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.

44

Boulahbal and Heifets

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.

Bacteriology of Tuberculosis

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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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Boulahbal and Heifets

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/

Genomics and Evolution of Tubercle Bacille

61

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.

62

Vincent et al.

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.

Genomics and Evolution of Tubercle Bacille

63

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.

64

Vincent et al.

70. Gutie´rrez MC, Brisse S, Brosch R, et al. Ancient origin and gene mosaicism of the progenitor of Mycobacterium tuberculosis. PLOS Pathogens 2005; 1:e5. 71. Mostowy S, Inwald J, Gordon S, et al. Revisiting the evolution of Mycobacterium bovis. J Bacteriol 2005; 187(18):6386–6395. 72. Gagneux S, DeRiemer K, Van T, et al. Variable host-pathogen compatibility in Mycobacterium tuberculosis. Proc Natl Acad Sci USA 2006; 103:2869–2873. 73. Kumar S, Filipski A, Swarna V, Walker A, Hedges SB. Placing confidence limits on the molecular age of the human-chimpanzee divergence. Proc Natl Acad Sci USA 2005; 102(52):18,842–18,847. 74. Stenger S, Hanson DA, Teitelbaum R, et al. An antimicrobial activity of cytolytic T cells mediated by granulysin. Science 1998; 282(5386):121–125.

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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6. Centers for Disease Control and Prevention. Trends in tuberculosis—United States. Morb Mortal Wkly Rep 2004; 53:209–213. 7. Lowell AM, Edwards LB, Palmer CE. Tuberculosis. Cambridge, MA: Harvard University Press, 1969:129–166. 8. Rust P, Thomas J. A method for estimating the prevalence of tuberculous infection. Am J Epidemiol 1975; 101:311–322. 9. Trump DH, Hyams KC, Cross ER, Struewing JP. Tuberculosis infection among young adults entering the US Navy in 1990. Arch Intern Med 1993; 153: 211–216. 10. Engel A, Roberts J. Tuberculin skin test reaction among adults 25–74 years, United States, 1971–72. DHEW Publication No. (HRA) 77–1649. Vital and Health Statistics: Series 11, No. 204. Hyattsville, MD: National Center for Health Statistics, 1977. 11. Comstock GW. Frost revisited: the modern epidemiology of tuberculosis. Am J Epidemiol 1975; 101:363–382. 12. Centers for Disease Control. Tuberculosis Program Management Report, Contact Followup, 1997. 13. Kochi A. The global tuberculosis situation and the new control strategy of the World Health Organization. Tubercle 1991; 72:1–6. 14. Styblo K. Surveillance of tuberculosis. Int J Epidemiol 1976; 5:63–68. 15. Styblo K. The impact of HIV infection on the global epidemiology of tuberculosis. Bull IUATLD 1991; 66:27–32. 16. Shashiphara AN, Chadha VK, Jagannatha PS, et al. The annual risk of tuberculous infection in Orissa state, India. Int J Tuberc Lung Dis 2004; 8:545–551. 17. Norval P-Y, Roustit C, San KK. From tuberculin to prevalence survey in Cambodia. Int J Tuberc Lung Dis 2004; 8:299–305. 18. Kaplan GJ, Fraser RI, Comstock GW. Tuberculosis in Alaska, 1970. The continued decline of the tuberculosis epidemic. Am Rev Respir Dis 1972; 105:920–926. 19. Grzybowski S, Barnett GD, Styblo K. Contacts of cases of active pulmonary tuberculosis. Bull Int Un Tuberc 1975; 50:90–106. 20. Loudon RG, Spohn SK. Cough frequency and infectivity in patients with pulmonary tuberculosis. Am Rev Respir Dis 1969; 99:109–111. 21. Narain R, Nair SS, Ramanatha Rao GR, Chandrasekhar P. Distribution of tuberculous infection and disease among households in a rural community. Bull WHO 1966; 34:639–654. 22. 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. 23. Dickinson JM, Lefford MJ, Lloyd J, Mitchison DA. The virulence in the guinea-pig of tubercle bacilli from patients with pulmonary tuberculosis in Hong Kong. Tubercle 1963; 44:446–451. 24. Morse WC, Weiser OL, Kuhns DM, et al. Study of the virulence of isoniazidresistant tubercle bacilli in guinea pigs and mice. A preliminary report. Am Rev Tuberc 1954; 69:464–468. 25. 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; 338:633–639. 26. Bishai WR, Dannenberg AM Jr., Parrish N, et al. Virulence of CDC1551 and H32Rv in rabbits evaluated by Lurie’s pulmonary tubercle count method. Infect Immun 1999; 67:4931–4394. 27. Comstock GW. Rogue pathogen, rogue patient, or the vagaries of chance? Am J Respir Crit Care Med (Letter) 2002; 166:1141–1142.

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Coberly and Comstock

28. Sutherland I, Fayers PM. The association of the risk of tuberculous infection with age. Tuberculosis Surveillance Research Unit Report No. 3. Bull Int Un Tuberc 1975; 50:70–81. 29. Holmes CB, Hausler H, Nunn P. A review of sex differences in the epidemiology of tuberculosis. Int J Tuberc Lung Dis 1998; 2:96–104. 30. Reichman LB, O’Day R. Tuberculous infection in a large urban population. Am Rev Respir Dis 1978; 117:705–712. 31. Comstock GW, O’Brien RJ. Tuberculosis. In: Evans AS, Brachman PS, eds Bacterial Infections of Humans. Epidemiology and Control. 2nd ed. New York: Plenum Medical Book Company, 1991:745–771. 32. Kuemmerer JM, Comstock GW. Sociologic concomitants of tuberculin sensitivity. Am Rev Respir Dis 1967; 96:885–892. 33. Kamat SR, Dawson JJY, Devadatta S, et al. A controlled study of the influence of segregation of tuberculous patients for one year on the attack rate of tuberculosis in a 5-year period in close family contacts in south India. Bull WHO 1966; 34:517–532. 34. Riley RL, Moodie AS. Infectivity of patients with pulmonary tuberculosis in inner city homes. Am Rev Respir Dis 1974; 110:810–812. 35. Snider DE Jr., Kelly GD, Cauthen GM, Thompson NJ, Kilburn JO. Infection and disease among contacts of tuberculosis cases with drug-resistant and drugsusceptible bacilli. Am Rev Respir Dis 1985; 132:125–132. 36. Stead WW, Lofgren JP, Warren E, Thomas C. Tuberculosis as an endemic and nosocomial infection among the elderly in nursing homes. N Engl J Med 1985; 312:1483–1487. 37. Perez-Stable EJ, Flaherty D, Schecter G, Slutkin G, Hopewell PC. Conversion and reversion of tuberculin reactions in nursing home residents. Am Rev Respir Dis 1988; 137:801–804. 38. Barry MA, Regan AM, Kunches LM, Harris ME, Bunce SA, Craven DE. Two-stage tuberculin testing with control antigens in patients residing in two chronic disease hospitals. J Am Geriatr Soc 1987; 35:147–153. 39. Thompson NJ, Glassroth JL, Snider DE Jr., Farer LS. The booster phenomenon in serial tuberculin testing. Am Rev Respir Dis 1979; 119:587–597. 40. Centers for Disease Control and Prevention. Prevention and control of tuberculosis in correctional institutions: Recommendations of the Advisory Council for the Elimination of Tuberculosis. Morb Mortal Wkly Rep 1996; 45(No. RR-8):1–27. 41. MacIntyre CR, Kendig N, Kummer L, Birago S, Graham NM. Impact of tuberculosis control measures and crowding on the incidence of tuberculous infection in Maryland prisons. Clin Infect Dis 1997; 24:1060–1067. 42. Stead WW. Undetected tuberculosis in prison. JAMA 1978; 240:2544–2547. 43. Nolan CM, Elarth AM, Barr H, Mahdi Saeed A, Risser DR. An outbreak of tuberculosis in a shelter for homeless men. Am Rev Respir Dis 1991; 143:257–261. 44. Stead WW, Senner JW, Reddick WT, Lofgren JP. Racial differences in susceptibility to infection by Mycobacterium tuberculosis. N Engl J Med 1990; 322:422–427. 45. Hoge CW, Fisher L, Donnell HD Jr., et al. Risk factors for transmission of Mycobacterium tuberculosis in a primary school outbreak: lack of racial difference in susceptibility to infection. Am J Epidemiol 1994; 139:520–530. 46. Rich AR. The Pathogenesis of Tuberculosis. Springfield, IL: Charles C. Thomas, 1944:779–810. 47. Ferebee SH. Controlled chemoprophylaxis trials in tuberculosis. A general review. Adv Tuberc Res 1970; 17:28–106. 48. Murthy KV, Nair SS, Gothi GD, Chakraborty AK. Incidence of tuberculosis among newly infected population and in relation to the duration of infected status. Indian J Tuberc 1976; 33:3–7.

