Research Topics in New Drug Development Research topic Development and evaluation of new drugs and new combination regimens 1. Evaluation of the use of new combination treatment regimens for TB Use of immunomodulators 2. Evaluation of the use of novel immunomodulators and adjunctive corticosteroids in treatment-shortening strategies 3. Evaluation of the use of novel immunomodulators and adjunctive corticosteroids in limiting immunopathology in TB disease Surrogate markers of disease 4. Development and validation of surrogate end points and specific immunological, bacteriological, and biochemical biomarkers that can be used for treatment evaluation, disease cure, relapse, and reinfection to shorten clinical trials of novel drugs and treatment regimens Development of natural products for TB treatment 5. Independent evaluation of natural products developed for use in TB treatment Implementation research: health systems and operations 6. Studies to define attributable benefit of new regimens (effectiveness, cost-effectiveness) 7. Mathematical models, including simulation models, of resource needs, costs, and impacts of new treatment regimens (to be used to inform clinical trial design)

Abbreviations: HAART, highly active antiretroviral therapy; IRIS, immune reconstitution inflammatory response; ARV, antiretroviral therapy. Source: From Ref. 7.

Treatment simplification: more effective treatment with shorter duration 1. Evaluation of newer drug regimens, e.g., containing gatifloxacin, or moxifloxacin or newer drugs in shortening TB treatment from six to four months 2. Assessment of the efficacy and safety of fixed-dose combinations of anti-TB medications versus ‘‘loose’’ anti-TB medications in improving treatment compliance Patient support strategies 3. Assessment of effectiveness of patient ‘‘treatment literacy’’ programs prior to treatment initiation 4. Evaluation of impact of DOT and other adherence support strategies (including site-based vs. community-based support, and frequency and duration of support interventions) on treatment outcomes 5. Evaluation of impact of DOT and other adherence support strategies on treatment outcomes in TB–HIV coinfection Treatment of MTb-HIV coinfection 6. Evaluation of optimal treatment initiation (timing, dosing, specific drugs) for TB HIV coinfected patients (including TB-HAART randomized trials) 7. Evaluation of optimal duration of treatment using existing regimens for pulmonary and extrapulmonary TB in HIV-infected people 8. Pharmacokinetic and pharmacodynamic studies of treatment regimens in TB–HIV coinfected patients 9. Evaluation of optimal protocols for isoniazid preventive treatment in HIV-infected people with latent TB infection 10. Evaluation of optimal protocols for co-trimoxazole treatment in TB–HIV coinfection 11. Development and validation of case definitions for IRIS in TB–HIV coinfected patients under ARV treatment 12. Epidemiologic studies of IRIS in TB–HIV coinfected patients under ARV treatment 13. Immunologic assessment of IRIS in TB–HIV coinfected patients under ARV treatment 14. Evaluation of clinical management strategies of IRIS in TB–HIV coinfected patients under ARV treatment Treatment of multiply-infected patients 15. Evaluation of safety and toxicity issues in defining optimal treatment regimens across neglected diseases 16. Pharmacokinetic and pharmacodynamic studies of treatment regimens in multiply-infected patients Treatment of pediatric tuberculosis 17. Evaluation of safety and efficacy of current drug formulations in pediatric TB infection

Research topic

Table 7 Research Topics in Clinical Management of Tuberculosis

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economic, and behavioral questions related to TB. Social science questions arise in nearly every area of TB research. They include such questions as identifying the constraints on health-seeking behavior (constraints in accessing diagnosis and care); gender differentials in the epidemiology of the disease, in case detection and treatment success; and adherence issues related to treatment response, including the impact of user fees and treatment adherence support strategies. The central focus of social science research is on identifying the barriers to timely case detection, diagnosis, and treatment in the context of poverty and social inequality, and enabling interventions that would reduce these constraints. Because there is a proven intervention for TB that remains poorly implemented, social, economic, and behavioral research that understands the context of why there is poor implementation lies at the heart of many unanswered questions. Both health policy and system research are thus integral to what we refer to as ‘‘implementation research,’’ which addresses the challenges to implementing proven interventions. Although the two types of research overlap, they are separated in this chapter to emphasize the importance of each to TB control efforts. Central themes in social science research on TB are highlighted here. Four key domains of social science research as it relates to TB are identified, and key research topics are further explored here. Key Domains in Social Research for TB Control

The following four key domains are identified within which social science research on TB operates (7): 1. 2. 3. 4.

Determinants of risk and vulnerability to TB Impact of poverty on TB Effects of gender inequality on disease risk, disease severity, and case detection Impact of community factors on TB control efforts

Each of these domains is explored briefly below. Within each domain, key research topics are identified, through which related questions of epidemiology, access to care, diagnosis, treatment, and implementation should be further addressed. It should be noted that the social science research areas identified here focus on research that can inform TB control efforts, including providing input into the development of new tools and the implementation of existing control programs—rather than on descriptive studies cataloguing risk and vulnerability. Determinants of Risk and Vulnerability to TB

Vulnerability to disease and ill health results from several major overlapping factors, including socioeconomic, biological, and environmental factors. The link between TB and social inequality are well established; additional research defining the determinants of risk for and vulnerability to TB will help identify specific challenges to implementation, in access to care, diagnosis, and successful treatment (32).

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Key research topics:
How does malnutrition and other comorbidities (such as malaria and HIV), contribute to susceptibility to TB, and what interventions effectively reduce risk?
How does difficulty in access to food affect access to care and case detection?
How can TB programs reach out to hard-to-reach populations?
How can community-based social research enhance the identification of the most vulnerable subgroups and define strategies to enroll them in quality TB care?
Why are technologies and resources for TB diagnosis and treatment not available where they are needed most?
How does difficulty in access to food affect treatment outcomes?
How can DOTS be enhanced through social and economic support mechanisms for vulnerable groups?
What can be learned from polio eradication campaigns to reach out to remote populations? Impact of Poverty on Tuberculosis

While TB is not exclusively a disease of the poor, the association between poverty and TB is well established and widespread. Impoverished communities and social groups are at higher risk of infection with MTb compared with the general population, because of overcrowded living or working conditions, poor nutrition, coinfections (such as HIV/AIDS) and migration from or to higher-risk communities. In addition, patients suffering from TB are less able to work and to generate income for themselves and their dependents. These factors pose significant additional economic hardships on patients and households, with a disproportionate impact on the poor, further limiting their access to care (32). Key research topics:
What kind of financing schemes can enhance patients’ access to TB diagnosis and treatment?
What type of social and economic incentives for patients and DOTS workers can improve case finding and adherence to therapy?
How can health providers outside of the public health sector, including private practitioners and traditional healers, contribute to case detection and access to care?
How can health providers outside of the public health sector, including private practitioners and traditional healers, contribute to clinical management?
How can TB programs respond to poverty-related inequities, which constrain patients’ ability to seek health care, cope with illness and suffering, and adhere to therapy?
How can communities in resource-poor settings with weak social cohesion be enrolled in TB control?

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Effects of Gender on Disease Risk, Disease Severity, and Case Detection

Gender-specific barriers to TB diagnosis and care are seen in both women and men. These barriers, which vary in different settings, require thorough assessment and evaluation to identify interventions that can reduce these barriers. Poor women, in general, access health-care services less frequently than men due to financial constraints. On the other hand, working men who are unemployed may be discouraged from seeking care on account of the potential fear of job loss. This subsequently results in delayed diagnosis and treatment. As a result, underdetection of TB may mask the true incidence of the disease in both women and men (32). The stigma of TB is often more pronounced among women than men. Poor women with TB are likely to suffer from fear of rejection by their families and community. While men usually worry more about loss of income and capacity for work, women worry most about social rejection—from husbands, in-laws, and the community in general—if they have TB. Women in many countries have to overcome several barriers before they can access health care. Where they undertake multiple roles in reproduction, production, and childcare, they may be left with less time to reach diagnostic and curative services than men. Women may be given less priority for health needs and generally have less decision-making power over the use of household resources. They often have less knowledge of TB, especially of its signs and symptoms, than men. This may be related to the higher rate of illiteracy among women than among men worldwide. Key research topics:
How do malnutrition and other comorbidities (such as malaria and HIV), relate to women and girls’ susceptibility to TB?
In populations where women need to access health care accompanied by a man, what interventions would improve health seeking for women?
How can provider delays for women, men, and children be reduced?
What are the gender-specific barriers to TB diagnosis and care in different settings and how can they be translated into appropriate gender-sensitive interventions? Impact of Community Factors on Health Services and DOTS Programs

Community-based interventions have long been linked to TB control efforts (5). Effectively treated and cured patients living within their home communities are often the best advocates for TB services and may become drivers of social mobilization to support TB control. While many community-based programs have been developed by private NGOs, community approaches— particularly for active case finding and TB treatment support—have been increasingly incorporated into public sector programs. Studies are needed that evaluate the most effective strategies for scaling up TB treatment,

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including DOTS implementation, through community-based programs. Community studies are also useful to reveal people’s perception of health services. Findings from social and behavioral research in the community can then be used to eliminate practices that may discourage the poor and other vulnerable groups from seeking diagnosis and treatment. One particular concern is stigmatization within communities. Stigma toward TB exists to differing degrees in most countries, and may be particularly problematic among the hard-to-reach populations. Staff attitudes and behavior can reinforce stigma, through their own practices and interactions with TB patients. It is not uncommon, for example, to see health professionals wearing surgical masks in the presence of TB patients. During health education sessions, stigma can be reinforced by emphasizing the importance of safe disposal of sputum at the expense of conveying the message that modern treatment rapidly renders patient noninfectious. Key research topics:
How does effective TB therapy and support systems contribute to diminish fear and stigma?
How can case finding and case holding be improved by social research on TB- and AIDS-related stigma?
If health-care workers stigmatize patients and each other, how can the stigmatization be overcome?
How can networks of people living with HIV mobilize to contribute to TB education, screening, and adherence to TB and TB–HIV therapy?
How can the quality of health-care services and DOTS programs become more responsive to the needs of the community?
How can community-directed interventions and community-based insurance schemes be designed to improve TB care? D. Operational and Implementation Research Political Will, Financial Constraints, and Human Resources

The lack of political will and commitment in governments and donors is a key factor that hinders TB control. The priority research response is development through research of convincing evidence-based arguments for presentation and adoption by politicians. Cost-effectiveness data of TB control activities are required because economics is the driving force of the political process in most developing countries (33). Studies of peoples’ perception of the importance of TB are important because politicians depend on support from the people. This is also important for social mobilization. Financial constraints are a major hindrance of progress in TB control. There is also a requirement for better spending, transparency, and accountability. Underfinancing leads to poor management of TB control services, the direct result of inadequately trained and qualified human resources, and lack of a reliable anti-TB drug supply. Importantly,

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the question arises ‘‘how to maintain and improve the control of TB in the face of enormous increases in caseload attributable to the HIV/AIDS epidemic?’’ Operations Research

Operational (or operations) research involves the use of advanced analytic techniques to solve optimization problems under conditions of uncertainty and constraints. Classic operational research has only recently been applied to public health problems. Applied to TB control, the research questions can be condensed to how can TB interventions—case finding, diagnosis, and treatment—be optimized, given resource constraints? Operations research for TB control can greatly assist efforts to bring effective interventions to a greater number of people. As new tools are developed, operational research methods can also be used to guide implementation of new drug regimens, clinical trial design, and vaccine trial design. Operational research offers significant gains at relatively low cost, but its application to TB has been relatively neglected (33). The development of WHO’s DOTS strategy for TB control in 1995 led to expansion, adaptation, and improvement of the operational research in this area. Given the needs of TB control programs worldwide, efforts need to be increased in ‘‘implementation’’ research—defined as the application of a number of different research methods (social science research, health systems research, outcomes research, and operations research) to address questions of how TB disease control can best be implemented, and how treatment and other program outcomes can be optimized. Implementation research is aimed at ensuring that existing tools are applied to their maximum benefit, and that once new tools and new strategies are shown to be effective, they can be readily adopted by control programs. Thus, the overall objective of this research is to significantly improve access to efficacious interventions against tropical diseases by developing practical solutions to common, critical problems in the implementation of these interventions. The practical realities in many resource—limited settings—as well as in developed countries—mean that many proven interventions fail to reach the people who need them most. Although not often considered part of the traditional research, the implementation of proven interventions is in fact a critical area for research relevant to disease control. This is especially true for TB, where proven treatments exist but these reach only a fraction of people with active disease. Thus, implementation research stands at the opposite end of the research spectrum from discovery research—and closest to the problems facing public health programs. Implementation research makes use of a number of different research methods. In addition to social science research, implementation research encompasses policy research, health systems research, and operational research. All of these disciplines can address questions of how TB disease control can best be implemented, and how treatment and other program outcomes can be optimized.

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Policy Research

Research under this rubric includes those on access to health care, healthcare economics, health status and conditions, health insurance coverage, disparities in health service provided to different populations, and methodological studies on data collection for public health policy. Research examines these issues in local and national terms, and also develops small area estimation techniques to provide statistical estimations for local geographic or epidemiological areas most relevant to communities and policy makers. Health Systems Research

Rapid progress toward TB disease control targets in developing countries is greatly hampered by weak, poorly functioning, or in some cases nonexistent health systems. It is critical to know how best to approach health system strengthening, and what specific actions are appropriate in different settings. There is some information known about the barriers or constraints to ‘‘scaling up’’ health services. However, very little is known about how best to relax these constraints. How can knowledge of health systems be significantly increased and effectively applied to improve the health of the worst off of the world’s population? Some important insights have been gained in studying health policy and systems research:









Health systems research can significantly contribute to health policies and programs. Lack of research can lead to undesirable results. Research can contribute most when issues are formulated through clear and verifiable hypotheses. Health systems research can develop a rich body of knowledge to support evidence-based policy making. Funding for health systems research in developing countries is far too low to ensure an impact—0.02% of health expenditure. Only 5% of information on health systems worldwide focus on developing countries. Priorities can be harmonized to advocate for increased impact and funding. Getting research to policy and practice can be enhanced through affordable interventions. Research capacity has to be strengthened.

Challenges and Opportunities

Implementation as well as operational research brings important challenges to research. First, close collaboration between researchers, national TB control programs, Ministries of Health, and other partners is essential to this research. Bridges between groups that do not traditionally work together need to be built. In addition to the challenges and opportunities in the areas of case finding, diagnostics, and clinical management of TB described in earlier chapters, several issues in TB control are uniquely suited to implementation research approaches. The following are examples.

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Globally, in 2003, DOTS programs reached only 45% of the estimated number of 3.9 million sputum smear–positive TB patients. In addition, DOTS treatment success rates remain well below targets in some regions, notably Africa and Eastern Europe. The poorer and more vulnerable patients comprised a substantial proportion of those not served, facing the greatest barriers to diagnosis and treatment, and are considered likely to be among the drivers of ongoing TB transmission. The HIV epidemic has increased their vulnerability and accelerated the spread of TB among the poor. What accounts for the low case detection and cure rates? One key factor is access to TB care. People infected with TB must take several steps to receive effective care. Each step can be associated with significant costs and other potential barriers. At each step there may be some combination of the following costs:
Charges for health services (user fees)
Transportation, accommodation, and subsistence costs
Lost income, productivity, and time Certain social groups—such as women, the unemployed, and the homeless— experience longer delays in achieving cure than TB infected people in less vulnerable groups (32). These groups include larger numbers of poor people, who can ill afford the costs imposed by delays in diagnosis and treatment. A proportion of patients, particularly those from the poor and vulnerable groups, may drop out completely at any stage on the path to successful treatment. Barriers to accessing care have cascading effects on TB control: the longer the delay in case detection, the more opportunities for transmission, the lower the treatment success rates, and the more costs the patient has to bear. Challenges and Opportunities in Case Finding and Access to Care Case Finding in Vulnerable Populations

Because roughly half of all cases of active TB currently go undetected, there is a compelling need to pursue research aimed at improving case finding, particularly among hard-to-reach populations and smear-negative disease. These populations include the following:
Poor populations in remote rural areas
Urban slum dwellers and other urban poor, including street children and other homeless people
Populations in conflict areas
HIV-positive populations
Orphaned children
Migrant populations, internally displaced populations, refugees, and asylum seekers
Workers in exploitative employment situations, such as miners, plantation workers, factory workers, and sex workers

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Drug users Incarcerated people and those released from prison

Intensified Case Finding

Expanding DOTS and improving the existing DOTS strategy is the priority for national TB programs. However, intensified case finding for TB, used successfully on a wide scale and with appropriate emphasis, has the potential to increase case-detection rates and improve TB control. Generally, research should target the following: 1.

2.

3.

4.

Performing prevalence surveys: National prevalence surveys would help to define the burden of prevalent TB and provide the basis for more accurately estimating case-detection rates and time trends. Further, measuring HIV prevalence in the same surveys enables important questions on the impact of HIV on TB prevalence to be addressed. Defining the threshold, if any, for starting intensified case-finding activities for national TB programs and national HIV/AIDS control programs: Targeted-intensified case finding is recommended in populations with a high prevalence of HIV (see the ‘‘Interim policy on collaborative TB/HIV activities’’) or the congregate epidemiological interaction between the HIV prevalence and the TB incidence needs to be understood better to define the best threshold of TB incidence (or prevalence) and HIV prevalence for starting intensified case-finding activities. Improving case-detection strategies in clinical settings and where there is unmet need: TB case finding among people living with HIV/AIDS in clinics and hospitals, as well as household contacts, populations especially vulnerable to HIV infection, and congregate settings should be intensified by improving testing algorithms and developing models to deliver this intervention. In particular, operational aspects of delivering intensified case finding through existing community structures (shops, churches, schools, and community-based and home-based care volunteers) should be better investigated. Further, operational research on the feasibility of integrating intensified case finding with outreach activities, such as needle-exchange programs, should be a priority in the countries of the former Soviet Union and countries in Southeast Asia, where epidemics of injecting drug use, TB, and HIV are closely linked. Collaboration between the national TB and HIV/AIDS programs is essential in improving TB control in settings with a high HIV prevalence. Validating screening methods: The relative sensitivity and specificity of radiology, microbiology (either smear or culture), or specific symptom-screening questions and their predictive value for most target groups or at the population level are not known.

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Research Priorities

Table 8 lists the research topics on case finding and access to care, and Table 9 lists the social science and implementation research topics in case finding and access to care. Smear-Negative Tuberculosis

The HIV epidemic has been associated with a significant increase in the incidence of smear-negative pulmonary TB among people living with HIV/AIDS. However, national TB control activities have focused less on diagnostic strategies and on documenting the treatment outcome of

Table 8 Research Topics on Access to Care and Case Finding Research topic Case finding 1. What factors lead to delays in establishing a diagnosis of tuberculosis? Where are the missing cases? 2. Which factors contribute to the low global case-detection rate (diagnostic gap)? 3. What is the role of active case finding, especially in hard-to-reach populations and areas of high HIV prevalence? User fees 4. How do user fees affect access to care, case detection, diagnosis, and treatment? Community-based research 5. How can community-based social research enhance the identification of the most vulnerable subgroups and define strategies to enroll them in quality TB care? Transportation and other opportunity costs 6. How significant are the barriers created by indirect costs of care, such as transportation costs, and what are the most effective strategies to remove the barriers they create? Case finding and access to care in the private sector 7. What are the most effective, easy to leverage private sector capacity to achieve TB control goals? Diagnostics in support of case finding 8. What are the implications of changing current symptom-based and laboratorybased diagnostic algorithms for case finding? 9. What is the sensitivity and specificity of various thresholds for chronic cough (e.g., 2 vs. 3 wk) as screening tests for tuberculosis? 10. What is the role of culture-based detection methods on case finding? Source: From Ref. 7.

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Table 9 Social Science Research Topics in Case Finding and Access to Care Social science research—determinant of risk, poverty, gender, and community factors: 1. How does effective TB therapy and support systems contribute to diminish fear and stigma? 2. How can case finding and case holding be improved by social research on TB- and AIDS-related stigma? 3. If health-care workers stigmatize patients and each other, how can the stigmatization be overcome? 4. How do malnutrition and other comorbidities (such as malaria and HIV) relate to susceptibility of women and girls to TB? 5. Is there a gender differential in TB case finding? What factors contribute to such differentials? 6. How does difficulty in access to food affect access to care and case detection? Source: From Ref. 7.

smear-negative and extrapulmonary TB cases, although they constitute a large proportion of TB cases. User Fees

Provision of anti-TB drugs free of charge is embodied within the enhanced DOTS strategy. Many programs also offer reimbursement to patients for smear microscopy. But even under these circumstances, where services are ostensibly free, charges are often incurred: some providers may advocate additional drugs in addition to the free anti-TB drugs, especially if motivated by cost-recovery schemes. Thus, even where consultation, diagnosis, and treatment are officially provided free of charge, patients may face unofficial (under-the-table) charges imposed by hard-pressed or unscrupulous health providers. The extent to which user fees—charges for consultation, diagnostic tests, and drug treatment, whether set by governments or imposed by providers—present significant barriers to care, should be clearly established, and research should focus upon the different kinds of financing schemes that can support access to care. Transportation Costs and Opportunity Costs

Payments for transport to and from health facilities for patients and caregiver(s) for several visits make up a large proportion costs before diagnosis is established, and are likely a significant barrier to care. If treatment requires frequent travel (e.g., for observation of treatment), then these transport costs may continue to accumulate after diagnosis, even if the distances travelled are not very great. The time lost in repeat visits to health providers is also a cost borne by the patient through reduced productivity, lost earnings, and neglected household responsibilities. The impact of these indirect costs and the effectiveness of interventions designed to reduce indirect cost-related barriers to TB control should be investigated.

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Private Sector Tuberculosis Care

Little is currently known about the incentives, attitudes, practices, quality, and performances of treatment providers in the private sector. It is important to conduct research that addresses how the private sector is integrated into case finding and access to care. Research Capacity Strengthening in Implementation Research

The need to develop implementation research capacity is obvious. The need for and value of such a focus is even more urgent and important at this time. Linking the findings of operational research studies and other implementation research programs with national TB and HIV programs is essential to focus the research on relevant questions and rapidly bring research findings to bear. The priorities in implementation research are listed in Table 10. While clinical trials provide some answers to these questions, mathematical modelling, operations research, and other implementation research methods should provide important ancillary approaches. E. Immunopathogenesis and Vaccine Studies Immunity to M. tuberculosis and Vaccine Development

Now entering its ninth decade of use, BCG remains the only available vaccine against TB. The use of BCG to prevent TB, however, is limited to the prevention of severe pediatric disease; its efficacy against adult disease wanes in high-burden regions where TB protection is most needed. Nonetheless, with accelerating progress in deciphering the MTb genome and proteome, and new insights into the immunopathogenesis of TB infection, significant progress has been made in TB vaccine development over the past five years. As of late 2005, there are promising indications of improvements in BCG efficacy: at least five vaccine candidates are in Phase I clinical trials, and several more candidates are in preclinical development (34). Many current vaccine candidates are based on modifications to BCG, yet our understanding of the immunobiology underlying BCG’s ineffectiveness remains incomplete (35). Indeed, our understanding of the distinction between protective immune responses and immunopathology, though improving, remains blurred (36). In vaccine evaluation, study design is impeded by the lack of known immune correlates of protection against TB infection. Thus, dependence on immunologic end points for interpretation of vaccine efficacy is not reliable and difficult to interpret, whereas use of clinical end points delays assessment of vaccine efficacy, requiring several years and/or tens of thousands of subjects. Collectively, these gaps in our knowledge make the design of vaccine assessment strategies difficult. The need for both pre-exposure (or ‘‘prime’’ strategies) and postexposure (or ‘‘boost’’ strategies) vaccination is widely accepted, but the specific timing and vaccine component design remains to be established. Further research into the basic immunobiology of TB is therefore necessary to guide vaccine and drug development—particularly in the

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Table 10 Implementation Research Topics Case finding and access to care 1. Assemble available data on implementation and outcomes of case finding and detection 2. Which financing schemes enhance patients’ access to TB diagnosis and treatment? 3. Determine the impact of including culture in the case-detection strategy 4. Evaluate different models/strategies for case finding especially in hard-to-find populations 5. Evaluate different models/strategies to optimize configuration of laboratory systems for case detection 6. How can health providers outside of the public health sector, including private practitioners and traditional healers, contribute to case detection? New TB diagnostics 7. How can the uptake of proven new diagnostic tests be accelerated in both public and private settings? 8. What measures will be helpful in shortening the duration of TB workup (diagnostic pathway) and the number of consultation visits before a diagnosis is made? 9. How can laboratory workload be reduced in high-burden countries? New TB drug development 10. Studies to define attributable benefit of new regimens (effectiveness, cost-effectiveness) 11. Mathematical models, including simulation models, of resource needs, costs, and impacts of new treatment regimens (to be used to inform clinical trial design) Clinical management of tuberculosis 12. Studies to define effectiveness of HIV case finding in TB programs, including availability and uptake of HIV testing 13. Operations research studies (including mathematical and simulation models) of resource needs, delivery sites, care models, costs, and impacts of TB–HIV program integration 14. Assessment of training needs and training effectiveness for HIV and TB treatment providers 15. Development and validation of systems to generate, process, and use pharmacovigilance data, and impact on treatment outcomes Source: From Ref. 7.

context of protective immune responses to MTb, mycobacterial latency and dormancy, mycobacterial reactivation and the geographic variation in immune responses and immune correlates of protection: 1.

Protective immune responses to MTb, mycobacterial latency, and dormancy leading to long-term survival and mycobacterial reactivation: One-third of the world’s population is latently infected with MTb, and in areas of low endemicity, many cases of active

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Onyebujoh et al. TB arise out of reactivation of latent bacille. MTb can persist intracellulary in lung tissue without histological evidence of tuberculous lesions (37). In most individuals with latent MTb infection (LTBI) it is kept under control by the immune system and in only 10% cases does it lead to disease. There is ample circumstantial evidence from observation of the natural history of TB in humans and experimental animals that MTb is capable of adapting to prolonged periods of dormancy in tissues, and that these dormant bacille are responsible for latency of the disease itself. Furthermore, the dormant bacille are resistant to killing by antimycobacterial agents. A systematic evaluation of the mechanism of dormancy, and of attempts to abrogate latency, will require a better understanding of the physiologic events that attend the shiftdown into dormancy (36,38–41). There are probably two or more stages in the shiftdown of MTb from active replication to dormancy, as bacille in unagitated cultures settle through a self-generated O2 gradient into a sediment where O2 is severely limited. One step involves a shift from rapid to slow replication (42). The other involves complete shutdown of replication, but not death. Presumably this last step includes completion of a round of DNA synthesis. The shiftup on resumption of aeration includes at least three discrete sequential steps: the production of RNA, the ensuing synchronized cell division and, finally, the initiation of a new round of synthesis of DNA. Three markers of the process of shiftdown of MTb to dormancy have been described, namely the changes in tolerance to anaerobiosis, the production of a unique antigen, and the 10-fold increase in glycine dehydrogenase production. Additional markers represented in the shiftup and shiftdown process may yet be discovered, and determination of their specific functions should provide insights into the mechanisms of dormancy and latency in TB, and into strategies for preventing reactivation of the bacille and development of disease. MTb is a successful pathogen that overcomes numerous challenges presented by the immune system of the host (41). This bacterium usually establishes a chronic infection in the host where it may silently persist inside a granuloma until a failure in host defenses leads to manifestation of the disease. None of the conventional anti-TB drugs are able to target these persisting bacille. Development of drugs against such persisting bacille is a constant challenge because the physiology of these dormant bacteria is still not understood at the molecular level (43,44). Some evidence suggests that the in vivo environment encountered by the persisting bacteria is anoxic and nutritionally starved. Based on these assumptions, anaerobic and starved cultures are used as models to study the molecular basis of dormancy. Research into the study

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of mycobacterial latency and dormancy is crucial to the designing of new drugs for the treatment of latency and the development of newer TB vaccines. MTb latency and T-cell–based assays: A major challenge in TB control is the diagnosis and treatment of latent TB infection. Until recently, there were no alternatives to the tuberculin skin test (TST) for diagnosing latent TB. However, an alternative has now emerged in the form of a new in vitro test: the interferon-gamma assay (44,45). A systematic review to assess the performance of interferon-gamma assays in the immunodiagnosis of TB was performed by Pai et al. (46). By searching databases, and contacting experts and test manufacturers, they identified 75 relevant studies. The results suggest that interferon-gamma assays that use MTbspecific region of difference 1 (RD1) antigens such as early secretory antigenic target 6 (ESAT-6) and culture filtrate protein 10 (CFP-10) may have advantages over the TST, in terms of higher specificity, better correlation with exposure to M. tuberculosis, and less cross-reactivity due to BCG vaccination and nontuberculous mycobacterial infection. However, interferon-gamma assays that use RD1 antigens in isolation may maximize specificity at the cost of sensitivity. Assays that use cocktails of RD1 antigens seem to overcome this problem, and such assays have the highest accuracy. RD1-based interferon-gamma assays can potentially identify those with latent TB who are at high risk for developing active disease, but this requires confirmation. There is inadequate evidence on the value of interferon-gamma assays in the management of immunocompromised individuals, children, patients with extrapulmonary or nontuberculous mycobacterial disease, and populations in countries where TB is endemic. Current evidence suggests that interferon-gamma assays based on cocktails of RD1 antigens have the potential to become useful diagnostic tools. Whether this potential can be realized in practice remains to be confirmed in well-designed, long-term studies. Geographical variation in immune responses and identification of immune correlates of protection for vaccine studies: Known discrepancies have been identified in immune responses in developed and developing countries (47). In developing countries, primed Th1 and Th2 responses evoked by environmental mycobacteria appear to interfere with vaccine immunity. Helminth infections can also trigger Th2 responses, particularly along the interleukin (IL) -4 pathway, which is known to be integral to TB pathogenesis. In developing countries with high helminth burdens, vaccine-mediated immunity may be further impaired. Elucidating the mechanisms underlying mycobacterial immunity remains central to vaccine development efforts. One of the scientific challenges in vaccine research relates to the scientific

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Figure 1 Potential value of immunomodulatory treatment. Abbreviations: IL, interleukin; BCG, bacille Calmette–Gue´rin; RT-PCR, reverse trancriptase–polymerase chain reaction; ELISA, enzyme-linked immunosorbent assay; FACS, flourescence activated cell sorter. Source: From Ref. 47.

uncertainty about protective immunity to TB and the current lack of experience with new TB vaccines in human populations. In spite of recent advances in our understanding of host responses to MTb infection and TB disease, a lot of work remains to be done in determining the immune correlates of consistent protection against TB. Competing hypotheses have been offered to explain the poor efficacy of BCG vaccine in high-burden countries (47). The interplay between exposure to environmental mycobacteria and helminths, and the level of IL-4 levels may be central to TB immunopathology (Fig. 1). These issues have significant implications for vaccine design, the selection of animal models, and the design of vaccine-efficacy trials, particularly site selection (Fig. 2). Further research in immunology is needed to support development of evaluation criteria for vaccines in phase II/IIB trials and for the identification of correlates of immunity for eventual use in phase III trials. The interplay between exposure to environmental mycobacteria and helminths, and the level of IL-4 may be central to TB immunopathology (Fig. 1). In this regard, competing

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Figure 2 Potential vaccine targets. Abbreviations: BCG, bacille Calmette–Gue´rin; Th1, helper T-cells; IL, interleukin.

hypotheses have been offered to explain the poor efficacy of BCG vaccine in high-burden countries (48). Development and Evaluation of New TB Vaccine Candidates

Five vaccine candidates are presently under evaluation (Table 11). A vaccinia virus–vectored subunit vaccine based on a secreted antigen (Ag85A) of MTb, developed at Oxford University, underwent phase I clinical evaluation in 2004. Encouraging safety and immunogenicity results have been reported, especially when used as ‘‘booster’’ dose on top of BCG vaccination, even when the BCG had been given decades previously. Additional phase I safety and immunogenicity trials have now been completed in The Gambia. Phase II studies in latently infected subject are currently ongoing in The Gambia and South Africa. A fusion protein (Mtb72f) vaccine developed by Corixa in Seattle, Washington, U.S.A., and delivered with an adjuvant formulation developed by GlaxoSmithKline, has completed phase I clinical trials in the United States, and a phase I/II trial in Europe. A phase II safety and immunogenicity study in healthy PPDþ/ TB infected adults started in 2005. Evaluation of vaccine candidates will require a transition through a series of clinical trials of increasing size, complexity, and cost to progressively evaluate their safety, immunogenicity, and eventual efficacy. Despite considerable progress, there is a need to expand discovery and translational

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Table 11 New Vaccines in the Clinical Trial Pathway Vaccine name rBCG30

rBCG: D ureC-lloþ

MVA-85A

Ag85B-ESAT-6

Mtb72f

Notes Live, recombinant BCG Tice, overexpressing Ag85B from Mycobacterium tuberculosis produced by the group of Dr. M. Horwitz from the University of California at Los Angeles, in the United States. Intended to stimulate a stronger, longer-lasting response than conventional BCG. Completed clinical phase I trials at St. Louis University Live, recombinant BCG, urease-deficient mutant, which expresses the Lysteriolysin O gene from Listeria monocytogenes. Produced by the group of Prof. S. H. E. Kaufmann from Max Planck Institute of Infectious Biology, Berlin, Germany. Intended to promote ‘‘leakage’’ of antigens from the phagosome to improve CD8 responses via cross-priming. Currently scheduled to enter clinical trials in 2006 Live, recombinant, replication-deficient vaccinia virus, expressing Ag 85A from M. tuberculosis. Produced by the group of Prof. A.V. S. Hill from Oxford University, United Kingdom. Can stimulate a strong primary immune response, but intended primarily as a booster vaccine for individuals previously vaccinated with BCG. Completed clinical phase I trials in the United Kingdom and currently in clinical trials in the Gambia Recombinant protein, composed of a fusion of ESAT-6 and Ag85B from M. tuberculosis produced by the group of Dr. P. Andersen at the Statens Serum Institute, Copenhagen, Denmark. Delivered in the IC31 adjuvant (from Intercell, AG of Austria). Can stimulate a strong primary immune response, but intended primarily as a booster vaccine for individuals previously vaccinated with BCG. Currently in clinical phase I trials in Leiden, the Netherlands Recombinant protein, composed of a fusion of Rv1196 and Rv0125 from M. tuberculosis produced by GSK. Delivered in an oil-in-water emulsion containing the immunostimulant 3-deacylated-monophosphoryl lipid A and a purified fraction of Quillaria saponaria (Quil A), also produced by GSK. Can stimulate a strong primary immune response, but intended primarily as a booster vaccine for individuals previously vaccinated with BCG. Completed clinical phase I trials in the United States, and is currently recruiting for phase II trials in Lausanne, Switzerland

Abbreviations: BCG, bacille Calmette–Gue´rin; ESAT-6, early secretory antigenic target 6; GSK, Glaxo-Smith Kline. Source: From Ref. 7.

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research on vaccines. As discussed earlier, many current vaccine candidates are based on modifications to BCG, yet our limited understanding of BCG’s ineffectiveness heralds potential for failure. The early success of current clinical candidates does not signal an end of discovery research, but rather provides novel opportunities to link fundamental research to human studies. It is likely that experience gained as current candidates move through clinical trials will contribute to development of new sets of candidates in an iterative process of refinement. A recombinant BCG vaccine overexpressing Ag85A developed at University of California Los Angeles (UCLA) has just completed phase I trials in the United States. An adjuvant fusion protein (Ag85B-ESAT6) developed at the Statens Serum Institut in Copenhagen, Denmark, is scheduled for two clinical trial assessments in 2005/2006. The first of these will test the vaccine in a conventional parenteral vaccination strategy, using a mixture of oligodeoxynucleotides and polycationic amino acids as the adjuvant (IC31). The second trial, running in parallel, will test the same antigen by the nasal route, using LTK63 from Chiron, a modified, heat-labile enterotoxin from Escherichia coli as an adjuvant. A BCG vaccine carrying the listeriolysin gene as well as an urease deletion has been developed at the Max-Planck-Institute for Infection Biology in Berlin and is scheduled to enter phase I trials in the second half of 2006. F. Improved Program Performance and Capacity Building Research Capacity Strengthening in High-Burden Countries

Research capacity strengthening (RCS) is a cross cutting program area with a basket of activities according to the needs of each country (7,49). For the least developed countries, there is a focus on training of individuals and strengthening of institutions, and on provision of information. For more developed countries, the focus changes to partnerships. For advanced developing countries, there is an emphasis on utilization of the capacity already developed in these countries, especially on training and certification in good clinical practice (GCP) and good laboratory practice. This works on the principle that successful long-term outcomes require comprehensive capacity-strengthening programs that provide continuing professional development, support, and an enabling environment, rather than scientific training alone. During 2003 and 2004, WHO-TDR RCS activities became more fully integrated into the program’s research activities through its RCS-Plus Initiatives. Following this change, the RCS program activities are increasingly being driven by WHO-TDR research agenda, and are becoming more pertinent to the research needs of each country’s population. RCS-Plus grants are intended to support projects based on targeted R&D-driven capability-strengthening initiatives. The initiatives address priority issues ranging from laboratory-based research, through field intervention research, to social, economic, and behavioral research. The

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WHO-TDR 2005 SWG (7) emphasized the need for RCS in applied immunology, drug development, pharmacovigilance, and implementation research, including social science research, health systems research, and operations research. With an expanding number of new drugs, vaccines, and diagnostics at different phases of development, enhancement of clinical trial capacity in high TB burden countries and especially within TB programs is paramount. In this effort, there should be continued emphasis on training in and use of GCPs, aimed to promote better conduct of research and the production of reliable, credible, and internationally acceptable data, particularly in resource-poor environments. Mechanisms were suggested to increase and sustain the use of scientific and institutional capacity already developed by WHO-TDR and others, which by now represents a critical mass with a comparative advantage for undertaking cutting-edge research in tropical diseases. Clinical trial sites either receiving WHO-TDR institutional grants or involved in the WHO-TDR–sponsored clinical trials should be continuously evaluated and monitored for possible involvement in other clinical trials and research and development activities. Sites that cross therapeutic areas should be identified and enhanced. It was recommended that a catalogue of available sites should be created, enabling communication of this information to drug, vaccine, and diagnostic developers, which would promote these sites and their continual use, allow more adequate resource allocation to them, and thereby increase the number of researchers doing GCP trials in disease-endemic countries. Linking Research with National Tuberculosis Control Programs

The early involvement of national TB control programs is a critical element to facilitate adoption of new drugs, tools, and vaccines. Interventions need to be country program owned and sustainable. For that to occur, research activities and priorities should involve early consultation and collaboration with country programs. Linkages between these control programs and academic institutions should facilitate institutional capacity strengthening and research capacity development to ensure the quality of the expected output. These links will facilitate the ready availability of research findings to national programs and ensure that critical knowledge drives policy and practice. TDR would be specially positioned to interface with national TB control programs and support this approach to ensure that the research activities planned are well conducted and attract the requisite resources. Tuberculosis/HIV Treatment Integration

High morbidity and mortality among TB/HIV coinfected patients demands a renewed focus on research to identify practical diagnostic tools for coinfected patients, appropriate treatment strategies, and new models of collaboration and integration between TB and HIV programs and services. Crucial issues to be addressed include the following:

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Availability and uptake of HIV counselling and testing in TB patients Diagnosis of TB and LTBI in HIV-infected patients Testing and implementation of clinical and laboratory algorithms effectively, including best strategies to ensure uptake Definition of the optimal time to start ARV therapy in a patient with active TB Sites and personnel for HIV and TB care delivery

Coordinating Tuberculosis/HIV Research

A wealth of evidence has been collected about implementing collaborative TB/ HIV activities. This has led to the development of the essential policy to implement joint activities. In particular, the ‘‘Interim policy on collaborative TB/HIV activities’’ has set out which joint activities should be implemented according to the level of HIV prevalence. Although many questions remain unanswered, it is generally felt that, given the evidence available, evaluating the implementation of the current policy should be emphasized more strongly than generating more research questions. The role of research in supporting improved TB and HIV control should be highlighted. Mechanisms to avoid redundancy of research should be identified and knowledge disseminated properly. Basic Social, Economic, and Behavioral Research in National Programs

Several questions remain unanswered:


Studies to identify needs and opportunities for increasing political will for TB control: ¤




Studies to examine the impact of TB and TB control on poverty: ¤




To what extent do sex differences in case notification rates reflect gender-related differences in access to TB care? How can effective TB care be ensured for marginalized populations?

Studies on infection and transmission: ¤




What are the contributions of TB control to poverty alleviation?

Studies to identify needs and opportunities for ensuring equity in TB control: ¤




What are the factors/processes that influence the creation of political commitment for TB control?