Epidemiology of Tuberculosis

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49. Horwitz O, Wilbek E, Erickson PA. Epidemiological basis of tuberculosis eradication. 10. Longitudinal studies on the risk of tuberculosis in the general population of a low-prevalence area. Bull WHO 1969; 41:95–113. 50. Comstock GW, Ferebee SH, Hammes LM. A controlled trial of community-wide isoniazid prophylaxis in Alaska. Am Rev Respir Dis 1967; 95:935–943. 51. Comstock GW, Livesay VT, Woolpert SF. The prognosis of a positive tuberculin reaction in childhood and adolescence. Am J Epidemiol 1974; 99:131–138. 52. Comstock GW, Livesay VT, Woolpert SF. Evaluation of BCG vaccination among Puerto Rican children. Am J Public Health 1974; 64:283–291. 53. Sutherland I. The evolution of clinical tuberculosis in adolescents (abstract). Tubercle 1966; 47:308. 54. Tuberculosis Research Centre (ICMR), Chennai, India. Association of initial tuberculin sensitivity, age and sex with incidence of tuberculosis in South India: a 15-year follow-up. Int J Tuberc Lung Dis 2003; 7:1083–1091. 55. Balasubramanian R, Garg R, Santha T, et al. Gender disparities in tuberculosis: report from a rural DOTS program in south India. Int J Tuberc Lung Dis 2004; 8:323–332. 56. Comstock GW, Palmer CE. Long-term results of BCG vaccination in the southern United States. Am Rev Respir Dis 1966; 93:171–183. 57. Comstock GW, Edwards LB, Livesay VT. Tuberculosis morbidity in the US Navy: its distribution and decline. Am Rev Respir Dis 1974; 110:572–580. 58. Narain R, Naganna K, Murthy SS. Incidence of pulmonary tuberculosis. Am Rev Respir Dis 1973; 107:992–1001. 59. Palmer CE, Edwards LB, Hopwood L, Edwards PQ. Experimental and epidemiologic basis for the interpretation of tuberculin sensitivity. J Pediatr 1959; 55: 413–429. 60. American Thoracic Society. Diagnostic standards and classification of tuberculosis. Am Rev Respir Dis 1990; 142:725–735. 61. 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. 62. Flick JA. Does measles really predispose to tuberculosis? Am Rev Respir Dis 1976; 114:257–265. 63. Edwards LG, Livesay VT, Acquaviva FA, Palmer CE. Height, weight, tuberculous infection, and tuberculous disease. Arch Environ Health 1971; 22:106–112. 64. Lurie M. Resistance to Tuberculosis: Experimental Studies in Native Acquired Defensive Mechanisms. Cambridge: Harvard University Press, 1984. 65. Bellamy R. Genetic susceptibility to tuberculosis. Clin Chest Med 2005; 26:233–246. 66. Dubos R, Dubos J. The White Plague: Tuberculosis, Man and Society. Boston: Little, Brown and Co., 1952. 67. Motulsky A. Metabolic polymorphisms and the role of infectious disease in human evolution. Hum Biol 1960; 32:28–62. 68. Sousa A, Salem JI, Lee FK, et al. An epidemic of tuberculosis with a high rate of tuberculin anergy among a population previously unexposed to tuberculosis, the Yanomami Indians of the Brazilian Amazon. Proc Natl Acad Sci USA 1997; 94:13227–13232. 69. Kallmann F, Reisner D. Twin studies on the significance of genetic factors in tuberculosis. Am Rev Tuberc 1942; 47:549–574. 70. Simonds B. Tuberculosis in Twins. London: Pitman Medical Publishing Company, 1963. 71. Comstock GW. Tuberculosis in twins: a re-analysis of the Prophit survey. Am Rev Respir Dis 1978; 117:621–624.

96

Coberly and Comstock

72. Overfield T, Klauber MR. Prevalence of tuberculosis in Eskimos having blood group B gene. Human Biol 1980; 52:87–92. 73. Stead W, Dutt AK. Epidemiology and host factors. In: Schlossberg D, ed. Tuberculosis. New York: Springer-Verlag, 1994:1–16. 74. Bellamy R, Ruwende C, Corrah T, McAdam KP, Whittle HC, Hill AV. Variations in the NRAMP1 gene and susceptibility to tuberculosis in West Africans. NEJM 1998; 338(10):640–644. 75. Goldfeld A, Delgado JC, Thim S, et al. Association of an HLA-DQ allele with clinical tuberculosis. JAMA 1998; 279:226–228. 76. Casanova J-L, Blanche S, Emile J-F, et al. Idiopathic disseminated bacillus Calmette-Guerin infection: a French national retrospective study. Pediatrics 1996; 98(4):774–778. 77. Jouanguy E, Altare F, Lamhamedi S, et al. Interferon-a˜-receptor deficiency in an infant with fatal bacille Calmette-Guerin infection. NEJM 1996; 335(26):1956–1961. 78. 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. 79. Leung C, Li T, Lam TH, et al. Smoking and tuberculosis among the elderly in Hong Kong. Am J Respir Crit Care Med 2004; 170:1027–1033. 80. Abal A, Jayakrishnan B, Parwer S, ElShamy A, Abahussain E, Sharma PN. Effect of cigarette smoking on sputum smear conversion in adults with active pulmonary tuberculosis. Respir Med 2005; 99:415–420. 81. Boelaert J, Gomes MS, Gordeuk VR. Smoking, iron, and tuberculosis. Lancet 2003; 362:1243–1244. 82. Fox W. The John Barnwell Lecture. Changing concepts in the chemotherapy of pulmonary tuberculosis. Am Rev Respir Dis 1968; 97:767–790. 83. Stead WW, Jurgens GH. Productivity of prolonged follow-up after chemotherapy for tuberculosis. Am Rev Respir Dis 1973; 108:314–320. 84. Kopanoff DE, Snider DE Jr., Johnson M. Recurrent tuberculosis: Why do patients develop disease again? Am J Public Health 1988; 78:30–33. 85. 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. 86. 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. 87. Hong Kong Chest Service/British Medical Research Council. Five-year follow-up of a controlled trial of five 6-month regimens of chemotherapy for pulmonary tuberculosis. Am Rev Respir Dis 1987; 136:1339–1342. 88. Combs DL, O’Brien RJ, Geiter LJ. USPHS tuberculosis short-course chemotherapy trial 21: effectiveness, toxicity, and acceptability. Ann Intern Med 1990; 112: 397–406. 89. Horwitz O. Public health aspects of relapsing tuberculosis. Am Rev Respir Dis 1969; 99:183–193. 90. Comstock GW. Untreated inactive pulmonary tuberculosis: risk of reactivation. Public Health Rep 1962; 77:461–470. 91. Edwards LB, Doster B, Livesay VT, Ferebee SH. Risk of tuberculosis in people with not active-not treated lesions. Bull Int Un Tuberc 1972; 47:151–156. 92. Springett VH. Tuberculosis risk in people with ‘‘fibrotic’’ lesions. Bull Int Un Tuberc 1972; 47:157–159. 93. Pamra SP, Prasad G, Mathur GP. Relapse in pulmonary tuberculosis. Am Rev Respir Dis 1976; 113:67–72.

Epidemiology of Tuberculosis

97

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.

Epidemiology of Tuberculosis

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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.

Pathogenesis from a Cellular and Molecular Perspective

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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.

Pathogenesis from a Cellular and Molecular Perspective

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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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This work was supported by NHLBI 2R01HL51630–06. References 1. Bates JH. Transmission and pathogenesis of tuberculosis. Clin Chest Med 1980; 1(2):167–174. 2. Comstock GW, Livesay VT, Woolpert SF. The prognosis of a positive tuberculin reaction in childhood and adolescence. Am J Epidemiol 1974; 99(2):131–138. 3. Houk VN, Baker JH, Sorensen K, et al. The epidemiology of tuberculosis infection in a closed environment. Arch Environ Health 1968; 16(1):26–35. 4. Houk VN. Spread of tuberculosis via recirculated air in a naval vessel: the Byrd study. Ann NY Acad Sci 1980; 353:10–24. 5. Ratcliffe HL. Tuberculosis induced by droplet nuclei infection; pulmonary tuberculosis of predetermined initial intensity in mammals. Am J Hyg 1952; 55(1):36–47. 6. Riley RL, Mills CC, O’Grady F, et al. 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. 7. Grzybowski S, Barnett GD, Styblo K. Contacts of cases of active pulmonary tuberculosis. Bull Int Union Tuberc 1975; 50(1):90–106. 8. Proudfoot AT, Akhtar AJ, Douglas AC, et al. Miliary tuberculosis in adults. Br Med J 1969; 2(652):273–276. 9. Tead WW, Kerby GR, Schlueter DP, et al. The clinical spectrum of primary tuberculosis in adults. Confusion with reinfection in the pathogenesis of chronic tuberculosis. Ann Intern Med 1968; 68(4):731–745. 10. Khan MA, Kovnat DM, Bachus B, et al. Clinical and roentgenographic spectrum of pulmonary tuberculosis in the adult. Am J Med 1977; 62(1):31–38. 11. Schlesinger LS. Entry of Mycobacterium tuberculosis into mononuclear phagocytes. Curr Top Microbiol Immunol 1996; 215:71–96. 12. Hirsch CS, Ellner JJ, Russell DG, et al. Complement receptor-mediated uptake and tumor necrosis factor-alpha-mediated growth inhibition of Mycobacterium tuberculosis by human alveolar macrophages. J Immunol 1994; 152(2):743–753. 13. Tailleux L, Schwartz O, Herrmann JL, et al. DC-SIGN is the major Mycobacterium tuberculosis receptor on human dendritic cells. J Exp Med 2003; 197(1): 121–127. 14. Geijtenbeek TB, Van Vliet SJ, Koppel EA, et al. Mycobacteria target DC-SIGN to suppress dendritic cell function. J Exp Med 2003; 197(1):7–17. 15. Maeda N, Nigou J, Herrmann JL, et al. The cell surface receptor DC-SIGN discriminates between Mycobacterium species through selective recognition of the mannose caps on lipoarabinomannan. J Biol Chem 2003; 278(8):5513–5516. 16. Kaufmann SH, Schaible UE. A dangerous liaison between two major killers: Mycobacterium tuberculosis and HIV target dendritic cells through DC-SIGN. J Exp Med 2003; 197(1):1–5. 17. Tailleux L, Pham-Thi N, Bergeron-Lafaurie A, et al. DC-SIGN induction in alveolar macrophages defines privileged target host cells for mycobacteria in patients with tuberculosis. PLoS Med 2005; 2(12):e381. 18. Porcelli S, Morita CT, Brenner MB. CD1b restricts the response of human CD4– 8-T lymphocytes to a microbial antigen. Nature 1992; 360(6404):593–597. 19. Beckman EM, Melian A, Behar SM, et al. CD1c restricts responses of mycobacteria-specific T cells. Evidence for antigen presentation by a second member of the human CD1 family. J Immunol 1996; 157(7):2795–2803.