What is the relation between infection and transmission?

Studies to provide better data used for modelling purposes. ¤

What are the implications of health system research for TB control? National public health regulations: what are their effects

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¤ ¤

on TB control? What models of health legislation/regulation can support TB control? What can be learnt from specific country successes and failures? What are effective models of drug procurementf?

Studies to Improve NTP Management

Questions remaining unanswered are as follows:
How can NTP staff be motivated to perform optimally?
How can programs retain good people (service providers and researcher) in poor resource settings?
How should/do countries develop human resource capacity for disease control?
How do program structure and management relate to program performance? (evaluation of managerial interventions, e.g., supervision mechanisms). Studies to Develop and Evaluate Alternative TB Care Delivery Strategies


How can demand for services be increased?
How can case-detection rates be improved?
What are the major sources of diagnostic delays, and how can these be addressed? (both patient and health system sources of delay).
How can treatment adherence be improved? (in particular, could the use of fixed-dose combinations improve adherence?).
What are alternate strategies for TB control in differing health system environments? What alternative treatment of delivery mechanisms might be delivered?
What is the impact of information, education, and communication on TB related health seeking behavior and treatment adherence?
To what extent are current control strategies supported by evidence from research (establish evidence base and guidelines for the type of evidence needed to assess new interventions, such as efficacy, effectiveness, cost-effectiveness, feasibility, and sustainability)? G. Epidemiological Research in Tuberculosis Macroepidemiology of Tuberculosis

Comprehensive assessments of global TB burden published in 2005 review recent data on case notification and case-detection rates, as well as available information on the prevalence of latent TB infection via tuberculin surveys (1). Global prevalence of latent TB infection is estimated at 32% of the world’s population, some 1.86 billion people. The total number of new cases is estimated at 8.8 million per year, including 3.9 million cases of infectious pulmonary disease; point-prevalence estimates indicate more than 16 million cases of active disease. Eighty percent of all incident cases of TB are found in 22 countries and more than half of the cases occur in five populous Southeast Asian countries. Of the 15 countries with the highest

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per capita rates of smear-positive disease, 10 are located in Africa. The prevalence of TB/HIV coinfection worldwide is estimated at 0.18%; some 656,000 new TB cases were coinfected with HIV in 2003. An estimated 1.7 million people die of TB each year. The global case-fatality rate is 23%, but exceeds 50% in some African countries with high HIV burden (1). Although these staggering numbers represent a consensus among TB experts, the uncertainty surrounding the incidence and mortality estimates is quite large, due to the poor quality of the underlying data. Uncertainty analysis for the 22 highest-burden countries suggests that global incidence and prevalence could be as much as 21% lower or 40% higher; there could be 23% fewer or 47% more deaths each year (50). Each of the two main approaches to calculating TB incidence rates—case notifications and the ‘‘annual risk of infection’’ method—present methodological and dataquality issues. Case notification approaches are beset by detection and reporting deficiencies. TB cases are often underreported; case detection and notification is significantly less than 100%. The proportion of patients underreported is likely to be partially offset by overdiagnosis and double reporting of individual cases. Information on smear-positive cases is more reliable; however, in countries with low DOTS coverage, rates must be estimated from data on health systems coverage, drug availability, and patient condition. To calculate incidence rates based on the annual risk of infection, epidemiologists have used a ratio of 1:50, since an increase of 1% point in the annual risk has been associated with an increase in 49 smear-positive cases per 100,000 population. However, this method was established from only six studies of incidence, prevalence, and mortality, and computer simulation models used to validate this rule have determined its applicability only in situations where greater than 5% of TB cases are coinfected with HIV (51). Thus there is some degree of imprecision in global TB estimates within large populations, and better evidence is needed. Nonetheless, there is a high degree of confidence in the estimated range of TB incidence and prevalence worldwide. There are several socioeconomic factors that play important roles in the dynamics of TB epidemics. These include tobacco smoking, alcohol consumption, diabetes, poverty, living in overcrowded conditions, and unemployment. According to a recent study, there is an increase in TB case rates of between two- and four-fold for those smoking in excess of 20 cigarettes a day, but it may be difficult to control for other factors, particularly alcohol consumption (52). A phenomenon that has important control implications and which highlights the difficulties in interpreting the available epidemiological information is the case-detection gap. Globally estimated case-detection rates under the DOTS strategy lag well behind geographic DOTS strategy coverage. Linear extrapolation implies that, with 100% geographic coverage, only half of all new infectious cases would be detected under the DOTS strategy. A similar comparison of geographic coverage versus case detection under the DOTS strategy per country reveals that full geographic DOTS strategy

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coverage is paralleled by the achievement of the 70% case-detection target in only a few settings. The likely reason for the low case-detection rate is that many infectious patients do not have access to health facilities where TB care (diagnosis and treatment) consistent with the DOTS strategy is available. Strategies that improve case finding and access hard-to-reach populations have the potential to positively impact on the current case-detection gap. A number of questions remain in relation to the timing of diagnosis and its potential impact on TB transmission. At present, it remains unclear how early TB diagnosis needs to occur to prevent transmission in different patient populations such as people living with HIV/AIDS, infants, and pregnant women. For comprehensive TB and HIV prevention, care, and support, there is compelling need for research on specific elements of the interaction between HIV infection and TB, including a better understanding of the epidemiology of coinfection, including a definition on the timing of development of TB after HIV infection, and the effect of comorbidity in TB susceptibility. Microepidemiology of Tuberculosis

The prevalence of TB can vary widely between neighboring villages and within different parts of the same village. Both genetic and environmental factors are likely to contribute to these microepidemiologic variations. Genetic factors, including immune response genes, should cluster in households, and may contribute to differences in the prevalence of TB within a village. Environmental factors, however, including social factors, probably play a major role in explaining these microepidemiologic differences between villages. In addition, there is a growing body of evidence on the role of mycobacterial factors on local TB disease epidemiology. Both molecular genotyping techniques developed during the past decade and conventional epidemiological methods have been used to study the transmission and pathogenesis of TB, and have allowed tracking of strains of MTb as they spread through communities. It is clear that in certain geographic areas a restricted set of MTb strains is causing a disproportionate number of cases of the disease. Molecular epidemiologic approaches have also enabled an assessment of the transmission of drug-resistant strains. This information has the potential to influence TB control and prevention strategies in the future. However, there are still limitations in these techniques and their results. In the near future, the use of molecular epidemiology, bacterial population genetics, comparative genomics, immunology, and other disciplines will further our understanding of TB transmission and pathogenesis, contributing to the development of effective drugs and a vaccine against this important human pathogen. The importance of local variations in patterns of health and disease are increasingly recognized, but available methods for characterizing disease clusters in time and space have been limited. There is a need for new quantitative bioinformatic approaches to study MTb microepidemiology from the level of individual hosts to small communities.

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Challenges and Opportunities

Increasing the quality of surveillance data will provide a more accurate picture of the epidemic, and illuminate the global impact of TB control efforts. There is a clear need to improve case-notification reliability; however, it is recognized that, given current diagnostic limitations, certain active cases, notably smear-negative disease, will remain difficult to identify even in ideal circumstances. Accurate estimates of the TB burden in selected countries can be obtained from special surveys of the prevalence of disease and infection. Unfortunately, good surveys are scarce and there are not enough resources to obtain survey information on a global scale. In addition, countries where the rates of HIV/TB coinfection are high or TB incidence rates are in decline make survey information hard to interpret. It is clear, though, that assessment of the impact of novel public health strategies for controlling TB in population- or community-level intervention studies will require higher quality epidemiological data. The corollary is that baseline active TB prevalence surveys are needed to determine whether the culturepositive prevalence estimates are accurate, and to test sampling systems for outcome surveys. Furthermore, measurement of the baseline prevalence of TB infection will provide additional information to study communities. Measurements through tuberculin skin testing, however, are cumbersome and time consuming; novel diagnostic methods for use in TB prevalence surveys are highly desirable. An additional and promising element in TB epidemiology would be the ability to disaggregate data from national TB programs (Table 12). The further implementation of computerized databases at the district level promises to provide TB notification data, which allows a closer, more detailed look at relevant local and district-level microepidemiology, including data on poor, vulnerable, and hard-to-reach populations.

Table 12 Research Topics in Epidemiology of Tuberculosis Research topic Macroepidemiology 1. How early does diagnosis need to occur to have an impact on TB transmission? 2. How soon after HIV infection does TB develop? Microepidemiology 3. Development of systems to disaggregate national program data for use in studying local and hard-to-reach subpopulations Diagnostics in support of epidemiologic research 4. Development of new diagnostic tools for identifying latent TB infection and conducting TB prevalence surveys 5. Can interferon-gamma assays be used in surveys on annual risk of TB infection? Source: From Ref. 7.

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TB infection is transmitted more readily in the environmental conditions of poverty: overcrowding, inadequate ventilation, and malnutrition. Furthermore, there has been growing recognition that TB itself diminishes the livelihoods of those affected and that TB control is therefore a potential poverty-alleviation tool (53,54). A growing body of evidence shows that better health contributes to greater economic security and growth (55). Within the poorest 20% of the world’s population, communicable diseases represent the greatest burden (and in adults, the three leading causes of communicable disease burden are TB, HIV, and malaria). Among this group, communicable diseases are responsible for 59% of deaths and 64% of disability-adjusted life-years lost. Among the richest 20% of the globe, the figures are 8% and 11%, respectively (56). Furthermore, there is an interplay between poverty and the barriers to access to diagnosis and treatment, which supports nonadherence to TB treatment with consequent impact and challenges to TB control activities. Improvements in socioeconomic conditions should lead to reductions of TB incidence. They should also lead to improvements in access to care, its rational use, and the quality of care. In response to the increasing evidence of need for action to address TB and poverty, the Network for Action on TB and Poverty Sub-Group of the DOTS Expansion Working Group was recently established. In 2005, the Subgroup together with the Network for Action on TB and Poverty and the WHO Stop TB Department published a normative document outlining options for national TB program managers to choose from in addressing poverty issues in DOTS implementation in the implementation of activities of the Global Plan to Stop TB, 2006–2015 (3,32). Pediatric Tuberculosis Infection

Pediatric TB is a growing problem in developing countries. Probably as a result of the fact that HIV-related TB remains largely an adult infection, and pediatric infection with either TB or HIV contributes little to the spread of either disease, there is a clear gap in research in the pediatric population. In addition, all issues identified as priority research items for adults remain a research element also for children. Children rarely have sputum–smear– positive TB, and diagnosing TB in children is difficult. Although a good TB control program is the best way to prevent TB in children, studies are urgently needed to improve diagnosis of TB (both extrapulmonary and pulmonary) in children. The best way and models to integrate this revised algorithm into the WHO PAL and IMAI strategies need to be explored. Many of the priorities for TB research in adult populations are applicable to children. There is a clear need for evidence of efficacy/safety of drug formulations in use, a need for information on pediatric pharmacokinetics in different epidemiological contexts, and a need to focus on the special

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challenges of diagnosis of TB in children. As highlighted in the ‘‘TB/HIV Research Priorities in Resource Limited Settings’’ (WHO/HTM/TB/ 2005.355 and WHO/HIV/2005.03), there are a number of definite issues within the pediatric population including the following:









The need for improved diagnostic methods to detect active disease among infants and children and to determine effectiveness of INH preventive treatment programs in this group. This requires the use of T-cell gamma interferon assays in early detection of active disease Validation of clinical and laboratory diagnostic algorithms in children The role of co-trimoxazole or other antibiotic treatment and prophylaxis in HIV-positive children with TB, including efficacy, incidence of side effects, and how to manage complications in children Establishing clear guidelines for the use of anti-TB treatment with antiretrovirals in HIV-infected children with active TB

In addition, a number of issues have been identified for work in pediatric TB. Downstream adoption issues have been identified, notably the need for better evaluation of currently available fixed-dose combinations. There is also a clear need for the evaluation of treatment regimens in MDR and the evaluation of management strategies for MDR contacts. Multidrug-Resistant Tuberculosis

Along with HIV/AIDS, MDR-TB is considered the most important threat to TB control. Strategies to combat resistance focus on both prevention of the development of resistance through application and strengthening of DOTS and appropriate treatment of resistant cases, DOTS-Plus. Three rounds of surveys coordinated by WHO and the IUATLD between 1996 and 2002 have yielded data on anti-TB drug resistance among new and previously treated cases. The third round of surveys included new data from 77 settings or countries, collected between 1999 and 2002, and provided a balanced appraisal of the available epidemiological evidence. From this information, it is clear that MDR remains a locally severe problem. Although drug-resistant TB is present in all the settings surveyed, the prevalence of MDR is high only in some settings. The prevalence of resistance to at least one anti-TB drug (any resistance) among new cases ranged from 0% in some Western European countries to 57.1% in Kazakhstan (median, 10.2%). Among previously treated cases, the median prevalence of resistance to at least one drug (any resistance) was 18.4%, with the highest prevalence, 82.1%, in Kazakhstan (262/319). With this information, a three-pronged strategy has been proposed for MDR-TB: widespread implementation of SCC, improved resistance testing and surveillance, and the careful introduction of second-line drugs following proper evaluation of cost-effectiveness and feasibility (3). Current

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research areas identified by the DOTS-Plus Working Group include the following:
Quality assurance of DST to second-line drugs and resistance criteria for second-line drugs
Transmissibility and fitness of MDR-TB strains; effect of HIV epidemic on MDR-TB epidemic
Management of MDR-TB
Economic evaluation of DOTS Plus
Availability of second-line drugs. There are presently seven studies ongoing and three studies under evaluation The development of an early warning system for drug resistance; identifying and evaluating optimal treatment regimens; and assessment of management strategies of MDR contacts and special populations (HIV-positive patients, pregnant women, and children) are needed. Regulatory Issues for Diagnostics, Drugs, and Vaccines

In the development and registration of new tools for the diagnosis, treatment, and prevention of TB, early and close consultation with regulatory authorities will be the key to timely registration. In 2000, WHO-TDR initiated dialogue with national regulatory agencies (NRAs) to standardize guidelines for the registration of new chemical entities effective against TB and the registration of the new four-drug fixed-dose combinations. A meeting of NRAs from developed and developing countries with industry representatives, other government agencies, and academic establishments was convened in September 2000, at which NRA representatives accepted the proposed guidelines and agreed to lobby for their formal adoption by their respective agencies. Regulatory uniformity and agreement to expedited registration by national agencies would help remove some of the current disincentives to TB drug development. Ethical Issues in Tuberculosis Research

As the research community now moves away from ‘‘colonial parachute research’’ and the concept of equal partnerships arises, focus is now on ethical issues governing these developed countries–developing countries partnerships. Performing the clinical trials of new drugs or interventions in Africa, which if found effective will not be affordable by countries in which research is performed, highlights the ethical issues surrounding current clinical trials. A number of TB and TB/HIV research program activities, especially in developing countries in the recent past have fostered the discussion around research ethics and helped to establish bioethics as an integral part of health research in resource-limited settings. WHOTDR helped to set up a global Strategic Initiative for Developing Capacity in Ethical Review (SIDCER), ensuring that appropriate and competent ethics committees are established in countries where research is carried

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out. Already under SIDCER, six regional forums and more than 15 national forums have been established. Guidelines for ethics committees that review biomedical research were developed by TDR (in 2000) and were widely distributed. Guidelines were later established on surveying and evaluating ethical review practices. Guidelines on data and safety monitoring boards are now being finalized through coordination with the local government to ensure political endorsement. Training of local ethics committee staff in developing countries has become a high priority and should be vigorously pursued. Audit and follow-up of ethics committees’ decisions and outcome of trials with subsequent actions on making the product available at affordable prices should be a priority. TB research should focus on addressing the current challenges posed by failing health systems and the increasing burden of disease within the context of limited resources, and should acknowledge the need for a multisectoral approach in responding to control needs and available scientific opportunities. The specifics of national programs and cultural sensitivities for target populations in high-burden countries should be addressed. Efforts should be made to promote a culture of research within national control programs to facilitate feasibility of developed interventions and guidelines. Resource identification for research should form part of main program planning, and major funding agencies should be encouraged to provide more meaningful funding for TB research. References 1. World Health Organization. Global tuberculosis control: surveillance, planning, financing. WHO report 2005. Geneva: World Health Organization (WHO/HTM/ TB/2005.349). 2. Dye C. The global epidemiology of tuberculosis. Lancet 2006; 367:935–940. 3. Stop TB Partnership and World Health Organization. Global Plan to Stop TB 2006– 2015. Geneva: World Health Organization, 2006 (WHO/HTM/STB/2006.35). 4. Dye C, Watts C, Bleed D, et al. Evolution of tuberculosis control and prospects for reducing tuberculosis incidence, prevalence and deaths globally. JAMA 2005; 293:2767–2775. 5. Elzinga G, Raviglione MC, Dermot M. Scale up: meeting targets in global tuberculosis control. Lancet 2004; 363:814–819. 6. The UN Millenium Development Goals. Available at: http://www.un.org/ milleniumgoals. 7. WHO/TDR Report: Scientific Working Group on Tuberculosis. Geneva, Switzerland: World Health Organization, In press. 8. WHO Report: Interim policy on collaborative TB/HIV activities. Geneva, Switzerland: WHO (WHO/HTM/TB/2004.330, WHO/HTM/HIV/2004.1). 9. Global Alliance for TB Drug Development. The TB Alliance portfolio. Available at: http://www.tballiance.org/3_1_2_AportfolioofDrugCandidates.asp. 10. Andries K, Verhasselt P, Guillemont J, et al. A diarlyquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science 2005; 307(5707):223–227. 11. Harries A, Chimzizi R, Zachariah R. Safety, effectiveness and outcomes of concomitant usage of HAART or malaria therapy with anti-TB drugs in resource-poor settings. Lancet 2006; 367:944–945.

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12. WHO Report: TB/HIV research priorities in resource-limited settings. Scientific working group on Tuberculosis, Report of an expert consultation, 14–15 February 2005, Geneva, Switzerland: WHO (WHO/HTM/TB/2005.355, WHO/HIV/2005.03). 13. Perkins M, Roscigno G, Zumla A. Progress towards improved tuberculosis diagnostics in developing countries. Lancet 2006; 367:942–943. 14. Hargreaves NJ, Kadzakumanja O, Whitty CJ, et al. ‘Smear-negative’ pulmonary tuberculosis in a DOTS programme: poor outcomes in an area of high HIV seroprevalence. Int J Tuberc Lung Dis 2001; 5(9):847–854. 15. www.finddiagnostics.org. 16. Cheng K, Yew WW, Yuen KY. Molecular diagnostics in tuberculosis. Eur J Clin Micro Infect Dis 2005; 24(11):711–720. 17. Squire SB, Belaye AK, Kashoti A, et al. ‘Lost’ smear-positive pulmonary tuberculosis cases: where are they and why did we lose them? Int J Tuberc Lung Dis 2005; 9:25–31. 18. Aderaye G, Bruchfeld J, Assefa G, et al. The relationship between disease pattern and disease burden by chest radiography, M. tuberculosis load, and HIV status in patients with pulmonary tuberculosis in Addis Ababa. Infection 2004; 32:333–338. 19. Chintu C, Mwaba P. Tuberculosis in children with human immunodeficiency virus infection. Int J Tuberc Lung Dis 2005; 9:477–484. 20. Sensi P, Margalith P, Timbal MT. Rifamycin, a new antibiotic-preliminary report [Correspondence]. Farmaco Ed Sci 1959; 14:146–147. 21. Sensi P. A family of new antibiotics, the rifamycins. Res Prog Org Biol Chem 1964; 1:338–421. 22. Banda H, Kangombe C, Harries AD, et al. Mortality rates and recurrent rates of tuberculosis in patients with smear-negative pulmonary tuberculosis pleural effusion who have completed treatment. Int J Tuberc Lung Dis 2000; 4:968–974. 23. World Health Organization. Strategic framework to decrease the burden of TB/HIV (WHO/CDS/TB/2002.296). 24. Stop TB Partnership. Global Plan to Stop TB. Phase one, 2001 to 2005. Geneva: WHO (WHO/CDS/STB/2001.16). Available at: http://www.stoptb.org/GPSTB/ assets/documents/Global_PLAN_TO_STOP_TB 2001–2005.pdf. 25. Sharma S, Liu L. DOTS for TB control progress. Lancet 2006; 367:951–952. 26. World Health Organization. Stop TB Partnership TB/HIV working group. Draft August 2005 strategic plan 2006–2015. Available at: http://www.stoptb.org/wg/tb_hiv. 27. Gillespie S, Spigelman M. Current progress in TB Drug development. Lancet 2006; 367:945–947. 28. O’Brien, Spigelman M. New drugs for tuberculosis: current status and future prospects. Clin Chest Med 2005; 26(2):327–340. 29. Dooley DP, Carpenter JL, Radhemacher S. Adjunctive corticosteroid therapy for tuberculosis: a critical reappraisal of the literature. Clin Infect Dis 1997; 25(4):872–887. 30. Shelburne SA, Montes M, Hamill RJ. Immune reconstitution inflammatory syndrome: more answers, more questions. J Antimicrob Chemother 2006; 57:167–170. 31. Kumarasamy N, Chaguturu S, Mayer KH. Incidence of immune reconstitution syndrome in HIV/tuberculosis-coinfected patients after initiation of generic antiretroviral therapy in India. J Acquir Immune Defic Syndr 2004; 37(5):1574–1576. 32. Report WHO. ‘‘Addressing Poverty in TB Control. Options for National TB Control Programmes’’ WHO/HTM/TB/2005.352. 33. Nunn P, Harries A, Godfrey-Faussett, et al. The research agenda for improving health policy, systems performance, and service delivery for tuberculosis control: a WHO perspective. Bull WHO 2002; 80(6):471–476.

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34. Andersen P, Doherty TM. The success and failure of BCG – implications for a novel tuberculosis vaccine. Nat Rev Microbiol 2005; 3:656–662. 35. Doherty TM, Andersen P. Vaccines for tuberculosis: novel concepts and recent progress. Clin Micro Rev 2005; 18(4):687–702. 36. Demissie A, Abebe M, Aseffa A, et al. Healthy individuals that control a latent infection with M. tuberculosis express high levels of Th-1 cytokines and the IL-4 antagonist IL-4delta2. J Immunol 2004; 172:6938–6943. 37. Hernandez-Pando R, Jeyananthan M, Mengistu G, et al. Persistence of DNA from Mycobacterium tuberculosis in superficially normal lung tissue during latent infection. Lancet 2000; 356:9248. 38. Wilkinson KA, Kon OM, Newton SM, et al. Effect of treatment of latent tuberculosis infection on the T cell response to Mycobacterium Tuberculosis antigens. J Infect Dis 2006; 193:354–359. 39. Stewart GR, Robertson BD, Young DB. Tuberculosis: a problem with persistence. Nat Rev Microbiol 2003; 1:97–105. 40. Zhang Y. Persistent and dormant tubercle bacilli and latent tuberculosis. Front Biosci 2004; 1(9):1136–1156. 41. Wayne LG. Dormancy of Mycobacterium tuberculosis and latency of disease. Eur J Clin Microbiol Infect Dis 1994; 13(11):908–914. 42. Smith CV, Sharma V, Sacchettini JC. TB drug discovery: addressing issues of persistence and resistance. Tuberculosis 2004; 84:45–55. 43. Zhang Y. The magic bullets and the tuberculosis drug targets. Ann Rev Pharmacol Toxicol 2005; 45:529–562. 44. Rothel JS, Andersen P. Diagnosis of latent Mycobacterium tuberculosis infection: is the demise of the Mantoux test imminent?. Expert Rev Anti Infect Ther 2005; 6:981–993. 45. Codecasa LR, Ferrarese M, Penati V, et al. Comparison of tuberculin skin test and Quantiferon immunological assay for latent tuberculosis infection. Monaldi Arch Chest Dis 2005; 63(3):158–162. 46. 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. 47. Rook GAW, Dheda K, Zumla A. Immune responses to TB in developing countries: implications for new vaccines. Nat Rev Immmunol 2005; 5:661–667. 48. Rook GAW, Doherty M. Progress and Hindrances in tuberculosis vaccine development. Lancet 2006; 367:947–949. 49. Onyebujoh P, Rodriguez W, Mwaba P. Current priorities in tuberculosis research. Lancet 2006; 367:940–942. 50. Dye C, Scheele S, Dolin P, et al. 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. 51. Centers for Disease Control and Prevention. Nosocomil transmission of multi-drug resistant TB in HIV-Infected persons-Florida and New York, 1988–1999. MMWR Morb Mortal Wkly Rep 1991; 40:585–591. 52. Davis PDO, Yew WW, Ganguly D, et al. Smoking and tuberculosis: the epidemiological association and immunopathogenesis. Trans R Soc Trop Med Hyg 2005 [Epub ahead of print]. 53. Hanson CL. ‘‘Tuberculosis, poverty and inequity: a review of the literature and discussion of issues.’’ Stop TB Partnership, World Health Organization, Geneva, 2002. 54. Nhlema B, et al. ‘‘A systematic analysis of TB and poverty’’. Stop TB Partnership, World Health Organization, Geneva, 2003.

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55. Report 2000: Better health for poor people. Strategies for achieving the international development targets. United Kingdom Department for International Development. London, 2000. 56. Gwatkin D, Guillot M. Report: The burden of disease among the global poor – current situation, future trends and implications for strategy. Global Forum for Health Research/World Bank, 2000.

50 The New Stop TB Strategy of WHO: Reaching Global Targets

MUKUND UPLEKAR, DIANA E. C. WEIL, and MARIO C. RAVIGLIONE Stop TB Department, World Health Organization, Geneva, Switzerland

I. Introduction The World Health Assembly (WHA) resolution of 1991, recognizing tuberculosis (TB) as a major global public health problem, reinvigorated global efforts to control TB and established, for the first time, clear targets to be reached by all countries (1). In 1994, the internationally recommended control strategy, later named DOTS, was launched (2). Its key components included: government commitment; case detection by predominantly passive case finding; standardized short-course chemotherapy for (at least) all confirmed sputum smear-positive cases, provided under proper case management conditions; a system of regular drug supply; and a monitoring system for program supervision and evaluation. The DOTS framework has subsequently been expanded (3), further clarified, and implemented in 182 countries. DOTS implementation has helped countries to improve National TB Programs (NTPs) and make major progress in TB control. By 2004, over 20 million patients had been treated in DOTS programs worldwide and over 16 million of them had been cured. Mortality due to TB has been declining and incidence diminishing or stabilizing in all world regions except

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sub-Saharan Africa and, until recently, Eastern Europe. The global treatment success rate among new smear-positive TB cases has reached 83% (just short of the WHA target of 85% by 2005), and in 2004, the case-detection rate was 53% (against the target of 70% by 2005). However, the case-detection rate has accelerated globally since 2001 (4). Building on current achievements and in accordance with the 2005 WHA resolution on sustainable financing for TB control (5), the major task for the next decade is to achieve the Millennium Development Goal (MDG) and Stop TB Partnership targets for TB control, which have been set for 2015 (6). As with the DOTS strategy, there are targets related to TB diagnosis and cure. There are also targets related to epidemiological impact, including reversing incidence and halving the 1990 level of TB prevalence and death rates. Meeting these targets requires a coherent strategy that is capable of sustaining existing achievements and addressing remaining constraints and challenges more effectively. This chapter defines such a strategy, called the Stop TB Strategy. Table 1 outlines the strategy at a glance. The following section outlines the current challenges to global TB control and opportunities to address them effectively. Section ‘‘Goals and Targets’’ presents the goals and targets that the Stop TB Strategy is designed to achieve. The six principal components of the Stop TB Strategy are outlined in Section ‘‘Components of the Stop TB Strategy.’’ The final section discusses the measurement of the progress and impact of global TB control efforts and some key indicators thereof. This chapter builds on the themes of TB control and research dealt with in detail in-depth in the relevant chapters in the book, attempting to bring them together, converging toward the final aim of TB control and elimination. II. Challenges and Opportunities It has been acknowledged that current rates of progress are insufficient to achieve the targets of halving TB mortality and prevalence by 2015 (7). Particularly, urgent action is needed where the epidemic is worsening, notably in Africa but also in Eastern Europe. Sub-Saharan Africa has to face the challenge of managing the rapid rise in TB cases produced by the HIV epidemic, often in places where the human resources in the health-care sector were already overburdened. In Eastern Europe, the socioeconomic crisis that followed the dismantling of the Soviet Union in the early 1990s and impoverished public health systems have contributed to a major increase in the incidence and prevalence of TB, including its multidrug-resistant form (MDR-TB). Although these two regions have experienced worsening trends, Asia also demands increased and sustained attention. Asia continues to bear the largest burden of TB with two-thirds of all cases reported in the continent, and with India and China ranking first and second worldwide in terms of total number of TB cases. An emerging HIV epidemic also threatens recent progress in TB control and MDR-TB is a major problem in certain parts of China. In all regions, identifying and reaching all those

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Table 1 The Stop TB Strategy at a Glance Vision A world free of TB Goal To dramatically reduce the global burden of TB by 2015 in line with the MDGs and the Stop TB Partnership targets Objectives  Achieve universal access to high-quality diagnosis and patient-centered treatment  Reduce the human suffering and socioeconomic burden associated with TB  Protect poor and vulnerable populations from TB, TB/HIV, and MDR-TB  Support development of new tools and enable their timely and effective use Targets  MDG 6, Target 8: halt and begin to reverse the incidence of TB by 2015  Targets linked to the MDGs and endorsed by the Stop TB Partnership by 2005: detect at least 70% of new sputum smear-positive TB cases and cure at least 85% of these cases by 2015: reduce TB prevalence and death rates by 50% relative to 1990 by 2050: eliminate TB as a public health problem (one case per million population) Components of the strategy and implementation approaches 1. Pursue high-quality DOTS expansion and enhancement  Political commitment with increased and sustained financing  Case detection through quality-assured bacteriology  Standardized treatment with supervision and patient support  An effective drug supply and management system  Monitoring and evaluation system, and impact measurement 2. Address TB/HIV, MDR-TB, and other challenges  Implement collaborative TB/HIV activities  Prevent and control multidrug-resistant TB  Address prisoners, refugees, and other high-risk groups and special situations 3. Contribute to health system strengthening  Actively participate in efforts to improve system-wide policy, human resources, financing, management, service delivery, and information systems  Share innovations that strengthen systems, including the Practical Approach to Lung Health (PAL)  Adapt innovations from other fields 4. Engage all care providers  Public–Public, and Public–Private mix (PPM) approaches  International Standards for TB Care (ISTC) 5. Empower people with TB, and communities  Advocacy, communication, and social mobilization  Community participation in TB care  Patients’ Charter for TB Care 6. Enable and promote research  Program-based operational research  Research to develop new diagnostics, drugs, and vaccines Abbreviations: MDG, Millennium Development Goal; MDR-TB, multidrug-resistant tuberculosis.

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in need of care, especially the poorest of the poor, poses a major challenge. Related to this, efforts to control TB must progress hand-in-hand with efforts to strengthen health systems as a whole. The ultimate goal of eliminating TB will be elusive without new diagnostics, drugs, and vaccines and while new strategies to overcome obstacles to TB control have been developed, far more resources are needed so that these strategies can be widely implemented. World Health Organization (WHO) and partners’ efforts over the last decade on complementary policies and strategies present opportunities to address the current major constraints to TB control. These include expanding access to diagnosis and treatment through community TB care, and public– private mix (PPM) strategies aimed at engaging all care providers, public and non-state, in DOTS implementation. Innovative mechanisms such as the Global Drug Facility (GDF) and the Green Light Committee (GLC) have been developed to improve access to quality-assured and affordable drugs in resource-poor settings. The collaborative activities that need to be implemented by TB and HIV/AIDS programs have been defined, and strategies to manage MDR-TB have been developed and tested. To evaluate progress toward the MDGs, impact assessment is being pursued. New partnerships and academic research initiatives for development of new tools are beginning to produce results and several new diagnostics, new drugs, and even new candidate vaccines are in the pipeline. New resources are becoming available, from increased domestic funding in high burden countries and rising international funding, including from the Global Fund to fight against AIDS, TB, and Malaria, development banks and bilateral development agencies. Partnerships are being developed across and within countries and among a wide array of stakeholders to respond to health system and disease-control challenges. III. Goals and Targets The Stop TB Strategy has been developed within the context of an overall vision for TB control. This vision is a world free of TB. The goal of the Stop TB Strategy is to dramatically reduce the global burden of TB by 2015 in line with the MDGs and the Stop TB Partnership targets and to achieve major progress in the research and development of new tools needed for TB elimination. The Stop TB Strategy has four major objectives, which in combination are designed to achieve the goal. These are 1. 2. 3. 4.

to achieve universal access to high-quality diagnosis and patientcentered treatment for all people with TB; to reduce the human suffering and socioeconomic burden associated with TB; to protect vulnerable populations from TB, TB/HIV, and MDRTB; and to support development of new tools and enable their timely and effective use.

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Targets for TB control have been established by the WHA (1), by the United Nations as part of the MDGs (6), and by the Stop TB Partnership (8). The Stop TB Strategy is designed to achieve the targets that apply between 2006 and 2015. In 1991, all countries adopted the 44th WHA resolution setting two TB control targets for the year 2000: ‘‘to attain a global target of cure of 85% sputum-positive patients under treatment and detection of 70% of cases by the year 2000’’ (1). These targets were based on epidemiological modeling, which suggested that if an 85% cure rate and a 70% case detection are achieved, the prevalence of infectious (sputum smear-positive) TB cases, the number of infected contacts, and the incidence of infectious cases will be reduced (9,10). Reaching the targets of 70% case detection and 85% cure (measured as treatment success, i.e., the sum of cases cured and those who completed treatment) is expected to cause a decline in the annual TB incidence rate of 7% to 12% per year, in the absence of HIV coinfection (11). By 1998, it was apparent that the targets would not be met in the year 2000. In 2000, the 53rd WHA postponed the target year to 2005 (12). The MDGs established by the United Nations provide a framework as well as an opportunity for international cooperation to reduce poverty, including improving the health of the poor. As a disease of poverty, responsible for the loss of more years of healthy life than any other communicable disease except HIV/AIDS, TB is one of the priorities included within the MDGs. The MDG target relevant to TB (Goal 6, Target 8) is ‘‘to have halted and begun to reverse incidence by 2015 (Table 2) (13). The interpretation of Target 8 is that the incidence rate of all forms of TB should be falling by 2015. Two indicators have been defined for MDG 6 Target 8. These are TB prevalence and death rates (indicator 23), and the proportion of cases detected and successfully treated under the DOTS strategy (indicator 24). The Stop TB Partnership has endorsed two epidemiological targets that are linked to MDG 6, Target 8. These are to decrease TB prevalence and death by 50% by 2015, in comparison with a 1990 baseline rates (Table 3) (8). Achievement of these ‘‘impact’’ targets globally requires sustained progress in implementation (7). That is, national control programs around the world must reach at least 70% case detection and 85% treatment success, but they must also implement the wider range of activities

Table 2 Millennium Development Goal, Targets, and Indicators for Tuberculosis Millennium Development Goal 6: Combat HIV/AIDS, malaria, and other diseases Target 8: 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

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Table 3 Stop Tuberculosis Partnership Targets By 2005: At least 70% of people with infectious TB will be diagnosed (under the DOTS strategy) and at least 85% cured By 2015: The global burden of TB (disease prevalence and death rates) will be reduced by 50% relative to 1990 levels. Specifically, this means reducing prevalence to 155 per 100,000 or lower and deaths to 14 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 disease will be less than one case per million population per year (the criterion for TB ‘‘elimination’’ adopted within the United States)

described in the Stop TB Strategy and the related second Global Plan to Stop TB, 2006–2015 (14). In addition, the Stop TB Partnership has made a commitment to eliminate TB as a public health problem by 2050 (Table 3) (8,15). IV. Components of the Stop TB Strategy The Stop TB Strategy builds on the DOTS strategy while also broadening its scope to address remaining constraints and modern challenges in TB control (16). It should be viewed as a key component of broader international, national, and local strategies to alleviate poverty. It is crucial to understand that the implementation sequence, the scale, and the speed of activities building on DOTS will vary depending on the setting and the soundness of the essential DOTS implementation. The six principal components of the Stop TB Strategy are as follows: 1. 2. 3. 4. 5. 6.

Pursue high-quality DOTS expansion and enhancement. Address TB/HIV, MDR-TB, and other special challenges. Contribute to health system strengthening. Engage all care providers. Empower people with TB, and communities. Enable and promote research.

The six principal components are discussed below. A. Pursue Quality DOTS Expansion and Enhancement

To enable known constraints and new challenges to be addressed, further strengthening of the basic components of the DOTS strategy is required on the following lines: Political Commitment with Increased and Sustained Financing

Clear and sustained political commitment by national governments is crucial if DOTS and the whole Stop TB Strategy are to be effectively

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implemented. Political commitment is needed to foster national and international partnerships, which should be linked to a long-term strategic action plan prepared by the NTP. These plans should address technical and financial requirements and promote accountability for results at all levels of the health system. Local partnerships with the many potential contributors will help improve TB care in terms of access, equity, and quality. TB-related and other relevant indicators should be included in national strategic plans and, where appropriate, political commitment should be backed up by national legislation (17). Adequate funding is essential. Current resources are inadequate, and more effort is required to mobilize additional resources from domestic as well as international sources. In the long term, ideally national financing should progressively increase and external funds decrease. Even with adequate financing, critical deficiencies in human resources in the public health sector will impede progress in many low- and middle-income countries, especially in Africa. Overall, structural and financial changes are required to improve the availability, distribution, and motivation of human resources for health care in general, and TB care in particular (18,19). Case Detection Through Quality-Assured Bacteriology

The recommended method of TB case detection remains bacteriology, first using sputum-smear microscopy, and then culture and drug sensitivity tests when indicated. The latter are necessary today for diagnosis and monitoring of smear-negative and drug-resistant TB cases. Access to quality-assured sputum-smear microscopy means that health services with properly equipped laboratories and well-trained personnel need to be widely available and accessible. This is likely to require additional investments in the laboratory network in many countries. In addition, countries should have a well-resourced and functioning national reference laboratory. The laboratory network should be based on the following principles:    

Adoption of national standards in accordance with international guidelines. Decentralization of diagnostic services while maintaining high proficiency levels. Continuous interaction between members at various levels of the network. Functional internal and external quality management including supervision.

Culture and drug-sensitivity testing services should be introduced in a phased manner, at appropriate referral levels of the health system. Their functions should include diagnosis of sputum smear-negative TB, diagnosis of TB among HIV-positive patients and children, diagnosis, and monitoring of drugresistant TB, and testing related to periodic surveys of the prevalence of drug resistance. Maintaining the quality of the laboratory network depends on regular training, supervision and support, and motivation of laboratory staff. Existing public and private laboratories should be used optimally.