The Human Host: Immunology and Susceptibility

141

20. 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. 21. Sieling PA, Chatterjee D, Porcelli SA, et al. CD1-restricted T cell recognition of microbial lipoglycan antigens. Science 1995; 269(5221):227–230. 22. Stenger S, Hanson DA, Teitelbaum R, et al. An antimicrobial activity of cytolytic T cells mediated by granulysin. Science 1998; 282(5386):121–125. 23. Nathan CF, Prendergast TJ, Wiebe ME, et al. Activation of human macrophages. Comparison of other cytokines with interferon-gamma. J Exp Med 1984; 160(2): 600–605. 24. Nathan CF, Murray HW, Wiebe ME, et al. Identification of interferon-gamma as the lymphokine that activates human macrophage oxidative metabolism and antimicrobial activity. J Exp Med 1983; 158(3):670–689. 25. Kaufmann SH. Recent findings in immunology give tuberculosis vaccines a new boost. Trends Immunol 2005. 26. Esser MT, Marchese RD, Kierstead LS, et al. Memory T cells and vaccines. Vaccine 2003; 21(5–6):419–430. 27. Rodrigues DS, Medeiros EA, Weckx LY, et al. Immunophenotypic characterization of peripheral T lymphocytes in Mycobacterium tuberculosis infection and disease. Clin Exp Immunol 2002; 128(1):149–154. 28. Cooper AM, Dalton DK, Stewart TA, et al. Disseminated tuberculosis in interferon gamma gene-disrupted mice. J Exp Med 1993; 178(6):2243–2247. 29. Flynn JL, Chan J, Triebold KJ, et al. An essential role for interferon gamma in resistance to Mycobacterium tuberculosis infection. J Exp Med 1993; 178(6): 2249–2254. 30. Jouanguy E, Lamhamedi-Cherradi S, Altare F, et al. Partial interferon-gamma receptor 1 deficiency in a child with tuberculoid bacillus Calmette–Guerin infection and a sibling with clinical tuberculosis. J Clin Invest 1997; 100(11):2658–2664. 31. Jouanguy E, Altare F, Lamhamedi-Cherradi S, et al. Infections in IFNGR-1deficient children. J Interferon Cytokine Res 1997; 17(10):583–587. 32. Tena GN, Young DB, Eley B, et al. Failure to control growth of mycobacteria in blood from children infected with human immunodeficiency virus and its relationship to T cell function. J Infect Dis 2003; 187(10):1544–1551. 33. Silver RF, Li Q, Boom WH, et al. Lymphocyte-dependent inhibition of growth of virulent Mycobacterium tuberculosis H37Rv within human monocytes: requirement for CD4þ T cells in purified protein derivative-positive, but not in purified protein derivative-negative subjects. J Immunol 1998; 160(5):2408–2417. 34. Bonecini-Almeida MG, Chitale S, Boutsikakis I, et al. Induction of in vitro human macrophage anti-Mycobacterium tuberculosis activity: requirement for IFN-gamma and primed lymphocytes. J Immunol 1998; 160(9):4490–4499. 35. Condos R, Hull FP, Schluger NW, et al. Regional deposition of aerosolized interferon-gamma in pulmonary tuberculosis. Chest 2004; 125(6):2146–2155. 36. Sharma S, Sharma M, Roy S, et al. Mycobacterium tuberculosis induces high production of nitric oxide in coordination with production of tumour necrosis factor-alpha in patients with fresh active tuberculosis but not in MDR tuberculosis. Immunol Cell Biol 2004; 82(4):377–382. 37. Bose M, Farnia P, Sharma S, et al. Nitric oxide dependent killing of Mycobacterium tuberculosis by human mononuclear phagocytes from patients with active tuberculosis. Int J Immunopathol Pharmacol 1999; 12(2):69–79. 38. Kuo HP, Wang CH, Huang KS, et al. Nitric oxide modulates interleukin-1b and tumor necrosis factor-alpha synthesis by alveolar macrophages in pulmonary tuberculosis. Am J Respir Crit Care Med 2000; 161(1):192–199.

142

Schwander and Ellner

39. Nicholson S, Bonecini-Almeida M, Lapa e Silva JR, et al. Inducible nitric oxide synthase in pulmonary alveolar macrophages from patients with tuberculosis. J Exp Med 1996; 183(5):2293–2302. 40. Rich EA, Torres M, Sada E, et al. Mycobacterium tuberculosis (MTB)-stimulated production of nitric oxide by human alveolar macrophages and relationship of nitric oxide production to growth inhibition of MTB. Tuber Lung Dis 1997; 78(5–6):247– 255. 41. Carranza C, Juarez E, Torres M, et al. Mycobacterium tuberculosis growth control by lung macrophages and CD8 cells from patient contacts. Am J Respir Crit Care Med 2005, 2005 Oct 6; Epub http://ajrccm.atsjournals.org/cgi/reprint/200503–411OCv1. 42. Roy S, Sharma S, Sharma M, et al. Induction of nitric oxide release from the human alveolar epithelial cell line A549: an in vitro correlate of innate immune response to Mycobacterium tuberculosis. Immunology 2004; 112(3):471–480. 43. Kwon OJ, Kim JH, Kim HC, et al. Nitric oxide expression in airway epithelial cells in response to tubercle bacilli stimulation. Respirology 1998; 3(2):119–124. 44. Wang CH, Liu CY, Lin HC, et al. Increased exhaled nitric oxide in active pulmonary tuberculosis due to inducible NO synthase upregulation in alveolar macrophages. Eur Respir J 1998; 11(4):809–815. 45. Choi HS, Rai PR, Chu HW, et al. Analysis of nitric oxide synthase and nitrotyrosine expression in human pulmonary tuberculosis. Am J Respir Crit Care Med 2002; 166(2):178–186. 46. Nozaki Y, Hasegawa Y, Ichiyama S, et al. Mechanism of nitric oxide-dependent killing of Mycobacterium bovis BCG in human alveolar macrophages. Infect Immun 1997; 65(9):3644–3647. 47. Brightbill HD, Libraty DH, Krutzik SR, et al. Host defense mechanisms triggered by microbial lipoproteins through Toll-like receptors. Science 1999; 28(5428):732–736. 48. Campos MA, Closel M, Valente EP, et al. Impaired production of proinflammatory cytokines and host resistance to acute infection with Trypanosoma cruzi in mice lacking functional myeloid differentiation factor 88. J Immunol 2004; 172(3): 1711–1718. 49. Keane J, Balcewicz-Sablinska MK, Remold HG, et al. Infection by Mycobacterium tuberculosis promotes human alveolar macrophage apoptosis. Infect Immun 1997; 65(1):298–304. 50. Fratazzi C, Arbeit RD, Carini C, et al. Macrophage apoptosis in mycobacterial infections. J Leukoc Biol 1999; 66(5):763–764. 51. Kornfeld H, Mancino G, Colizzi V. The role of macrophage cell death in tuberculosis. Cell Death Differ 1999; 6(1):71–78. 52. Nau GJ, Richmond JF, Schlesinger A, et al. Human macrophage activation programs induced by bacterial pathogens. Proc Natl Acad Sci USA 2002; 99(3): 1503–1508. 53. Ni K, O’Neill HC. The role of dendritic cells in T cell activation. Immunol Cell Biol 1997; 75(3):223–230. 54. Hertz C, Kiertscher S, Godowski P, et al. Microbial lipopeptides stimulate dendritic cell maturation via Toll-like receptor 2. J Immunol 2001; 166(4):2444–2450. 55. Holt PG. Antigen presentation in the lung. Am J Respir Crit Care Med 2000; 162(4 Pt 2):S151–S156. 56. Sertl K, Takemura T, Tschachler E, et al. Dendritic cells with antigen-presenting capability reside in airway epithelium, lung parenchyma, and visceral pleura. J Exp Med 1986; 163(2):436–451. 57. Henderson RA, Watkins SC, Flynn JL. Activation of human dendritic cells following infection with Mycobacterium tuberculosis. J Immunol 1997; 159(2):635–643.

The Human Host: Immunology and Susceptibility

143

58. Giacomini E, Iona E, Ferroni L, et al. Infection of human macrophages and dendritic cells with Mycobacterium tuberculosis induces a differential cytokine gene expression that modulates T cell response. J Immunol 2001; 166(12): 7033–7041. 59. Remoli ME, Giacomini E, Lutfalla G, et al. Selective expression of type I IFN genes in human dendritic cells infected with Mycobacterium tuberculosis. J Immunol 2002; 169(1):366–374. 60. Fortsch D, Rollinghoff M, Stenger S. IL-10 converts human dendritic cells into macrophage-like cells with increased antibacterial activity against virulent Mycobacterium tuberculosis. J Immunol 2000; 165(2):978–987. 61. Boom WH. The role of T-cell subsets in Mycobacterium tuberculosis infection. Infect Agents Dis 1996; 5(2):73–81. 62. Boom WH, Canaday DH, Fulton SA, et al. Human immunity to M. tuberculosis: T cell subsets and antigen processing. Tuberculosis (Edinb) 2003; 83(1–3):98–106. 63. 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. 64. Di Perri G, Cazzadori A, Vento S, et al. Comparative histopathological study of pulmonary tuberculosis in human immunodeficiency virus-infected and non-infected patients. Tuberc Lung Dis 1996; 77(3):244–249. 65. Serbina NV, Lazarevic V, Flynn JL. CD4(þ) T cells are required for the development of cytotoxic CD8(þ) T cells during Mycobacterium tuberculosis infection. J Immunol 2001; 167(12):6991–7000. 66. Ladel CH, Daugelat S, Kaufmann SH. Immune response to Mycobacterium bovis bacille Calmette Guerin infection in major histocompatibility complex class Iand II-deficient knock-out mice: contribution of CD4 and CD8 T cells to acquired resistance. Eur J Immunol 1995; 25(2):377–384. 67. Serbina NV, Flynn JL. CD8(þ) T cells participate in the memory immune response to Mycobacterium tuberculosis. Infect Immun 2001; 69(7):4320–4328. 68. 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. 69. Behar SM, Dascher CC, Grusby MJ, et al. Susceptibility of mice deficient in CD1D or TAP1 to infection with Mycobacterium tuberculosis. J Exp Med 1999; 189(12):1973–1980. 70. Cho S, Mehra V, Thoma-Uszynski S, et al. Antimicrobial activity of MHC class Irestricted CD8þ T cells in human tuberculosis. Proc Natl Acad Sci USA 2000; 97(22):12210–12215. 71. Tan JS, Canaday DH, Boom WH, et al. Human alveolar T lymphocyte responses to Mycobacterium tuberculosis antigens: role for CD4þ and CD8þ cytotoxic T cells and relative resistance of alveolar macrophages to lysis. J Immunol 1997; 159(1):290–297. 72. Canaday DH, Wilkinson RJ, Li Q, et al. 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. 73. Canaday DH, Ziebold C, Noss EH, et al. Activation of human CD8þ alpha beta TCRþ cells by Mycobacterium tuberculosis via an alternate class I MHC antigenprocessing pathway. J Immunol 1999; 162(1):372–379. 74. Heinzel AS, Grotzke JE, Lines RA, et al. HLA-E-dependent presentation of Mtbderived antigen to human CD8þ T cells. J Exp Med 2002; 196(11):1473–1481.

144

Schwander and Ellner

75. Lewinsohn DA, Heinzel AS, Gardner JM, et al. Mycobacterium tuberculosisspecific CD8þ T cells preferentially recognize heavily infected cells. Am J Respir Crit Care Med 2003; 168(11):1346–1352. 76. Lalvani A, Brookes R, Wilkinson RJ, et al. Human cytolytic and interferon gammasecreting CD8þ T lymphocytes specific for Mycobacterium tuberculosis. Proc Natl Acad Sci USA 1998; 95(1):270–275. 77. Smith SM, Klein MR, Malin AS, et al. Human CD8(þ) T cells specific for Mycobacterium tuberculosis secreted antigens in tuberculosis patients and healthy BCGvaccinated controls in the Gambia. Infect Immun 2000; 68(12):7144–7148. 78. Mohagheghpour N, Gammon D, Kawamura LM, et al. CTL response to Mycobacterium tuberculosis: identification of an immunogenic epitope in the 19-kDa lipoprotein. J Immunol 1998; 161(5):2400–2406. 79. Geluk A, van Meijgaarden KE, Franken KL, et al. Identification of major epitopes of Mycobacterium tuberculosis AG85B that are recognized by HLA-A0201restricted CD8þ T cells in HLA-transgenic mice and humans. J Immunol 2000; 165(11):6463–6471. 80. Stenger S, Modlin RL. Cytotoxic T cell responses to intracellular pathogens. Curr Opin Immunol 1998; 10(4):471–477. 81. Thoma-Uszynski S, Stenger S, Modlin RL. CTL-mediated killing of intracellular Mycobacterium tuberculosis is independent of target cell nuclear apoptosis. J Immunol 2000; 165(10):5773–5779. 82. Ernst WA, Thoma-Uszynski S, Teitelbaum R, et al. Granulysin, a T cell product, kills bacteria by altering membrane permeability. J Immunol 2000; 165(12):7102–7108. 83. Brookes RH, Pathan AA, McShane H, et al. CD8þ T cell-mediated suppression of intracellular Mycobacterium tuberculosis growth in activated human macrophages. Eur J Immunol 2003; 33(12):3293–3302. 84. Schwander SK, Sada E, Torres M, et al. T lymphocytic and immature macrophage alveolitis in active pulmonary tuberculosis. J Infect Dis 1996; 173(5):1267–1272. 85. Shams H, Wizel B, Weis SE, et al. Contribution of CD8(þ) T cells to gamma interferon production in human tuberculosis. Infect Immun 2001; 69(5):3497–3501. 86. Harty JT, Bevan MJ. Responses of CD8(þ) T cells to intracellular bacteria. Curr Opin Immunol 1999; 11(1):89–93. 87. Vankayalapati R, Klucar P, Wizel B, et al. NK cells regulate CD8þ T cell effector function in response to an intracellular pathogen. J Immunol 2004; 172(1):130–137. 88. Brill KJ, Li Q, Larkin R, et al. Human natural killer cells mediate killing of intracellular Mycobacterium tuberculosis H37Rv via granule-independent mechanisms. Infect Immun 2001; 69(3):1755–1765. 89. Gerosa F, Baldani-Guerra B, Nisii C, et al. Reciprocal activating interaction between natural killer cells and dendritic cells. J Exp Med 2002; 195(3):327–333. 90. Gansert JL, Kiessler V, Engele M, et al. Human NKT cells express granulysin and exhibit antimycobacterial activity. J Immunol 2003; 170(6):3154–3161. 91. Rojas RE, Torres M, Fournie JJ, et al. Phosphoantigen presentation by macrophages to Mycobacterium tuberculosis—reactive Vgamma9Vdelta2þ T cells: modulation by chloroquine. Infect Immun 2002; 70(8):4019–4027. 92. Rojas RE, Chervenak KA, Thomas J, et al. V delta 2þ gamma delta T cell function in Mycobacterium tuberculosis- and HIV-1-positive patients in the United States and Uganda: application of a whole-blood assay. J Infect Dis 2005; 192(10): 1806–1814. 93. Boom WH, Chervenak KA, Mincek MA, et al. Role of the mononuclear phagocyte as an antigen-presenting cell for human gamma delta T cells activated by live Mycobacterium tuberculosis. Infect Immun 1992; 60(9):3480–3488.

The Human Host: Immunology and Susceptibility

145

94. Balaji KN, Schwander SK, Rich EA, et al. Alveolar macrophages as accessory cells for human gamma delta T cells activated by Mycobacterium tuberculosis. J Immunol 1995; 154(11):5959–5968. 95. Barnes PF, Grisso CL, Abrams JS, et al. Gamma delta T lymphocytes in human tuberculosis. J Infect Dis 1992; 165(3):506–512. 96. Li B, Rossman MD, Imir T, et al. Disease-specific changes in gammadelta T cell repertoire and function in patients with pulmonary tuberculosis. J Immunol 1996; 157(9):4222–4229. 97. Li B, Bassiri H, Rossman MD, et al. Involvement of the Fas/Fas ligand pathway in activation-induced cell death of mycobacteria-reactive human gamma delta T cells: a mechanism for the loss of gamma delta T cells in patients with pulmonary tuberculosis. J Immunol 1998; 161(3):1558–1567. 98. Hoft DF, Brown RM, Roodman ST. Bacille Calmette-Guerin vaccination enhances human gamma delta T cell responsiveness to mycobacteria suggestive of a memorylike phenotype. J Immunol 1998; 161(2):1045–1054. 99. Jiang H, Chess L. An integrated view of suppressor T cell subsets in immunoregulation. J Clin Invest 2004; 114(9):1198–1208. 100. O’Garra A, Vieira PL, Vieira P, et al. IL-10-producing and naturally occurring CD4þ Tregs: limiting collateral damage. J Clin Invest 2004; 114(10):1372–1378. 101. Fehervari Z, Sakaguchi S. CD4þ Tregs and immune control. J Clin Invest 2004; 114(9):1209–1217. 102. Caramalho I, Lopes-Carvalho T, Ostler D, et al. Regulatory T cells selectively express Toll-like receptors and are activated by lipopolysaccharide. J Exp Med 2003; 197(4):403–411. 103. Boussiotis VA, Tsai EY, Yunis EJ, et al. IL-10-producing T cells suppress immune responses in anergic tuberculosis patients. J Clin Invest 2000; 105(9):1317–1325. 104. Delgado JC, Tsai EY, Thim S, et al. Antigen-specific and persistent tuberculin anergy in a cohort of pulmonary tuberculosis patients from rural Cambodia. Proc Natl Acad Sci USA 2002; 99(11):7576–7581. 105. Gong JH, Zhang M, Modlin RL, et al. Interleukin-10 downregulates Mycobacterium tuberculosis-induced Th1 responses and CTLA-4 expression. Infect Immun 1996; 64(3):913–918. 106. Belkaid Y, Rouse BT. Natural regulatory T cells in infectious disease. Nat Immunol 2005; 6(4):353–360. 107. 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(26):15688–15693. 108. Costello AM, Kumar A, Narayan V, et al. Does antibody to mycobacterial antigens, including lipoarabinomannan, limit dissemination in childhood tuberculosis? Trans R Soc Trop Med Hyg 1992; 86(6):686–692. 109. Hussain R, Shiratsuchi H, Ellner JJ, et al. PPD-specific IgG1 antibody subclass upregulate tumour necrosis factor expression in PPD-stimulated monocytes: possible link with disease pathogenesis in tuberculosis. Clin Exp Immunol 2000; 119(3):449–455. 110. Hussain R, Shiratsuchi H, Phillips M, et al. Opsonizing antibodies (IgG1) upregulate monocyte proinflammatory cytokines tumour necrosis factor-alpha (TNF-alpha) and IL-6 but not anti-inflammatory cytokine IL-10 in mycobacterial antigen-stimulated monocytes-implications for pathogenesis. Clin Exp Immunol 2001; 123(2):210–218. 111. Glatman-Freedman A. Advances in antibody-mediated immunity against Mycobacterium tuberculosis: implications for a novel vaccine strategy. FEMS Immunol Med Microbiol 2003; 39(1):9–16.