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The mainstay of TB control is the organization and administration of standardized treatment country wide for all adult and paediatric TB cases—whether those cases are sputum smear-positive, smear-negative, or extrapulmonary. In all cases, WHO recommendations in published guidelines on patient categorization and management should be followed (20). These guidelines emphasize the use of the most effective standardized, short-course regimens, and of fixed-dose combinations (FDCs) to facilitate adherence and prevent the risk of acquiring drug resistance. Separate WHO guidelines are also available for management of patients with drug-resistant TB (21). Services for TB care should identify and address factors that may make patients interrupt or stop treatment. Supervised treatment, which may have to include Directly Observed Therapy (DOT), helps patients take their drugs regularly and complete treatment, thus achieving cure and preventing the development of drug resistance. Supervision must be carried out in a context-specific and patient-sensitive manner, and is meant to ensure adherence on the part of both providers (by giving proper care and support) and patients (by taking regular treatment). Depending on the local conditions, supervision may be undertaken at a health facility, in the workplace, in the community, or at home. It should be provided by a treatment partner or treatment supporter who is acceptable to the patient and is trained and supervised by health services. Patient and peer support groups can help to encourage adherence to treatment. Strict DOT has to be undertaken for selected patient groups such as, for example, patients with mental illness, some prison inmates, and severe drug addicts. Locally appropriate measures should be consciously undertaken to identify and address physical, financial, social and cultural as well as health system barriers to accessing TB treatment services. Particular attention should be paid to the poorest and most vulnerable groups. Examples of actions that may be appropriate include expanding treatment outlets in the poorest rural and urban settings, involving providers that practice close to where patients live, ensuring that services are provided free of charge, offering psychological and legal support, addressing gender issues, improving staff attitudes, and undertaking advocacy and communication activities. Effective Drug Supply and Management System

An uninterrupted and sustained supply of quality-assured anti-TB drugs is fundamental to TB control. For this purpose, an effective drug supply and management system is essential. A reliable system of procurement and distribution of all essential anti-TB drugs to all relevant health facilities should be in place. Anti-TB drugs should be available free of charge to all TB patients, both because many patients are poor and may find them difficult to afford, and because treatment has benefits that extend to society as a

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whole (successful treatment prevents transmission to others). Legislation related to drug regulation should be in place and use of anti-TB drugs by all providers should be strictly monitored. The use of FDCs of proven bioavailability and innovative packaging, such as patient kits, can help improve drug supply logistics as well as drug administration, reduce non-adherence to treatment, and prevent development of drug resistance. The GDF and the GLC offer countries with limited capacity the benefit of access to quality-assured TB drugs at reduced prices and also facilitate access to training on drug management (22,23). Monitoring and Evaluation System, and Impact Measurement

Establishing a reliable monitoring and evaluation system with regular communication between the central and peripheral levels is vital. This requires standardized recording of individual patient data, including information on treatment outcomes, which are then used to compile quarterly treatment outcomes in cohorts of patients. These data, when compiled and analyzed, can be used at the facility level to monitor treatment outcomes, at the district level to identify local problems as they arise, at a provincial or national level to ensure the consistency of TB control across geographical areas, and nationally and internationally to evaluate the performance of each country. Regular program supervision should be carried out to verify the quality of information and to address performance problems. Both developed and developing countries now have additional diagnostic information at their disposal, including sputum culture, drug sensitivity, and HIV test results. These can all be used to guide patient management. TB program managers also need to monitor records and reports from care providers outside the public sector. Special attention must be paid to securing confidentiality of patient information. Currently, WHO and its partner organizations are considering what additional data should be routinely collected and how these data should be compiled, collated, analyzed, and used to inform TB control. Use of electronic recording systems will also be considered where appropriate. To make the best use of data at all levels, many countries will need to train staff in the analysis and interpretation of data, as well as in the use of computer software that can greatly facilitate this work. As electronic recording systems become more widely available, consideration should be given to storing individual patient data, which will make it possible to carry out more detailed analyzes using aggregated data. B. Address TB/HIV, MDR-TB, and Other Challenges TB/HIV Collaborative Activities

HIV promotes the progress of recent and latent infection due to Mycobacterium tuberculosis to active TB. It also increases the rate of recurrent TB. The HIV epidemic has caused a substantial increase in the percentage of TB cases that have smear-negative pulmonary and extrapulmonary TB

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disease. HIV-positive smear-negative pulmonary TB patients have inferior treatment outcomes and higher early mortality compared with HIV-positive smear-positive pulmonary TB patients. In the long term, only effective control of the HIV epidemic will reverse the associated increase in TB incidence. However, until then, interventions to reduce HIV-related TB morbidity and mortality need to be implemented (24). WHO has published an interim policy on collaborative TB/HIV activities (25). Twelve collaborative activities are recommended in three broad categories: establishing the mechanisms for collaboration, decreasing the burden of TB in people living with HIV/AIDS, and decreasing the burden of HIV in TB patients. TB programs should undertake all relevant collaborative activities themselves or establish referral linkages with the HIV programs for that purpose. These activities should be a part of the national TB control plans. Prevention, Treatment, and Control of Drug- and MDR-TB

Global surveillance of anti-TB drug resistance indicates that drug-resistant TB is present everywhere, and that it is especially prevalent in countries of the former Soviet Union and parts of China. In these areas, TB cannot be controlled if MDR-TB is not properly addressed. This means that every patient with MDR-TB should receive adequate treatment and that secondline anti-TB drugs are used rationally. Increasing evidence shows that management of MDR-TB under programmatic conditions is feasible, effective, and cost-effective when implemented in the context of a wellfunctioning DOTS program and based on WHO’s MDR-TB management DOTS-Plus policy guidelines (21). Detection and treatment of all forms of drug-resistant TB should be an integral part of NTP activities. Although the challenges involved in ensuring that such integration occurs should not be underestimated, NTPs need to take steps to ensure that patients with drug-resistant TB have access to the right treatment, which is often lifesaving. Experience shows that this can strengthen the program’s overall capacity to implement TB control measures. The key actions to prevent and control drug-resistant TB include use of adequate treatment regimens, a reliable supply of quality-assured first- and second-line anti-TB drugs, and adherence to treatment by patients and to its proper provision by health-care providers. The WHO guidelines on the management of drug-resistant TB, prepared on the basis of evidence, provide full details about how to implement activities to control drugresistant TB (21). Addressing Risk Groups and Special Situations

TB programs need to pay specific attention to certain population groups and special situations that are exposed to a higher risk of contracting TB. The risk groups requiring special attention include prison populations, refugees, migratory workers, illegal immigrants, cross-border populations, the

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orphaned and homeless, ethnic minorities, other marginalized groups, and alcohol and injecting drug users. Diabetics and smokers are other common examples of risk groups. Special situations requiring extra attention include unexpected population movements such as, e.g., political unrest, war, natural disaster, and other conditions causing refugee movements. In both the circumstances, there may be a disruption of social networks. TB services need to adapt to address the specific needs of the special risk groups and situations (26). Each health care and congregate setting should have a TB infection control plan that includes administrative, environmental, and personal protection measures to minimize the risk of TB transmission (27). Implementation should be undertaken in a phased manner with support of and in coordination with relevant partners, care providers, and the beneficiaries themselves. C. Contribute to Health-System Strengthening Active Participation in Efforts to Improve System-Wide Policy, Human Resources, Financing, Management, Service Delivery, and Information Systems

Progress on all of the health-related MDGs depends, to a substantial degree, on the strengthening of health systems. This is particularly true in Africa. As clearly stated by the Second Ad-hoc Committee on the TB epidemic, if access to quality health services can be increased and sustained, this should have major benefits for TB control (28). Health system strengthening is defined as ‘‘improving capacity in some critical components of health systems, in order to achieve more equitable and sustained improvement across health services and outcomes’’ (29). TB control programs and their partners should participate actively in country-led as well as global efforts to improve action across all major areas of the systems, including policy, human resources, financing, management, service delivery (infrastructure and supply systems), and information systems. It also means working across all levels of systems and with all actors in the public sector, non-state sector, and communities (3). In some cases, this will mean ongoing contributions to well-defined sector strategies and plans, and in others helping building system wide responses or in working on initiatives to devise, test, and share new solutions. Many TB programs began this type of work in response to health-reform initiatives of the last 10 years. WHO guidelines produced in 2002 are still highly relevant and will be supplemented with new tools (30). Partners should also help to reduce any duplication or distortions caused in local systems by the rapid scaling up and/or expanded financing for TB efforts, and help to build coordination across disease-specific initiatives. Sharing Innovations from TB Control that Strengthen Systems

TB programs are implementing a variety of new approaches to accelerate and sustain TB control impact, and these are now part of the Stop TB

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Strategy. Among these are community TB care (31), PPM approaches to engage all care providers (32–34), a syndromic approach to addressing respiratory care (see below), and innovations in health information and drug management systems. They all seek to use more efficiently the health system resources that are in short supply (e.g., human resources, infrastructure, and information). These innovations should be adapted and scaled up in ways that allow their broader application to advance a range of health outcomes, and best practices need to be shared across health systems and countries. Practical Approach to Lung Health

The Practical Approach to Lung Health (PAL) is among the innovations initiated within the TB control community, which can strengthen the health system as a whole (Chapter 43). Pulmonary TB often manifests as a cough, and persons with TB symptoms first present themselves to primary care services as respiratory patients (35). By linking TB control activities to proper management of all common respiratory conditions, TB programs and staff implementing DOTS services at local level can help to improve the efficiency and quality with which care is provided. To do this in practice, a systematic, standardized, and symptom-based approach is required. Based on operational research in diverse country settings, WHO has developed PAL (36). This is designed to help integrate TB services within primary care, strengthen general health services, prevent irrational use of drugs, and improve management of resources. Implementing PAL can improve TB case detection and also enhance the quality of care for common respiratory illnesses (37). Adapting Innovations from Other Fields

To respond to all six elements of the Stop TB Strategy, TB programs and their partners can adapt approaches that have been applied in other priority public health fields, and build further on some of the common systems that are already in place. This may include: further integration of TBcontrol activities within the community and primary care outreach pursued in maternal and child health programs; social mobilization along the lines used by HIV/AIDS programs and partners; regulatory actions that have been used in tobacco control; and financing initiatives and methods to reach the poorest that have been developed by immunization services. It can also include further collaboration with broader information platforms (surveys, etc.) to advance TB surveillance and program monitoring. Effective integration of delivery systems depends on testing, adapting, scaling up, and evaluating common approaches. D. Engage All Care Providers Public–Public and Public–Private Mix Approaches

In most settings, patients with symptoms suggestive of TB seek care from a wide array of health-care providers within and outside the public sector

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TB services. These may include private clinics operated by formal and informal practitioners, and institutions owned by the public, private, voluntary, and corporate sectors (e.g., general and specialty public hospitals; non-governmental organizations (NGOs); prison, military, and railway health services; and health-insurance organizations). These non-NTP providers may serve a large proportion of TB symptomatic patients while not always applying recommended TB management practices or reporting their cases to NTPs. Some settings have large private and NGO sectors while others have public sector providers (such as general and specialty hospitals) that operate outside the structure of NTPs. Evidence suggests that failure to involve all care providers used by TB symptomatic patients hampers case detection, delays diagnosis, causes improper diagnosis as well as inappropriate and incomplete treatment, increases drug resistance and places a large and unnecessary financial burden on patients (32). WHO has produced guidelines on how to engage all care providers in TB control (33). The feasibility, effectiveness, and cost-effectiveness of involving different types of care providers using a PPM approach have been demonstrated (34). NTPs should aim to engage all care providers in DOTS implementation to help achieve the TB control targets, improve access to care, standardize the quality of TB care across providers and save costs of care for patients. Priority should be given to identifying and setting up collaboration with health-care providers who diagnose and treat a large number of TB patients and suspects, and are used by the poor sections of the population. International Standards for TB Care

The ‘‘International Standards for TB Care’’ (ISTC) have been formulated based on a wide global consensus of appropriate practices in TB diagnosis and treatment. They should be actively promoted and used to help engage all care providers in DOTS implementation, and are particularly complementary to the PPM approaches described above. The standards of care are evidence based. They can be used to secure a broad base of support for TB control efforts—from NTPs, and professional, medical, and nursing societies, academic institutions, NGOs, and HIV-focused organizations. They can also help to create peer pressure to encourage providers to conform to the principles, and serve as a basis for pre-service and in-service training (38). E. Empower People with TB, and Communities Advocacy, Communication, and Social Mobilization

In the context of wide-ranging partnerships for TB control, advocacy, communication, and social mobilization (ACSM) can help build greater commitment to fighting TB. Advocacy is intended to secure support of key constituencies in relevant local, national, and international policy discussions and is expected to prompt greater accountability from governmental and international actors (Chapter 25). Communication is concerned with informing and enhancing knowledge among the general public and people with TB,

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and empowering them to express their needs and take action. Encouraging providers, at the same time, to be more receptive to expressed wishes and views of people with TB and community members will make TB services more responsive to community needs. Social mobilization is the process of bringing together all feasible and practical intersectoral allies to raise people’s knowledge of, and demand for, quality TB care and health care in general, to assist in the delivery of resources and services and to strengthen community participation for sustainability. ACSM efforts in TB control should be linked with overarching efforts to promote public health and social development. Community Participation in TB Care

Community participation in TB control implies establishing a working partnership between the health sector and the community—the local population especially the poor in general and TB patients, current as well as cured, in particular. Enabling people with TB and communities to be informed about TB, to enhance general awareness about the disease and to share responsibility for TB care can lead to effective patient empowerment and community participation, by increasing the demand for health services and bringing care closer to the community. For this purpose, TB programs should provide support to frontline health workers to help create an empowering environment by, i.e., facilitating setting-up of patient groups, encouraging peer education and support, and linking with other self-help groups in the community. Community volunteers also need regular support, motivation, instruction, and supervision. Evidence shows that community-based TB care is cost-effective compared to hospital-based care and other ambulatory care models (31). Inspiring communities and obtaining their continued support in identifying and providing care for people with TB is essential to sustain community TB initiatives. Patients’ Charter for TB Care

Developed by patients from around the world, the Patients’ Charter outlines the rights and responsibilities of people with TB and complements the International Standards for TB Care intended for health-care providers (39). It is based on the principles of various international and national charters and conventions on health and human rights. It aims to empower people with TB and the communities and make the patient–provider relationship mutually beneficial. The charter sets out the ways in which patients, communities, health-care providers, and governments can work as partners and help enhance the effectiveness of health services in general and TB care in particular. The charter provides a useful tool to achieve greater involvement of people in TB care. F. Enable and Promote Research Program-Based Operational Research

The Stop TB Strategy consolidates DOTS implementation and involves the implementation of several new approaches to tackle challenges facing NTPs.

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To put them into practice, program-based operational research should be a core component of NTP work. Designing and conducting locally-relevant operational research can help identify problems, determine workable solutions, test them in the field and plan for scale up. For this purpose, collaboration between program managers and researchers is essential. Acquiring basic skills in identifying and addressing issues related to program operations and performance can help program managers to initiate operational research in collaboration with researchers and academia. This can then help to sustain and strengthen TB control efforts by expanding existing activities and introducing new strategies effectively. For this purpose, sustainable partnerships and networks could be established for productive collaboration on operational research. Research to Develop New Diagnostics, Drugs, and Vaccines

Existing tools for prevention and treatment of TB make standard TB care demanding for both patients and their care providers. The tools include a century-old, tedious, weakly sensitive, smear microscopy test for diagnosis (although it is the best method available today to identify highly infectious cases) and a relatively long ‘‘short-course’’ chemotherapy with several drugs. A truly effective vaccine is lacking. The need to rely on these tools has substantially hindered the pace of progress in global TB control. Facilitating the concerted efforts of the Stop TB Partnership’s Working Groups on New Diagnostics, Drugs, and Vaccines for TB is therefore a key component of the Stop TB Strategy. In the spirit of partnership, TB programs should actively encourage and participate in this process. Countries should advocate for new tools development, help speed up the field testing of new products, and prepare for swift adoption and roll out of new diagnostics, drugs, and vaccines as they become available.

V. Measuring Global Progress and Impact A. Measurement of Program Outcomes and Impact on Burden of Disease

The Stop TB Strategy is designed to achieve the MDG and related Stop TB Partnership targets (explained in Section ‘‘Goals and Targets’’). As well as a final assessment of whether targets have been reached in 2015, progress toward the targets needs to be regularly measured. Table 4 shows the indicators that apply for each of the targets, and how they can be measured. The MDG and related Stop TB Partnership targets include three impact indicators, i.e., indicators to measure the reduction in burden of disease: incidence, prevalence, and death rates. TB incidence rates can be estimated through longitudinal population-based surveys, or from notification data where these are complete. TB prevalence rates can be measured through cross-sectional population-based surveys, and also from the product of estimated incidence and duration of disease. Mortality rates can be

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Table 4 Selected Indicators for Monitoring Tuberculosis Programs Indicator

Target

Measurement

Prevalence of disease: Number of people per 100,000 population who have TB disease at a given time

Halve 1990 prevalence rate by 2015

Cross-sectional surveys (preferably), or estimated from incidence and duration of disease (approximate)

Incidence of disease: Number of new cases of TB disease (all forms) per 100,000 population per year

Incidence rate in decline by 2015

Longitudinal surveys, or from case notifications (where complete)

Halve 1990 mortality rate by 2015

From vital registration (where complete), verbal autopsy surveys, or from incidence and case fatality rates (approximate)

70% by 2005

From notification data and estimates of incidence

85% by 2005

Routinely collected data on cohorts of patients undergoing treatment

Mortality rate: Number of TB deaths (all forms) per 100,000 population per year

Case-detection rate: Number of new smear-positive cases notified in one year divided by the annual incidence Treatment success rate: Percentage of new smear-positive TB cases registered for treatment that are cured or completed treatment

estimated from vital registration records, from verbal autopsy studies, or from the product of estimated incidence and case fatality rates. Countries should consider carrying out surveys of disease prevalence or incidence over the next 10 years in order to measure the change in burden, though it should be borne in mind that such surveys are costly and logistically complex. The other two targets relate to the implementation and quality of TB control programs: the case-detection rate, and the treatment success rate. In assessing trends in the total burden of TB and the quality of TBcontrol efforts, it is valuable to take into account, where possible, factors such as the age and sex of the patients, the level of MDR-TB and the prevalence of HIV, all of which may affect case detection and treatment outcomes. As more countries develop better systems for collecting health information routinely, it should be possible to assess the state of the epidemic and the quality of control using annual TB surveillance data, together with

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data from vital registration. To complement and check the quality of routine surveillance data, it will be important to carry out population-based surveys of disease prevalence or infection. B. Financing for TB Control

Achieving the MDG and Stop TB Partnership targets will require increased and sustained financing for TB control, as reflected in Component 1 of the Stop TB Strategy. Financing of TB control needs to be monitored and evaluated at subnational, national, and international level, to document trends in NTP budgets, available funding for these budgets, funding gaps, expenditures, and total TB control costs (total TB control costs include costs reflected in NTP budgets plus costs associated with using general healthservices staff and infrastructure). A consistent categorization of budget line items and funding sources should be used to allow analysis of changes over time. These categories may be modified periodically—for example, to reflect the introduction of a major new source of funding or when a major shift in strategy alters the line items for which it is relevant to collect data. WHO collects financial data through a questionnaire, which is sent to all countries annually. These data are analyzed and presented in the annual WHO report on global TB control. Some of the key indicators that are relevant to financial monitoring and evaluation of TB control include the annual NTP budget requirement, the NTP budget per patient treated, the percentage of the NTP budget that is funded, the percentage of the NTP budget that is funded by the government (including loans), the percentage of available funding that is spent, the total annual cost of TB control, the cost per patient treated, and the cost per patient successfully treated. Unlike the outcome and impact indicators described above, national and international targets for financing have not been established. Nevertheless, monitoring changes over time is useful and should be undertaken regularly. VI. Conclusion The Stop TB Strategy, equipped with the lessons from DOTS implementation in diverse country settings, field-tested approaches to tackle current challenges, renewed efforts in developing new tools, and a strong Stop TB Partnership of all stakeholders, comprehensively addresses the problem of TB. The strategy also provides the basis and the context to the recently launched second Global Plan to Stop TB, 2006–2015 (14). This inclusive plan exploits the various synergies and new approaches, and carries an estimated cost of US $56 billion over the decade. The strength of global efforts to control TB lies in the coordinated and collaborative efforts of the Stop TB Partnership, the secretariat of which is based in WHO. With a clear global strategy and related global plan, the framework is in place for unprecedented efforts in TB control over the next 10 years. Full implementation will require substantial resources. Although funding is rising,

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more is needed if we are to achieve the MDG and the Stop TB Partnership targets for TB control and set ourselves on the path toward elimination of this ancient scourge of humanity.

Acknowledgments We, the authors, acknowledge that this chapter is an adaptation of the WHO document ‘‘The Stop TB Strategy: Building on and Enhancing DOTS to meet the TB-related MDGs’’ and are grateful to all those who contributed to it. In particular, as the Stop TB Strategy summarized in this paper has been approved by the WHO’s Strategic, Technical, and Advisory Group (STAG) on TB, we thank the members of STAG for their input. We also thank the members of the Coordinating Board of the Stop TB Partnership for their contribution to the development of the Strategy. We acknowledge the contributions of the staff of the Stop TB Department at WHO, Geneva, especially Le´opold Blanc, Chris Dye, Katherine Floyd, Giuliano Gargioni, Haileyesus Getahun, Ernesto Jaramillo, Knut Lo¨nnroth, Dermot Maher, Paul Nunn, and Brian Williams. We also thank the Stop TB Partnership Secretariat based at WHO, Geneva, and especially Marcos Espinal; the TB teams of WHO’s regional and country offices; and members of all Working Groups and Subgroups of the Stop TB Partnership for their input. References 1. World Health Organization. Forty-fourth World Health Assembly. WHA44/1991/ REC/1. Geneva: WHO, 1991. 2. World Health Organization. Framework for effective tuberculosis control. WHO/ TB/94.179. Geneva: WHO, 1994. 3. World Health Organization. An expanded DOTS framework for effective tuberculosis control. WHO/CDS/TB/2002.297. Geneva: WHO, 2002. 4. World Health Organization. Global tuberculosis control—surveillance, planning, financing, WHO Report 2006. WHO/HTM/TB/2006.362 and ISBN 92 4 156314 1. Geneva: WHO, 2006. 5. World Health Organization. Fifty-eighth World Health Assembly. WHA58/2005/ REC/1. Geneva: WHO, 2005. 6. Dye C, Maher D, Weil D, Raviglione MC, Espinal M. Targets for global tuberculosis control. Int J Tuberc Lung Dis 2006, 10(4):460–462. 7. Dye C, Watt J, Bleed DM, et al. Evolution of tuberculosis control and prospects for reducing tuberculosis incidence, prevalence, and deaths globally. JAMA 2005; 293:2767–2775. 8. World Health Organization. The global plan to stop tuberculosis 2006–2015—Stop TB Partnership. WHO/CDS/STB/2001.16 Geneva: WHO, 2001. 9. Styblo K, Bumgarner JR. Tuberculosis can be controlled with existing technologies: evidence. Tuberculosis Surveillance Research Unit Progress Report, 1991; 2: 60–72. 10. Styblo K. Epidemiology of tuberculosis. Selected Papers. Vol. 24. KNCV, 1991. 11. Dye C, Garnett GP, Sleeman K, Williams BG. Prospects for worldwide tuberculosis control under the WHO DOTS strategy. Lancet 1998; 352:1886–1891.