146

Schwander and Ellner

112. Ellner JJ. Suppressor adherent cells in human tuberculosis. J Immunol 1978; 121(6):2573–2579. 113. Ellner JJ. Regulation of the human immune response during tuberculosis. J Lab Clin Med 1997; 130(5):469–475. 114. Fujiwara H, Kleinhenz ME, Wallis RS, et al. Increased interleukin-1 production and monocyte suppressor cell activity associated with human tuberculosis. Am Rev Respir Dis 1986; 133(1):73–77. 115. Toossi Z, Kleinhenz ME, Ellner JJ. Defective interleukin 2 production and responsiveness in human pulmonary tuberculosis. J Exp Med 1986; 163(5):1162–1172. 116. Hirsch CS, Hussain R, Toossi Z, et al. Cross-modulation by transforming growth factor beta in human tuberculosis: suppression of antigen-driven blastogenesis and interferon gamma production. Proc Natl Acad Sci USA 1996; 93(8): 3193–3198. 117. Zhang M, Lin Y, Iyer DV, et al. T-cell cytokine responses in human infection with Mycobacterium tuberculosis. Infect Immun 1995; 63(8):3231–3234. 118. Hirsch CS, Ellner JJ, Blinkhorn R, et al. In vitro restoration of T cell responses in tuberculosis and augmentation of monocyte effector function against Mycobacterium tuberculosis by natural inhibitors of transforming growth factor beta. Proc Natl Acad Sci USA 1997; 94(8):3926–3931. 119. Hirsch CS, Toossi Z, Othieno C, et al. Depressed T-cell interferon-gamma responses in pulmonary tuberculosis: analysis of underlying mechanisms and modulation with therapy. J Infect Dis 1999; 180(6):2069–2073. 120. Fujiwara H, Okuda Y, Fukukawa T, et al. In vitro tuberculin reactivity of lymphocytes from patients with tuberculous pleurisy. Infect Immun 1982; 35(2): 402–409. 121. Vanham G, Edmonds K, Qing L, et al. Generalized immune activation in pulmonary tuberculosis: co-activation with HIV infection. Clin Exp Immunol 1996; 103(1):30–34. 122. Wallis RS, Amir-Tahmasseb M, Ellner JJ. Induction of interleukin 1 and tumor necrosis factor by mycobacterial proteins: the monocyte western blot. Proc Natl Acad Sci USA 1990; 87(9):3348–3352. 123. Toossi Z, Young TG, Averill LE, et al. Induction of transforming growth factor beta 1 by purified protein derivative of Mycobacterium tuberculosis. Infect Immun 1995; 63(1):224–228. 124. Hirsch CS, Toossi Z, Johnson JL, et al. Augmentation of apoptosis and interferongamma production at sites of active Mycobacterium tuberculosis infection in human tuberculosis. J Infect Dis 2001; 183(5):779–788. 125. Bergeron A, Bonay M, Kambouchner M, et al. Cytokine patterns in tuberculous and sarcoid granulomas: correlations with histopathologic features of the granulomatous response. J Immunol 1997; 159(6):3034–3043. 126. Fenhalls G, Squires GR, Stevens-Muller L, et al. Associations between Toll-like receptors and interleukin-4 in the lungs of patients with tuberculosis. Am J Respir Cell Mol Biol 2003; 29(1):28–38. 127. Toossi Z, Gogate P, Shiratsuchi H, et al. Enhanced production of TGF-beta by blood monocytes from patients with active tuberculosis and presence of TGF-beta in tuberculous granulomatous lung lesions. J Immunol 1995; 154(1):465–473. 128. Fenhalls G, Wong A, Bezuidenhout J, et al. In situ production of gamma interferon, interleukin-4, and tumor necrosis factor alpha mRNA in human lung tuberculous granulomas. Infect Immun 2000; 68(5):2827–2836. 129. Robinson DS, Ying S, Taylor IK, et al. Evidence for a Th1-like bronchoalveolar T-cell subset and predominance of interferon-gamma gene activation in pulmonary tuberculosis. Am J Respir Crit Care Med 1994; 149(4 Pt 1):989–993.

The Human Host: Immunology and Susceptibility

147

130. Fenton MJ, Vermeulen MW, Kim S, et al. Induction of gamma interferon production in human alveolar macrophages by Mycobacterium tuberculosis. Infect Immun 1997; 65(12):5149–5156. 131. Agostini C, Perin A, Semenzato G. Cell apoptosis and granulomatous lung diseases. Curr Opin Pulm Med 1998; 4(5):261–266. 132. Oddo M, Renno T, Attinger A, et al. Fas ligand-induced apoptosis of infected human macrophages reduces the viability of intracellular Mycobacterium tuberculosis. J Immunol 1998; 160(11):5448–5454. 133. Patiala J. Initial tuberculous pleuritis in the Finnish armed forces in 1939–1945 with special reference to eventual postpleuritic tuberculosis. Acta Tuberc Scand Suppl 1954; 36:1–57. 134. Roper WH, Waring JJ. Primary serofibrinous pleural effusion in military personnel. Am Rev Tuberc 1955; 71(5):616–634. 135. Ellner JJ. Pleural fluid and peripheral blood lymphocyte function in tuberculosis. Ann Intern Med 1978; 89(6):932–933. 136. Ellner JJ, Barnes PF, Wallis RS, et al. The immunology of tuberculous pleurisy. Semin Respir Infect 1988; 3(4):335–342. 137. Fujiwara H, Tsuyuguchi I. Frequency of tuberculin-reactive T-lymphocytes in pleural fluid and blood from patients with tuberculous pleurisy. Chest 1986; 89(4):530–532. 138. Barnes PF, Mistry SD, Cooper CL, et al. Compartmentalization of a CD4þ T lymphocyte subpopulation in tuberculous pleuritis. J Immunol 1989; 142(4): 1114–1119. 139. Mitra DK, Sharma SK, Dinda AK, et al. Polarized helper T cells in tubercular pleural effusion: phenotypic identity and selective recruitment. Eur J Immunol 2005; 35(8):2367–2375. 140. Aoki Y, Katoh O, Nakanishi Y, et al. A comparison study of IFN-gamma, ADA, and CA125 as the diagnostic parameters in tuberculous pleuritis. Respir Med 1994; 88(2):139–143. 141. Barnes PF, Lu S, Abrams JS, et al. Cytokine production at the site of disease in human tuberculosis. Infect Immun 1993; 61(8):3482–3489. 142. Barnes PF, Fong SJ, Brennan PJ, et al. Local production of tumor necrosis factor and IFN-gamma in tuberculous pleuritis. J Immunol 1990; 145(1):149–154. 143. Ogawa K, Koga H, Hirakata Y, et al. Differential diagnosis of tuberculous pleurisy by measurement of cytokine concentrations in pleural effusion. Tuberc Lung Dis 1997; 78(1):29–34. 144. Shimokata K, Saka H, Murate T, et al. Cytokine content in pleural effusion. Comparison between tuberculous and carcinomatous pleurisy. Chest 1991; 99(5): 1103–1107. 145. Gursel G, Gokcora N, Elbeg S, et al. Tumor necrosis factor-alpha (TNF-alpha) in pleural fluids. Tuberc Lung Dis 1995; 76(4):370–371. 146. Yokoyama A, Maruyama M, Ito M, et al. Interleukin 6 activity in pleural effusion. Its diagnostic value and thrombopoietic activity. Chest 1992; 102(4):1055–1059. 147. Zhang M, Gately MK, Wang E, et al. Interleukin 12 at the site of disease in tuberculosis. J Clin Invest 1994; 93(4):1733–1739. 148. Maeda J, Ueki N, Ohkawa T, et al. Local production and localization of transforming growth factor-beta in tuberculous pleurisy. Clin Exp Immunol 1993; 92(1):32–38. 149. Kaplan G, Freedman VH. The role of cytokines in the immune response to tuberculosis. Res Immunol 1996; 147(8–9):565–572. 150. Hodsdon WS, Luzze H, Hurst TJ, et al. HIV-1-related pleural tuberculosis: elevated production of IFN-gamma, but failure of immunity to Mycobacterium tuberculosis. AIDS 2001; 15(4):467–475.

148

Schwander and Ellner

151. Law KF, Jagirdar J, Weiden MD, et al. Tuberculosis in HIV-positive patients: cellular response and immune activation in the lung. Am J Respir Crit Care Med 1996; 153(4 Pt 1):1377–1384. 152. Taha RA, Kotsimbos TC, Song YL, et al. IFN-gamma and IL-12 are increased in active compared with inactive tuberculosis. Am J Respir Crit Care Med 1997; 155(3):1135–1139. 153. Law K, Weiden M, Harkin T, et al. Increased release of interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha by bronchoalveolar cells lavaged from involved sites in pulmonary tuberculosis. Am J Respir Crit Care Med 1996; 153(2):799–804. 154. Day RB, Wang Y, Knox KS, et al. Alveolar macrophages from HIV-infected subjects are resistant to Mycobacterium tuberculosis in vitro. Am J Respir Cell Mol Biol 2004; 30(3):403–410. 155. Schwander SK, Torres M, Sada E, et al. Enhanced responses to Mycobacterium tuberculosis antigens by human alveolar lymphocytes during active pulmonary tuberculosis. J Infect Dis 1998; 178(5):1434–1445. 156. Kurashima K, Mukaida N, Fujimura M, et al. Elevated chemokine levels in bronchoalveolar lavage fluid of tuberculosis patients. Am J Respir Crit Care Med 1997; 155(4):1474–1477. 157. Sadek MI, Sada E, Toossi Z, et al. 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(3):513–521. 158. Walrath J, Zukowski L, Krywiak A, et al. Resident Th1-like effector memory cells in pulmonary recall responses to Mycobacterium tuberculosis. Am J Respir Cell Mol Biol 2005; 33(1):48–55. 159. Rich EA, Panuska JR, Wallis RS, et al. Dyscoordinate expression of tumor necrosis factor-alpha by human blood monocytes and alveolar macrophages. Am Rev Respir Dis 1989; 139(4):1010–1016. 160. Vankayalapati R, Wizel B, Lakey DL, et al. T cells enhance production of IL-18 by monocytes in response to an intracellular pathogen. J Immunol 2001; 166(11): 6749–6753. 161. Zissel G, Baumer I, Schlaak M, et al. In vitro release of interleukin-15 by bronchoalveolar lavage cells and peripheral blood mononuclear cells from patients with different lung diseases. Eur Cytokine Netw 2000; 11(1):105–112. 162. Bonecini-Almeida MG, Ho JL, Boechat N, et al. Down-modulation of lung immune responses by interleukin-10 and transforming growth factor beta (TGF-b) and analysis of TGF-beta receptors I and II in active tuberculosis. Infect Immun 2004; 72(5):2628–2634. 163. Saukkonen JJ, Bazydlo B, Thomas M, et al. Beta-chemokines are induced by Mycobacterium tuberculosis and inhibit its growth. Infect Immun 2002; 70(4): 1684–1693. 164. Thoma-Uszynski S, Stenger S, Takeuchi O, et al. Induction of direct antimicrobial activity through mammalian Toll-like receptors. Science 2001; 291(5508): 1544–1547. 165. Means TK, Wang S, Lien E, et al. Human Toll-like receptors mediate cellular activation by Mycobacterium tuberculosis. J Immunol 1999; 163(7):3920–3927. 166. Means TK, Jones BW, Schromm AB, et al. Differential effects of a Toll-like receptor antagonist on Mycobacterium tuberculosis-induced macrophage responses. J Immunol 2001; 166(6):4074–4082. 167. Lawn SD, Pisell TL, Hirsch CS, et al. Anatomically compartmentalized human immunodeficiency virus replication in HLA-DRþ cells and CD14þ macrophages at the site of pleural tuberculosis coinfection. J Infect Dis 2001; 184(9):1127–1133.

The Human Host: Immunology and Susceptibility

149

168. Egede LE, Zheng D. Racial/ethnic differences in adult vaccination among individuals with diabetes. Am J Public Health 2003; 93(2):324–329. 169. Werneck-Barroso E, Bonecini-de-Almeida MD, Vieira MA, et al. Preferential recruitment of phagocytes into the lung of patients with advanced acquired immunodeficiency syndrome and tuberculosis. Respir Med 2000; 94(1):64–70. 170. Toossi Z, Johnson JL, Kanost RA, et al. Increased replication of HIV-1 at sites of Mycobacterium tuberculosis infection: potential mechanisms of viral activation. J Acquir Immune Defic Syndr 2001; 28(1):1–8. 171. Toossi Z, Nicolacakis K, Xia L, et al. Activation of latent HIV-1 by Mycobacterium tuberculosis and its purified protein derivative in alveolar macrophages from HIVinfected individuals in vitro. J Acquir Immune Defic Syndr Hum Retrovirol 1997; 15(5):325–331. 172. Hoshino Y, Tse DB, Rochford G, et al. Mycobacterium tuberculosis-induced CXCR4 and chemokine expression leads to preferential X4 HIV-1 replication in human macrophages. J Immunol 2004; 172(10):6251–6258. 173. Bermudez LE, Goodman J. Mycobacterium tuberculosis invades and replicates within type II alveolar cells. Infect Immun 1996; 64(4):1400–1406. 174. Lin Y, Zhang M, Barnes PF. Chemokine production by a human alveolar epithelial cell line in response to Mycobacterium tuberculosis. Infect Immun 1998; 66(3): 1121–1126. 175. Mehta PK, King CH, White EH, et al. Comparison of in vitro models for the study of Mycobacterium tuberculosis invasion and intracellular replication. Infect Immun 1996; 64(7):2673–2679. 176. Rivas-Santiago B, Schwander SK, Sarabia C, et al. Human {beta}-defensin 2 is expressed and associated with Mycobacterium tuberculosis during infection of human alveolar epithelial cells. Infect Immun 2005; 73(8):4505–4511. 177. Bermudez LE, Sangari FJ, Kolonoski P, et al. 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(1):140–146. 178. 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(9):545–550. 179. Di Perri G, Cruciani M, Danzi MC, et al. Nosocomial epidemic of active tuberculosis among HIV-infected patients. Lancet 1989; 2(8678–8679):1502–1504. 180. Tuberculosis and AIDS—Connecticut. Morb Mortal Wkly Rep 1987; 36(9):133–135. 181. Whalen CC, Nsubuga P, Okwera A, et al. Impact of pulmonary tuberculosis on survival of HIV-infected adults: a prospective epidemiologic study in Uganda. AIDS 2000; 14(9):1219–1228. 182. Farer LS, Lowell AM, Meador MP. Extrapulmonary tuberculosis in the United States. Am J Epidemiol 1979; 109(2):205–217. 183. Small PM, Schecter GF, Goodman PC, et al. Treatment of tuberculosis in patients with advanced human immunodeficiency virus infection. N Engl J Med 1991; 324(5):289–294. 184. Gilks CF, Brindle RJ, Otieno LS, et al. Extrapulmonary and disseminated tuberculosis in HIV-1-seropositive patients presenting to the acute medical services in Nairobi. AIDS 1990; 4(10):981–985. 185. Lucas SB, Hounnou A, Peacock C, et al. The mortality and pathology of HIV infection in a west African city. AIDS 1993; 7(12):1569–1579. 186. 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.

150

Schwander and Ellner

187. Zhang M, Gong J, Iyer DV, et al. T cell cytokine responses in persons with tuberculosis and human immunodeficiency virus infection. J Clin Invest 1994; 94(6): 2435–2442. 188. Wallis RS, Vjecha M, Amir-Tahmasseb M, et al. Influence of tuberculosis on human immunodeficiency virus (HIV-1): enhanced cytokine expression and elevated beta 2-microglobulin in HIV-1-associated tuberculosis. J Infect Dis 1993; 167(1):43–48. 189. Toossi Z, Sierra-Madero JG, Blinkhorn RA, et al. Enhanced susceptibility of blood monocytes from patients with pulmonary tuberculosis to productive infection with human immunodeficiency virus type 1. J Exp Med 1993; 177(5):1511–1516. 190. Toossi Z, Xia L, Wu M, et al. Transcriptional activation of HIV by Mycobacterium tuberculosis in human monocytes. Clin Exp Immunol 1999; 117(2):324–330. 191. Lederman MM, Georges DL, Kusner DJ, et al. Mycobacterium tuberculosis and its purified protein derivative activate expression of the human immunodeficiency virus. J Acquir Immune Defic Syndr 1994; 7(7):727–733. 192. Imperiali FG, Zaninoni A, La Maestra L, et al. Increased Mycobacterium tuberculosis growth in HIV-1-infected human macrophages: role of tumour necrosis factoralpha. Clin Exp Immunol 2001; 123(3):435–442. 193. Toossi Z, Mayanja-Kizza H, Hirsch CS, et al. Impact of tuberculosis (TB) on HIV-1 activity in dually infected patients. Clin Exp Immunol 2001; 123(2):233–238. 194. Mayanja-Kizza H, Johnson JL, Hirsch CS, et al. Macrophage-activating cytokines in human immunodeficiency virus type 1-infected and -uninfected patients with pulmonary tuberculosis. J Infect Dis 2001; 183(12):1805–1809. 195. Elliott AM, Hodsdon WS, Kyosiimire J, et al. Cytokine responses and progression to active tuberculosis in HIV-1-infected Ugandans: a prospective study. Trans R Soc Trop Med Hyg 2004; 98(11):660–670. 196. Ranjbar S, Ly N, Thim S, et al. Mycobacterium tuberculosis recall antigens suppress HIV-1 replication in anergic donor cells via CD8þ T cell expansion and increased IL-10 levels. J Immunol 2004; 172(3):1953–1959. 197. Ordway DJ, Costa L, Martins M, et al. Increased Interleukin-4 production by CD8 and gammadelta T cells in health-care workers is associated with the subsequent development of active tuberculosis. J Infect Dis 2004; 190(4):756–766. 198. Breton G, Duval X, Estellat C, et al. Determinants of immune reconstitution inflammatory syndrome in HIV type 1-infected patients with tuberculosis after initiation of antiretroviral therapy. Clin Infect Dis 2004; 39:1709–1712. 199. Hengel RL, Allende MC, Dewar RL, et al. Increasing CD4þ T cells specific for tuberculosis correlate with improved clinical immunity after highly active antiretroviral therapy. AIDS Res Hum Retrovirus 2002; 18(13):969–975. 200. Kindler V, Sappino AP, Grau GE, et al. The inducing role of tumor necrosis factor in the development of bactericidal granulomas during BCG infection. Cell 1989; 56(5):731–740. 201. Flynn JL, Goldstein MM, Chan J, et al. Tumor necrosis factor-alpha is required in the protective immune response against Mycobacterium tuberculosis in mice. Immunity 1995; 2(6):561–572. 202. Smith S, Liggitt D, Jeromsky E, et al. Local role for tumor necrosis factor alpha in the pulmonary inflammatory response to Mycobacterium tuberculosis infection. Infect Immun 2002; 70(4):2082–2089. 203. 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(15): 1098–1104. 204. Tuberculosis associated with blocking agents against tumor necrosis factor-alpha— California, 2002–2003. JAMA 2004; 292(14):1676–1678.