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12. World Health Organization. Fifty-third World Health Assembly. WHA53/2000/ REC/1. Geneva: WHO, 2000. 13. United Nations Statistics Division. Millennium indicators database. http:// unstats.un.org/unsd/mi/mi_goals.asp. 14. Stop TB Partnership and WHO. Global Plan to Stop TB 2006–2015. Actions for life—towards a world free of tuberculosis. WHO/HTM/STB/2006.35. Geneva: WHO, 2006. 15. Washington Commitment to Stop TB. First Stop TB Partners’ Forum, 22–23 October 2001. 16. Raviglione MC, Uplekar M. WHO’s new stop TB strategy. Lancet 2006; 367:952– 955. 17. World Health Organization. Good practice in legislation and regulations for TB Control: an indicator of political will. WHO/CDS/TB/2001.290. Geneva: WHO, 2001. 18. World Health Organization. Human resources development for TB control: report of a consultation held on 27–28 August 2003. WHO/HTM/TB/2004.340. Geneva: WHO, 2004. 19. World Health Organization. Check-list for the review of human resource development component of national plans to control tuberculosis. WHO/HTM/TB/ 2005.354. Geneva: WHO, 2005. 20. World Health Organization. Treatment of tuberculosis. Guidelines for national programmes—third edition. WHO/CDS/TB/2003.313. Geneva: WHO, 2003. 21. World Health Organization. Guidelines for the programmatic management of drugresistant tuberculosis. WHO/HTM/TB/2006.361. Geneva: WHO, 2006. 22. World Health Organization. Four million treatments in four years—GDF achievement report. WHO/HTM/STB/2005.32. Geneva: WHO, 2005. 23. Gupta R, Cegielski P, Espinal MA, et al. Increasing transparency in partnerships for health—introducing the Green Light Committee. Trop Med Int Health 2002; 7:970–976. 24. Nunn P, Williams B, Floyd K, Dye C, Elzinga G, Raviglione M. Tuberculosis control in the era of HIV. Nat Rev Immunol 2005; 5:819–826. 25. World Health Organization. Recommendations of the interim policy on collaborative TB/HIV activities. Wkly Epidemiol Rec 2004; 79:6–11. Geneva: World Health Organization, 2004. 26. World Health Organization. Addressing poverty in tuberculosis control: options for national TB control programmes. WHO/HTM/TB/2005.352. Geneva: WHO, 2005. 27. World Health Organization. Guidelines for the prevention of tuberculosis in health care facilities in resource-limited settings. WHO/TB/99.269. Geneva: WHO, 1999. 28. World Health Organization. Report on the meeting of the Second Ad-hoc Committee on the TB Epidemic—recommendations to Stop TB partners—Montreux, Switzerland, Sept. 2003. WHO/CDS/STB/2004.28. WHO, 2004. 29. World Health Organization. The ‘‘Montreux Challenge:’’: making health systems work meeting note for the record, 4–6 April 2005. Geneva: WHO, 2005. 30. World Health Organization. Expanding DOTS in the context of a changing health system. WHO/CDS/TB/2003.318. Geneva: WHO, 2003. 31. World Health Organization. Community contribution to TB care: practice and policy. WHO/CDS/TB/2002.318. Geneva: WHO, 2002. 32. Uplekar M, Pathania V, Raviglione M. Private practitioners and public health: weak links in tuberculosis control. Lancet 2001; 358:912–916. 33. World Health Organization. Guidance on implementing public-private mix for DOTS. Engaging all health care providers to improve access, equity and quality of TB care. WHO/HTM/TB/2006.360. Geneva: WHO, 2006.

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34. Lo¨nnroth K, Uplekar M, Arora VK, et al. Public-private mix for DOTS implementation: what makes it work? Bull World Health Organ 2004; 82(2):580–586. 35. World Health Organization. Respiratory care in care services—a survey in 9 countries. WHO/HTM/TB/2004.333. Geneva: WHO, 2004. 36. World Health Organization. Practical approach to lung health (PAL). A primary health care strategy for the integrated management of respiratory conditions in people five years of age or over. WHO/HTM/TB/2005.351. Geneva: WHO, 2005. 37. Fairall L, Zwarenstein M, Bateman E, et al. Educational outreach to nurses improves tuberculosis case detection and primary care of respiratory illness: a pragmatic cluster randomized controlled trial. BMJ 2005; 331:750–754. 38. Hopewell PC, Pai M. Tuberculosis, vulnerability and access to quality care. JAMA 2005; 293:2790–2793. 39. Patient’s character for Tuberculosis care. World care council, 2006. www.wcc-tb.org/ charter2006.php.

Index

Abdominal tuberculosis, 208, 324 Acid-fast bacillus (AFB), 558 detection of, 383 mycobacteria, 30 positive sputum smear, 308 smear-microscopy, 1158 smear-negative pulmonary tuberculosis, 1153 on Ziehl–Neelsen (ZN) stain, 363 Acid-fast stains, 327–328 Acquired immune deficiency syndrome (AIDS), 489, 801 Acquired resistance, diagnosis of, 848 Actinomycetes, 29 aerobic, 30 Active case finding (ACF), 934–936 Acute respiratory infections (ARIs), 1060, 1148 Adenosine triphosphate (ATP), 1142 Adhesive arachnoiditis, 208 Adolescents, tuberculosis in, 324 Advocacy, communication, and social mobilization (ACSM), 687, 1239 AFB. See Acid-fast bacillus Ag85A and Ag85B protein, 1159 Agar-based medium, 35 Age, effects of on immunocompetence, 348–351 on pharmacokinetics, 358–359 AIDS (Acquired immune deficiency syndrome), 489, 801

Alanine aminotransferase (ALT), 280 Alcoholic hepatitis, 204 Alveolar epithelial barrier, 132–133 Algorithm, optimal diagnostic, 1182 Alveolar-filling process, 158 Alveolar inflammation, 950 Alveolar macrophage (AM), 101, 120, 799 Alveoli, respiratory mucosa of, 950 Ambulatory treatment for tuberculosis, 599, 600 American Association of Thoracic Surgeons, treatment, pulmonary tuberculosis, 461 American Thoracic Society, tuberculosis control, 957 Aminoglycoside kanamycin, 419 Amplifier effect of short course chemotheraphy, 421 Anaerobiosis, 1208 Anamnestic reaction, 71 Anergy testing, 378–380 Antibacterial mucosal innate immunity, 132 Antibiotic therapy, prolonged, 1148 Antigen-presenting cells (APC), 120 Antigen processing, 122 Antigen-reactive T-cells, 126 Antigen-specific T-cells, 108 Antigenic protein MPB64, 546

I-1

I-2 Antimycobacterial agents, 184, 1144, 1208 Antimycobacterial immune responses, 133 Antiretroviral (ARV) agents concentration of, 191 intervention, 970 medications, 1137 Antiretroviral therapy (ART), 14, 134, 202, 294, 372, 389, 404, 954, 979, 1136, 1186 concomitant, 389 on tuberculosis control, impact of, 392 Antituberculosis agents interaction of, 202 treatments with, 208, 1143 Antituberculosis chemotherapy, 195, 504 history of, 184–185 Antituberculosis dispensaries, 732 Antituberculosis drugs, 5, 185–195, 610, 706, 732, 909, 1117 amikacin, 187, 194, 195 capreomycin, 188, 194, 195 for children, 330–332 clinical trials of, 333 cost reduction of, 711 cycloserine, 187, 194, 195 diamines, 1144–1145 diarylquinolines, 1141–1142 discovery of, 319 disposition of, 359 dosage forms for, 329 ethambutol, 42, 187, 192 ethionamide, 187, 194 fluoroquinolones, 1147 gatifloxacin, 189, 209 global report on, 825, 838 isoniazid, 5, 42, 78, 184–186, 190 kanamycin, 194, 195 levofloxacin, 189 macrolides, 1143-1144 monoresistance rates of, 827–828 moxiflooxacin, 189, 209 nitroimidazoles, 1139–1141 oxazolidinones, 1145 PAS, 188, 195

Index [Antituberculosis drugs] pharmacokinetics of, 329 preparation of, 186–189 pyrazinamide, 52, 186, 193–194 pyrroles, 1142–1143 quinolones, 42, 194, 209 regimens, 206 research and development of, 1184 resistance, 490, 774, 825–827, 1221 rifabutin, 186 rifampicin, 5, 42, 186 rifamycins, 190-192, 1145–1146 rifapentine, 186 streptomycin, 42, 184, 187, 192–193, 1136 surveys of, 736 toxic metabolites of, 359 use of, 332 Antituberculosis therapy, 127, 160, 781 Antituberculosis treatment history, 427 Antituberculosis vaccines, 117, 139 Antivitronectin receptor, 133 Apoptotic processes, 129 Arabinomannan-specific antibodies, 126 Arden House report of tuberculosis, 488, 489 Articular tuberculosis, 207 ART. See Antiretroviral therapy Aspartate aminotransferase (AST), 280, 285, 288 Autologous blood cells, 129

Bacille, reactivation of, 1208 Bacillus Calmette–Guerin (BCG), 108, 123, 157, 892 adverse reactions of, 550–551 benefits and limitations of, 1154 Cape Town trial of, 1163 cultures, 545 current use of, 549 deletions and duplications in, 544–555 dissemination, 550, 551 effectiveness, disparity in, 1154

Index [Bacillus Calmette–Guerin (BCG)] in guinea pig model, 1158, 1160 immunization practices, 548–549 immunization vaccination regimen, 1154 immunogenicity of, 1158 insertion sequence (IS) 6110 of, 545 in mice, 1160 nucleotide polymorphism of, 545 perfringolysin in, 1158 phylogeny of, 545 in prime-boost regimes, 1161 recombinant, 1155, 1158 region of deletion (RD) from, 545 strains, 544–546, 552, 1154, 1155 tuberculosis skin test and, 551 vaccination, 238, 423, 660 in children, 505, 507 clinical trials of neonatal, 1154 effects of, 240 in Europe, 733 false positive test, 225 impact of, 1154 in low-incidence countries, 762 vaccine, 313, 326, 489 Danish, 544, 547 efficacy trials, 542–548 future of, 551–552 history of, 541–544 live attenuated, 394 Pasteur, 544, 547 placebo-controlled, 1154 strain mutation, 542 BACTEC1 system, 424 Bacterial cell wall components, 131, 137 Bacterial replication, 124, 125 endogenous, 119 extracellular, 131 Bactericidal effects, 122, 125 Bacti-Alert1, 424 Battey antigen, 544 BCG. See Bacillus Calmette–Guerin Bilobectomy, 469 Biosynthesis, cell-wall, 192, 209 Blood monocytes, 106

I-3 Blood mononuclear cells, 243 Bone and joint tuberculosis, 207 Borrelia burgdorferi, 54 Brain tumor, 323 Breast-feeding, 970 Bronchi, operations on, 468 Bronchial calculi, formation of, 479 Bronchial obstruction, 335 Bronchial stenosis, 158 Bronchial stump infection, 205 Bronchiectasis, 158 Bronchoalveolar cells, 129 Bronchoalveolar lavage cells (BAC), 51, 119 Bronchoalveolar lavage fluid, 120 Bronchopleural fistula, 206 Bronchoscopic alveolar lavage (BAL), 383 Bronchoscopy, 800 Bystander effect, 137

Cancer, respiratory tract, 1060 Cardiac tuberculosis, 321 Case finding expansion of, 511 strategic objective of 70%, 512–513 Caseation necrosis, 108 Catalase–Peroxidase enzyme system, 185 Catheter, drainage, 470 Cavernomyoplasty, 472 Cavernoplasty, 471, 472 Cavernotomy, 472 Cavitary tuberculosis, 109 Cavitation, 800 Cavities operations on, 470–473 treatment of, 472 CD4-T-lymphocytes, 968 Cell-mediated immunity (CMI), 108, 120, 157 versus delayed-type hypersensitivity, 108 Cell membrane–trafficking processes, 137 Cellular immune function, 968 Cell-wall biosynthesis, 192, 209

I-4 Centers for Disease Control and Prevention (CDC), 486, 488, 766, 777–778 Global AIDS Program, 780 guidelines for prevention of Mycobacterium tuberculosis, 773 Central nervous system tuberculosis, 160, 194, 207–208 pathogenesis of, 322 Cerebrospinal fluid (CSF), 190, 192, 207 glucose level, 323 leukocyte cell count, 323 protein concentration, 208, 323 CFP10 antigens, 1158 Chemical quarantine, 487 Chemoprophylaxis, 502, 507–509 primary, 508 secondary, 508 selective secondary, 508 systematic mass secondary, 508 tertiary, 509 Chemotherapy, 8–10, 12, 314, 732, 736, 748 anti-tuberculosis, 504, 506 expanded use of, 487–488 impact of, 485–486 long-course, 491 multiple-drug, 490 preventive, 757, 762 short-course, 7, 491, 719, 723, 736–737, 748 standard, 492, 658 Chest radiograph, 158–159, 267, 318, 325, 800 abnormal, 805 examination, 732 presence of cavitation on, 933 Childhood tuberculosis epidemiology, 309–314 general characteristics of, 308–309 pathogenesis of, 314–315 timetable of, 314–315 trends of, 309 in the United States, 310–311 Chromosomal aberration, 50, 1140 Chronic obstructive pulmonary diseases (COPD), 1060

Index Chronic primary tuberculosis, 319–320, 324, 478 Chronic respiratory diseases (CRDs), 1077, 1080 monitoring and information system, 1076 Cluster epidemics, 757 Cluster investigations, reflects of, 640 CMI. See Cell-mediated immunity Cohan’s model, for bacterial speciation, 56 Cohort analyses, 849 Cold abscesses, 30 Collaborative tuberculosis/HIV activities, categories of, 1229 Collagen, 950 Collapsotherapy methods, 459 Community-level studies, 633–635 genotyping databases of, 641–642 laboratory cross-contamination of, 635–636 limitations of, 637–638 tuberculosis control, 638 Computerized axial tomography (CAT) scans, 442 Computer simulation models, 1217 Condensation reaction, 49 Congenital tuberculosis, manifestations of, 313 Contact investigations, fundamental aspects of, 772 Contact tracing active screening of, 570–571 for case/suspect, 559 characteristics, 557 concentric circle approach to, 566 decision-making process in, 559 diagnosis-related factors of, 571–572 epidemiologic factors of, 569 expansion of, 566 factors influencing, 558 field investigation, 563 in high-prevalence countries, 568–574 in low-prevalence countries, 563 medical evaluation of, 557, 564 methodologic factors, 570–571 patient characteristics in, 561

Index [Contact tracing] patient interview in, 564 place factors of, 560 prioritization process, 566 program guidelines of, 573–574 transmission risk assessment in, 560 treatment-related factors of, 572–573 Corticosteroids, 204 steroids, 391 therapy, 208 treatment, 205–206 Corynebacterium glutamicum, 49 Cotrimoxazole (CTX), 970 preventive therapy, 13, 403, 976 role of, 122 use of, 970 Cross-resistance, 419 Cross-site analysis, 989 Culture-dependent techniques, 838–839 Culture isolation method, 33 Culture-negative pulmonary tuberculosis, 160 Culture-positive patients, 836 Cycloserine, 332 Cytokine g-interferon, 444 Cytokines, prodution of, 123 Cytoplasmic adapter protein myeloid, 123 Cytotoxic effector cells, 125 Cytotoxicity, 130 Cytotoxic T-lymphocyte, 124

Danish vaccine, 544 Delayed-type hypersensitivity (DTH), 108 Dendritic cells, 106, 123–124 Developing Countries Project (DCPP), 666 Dexamethasone, 208 Diagnostic decision point, 1181 Diamines, 1144 Diarylquinolines, 209, 1141–1142 Diphtheria, 922 Directly observed therapy (DOT), 333, 564, 655, 860 community health agents involved in, 1052

I-5 [Directly observed therapy (DOT)] community-based, 598, 606 principles of, 762, 1057 in private nursing home, 997 Direct procurement service line, 708, 712, 714 Disease-endemic countries (DEC), 521, 524 DNA fragments of, 616 microarrays studies of, 123 synthesis of, 129, 1244 DNA/DNA hybridization, 47 DNA fingerprinting (genotyping), 376, 573, 757 application of, 376 Donor awareness, need for, 1052–1053 Dormancy and latency in tuberculosis, 1208 DOT. See Directly observed therapy DOTS, 1–12, 486–487, 592, 725 application of, 724 case detection rate in, 10–11 community-based, 599, 605 community factors, impact on, 1198 control strategy, 1046, 1115 coverage, 1048 activities, 932 constraints to, 721 in Europe, 73 diagnostic strategy, 1116 effect of, 13 enhanced, 13–14, 18 evolution of, 1005 expansion, 19–20 franchising, 990 implementation of, 511–517, 720, 722, 725, 916, 988 pilot, projects, 736, 739 principles of, 1187 in prisons, 922 programs, 706, 1118 public–private partnership for, 986, 1000 strategy, 686, 690, 773, 775, 832, 838 nursing role, 584–585

I-6 [DOTS] success of, 724–726 sustained, 13 DOTS expansion plan, 737 DOTS Expansion Working Group (DEWG), 711, 721, 833 DOTS-plus, 514 Double negative T-cells, 121 Droplet nuclei, 118 Drug(s), 309, 1171 acidic, 359 antituberculous, 332, 359 clinical trials of, 333 discovery of, 319 pharmacokinetics of, 329 use of, 332 combination, 360 development process, 1138–1139 distribution, 611, 706 emerging of, 1139 formulation and packaging, 610 injectable, 437 management, 706, 723 metabolites, 958 regimens, 610, 668 second-line, 838 therapy, 309 toxicity, 358–361 Drug–drug interaction, 191, 1141, 1144 Drug-induced, hepatitis, 773 Drug resistance, 5, 38–40, 388, 631, 709, 735, 953 BACTEC-460 method, 40–41 basic mechanisms of, 418–419 detection of, 38, 838, 1128 development of, 418, 968 epidemiological indicators on, 751 evolution and transmission of, 422–424 rapid detection of, 934 risk factors of, 834 trends of, 828–829 on tuberculosis control, 421 Drug resistance rates, to specific drugs, 827–828 Drug Resistance Surveillance (DRS), 762, 832–834, 852

Index Drug resistant tuberculosis, 334, 847 definition of, 847 development of, 292 epidemiology of, 851–855 etiology of, 850 and HIV, 422 management of, 514–517, 769 program implications of, 850 regimens for, 423–424 survey of, 835 transmission of, 1117 Drug-resistant mutants, 1142 Drug-resistant organisms, 70, 184, 194 Drug-resistant strains, 802, 816 transmission of, 802 Drug-sensitivity testing, 1233 Drug-susceptibility testing (DST), 34, 39, 527, 825, 1116 Drug users, intravenous, 372 Drugs, antituberculosis. See Antituberculosis drugs DST. See Drug-susceptibility testing Dust control, 941