The Human Host: Immunology and Susceptibility

151

205. Winthrop KL, Siegel JN. Tuberculosis cases associated with infliximab and etanercept. Clin Infect Dis 2004; 39(8):1256–1257. 206. Wallis RS, Broder MS, Wong JY, et al. Granulomatous infectious diseases associated with tumor necrosis factor antagonists. Clin Infect Dis 2004; 38(9):1261–1265. 207. Keane J. Tumor necrosis factor blockers and reactivation of latent tuberculosis. Clin Infect Dis 2004; 39(3):300–302. 208. Rieder HL, Cauthen GM, Comstock GW, et al. Epidemiology of tuberculosis in the United States. Epidemiol Rev 1989; 11:79–98. 209. Pai RK, Pennini ME, Tobian AA, et al. Prolonged Toll-like receptor signaling by Mycobacterium tuberculosis and its 19-kilodalton lipoprotein inhibits gamma interferon-induced regulation of selected genes in macrophages. Infect Immun 2004; 72(11):6603–6614. 210. Seah GT, Rook GA. Il-4 influences apoptosis of mycobacterium-reactive lymphocytes in the presence of TNF-alpha. J Immunol 2001; 167(3):1230–1237. 211. Demissie A, Abebe M, Aseffa A, et al. Healthy individuals that control a latent infection with Mycobacterium tuberculosis express high levels of Th1 cytokines and the IL-4 antagonist IL-4delta2. J Immunol 2004; 172(11):6938–6943. 212. Dheda K, Chang JS, Breen RA, et al. In vivo and in vitro studies of a novel cytokine, interleukin 4delta2, in pulmonary tuberculosis. Am J Respir Crit Care Med 2005; 172(4):501–508. 213. Borkow G, Weisman Z, Leng Q, et al. Helminths, human immunodeficiency virus and tuberculosis. Scand J Infect Dis 2001; 33(8):568–571. 214. Elias D, Wolday D, Akuffo H, et al. Effect of deworming on human T cell responses to mycobacterial antigens in helminth-exposed individuals before and after bacille Calmette-Guerin (BCG) vaccination. Clin Exp Immunol 2001; 123(2):219–225. 215. Pieters J, Gatfield J. Hijacking the host: survival of pathogenic mycobacteria inside macrophages. Trends Microbiol 2002; 10(3):142–146. 216. Young D, Hussell T, Dougan G. Chronic bacterial infections: living with unwanted guests. Nat Immunol 2002; 3(11):1026–1032. 217. Chua J, Vergne I, Master S, et al. A tale of two lipids: Mycobacterium tuberculosis phagosome maturation arrest. Curr Opin Microbiol 2004; 7(1):71–77. 218. Kincaid EZ, Ernst JD. Mycobacterium tuberculosis exerts gene-selective inhibition of transcriptional responses to IFN-gamma without inhibiting STAT1 function. J Immunol 2003; 171(4):2042–2049. 219. Nagabhushanam V, Solache A, Ting LM, et al. Innate inhibition of adaptive immunity: Mycobacterium tuberculosis-induced IL-6 inhibits macrophage responses to IFN-gamma. J Immunol 2003; 171(9):4750–4757. 220. Fortune SM, Solache A, Jaeger A, et al. Mycobacterium tuberculosis inhibits macrophage responses to IFN-gamma through myeloid differentiation factor 88-dependent and -independent mechanisms. J Immunol 2004; 172(10):6272–6280. 221. Gehring AJ, Rojas RE, Canaday DH, et al. The Mycobacterium tuberculosis 19-kilodalton lipoprotein inhibits gamma interferon-regulated HLA-DR and Fc gamma R1 on human macrophages through Toll-like receptor 2. Infect Immun 2003; 71(8):4487–4497. 222. Hanekom WA, Mendillo M, Manca C, et al. Mycobacterium tuberculosis inhibits maturation of human monocyte-derived dendritic cells in vitro. J Infect Dis 2003; 188(2):257–266. 223. Van Kooyk Y, Geijtenbeek TB. DC-SIGN: escape mechanism for pathogens. Nat Rev Immunol 2003; 3(9):697–709. 224. Manca C, Tsenova L, Barry CE, et al. Mycobacterium tuberculosis CDC1551 induces a more vigorous host response in vivo and in vitro, but is not more virulent than other clinical isolates. J Immunol 1999; 162(11):6740–6746.

152

Schwander and Ellner

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.

The Human Host: Immunology and Susceptibility

153

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 (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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a critical factor in tuberculosis diagnosis; therefore, ongoing training or experience with at-risk populations may be the clinicians’ greatest diagnostic tool. References 1. Schluger NW. The diagnosis of tuberculosis: what’s old, what’s new. Semin Respir Infect 2003; 18(4):241–248. 2. Prevention and control of tuberculosis in migrant farm workers. Recommendations of the Advisory Council for the Elimination of Tuberculosis. MMWR Recomm Rep 1992; 41(RR-10):1–15. 3. Braun MM, Truman BI, Maguire B, et al. Increasing incidence of tuberculosis in a prison inmate population. Association with HIV infection. JAMA 1989; 261(3): 393–397. 4. 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. 5. Cantwell MF, Snider DE Jr., Cauthen GM, Onorato IM. Epidemiology of tuberculosis in the United States, 1985 through 1992. JAMA 1994; 272(7):535–539. 6. McKenna MT, McCray E, Onorato I. The epidemiology of tuberculosis among foreign-born persons in the United States, 1986 to 1993. N Engl J Med 1995; 332(16):1071–1076. 7. Menzies D, Fanning A, Yuan L, Fitzgerald M. Tuberculosis among health care workers. N Engl J Med 1995; 332(2):92–98. 8. Stead WW. Tuberculosis among elderly persons: an outbreak in a nursing home. Ann Intern Med 1981; 94(5):606–610. 9. Targeted tuberculin testing and treatment of latent tuberculosis infection. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. This is a Joint Statement of the American Thoracic Society (ATS) and the Centers for Disease Control and Prevention (CDC). This statement was endorsed by the Council of the Infectious Diseases Society of America. (IDSA), September 1999, and the sections of this statement. Am J Respir Crit Care Med 2000; 161(4 pt 2):S221–S247. 10. Havlir DV, Barnes PF. Tuberculosis in patients with human immunodeficiency virus infection. N Engl J Med 1999; 340(5):367–373. 11. Snider DE Jr. The relationship between tuberculosis and silicosis. Am Rev Respir Dis 1978; 118(3):455–460. 12. Arango L, Brewin AW, Murray JF. The spectrum of tuberculosis as currently seen in a metropolitan hospital. Am Rev Respir Dis 1973; 108(4):805–812. 13. MacGregor RR. A year’s experience with tuberculosis in a private urban teaching hospital in the postsanatorium era. Am J Med 1975; 58(2):221–228. 14. Friedman LN, Selwyn PA. Pulmonary tuberculosis: primary, reactivation, HIV related, and non-HIV related. In: Friedman LN, ed. Tuberculosis: Current Concepts and Treatment. Boca Raton: CRC Press, 1994. 15. Samb B, Henzel D, Daley CL, et al. Methods for diagnosing tuberculosis among inpatients in eastern Africa whose sputum smears are negative. Int J Tuberc Lung Dis 1997; 1(1):25–30. 16. Hopewell PC. A clinical view of tuberculosis. Radiol Clin North Am 1995; 33(4):641–653. 17. Murray HW, Tuazon CU, Kirmani N, Sheagren JN. The adult respiratory distress syndrome associated with miliary tuberculosis. Chest 1978; 73(1):37–43.