Economic impact of tuberculosis at household level, 655–657 at national level, 654–655 Effector T-cells, 122, 124 Empyemectomy, 474 Endemic tuberculosis, control of, 8 Endobronchial tuberculosis, 206, 314 Endogenous bacterial replication, 119 Endosomal autoantigen 1 (EEA1), 105 Enhanced Mycobacterium tuberculosis direct (E-MTD), 384 Environmental factors for tuberculosis, 90 Enzyme-linked immunosorbent assays (ELISA), 328 Enzyme-linked immunospot (ELISPOT) assay, 245, 385 Enzymes, hepatic microsomal, 191 Epithelial barrier, alveolar, 132–133 Epithelial-endothelial barriers, 133 Epithelioid morphology, 108 Epituberculosis, 316 ESAT6 antigens, 1158

Index Escherichia coli, 1213 Ethambutol (EMB), 330, 332 Ethambutol-resistant strains, effect of, 192 Expanded Program on Immunization (EPI), BCG inclusion in, 542 External quality assurance (EQA), 522 rechecking, 534 Extracellular bacterial replication, 131 Extrapulmonary tuberculosis, 185, 196, 205–209

False-negative (FN) smears, 536 False-negative tuberculin tests, causes of, 222 False-positive (FP) smears, 536 FASTPlaque-TB1, 424 Fatal acute hepatitis, 362–363 Fibrotic lesions, 267 Fibrotic lung diseases, 949 Fibrotic tuberculosis, cases of, 465 Fixed-dose combination (FDC) tablets, 707, 709, 1235 Fluorochrome stain, 382 Fluoroquinolones, 194, 332, 873, 1142, 1147–1148 Foundation for Innovative New Diagnostics (FIND), 1119 Fuchsine powder, 529

Gamma interferon (IFN-g) production, 811 Gastric aspiration, 327 Gastrointestinal absorption, 850 Gene-dosage effect, 50 Genetics of tuberculosis cluster, 58 factors of, 75 homogeneity, 57 susceptibility, 90 typing, 30–31 Gene transfer, 55 Genitourinary tuberculosis, 207 Genome sequencing, 48 Genomic deletion analysis, 52 Genomic fragments, 59

I-7 Genomic relatedness, high level of, 47 Genotoxic potential, 1140 Global drug facility (GDF), 694, 705, 720, 1230 achievements of, 708–711, 713 aims of, 706, 709 history of, 706 operating mechanisms of, 707 patient kits, 707, 709 Global Fund for AIDS, Tuberculosis, and Malaria (GFATM), 689, 712, 1042 Global Plan to Stop Tuberculosis (GPSTB), 18–20, 689 Glycerin-extracted tuberculin, 489 Glycine dehydrogenase production, 1208 Gold-mining industry, 950 Good clinical practice (GCP), 1213 Good manufacturing practices (GMP), 708 Government health service, limitations of, 600 Gram-negative bacteria, 1140 Gram-positive aerobic bacteria, 1145 Gram stain, 328 Granulocyte macrophage, 125 Granuloma formation, 108 Granulomatous infectious diseases, 135 Granulomatous tissue reactions, 120, 128, 133, 138 Green Light Committee (GLC) mechanism process, 856, 1230 Guanylnucleoside triphosphate (GTP), 105

H37Rv genome, 48 Health care system and tuberculosis, 492, 1061, 1126 diagnostic needs at, 1121–1122 Health management information system (HMIS), 1064 Helicobacter pylori, 1140 Hemodialysis, 204 Hemolytic anemia, 191 Hemoptysis, 156

I-8 Hepatic microsomal enzymes, 191 Hepatic necrosis, 358, 360, 362–364 Hepatic toxicity, 1137 Hepatitis, 190 alcoholic, 204 drug-induced, 773 fatal acute, 362–365 Hepatotoxic antituberculosis drugs, 204, 282 Hepatotoxicity, 279–288, 352, 359, 364 High-efficiency particulate air (HEPA) filters, 807, 808 High-Level Working Group (HLWG), 738–739 Highly active antiretroviral therapy (HAART), 372, 392, 400, 1191–1193 High-resolution computed tomographic (HRCT) scanning, 365 Hilar adenopathy, 311, 316–318 HIV. See Human immunodeficiency virus Human immunodeficiency virus (HIV), 65, 309, 356, 357, 722, 922, 1060 coinfection with, 742, 1218 epidemiological studies in, 224 false-negative reactions, cause of, 221–223 HAART in, 1193 infection, 751, 768, 883 prevention methods in tuberculosis, 958–959, 969 rifampicin resistance in, 1145 studies in, 267–275 testing, 777, 970, 974–976 with tuberculosis, 1116, 1137 HIV–tuberculosis, 334–335, 780 in children, 312–314 coinfection, 1174 Human leukocyte antigen, 127 Human lung tissue, 123, 132 Human monocytic cell, 137 Human pathogens, 52, 57 Human resource (HR), tuberculosis control targets, 1042, 1056 Humoral immunity, 106, 126–127

Index Hybridization, in situ, 128 Hydrazine, 359–360 Hydroxymycolate, oxidation of, 1140 Hydroxymycolic acid, resultant accumulation of, 1140 Hypercalcemia, 156 Hypersensitivity reactions, 194 to thioacetazone, 971 Hyperuricemia, 194 Hyponatremia, 156

Immune activation, systemic, 120 Immune mechanisms, studies of, 128 Immune modulation, 444 Immune reconstitution inflammatory syndrome (IRIS), 135, 206, 391, 1193, 1194 Immunity, 106, 109, 126–127 Immunobiology of tuberculosis, 1095, 1206–1207 Immunocompetent hosts, studies in, 266–267 Immunomodulators, uses of, 1192 Immunopathogenesis and vaccine studies, 1174, 1206 Immunosuppression of tuberculosis, 120 agents of, 109 condition of, 291 degree of, 952 Infection bacterial and parasitic, 976 with human immunodeficiency virus, 356–357, 722 Inflammatory cells, 138, 216 Inflammatory infiltration, 110 Inflammatory mediators, 120 Integrated management of adolescent and adult illness (IMAI) guidelines, 1065, 1193 Inter-Agency Coordination Committees (ICC), 721 Intercellular adhesion molecule, 121 Interferon-gamma (IFN-g), 375, 1163 transcription, 349 Interferon-gamma release assays (IGRAs), 243–248, 1128, 1209

Index International Committee of Red Cross (ICRC), 930, 940 International Labour Organization (ILO), 950–951 International Organization for Migration (IOM), 871 International Union against Tuberculosis (IUAT), 266–267 International Union against Tuberculosis and Lung Disease (IUATLD) model, 435, 735, 747, 796, 1187 Intradermal injection, 217–218, 237 Intrapulmonary silica, residual, 950 Intravenous drug users, 372–375, 379 IS6110 bands, 618, 641 Isoniazid (INH) chemotherapy, 572 discovery of, 485–486 hepatotoxicity, 364 metabolite testing, 281 resistant organisms, 291 therapy, 266 toxic effects of, 331 Isoniazid-associated liver injury, history of, 291 Isoniazid preventive therapy (IPT), 7, 959, 975 Isothermal amplification methods, 1127

Jacobus PASER1, 445 Joint Learning Initiative (JLI), 1044 recommendations for health workforce, 1053

Kanamycin, 419 Klebsiella pneumoniae, 319 Koch’s lymph, 489

Langhans giant cells, 133 Latent tuberculosis infection (LTBI), 166, 555, 881 aspects of, 32 blood tests for detection, 575–576 diagnostic test, 1118

I-9 [Latent tuberculosis infection (LTBI)] ELISPOT test, 576 in pregnant women, 291 screening for, 890–893 treatment of, 190, 265, 291, 372, 396, 563–564, 894, 940, 943 efficacy of, 266–279 recommendations for, 288–292 safety and tolerability of, 279–286 See Chemoprophylaxis Lo¨wenstein–Jensen (LJ) process, 1118 Lipid enzymes, 49 metabolism, 48 in the pathogenesis of M. tuberculosis, 55–56 synthesis, 1140 Lipoarabinomannan (LAM), 106, 126, 169 binding to DC-SIGN, 108 Lipopolysaccharide (LPS), 126 induced DC maturation, 137 Liquid media systems, 35, 40 Listeriolysin, 1158, 1213 Liver disease, 190, 204 Liver function tests, 288 Long-course chemotherapy, 491 Lot quality assurance system (LQAS) method, 536 limitations of, 536–537 Low-and middle-income countries (LMIC), 1042, 1052 Lung damage, residual, 205 decortication, 473–474 granuloma, 128 immunity in tuberculosis, 127 studies, 127–133 resection of, 466, 468–469 as site for reactivation tuberculosis, 119 tissue, 1208 Lymphadenectomy, 478–479 Lymphadenopathy, 202 Lymphangitis, 221 Lymphatic tuberculosis, 206

I-10 Lymphocyte chemotactic activity, 130 Lymphoid organs, 122 Lysosomal bactericidal mechanisms, 137

Macroeconomic conditions and tuberculosis, 1099 Macrolides, 1143–1144 Macrophages and monocytes, 122–123 receptors, 104–105 Man-made drug-resistant infection, 493 Mantoux test, 325–326, 626, 732 Mathematical modeling, 13, 810 MDR-tuberculosis. See Multidrug resistant-tuberculosis Measles, 922 vaccination, 504 Mediastinal adenopathy, 158 Mediastinal lymph nodes, enlargement of, 158 Medication ingestion, observation of, 196 Meningeal inflammation, 192, 207 Meningitis, 322–323 childhood, 6 Metabolites, toxic, 359–360 MGIT1, 424 Microepidemics, resurgence of, 490 Microepidemiologic variations of tuberculosis, 1218 Microirrigator. See Catheter, drainage Migrants, tuberculosis control in, 871 Millennium Development Goals (MDGs), 686, 1042, 1098, 1171, 1228 public–private mix for DOTS and, 1001–1002 for tuberculosis, 690, 1185 Miliary tuberculosis, clinical manifestations of, 322 Minimum inhibitory concentration (MIC), 39 for BM212, 1143 against M. tuberculosis, 1144 of PA-824, 1139 MIRU–VNTR patterns, 631

Index Molecular epidemiology tuberculosis, 615, 636–637 genotyping techniques, 618–622, 630, 632 in suspected outbreaks, 631, 633 Molecular genotyping techniques of tuberculosis, 1218 Monitoring and evaluation (M&E) processes, 1043 Monitoring of tuberculosis biochemical, 281, 285 silicosis prevalence, 958 of treatment response, 442 Monoacetylhydrazine, plasma half-life of, 359 Monocytes and macrophages, 122–123 Monocyte/macrophage lineage, 106 Monoresistance, 848 definition of, 418 rifampicin, 862 Monoresistant disease, 835 Morbidity of tuberculosis, 951–952 Mortality of tuberculosis, 354–356, 950–951 Moxifloxacin, 194, 209, 781 MPB64, antigenic protein, 546 Mucopurulent sputum, 119 Multiantigen tests, 171 Multidrug resistance (MDR), 882 cases, 827–829 community-based program, 794 DOTS-plus strategy for, 1115–1117 rates of, 202, 829–830 Multidrug resistant-tuberculosis (MDR-tuberculosis), 5, 39, 386, 418, 633, 721, 1228, 1235–1236 case detection and diagnosis, 862 control of, 1118 control programs, 846–847 diagnosis of, 424–427, 859–860, 862, 1182–1184 emerging issues in, 861–863 epidemiology of, 824, 851–855 global response to, 855–858 infection control policies and practices, 864

Index [Multidrug resistant-tuberculosis (MDR-tuberculosis)] magnitude of, 829–832 management of, 739 patients, 739–740, 837 prevalence of, 830–831 strains, 573, 420 surgery in, 443–444 treatment, 427–445 in United Kingdom, 830 Multifunctional FadA/FadB proteins, 48 Multinucleated giant cells, 108 Multiorganism-infected patients, treatment needs of, 1193 Multiple-drug chemotherapy, 490 effectiveness of, 184 Multipuncture tests, results of, 217 Mumbai District Tuberculosis Control Society (MDTCS), 1016 Murine model, 124 studies of, 127 Mycobacteriaceae, 29 Mycobacterial antigens, 121, 168, 243, 1127 Mycobacterial culture, 1116, 1125 Mycobacterial growth, 122 microscopic observation of, 1126 Mycobacterial immunity, 1209 Mycobacterial infection, 122, 123, 136 Mycobacterial interspersed repetitive units (MIRUs), 54 Mycobacterial isolation, 34 Mycobacterial latency, 1209 Mycobacterial phagosome, 105 Mycobacterial proteins, 1127 Mycobacterial reactivation, 1207 Mycobacterial resistance, genetic mechanism of, 193 Mycobacterial survival, 105 Mycobacterial tests, 166 Mycobacterial vaccines, live, 1155 Mycobacteriology, 1180 Mycobacteriophages, 1127 Mycobacterium africanum– Mycobacterium bovis lineage, 51 Mycobacterium avium, 202, 380 intracellular, 157

I-11 Mycobacterium avium-intracellular infections, 332 Mycobacterium bovis, 124, 394, 489, 541–542, 1155 Mycobacterium caprae, 51 Mycobacterium microti, 47, 53 Mycobacterium microti. See also Vole Bacille vaccine Mycobacterium prototuberculosis, 57 Mycobacterium smegmatis, 1177 Mycobacterium tuberculosis, 2, 66, 101, 117, 215, 750, 768, 859, 884, 1117, 1169 animal infection models, 1146 Ag85A (MVA85A), 1157 ancient strains of, 631 antigens, 1158 antigen–specific memory T-cells, 122 auxotrophic mutants of, 1155 and BCG, 1155 biology of, 48 cause of human tuberculosis, 101 classification of, 642 common features of, 30 complex of, 29, 51 databases of, 641 drug resistant, 824 exposed host factors for, 802 founder strain of, 633 genotyping of, 618 granulomatous, 134 groups of, 29–30 growth, 124 hematogenous dissemination of, 119 history of, 118–120 host immune evasion mechanisms, 137 immunity, 122, 131 study of, 117 in vitro models in, 110 infection, 103, 120–121, 131–132, 1136 Kiel strain of, 631 laboratory detection of, 636 liparabinomannan (LAM), 126 mycobacterial species of, 1140

I-12 [Mycobacterium tuberculosis] opsonization of, 104 organism factors for, 802 polymorphism of, 55 population structure of, 55 progenitor of, 57 resistant strains, 1136 restriction fragment length polymorphism (RFLP) of, 624 source factors for, 802 strains of, 1117 survival mechanisms of, 112 Mycobacterium tuberculosis direct (MTD), 166 Mycobacterium vaccae, 136, 1161

N95 respirators, 810 National AIDS Control Programs (NACPs), 969, 972 National Health Accounts (NHA), 654 National Reference Laboratory (NRL), 525–526 National regulatory agencies (NRAs), 1222 National Tuberculosis Leprosy Program (NTLP), 950 National Tuberculosis Program (NTP), 523–525, 556, 664, 1011, 1083, 1227 National Working Group (NWG) on PAL, 1070 role of, 1106–1070 Natural killer cells, 125 Necrotic lymph nodes, removal of caseous, 479 Negative predictive value (NPV), 161 Neisseria meningitidis, 54 Nephrectomy, 207 Nephrotoxicity, 193 New York City Department of Health and Mental Hygiene (DOHMH), 1018–1019 Nitroimidazo-oxazines, discovery of, 1139 Nitroimidazoles, 1139 Nonpeptide phosphoantigens, 125 Nonreplicating persistence (NRP), 31

Index Nonsteroidal anti-inflammatory agents, treatment with, 202 Nontuberculosis diagnostic tests, 167 Nontuberculous bacterial infections, 971 Nontuberculous mycobacteria (NTM), 29, 67, 157, 217, 225, 544 disease, 949, 1209 geographic distribution of, 90 NTM. See Nontuberculous mycobacteria NTP. See National Tuberculosis Program Nucleic acid, 806 Nucleic acid amplification (NAA), 155 role of, 384 testing, 383–384, 558, 1116 uses of, 328 Nucleoside reverse transcriptases (NRTIs), 389 Nurse’s role as administrator, 593 as coordinator, 592 as educator, 586 as leader and advocate, 594

O2 gradient, self-generated, 1208 Ofloxacin (OFL), 837 Oleate-albumin-dextrosecatalase (OADC), 35 Oligodeoxynucleotides and polycationic amino acids, mixture of, 1213 Oligonucleotide probes, 627 Open scissor phenomenon, 523 Opportunistic infections, 1194 Optimal diagnostic algorithm, 1182 Oral bioavailability, 1144 Orcein stain, 363, 364 Organelle biogenesis, 137 Ototoxicity, 193 Oxazolidinones, 1145

P450 cytochromes (CYP450), 389 Para-amino salicylic acid (PAS), 184, 194, 485, 845 Parallel drug-resistant tuberculosis epidemic, 934 Parasitic infections, 971, 976

Index Paratracheal lymphadenopathy, 158 Parenchymal focus, 206 Parenchymal scars, 119 Partners in Health (PIH), 847 Pasteur BCG vaccine, 546–547 Pathogenesis, 120 Pathogens biology of, 119 human, 57 process, 101 virulent, 377 Patient management assessment step, 589 evaluation, 590 implementation, 590 planning, 590 progress recording and reporting for, 593 Patients sputum-smear negative, 800 sputum-smear positive, 723, 761, 838, 1128 Paucibacillary pulmonary tuberculosis, 1117 PCR. See Polymerase chain reaction Pediatric pharmacokinetics, 1193, 1220 Pediatric tuberculosis infection, 1220–1221 Peptidoglycan, 131, 137 Pericardial tuberculosis, 208 Pericardiectomy, 209 Pericarditis, 321 Peripheral neuropathy, 190, 1137 Personal respiratory protection (PRP), 809, 815 types of, 809, 810 Petroff decontamination/ homogenization technique, 530 Phagocytic host cells, 137 Phagocytosis, 132 molecular interactions to, 104 Phagosome–lysosome fusion, 104 Phagosome maturation, 105, 106 Phenolic glycolipid (PGL), synthesis of, 55 Phenotypes, 55 characterization of, 637 Phosphatidylinositol (PI), 105

I-13 Phosphatidylinositol-3-phosphate (PI3P), 105 Phospholipase encoding genes, 50 Phylogenetic lineages, 51, 55 Pleural effusion cells, 129 Pleural fluid cells, 129 Pleural tuberculosis, 206 Pleurectomy, 473–474 Pleuropneumonectomy, 474 Pneumoconiosis, types of, 949 Pneumocystis jiroveci pneumonia (PCP), 377 Pneumolysis, extrapleural, 461 Pneumonectomy, 461, 468–469 Pneumothorax, 460, 479 Polymerase chain reaction (PCR), 31, 627, 630 Polymorphonuclear cells, 323 Polyresistance, 848 Polysaccharide antigen, 169 Populations, foreign-and native-born tuberculosis among, 874, 878–884, 891 Positive predictive value (PPV), 161 Positive tuberculin reactions, 221, 227 skin, 266, 975 Post-tuberculosis stenosis, 475 Post-tuberculous lung disease, 952 Poverty Reduction Strategy Papers (PRSPs), 1106 Powered air-purifying respirator (PAPR) hood, 809 Practical Approach to Lung Health (PAL) strategy, 1059, 1193, 1238 adaptation of, 1066–1067 aims of, 1059 components of, 1065–1066 district health system management, 1079 drug prescription, 1076 guidelines, 1072 health education, 1066 implementation plan, 1067, 1073 National Working Group (NWG) on, 1070 objectives of, 1064–1065 perspectives of, 1078–1079 preliminary results of, 1075–1078

I-14 [Practical Approach to Lung Health (PAL) strategy] promotion of, 1067–1070 quality of life improvement, 1076 respiratory care services, 1078–1079 respiratory case management, 1075 stepwise process, 1067 test phases in, 1072–1073, 1074 training material for, 1072 Prechemotherapy era, 308 Pregnancy and breast-feeding, 203, 286, 291, 315 Prevalence surveys, national, 1203 Preventive therapy, 750, 959 community-wide, 959–960 effect of, 277 guidelines, 279 in HIV-infected patients, 278 intervention, 959 programs, 294 See also Chemoprophylaxis Primary health care (PHC), 1051, 1059 consultations, 1054 integration of respiratory case management in, 1111 Primary preventive therapy, 959 Primary tuberculosis, 118 in children, 314 Prison-civilian planning activities, 933 Prison DOTS program, implementation of, 933 Prison-population density, 934 Prisoner–prisoner control, 932 Private sector involvement, DOTS services, 988, 990 Progressive primary tuberculosis, 119 Proinflammatory cytokines, 55, 131 synthesis of, 123 Prophylaxis, post treatment, 509 Protective cytokines, 121 Protective immunity, 137, 1193 Protein binding, 359 Protein–peptidoglycan complex, 129 Protein synthesis, 1143 Psychosocial stress, 91 Public–private mix (PPM), 990–994

Index Public–private mix (PPM)-DOTS model, 989–994 policy, 986 strategies, 1230 Pulmonary disease, 333 chronic, 319–320 infectious, 1216 progressive, 319 with respiratory failure, 205 Pulmonary hemorrhage, 479 Pulmonary resection, 461, 468 Pulmonary segment, healing of, 318 Pulmonary tuberculosis, 6, 13, 156, 521, 726 adjunctive treatments, 204 diagnosis of, 166, 1115 indications for surgery of, 462–467 surgical methods for, 459–462, 476 Purified protein derivative(PPD), 125, 352, 380, 564 Pyogenic bacterial infection, 207 Pyogenic pneumonia, 386 Pyrazinamide (PZA), 36, 193, 266, 330, 773 addition of, 185 mechanism of, 193 role in, 331 sterilizing effects of, 491 Pyrazinamide-susceptibility testing, 426 Pyrroles, 1142–1143 PZA. See Pyrazinamide

Quality-assured tuberculosis sputum microscopy, 969 QuantiFERON1, 384 Quantiferon gold, 551 Quantiferon-tuberculosis, sensitivity of, 245 Quantiferon-TB1 test (QFT), 575 Quantiferon-TB1 test (QFT)-gold, 576 Quantitative bioinformatic approach, 1218 Quarantine chemical, 487 laws, 487 Quinolones, 837 See also Fluoroquinolones

Index Radiographic presentation post-tuberculous lung, 952 progressive disease, 958 of tuberculosis, 160, 199 Radiological screening, frequency of, 958 Radiosensitizing drugs, 1139 Reactivation pulmonary tuberculosis, 158 Reactivation tuberculosis, 119 Reactive nitrogen intermediates (RNI), 122 Receptor deficiencies, 122 Receptor–mediated phagocytosis, 104 Recrudescent disease, 954 Recurrent tuberculosis disease, study of, 956 Regulatory immune mechanisms, 125 Regulatory T-cells, 125 Research capacity strengthening (RCS), 1213 Resistance, mechanisms of, 418 Resistance mutations, frequency of, 209 Resistant organisms, in chronic excretor, 922 Respiratory distress syndrome, 158 Respiratory epithelial cells, 104, 122, 133 Respiratory failure, 950 Respiratory isolation, 804 Respiratory symptomatics (RS), investigation of, 935 Respiratory tract, cancer of, 1060 Restriction fragment length polymorphism (RFLP), 376, 615 application of, 30 IS6110-based on, 618 limitation of, 627 Revised National Tuberculosis Control Program (RNTCP), 1016, 1053 Rheumatoid arthritis, 135 Rib cage, 469 Ribosomal protein, synthesis of, 193 RIF. See Rifampicin Rifabutin, 191 Rifampicin, 266, 331, 755, 759 absorption of, 191 bactericidal activity of, 491

I-15 [Rifampicin] monoresistance, 862 multidurg resistance(MDR), 200 prophylaxis failure, 287 and pyrazinamide, 281 resistance, 202, 1128 Rifamycins, 389, 1139 long-acting, 1145–1146 monoresistance, 202 Rifapentine, 781 RNA polymerase, 111 Roll Back Malaria (RBM) program, 1042

Salmonella enteritica, 57 Salmonella typhimurium, 971 Sanatoria, 485 SCC. See Short-course chemotherapy Scientific Working Group (SWG), 1171 Secondary preventive therapy, 959 Secondary transmission, 267 Second-line drugs (SLDs), 846 Self-generated O2 gradient, 1208 Self-reactive T-cells, 126 Serial tuberculin testing, 237, 242 Serodiagnostic tests, 168, 1127 Serum aminotransferases, 288 Serum drug concentrations, monitoring of, 202 Severe acute respiratory syndrome (SARS), 922 Sexually transmitted infection (STI), syndromic management of, 923, 958 Short-course chemotherapy (SCC), 421, 491, 661, 662 amplifier effect of, 870 drug adherence of, 1210 implementation of, 824 standard short course chemotherapy, 661 Shrink intrathoracic nodes, 206 Sigma factor, 111 Signal–transmitting receptors, 128 Silica dust environment, 513 toxicity of, 957

I-16 Silicone plombage, use of extrapleural, 476 Silicosis, 949 chronic, 950 radiologically detectable, 951 Silicotuberculosis, 950, 952 Simultaneous mutations, probability of, 850 Single nucleotide polymorphisms (SNPs), 51 Skeletal tuberculosis, 207, 324 Skin test, tuberculin, 308, 313 Smear-based diagnosis, use of, 637 Smear conversion rate, 916 Smear microscopy examinations, 763 Smear-negative tuberculosis, 8, 494, 502, 657, 1117, 1171, 1202 diagnostic algorithms for, 1116 detection, 12 notification rate for new case, 1007 treatment for, 8, 10 Smear-positive pulmonary tuberculosis, 10, 556, 670, 718, 737, 1228 incidence of, 494, 502 Smear-positive specimens, 839 Smears and culture, 327–328 false-negative (FN), 536 false-positive (FP), 536 Social mobilization, 1198 definition of, 1032 strategic actions for, 1033 White Flag Strategy in Mexico, 1035 Spacer-oligo typing, 627 Specific tuberculosis-control strategies, 507 Specimen testing, 167 Spinal tuberculosis, 207 Spoligotype matches, 627 pattern generation, 627 applications of, 635 Spoligotype membranes, with spacers, 627 Sputum AFB smear microscopy, 1116

Index Sputum-based diagnosis, 988 Sputum-culture conversion, 1145 Sputum culture, sensitivity of, 159 Sputum digestion methods, 1126 Sputum, mucopurulent, 119 Sputum-positive tuberculosis cases, 832 Sputum production, induced, 327 Sputum samples, 719 Sputum-smear microscopy, 7, 519, 758, 772, 991, 1216 definition of, 1177 examinations per tuberculosis suspect, 538 external quality assurance (EQA) of, 535 optimization of, 1182 quality controls (QCs) of, 534 sensitivity of, 1182 in diagnosis, 534 Sputum smears, 327 Stains fluorochrome, 382 gram, 328 Standardized treatment regimens, 668, 709 Standard operating procedures (SOP), 526 Staphylococcus aureus, 319 Stenosis, bronchial, 159 Stop Tuberculosis Partnership, 1036, 1043 advocacy and communication activities for, 689 benefits and costs of, 698 framework of, 691 goals, 698 main strategic areas for, 691 structure and achievements of, 693 values of, 692 Stop TB Strategy, 510, 1107, 1228 adapting innovations from other fields, 1238 challenges and opportunities of, 1228–1230 DOTS strategy, 1232 financing for, 1243 goals and targets of, 1230

Index [Stop TB Strategy] implementation approaches, 1229 management system for, 1234 monitoring and evaluation system for, 1235 objectives of, 1229 on poverty alleviation, 1109 program-based operational research for, 1240 Strain variability, 802 Strategic Initiative for Developing Capacity in Ethical Review (SIDCER), 1222 Streptomyces erythreus, 1143 Streptomyces mediterranei, 1184 Streptomycin (S), 184, 331, 333 Streptomycin-resistant tuberculosis, 1136 Subgroup on Laboratory Capacity Strengthening (SLCS), goal of, 833 Subunit vaccines Ag85B/ESAT6 fusion protein, 1158 adjuvanted proteins, 1160 antigens expressed in vivo, 1159 antigens recognized by natural immune response, 1159 selection of candidate antigens, 1159 Sulfadoxine-pyrimethamine, 970 Superoxide dismutase (SOD), 1158 Supranational Tuberculosis Reference Laboratory (SRL) network, 852 Synonymous nucleotide variation, 57, 58 Synovectomy, 207 Systemic immune activation, 120

Tandem repeats, different number of, 629 Tantalum staples, 468 T-cell(s), 120, 1158 activation, 108 antigen-reactive, 126 antigen-specific, 108 based assays, 384 double negative, 121 effector, 122, 124

I-17 [T-cell(s)] function, 127 gamma interferon assays, 1221 regulatory, 125–126 self reactive, 126 Technical Review Committee (TRC), 707 Tension pneumothorax, 463 Th2 inhibitory effect, 1192 Therapeutic drug, measurements of, 202 Thioacetazone, 185, 388, 433, 971 Thiophen-2-carboxylic acid hydrazide (TCH), 53 Thoracoplasty, 461, 469–470 extrapleural, 460 Thoracostomy, 206, 474 Threshold limit value (TLV), 808 Thrombocytopenia, 191 Thromboembolic disease, 365 TICE BCG, 547 Tissue distribution, 1142 Toman’s predictions of tuberculosis, 491 Toxic metabolites, 359–360 Toxicity, 388 hepatic, 1137 silica, 950 Transcriptional regulator, 111 Transmission, airborne, 801 Transthoracic injection, 109 Treatment, cost-effectiveness and costbenefit of, 294 of endemic tuberculosis, 668 of epidemic tuberculosis, 669 Treatment of Latent Tuberculosis Infection (TLTI), 7, 660, 1137 See also Latent Tuberculosis Infection (LTBI) Treatment regimens, current, 196–201 T-regulatory cells, 122 Tubercle bacilli, 29, 484, 1127 evolution of, 47 transmission of, 504 Tuberculin hypersensitivity development, 316 injection, 156, 237 protein, 216 survey, 1007 testing, 71, 219, 757

I-18 Tuberculin-negative contacts, 489 Tuberculin-negative population, 508 Tuberculin-positive population, 286, 508 Tuberculin reaction, 216 initial, 238 Mantoux interpretation of, 326 Tuberculin skin test (TST), 325–327, 884 of child, 326–327 to control tuberculosis, 488 conversion, 291 history of, 215 interpretation of, 230 negative, 565 positive, 6, 373, 563 technical aspects of, 216–221 Tuberculin test results, Mantoux and Heaf tests, 220 Tuberculoma, 323, 462 Tuberculosis (TB) abdominal, 324 access to care, 881 in adolescents, 324 age at migration, 879 and AIDS Programs, 968 antigens, 169, 243 asymptomatic, 316 bacteriological diagnosis of, 32–33 culture isolation method for, 33 smear examination method for, 33 bone and joint, 207 cardiac, 321 cavitary, 109, 462 childhood. See Childhood tuberculosis chronic, 18 clinical features of, 380 clinical management of, 1184 clinical measures of, 1188 congenital infection, 313, 324 contact tracing activities, 574 controlling of, 958, 1005 control programs of, 909 country of origin, 878 Croftonians treating concept, 491 detection of, 1121 in developing countries, 491 diagnosis, 155, 378 in PHC settings, 1061

Index [Tuberculosis (TB)] [diagnosis] of serologic, 328–329 and treatment, 771 diagnostic algorithms, 1174 diagnostic tests for, 1115 disease localization, 881 drug resistance, 882–883 drug resistant, 334, 769, 1236 elimination of, 502, 516, 1052 ELISPOT test to, 576 endemic, 8 endobronchial, 314 epidemiology of, 882 ethnic minority status, 1102–1103 extrapulmonary, 160, 205, 1121 in females, 1103 fibrotic, 465 foreign-born, 769, 870 genetic polymorphisms for, 76 Global Partnership to Stop, 720–721, 783 with HIV, 75, 392–393, 775, 1185–1186 identification of, 34 amplification procedures for, 38 conventional tests for, 35–36 high-performance liquid chromatography, 37 niacin test, 36 nitrate reduction test, 36 nucleic acid probes for, 37–39 pyrazinamidase test, 36 immune-compromising conditions, 884–885 immune incompetence, 883 immunodiagnosis of, 1209 incidence rate, 8, 877 indicators for monitoring, 1242 infection, 313–314 interventions for, 894 laboratory network of, high prevalence countries, 521–525 laboratory performance indicators, 534 legal aspects, 895 in low prevalence countries, 1010 lymphatic, 206

Index [Tuberculosis (TB)] macroepidemiology of, 1216 malnutrition and, 1104 median age of, 311 meningitis, 310, 323 metabolism in, pathogenesis of, 314 microbiological examinations of, 834 monitoring and evaluation of, 1109–1110 morbidity and mortality, 79, 490, 725, 732–733, 1177 multidrug-resistant, 91–92, 769 new drugs for, 209 operational research, 1200 pathogenesis of, 375–376 patient-centered model for, 588 paucibacillary pulmonary, 1117 pediatric, clinical forms of, 316–325 pleural effusions, 320–321 poverty, 657, 742–743, 1197 prevalence of, 1218 HIV infection, 374–375 preventive treatment of, 487–488 primary, 314 provider perspective for treatment costs, 659 pulmonary, 11, 316 smear negative, 494, 502, 1117 smear positive, 494, 502 research priorities for, 1169–1170, 1241 risk factor for, 750, 908 skeletal, 324 sociodemographic factors, 879 in sub-Saharan Africa (SSA), 1044 subunit vaccine, 1159–1160 surgical treatment of, 468–479 contraindications to, 467–468 surveillance of, 762–763 system immunity in, 127 time in new country, 880 Toman’s predictions of, 491 transmission, 311–312 from foreign-to native-born populations, 873 within immigrant groups, 885

I-19 [Tuberculosis (TB)] vaccine, 776, 1153 in United States, 768 Tuberculosis bacilli, 823 Tuberculosis bacteriology services, 521, 524 Tuberculosis care, 1012 community contribution to, 597, 603–607, 1240 definition of, 598 health education, 1023 international standards for, 1239 Mexico, 1030 as part of NTP activities, 602 patients charter for, 1240 Tuberculosis case management strategy, 513 effectiveness of, 504 fatality and mortality, impact on, 506–507 implementation of, 510 morbidity, impact on, 505–506 risk of infection, 504–505 Tuberculosis in children diagnosis of, 308, 325, 328–329 Tuberculosis clinics, 484–485 Tuberculosis contact tracing definition of, 556 DNA fingerprinting (genotyping) use in, 575 in high-prevalence countries, 556 in low-prevalence countries, 558 new technologies in, 574–576 objectives, 557–558 social network analysis to, 574 Tuberculosis control, 848, 854, 986, 1070, 779–780 aim of, 10, 493 analysis of, 782 central/national reference laboratory level of, 526 clinical audit for, 594 cohort analysis of, 594 community involvement in, 503, 597, 599–600, 1156 cornerstone of, 487 cost and cost-effectiveness of, 571, 659, 664

I-20 [Tuberculosis control] developing countries project, 666 DOTS approaches treatment to, 689–696 and drug management, 739 economic impact of, 650, 677 evaluation of, 524–525 Fox concept of, 487 global targets for, 674, 748 health education of, 590 human resource development, 531–532 intermediate level laboratories, 526–527 interventions, 807 laboratory network concept in, 522–523 market analysis of, 658 metropolitan, 1006, 1013–1020 molecular epidemiology in, 619–620 in Mumbai, 1016–1018 nurse’s role in, 558 peripheral level laboratories of, 527 poverty alleviation, 657 and prevention, 780–782 principles of, 718–720 in prisons, 740 private clinics and practitioners in, 513 program, 190, 484, 709 research projects of, 595 social mobilization in, 1032–1034, 1074 workforce constraints in, 1041–1042 Tuberculosis control strategies, 1027 categories of, 502 efficacy of, 1046 prevention of risk factors, 509–510 Tuberculosis diagnostics, 24 for developing countries, 1120 development obstacles, 1118–1120 improvements required, 1116–1120 priorities, 1120–1122 Tuberculosis drugs development, 1137–1139 Bill and Melinda Gates foundation, 1175 global alliance for, 1137–1139

Index [Tuberculosis drugs] [development] Rockefeller Foundation, 1138 for latent tuberculosis infection, 660 market size for, 659, 706 Tuberculosis in elderly clinical presentation of, 353–356 diagnosis of, 357–358 epidemiology of, 346–348 mortality of, 354–356 preventive therapy of, 361–362 treatment of, 358–361 Tuberculosis elimination, 749, 750, 757, 775, 882 definition of, 749 epidemiologic trends in, 774–775 goals and objectives, 777–778 in low-incidence areas, 776, 780 strategies, 750, 755 in United States, 775 Tuberculosis epidemics, 626, 639 dynamics of, 1217 factors of, 768–769 global, 2–6 migration and, 869 regional, 2–6 scale and dynamics of, 2–6 in United States, 768–769 Tuberculosis Genotyping Program, 770 Tuberculosis glycolipid (TBGL), 169, 171 Tuberculosis–HIV activities, 972–973 coinfection, 511, 1055 epidemics, 493, 741, 990, 1116 guidelines, 494 infection, 823 research program activities, 1222 Tuberculosis –HIV collaborative initiatives, 1022 Tuberculosis incidence rate, 3, 5, 8, 18, 749 Tuberculosis infection causes of, 84 control in health-care settings, 976 diagnosis of, 378–385 pathogenesis of, 1128 dosage of, 74

Index [Tuberculosis infection] duration exposure of, 69 dynamics of, 960 immunosuppression, 75 intensity exposure of, 68 latent, 361, 749 medical conditions for, 88 personal risk factors for, 68 preventive therapy, 750, 793 reinfection, 72 risk of, 66, 756 smoking and, 77 socioeconomic status, 70 Tuberculosis infection control, 797 guidelines for, 796 key components of, 804 implementation strategy, 813 inherent barriers to, 805 prevalence of, 794, 803–811 in prisons, 815–816 web-based, 798 Tuberculosis lesions, 1208 Tuberculosis lymphadenitis diagonosis, 206 Tuberculosis lung granulomata, 122 Tuberculosis meningitis, 489 Tuberculosis model centers, 774 Tuberculous pericarditis, 208 Tuberculous pleuritis, 129 Tuberculosis prevalence, 717, 724, 725 Tuberculosis prevention and control program, 778, collective efforts, 1053–1055 components of, 1046, 1047 positioning, 1045–1049 prevalence and mortality of, 1099 proxy measures of, 1102 and system synergies, 1047 treatment of, 1105–1106 Tuberculosis research, public funding for, 1128 Tuberculosis screening, 504 advantages of, 888, 890 cost effectiveness, 892 limitations of, 891–892 postarrival of, 889 prearrival of, 882, 886 recommendations, 893

I-21 Tuberculosis surveillance system, 770 Tuberculosis training, 531–534, 1086–1087 of general practitioners (GPs), 1087 of health-care workers, 1087–1090 institutes and responsibilities, 1084 of laboratory technicians, 1089 method of, 533 of nurses, 1088 participation, 1093 planning in, 531 programs, 1093 of trainers, 1087, 1090 type of, 532 Tuberculosis transmission, 733, 740, 921, 928 concurrent reduction of, 987 cough frequency, 801 dynamics of, 783 modeling, 803 molecular epidemiology of, 955 nosocomial, 794, 801 Tuberculosis treatment, 183, 1135–1136 latent, 1137 outcome monitoring, 762–763 Tuberculosis vaccines, 1153, 1156–1157 projected timeline in development, 1161 Tuberculosis vaccine candidates clinical trials of, 1162–1164 delivery system for, 1155 Tumor, brain, 323 Tumor necrosis factor (TNF), 123, 128, 377 activity, 126 apoptosis, 129 expression of, 128 inhibitors of, 135 production, 134 role of, 135

Ubi pus—ibi evacua, 459 Urban tuberculosis epidemics, 1007–1010, 1013, 1043, 1053 Urine testing for drug metabolites, 958 UV germicidal irradiation (UVGI), 806 advantage of, 808

I-22 [UV germicidal irradiation (UVGI)] applications, 807 limitation of, 808 Vaccines, 1258 in clinical trial pathway, 1212 development, 1206 live mycobacterial, 1155–1159 subunit, 1159–1160 Validating screening methods, 1203–1204 Virulent pathogen, 377 Vole Bacille vaccine, 544 Voluntary counseling and testing (VCT), 958 evaluation of, 959 Vulnerable populations, case finding in, 1202 WHO. See World Health Organization Window period, definition of, 240

Index World Health Assembly (WHA), 719, 1228, 1231 World Health Organization (WHO), 326, 689, 825, 1098 African region, 2, 312 European region, 873 expert committee, 718 guidelines for the treatment of drug-susceptible pulmonary tuberculosis, 387 new stop tuberculosis strategy of, 1206 tuberculosis-control strategy, 780 Worldwide disease, 309–310

Yersinia pestis, 57

Ziehl–Neelsen (ZN) stain, 363 staining solutions for, 529, 530 technique, 529, 530