Diagnosis of Pulmonary and Extrapulmonary Tuberculosis

173

18. Catanzaro A, Perry S, Clarridge JE, et al. The role of clinical suspicion in evaluating a new diagnostic test for active tuberculosis: results of a multicenter prospective trial. JAMA 2000; 283(5):639–645. 19. Cameron SJ. Tuberculosis and the blood—a special relationship? Tubercle 1974; 55(1):55–72. 20. Abbasi AA, Chemplavil JK, Farah S, Muller BF, Arnstein AR. Hypercalcemia in active pulmonary tuberculosis. Ann Intern Med 1979; 90(3):324–328. 21. Chung DK, Hubbard WW. Hyponatremia in untreated active pulmonary tuberculosis. Am Rev Respir Dis 1969; 99(4):595–597. 22. Huebner RE, Schein MF, Bass JB Jr. The tuberculin skin test. Clin Infect Dis 1993; 17(6):968–975. 23. Canessa PA, Fasano L, Lavecchia MA, Torraca A, Schiattone ML. Tuberculin skin test in asymptomatic HIV seropositive carriers. Chest 1989; 96(5):1215–1216. 24. Lein AD, von Reyn CF, Ravn P, Horsburgh CR Jr., Alexander LN, Andersen P. Cellular immune responses to ESAT-6 discriminate between patients with pulmonary disease due to Mycobacterium avium complex and those with pulmonary disease due to Mycobacterium tuberculosis. Clin Diagn Lab Immunol 1999; 6(4): 606–609. 25. Clinicians Guide to QuantiFERON-TB Gold. Melbourne: AUS, Cellestis Ltd., 2005:1–13. 26. 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(1):59–64. 27. McAdams HP, Erasmus J, Winter JA. Radiologic manifestations of pulmonary tuberculosis. Radiol Clin North Am 1995; 33(4):655–678. 28. Palmer PE. Pulmonary tuberculosis—usual and unusual radiographic presentations. Semin Roentgenol 1979; 14(3):204–243. 29. Leung AN, Muller NL, Pineda PR, FitzGerald JM. Primary tuberculosis in childhood: radiographic manifestations. Radiology 1992; 182(1):87–91. 30. Miller WT, Miller WT Jr. Tuberculosis in the normal host: radiological findings. Semin Roentgenol 1993; 28(2):109–118. 31. Woodring JH, Vandiviere HM, Fried AM, Dillon ML, Williams TD, Melvin IG. Update: the radiographic features of pulmonary tuberculosis. Am J Roentgenol 1986; 146(3):497–506. 32. Lintin SN, Isaac PA. Miliary tuberculosis presenting as adult respiratory distress syndrome. Intensive Care Med 1988; 14(6):672–674. 33. 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(1):115–119. 34. Pitchenik AE, Rubinson HA. The radiographic appearance of tuberculosis in patients with the acquired immune deficiency syndrome (AIDS) and pre-AIDS. Am Rev Respir Dis 1985; 131(3):393–396. 35. Miller WT. Expanding options for the radiographic evaluation of tuberculosis. In: Rossman MD, MacGregor RR, eds. Tuberculosis: Clinical Management and New Challenges. New York: McGraw Hill, 1995. 36. Christie JD, Callihan DR. The laboratory diagnosis of mycobacterial diseases. Challenges and Common Sense. Clin Lab Med 1995; 15(2):279–306. 37. Fishman JA, Roth RS, Zanzot E, Enos EJ, Ferraro MJ. Use of induced sputum specimens for microbiologic diagnosis of infections due to organisms other than Pneumocystis carinii. J Clin Microbiol 1994; 32(1):131–134. 38. Guidelines for Preventing the Transmission of Mycobacterium tuberculosis in Health-Care Settings, 2005. Morb Mortal Wkly Rep 2005.

174

Lam et al.

39. Baughman RP, Dohn MN, Loudon RG, Frame PT. Bronchoscopy with bronchoalveolar lavage in tuberculosis and fungal infections. Chest 1991; 99(1):92–97. 40. Wallace JM, Deutsch AL, Harrell JH, Moser KM. Bronchoscopy and transbronchial biopsy in evaluation of patients with suspected active tuberculosis. Am J Med 1981; 70(6):1189–1194. 41. Conde MB, Soares SL, Mello FC, et al. Comparison of sputum induction with fiberoptic bronchoscopy in the diagnosis of tuberculosis: experience at an acquired immune deficiency syndrome reference center in Rio de Janeiro, Brazil. Am J Respir Crit Care Med 2000; 162(6):2238–2240. 42. Diagnostic standards and classification of tuberculosis in adults and children. This official statement of the American Thoracic Society and the Centers for Disease Control and Prevention was adopted by the ATS Board of Directors, July 1999. This statement was endorsed by the Council of the Infectious Disease Society of America, September 1999. Am J Respir Crit Care Med 2000; 161(4 pt 1): 1376–1395. 43. Daniel TM. Rapid diagnosis of tuberculosis: laboratory techniques applicable in developing countries. Rev Infect Dis 1989; 11(suppl 2):S471–S478. 44. Greenbaum M, Beyt BE Jr., Murray PR. The accuracy of diagnosing pulmonary tuberculosis at a teaching hospital. Am Rev Respir Dis 1980; 121(3):477–481. 45. Levy H, Feldman C, Sacho H, van der MH, Kallenbach J, Koornhof H. A reevaluation of sputum microscopy and culture in the diagnosis of pulmonary tuberculosis. Chest 1989; 95(6):1193–1197. 46. Long R, Scalcini M, Manfreda J, Jean-Baptiste M, Hershfield E. The impact of HIV on the usefulness of sputum smears for the diagnosis of tuberculosis. Am J Public Health 1991; 81(10):1326–1328. 47. Yajko DM, Nassos PS, Sanders CA, Madej JJ, Hadley WK. High predictive value of the acid-fast smear for Mycobacterium tuberculosis despite the high prevalence of Mycobacterium avium complex in respiratory specimens. Clin Infect Dis 1994; 19(2):334–336. 48. Cruciani M, Scarparo C, Malena M, Bosco O, Serpelloni G, Mengoli C. Meta-analysis of BACTEC MGIT 960 and BACTEC 460 TB, with or without solid media, for detection of mycobacteria. J Clin Microbiol 2004; 42(5): 2321–2325. 49. Gordin FM, Slutkin G, Schecter G, Goodman PC, Hopewell PC. Presumptive diagnosis and treatment of pulmonary tuberculosis based on radiographic findings. Am Rev Respir Dis 1989; 139(5):1090–1093. 50. Talavera W, Lessnau KK, Handwerger S. Extrapulmonary tuberculosis. In: Friedman LN, ed. Tuberculosis: Current Concepts and Treatment. Boca Raton: CRC Press, 1994. 51. Thornton GF. Extrapulmonary tuberculosis, excluding the central nervous system. In: Rossman MD, MacGregor RR, eds. Tuberculosis: Clinical Management and New Challenges. New York: McGraw Hill, 1995. 52. Christensen WI. Genitourinary tuberculosis: review of 102 cases. Medicine (Baltimore) 1974; 53(5):377–390. 53. Marshall JB. Tuberculosis of the gastrointestinal tract and peritoneum. Am J Gastroenterol 1993; 88(7):989–999. 54. Ribera E, Ocana I, Martinez-Vazquez JM, Rossell M, Espanol T, Ruibal A. High level of interferon gamma in tuberculous pleural effusion. Chest 1988; 93(2):308–311. 55. Valdes L, San Jose E, Alvarez D, et al. Diagnosis of tuberculous pleurisy using the biologic parameters adenosine deaminase, lysozyme, and interferon gamma. Chest 1993; 103(2):458–465.

Diagnosis of Pulmonary and Extrapulmonary Tuberculosis

175

56. Clarridge JE III, Shawar RM, Shinnick TM, Plikaytis BB. Large-scale use of polymerase chain reaction for detection of Mycobacterium tuberculosis in a routine mycobacteriology laboratory. J Clin Microbiol 1993; 31(8):2049–2056. 57. Eisenach KD, Sifford MD, Cave MD, Bates JH, Crawford JT. Detection of Mycobacterium tuberculosis in sputum samples using a polymerase chain reaction. Am Rev Respir Dis 1991; 144(5):1160–1163. 58. Woods GL. The mycobacteriology laboratory and new diagnostic techniques. Infect Dis Clin North Am 2002; 16(1):127–144. 59. Mathur P, Sacks L, Auten G, Sall R, Levy C, Gordin F. Delayed diagnosis of pulmonary tuberculosis in city hospitals. Arch Intern Med 1994; 154(3):306–310. 60. Alcala L, Ruiz-Serrano MJ, Hernangomez S, et al. Evaluation of the upgraded amplified Mycobacterium tuberculosis direct test (gen-probe) for direct detection of Mycobacterium tuberculosis in respiratory and non-respiratory specimens. Diagn Microbiol Infect Dis 2001; 41(1–2):51–56. 61. Bergmann JS, Woods GL. Enhanced amplified Mycobacterium tuberculosis direct test for detection of Mycobacterium tuberculosis complex in positive BACTEC 12B broth cultures of respiratory specimens. J Clin Microbiol 1999; 37(6): 2099–2101. 62. Bodmer T, Mockl E, Muhlemann K, Matter L. Improved performance of GenProbe Amplified Mycobacterium tuberculosis Direct Test when 500 instead of 50 microliters of decontaminated sediment is used. J Clin Microbiol 1996; 34(1): 222–223. 63. Chedore P, Jamieson FB. Routine use of the Gen-Probe MTD2 amplification test for detection of Mycobacterium tuberculosis in clinical specimens in a large public health mycobacteriology laboratory. Diagn Microbiol Infect Dis 1999; 35(3): 185–191. 64. Coll P, Garrigo M, Moreno C, Marti N. Routine use of Gen-Probe Amplified Mycobacterium Tuberculosis Direct (MTD) test for detection of Mycobacterium tuberculosis with smear-positive and smear-negative specimens. Int J Tuberc Lung Dis 2003; 7(9):886–891. 65. Gamboa F, Fernandez G, Padilla E, et al. Comparative evaluation of initial and new versions of the Gen-Probe Amplified Mycobacterium tuberculosis Direct Test for direct detection of Mycobacterium tuberculosis in respiratory and nonrespiratory specimens. J Clin Microbiol 1998; 36(3):684–689. 66. Jonas V, Alden MJ, Curry JI, et al. Detection and identification of Mycobacterium tuberculosis directly from sputum sediments by amplification of rRNA. J Clin Microbiol 1993; 31(9):2410–2416. 67. O’Sullivan CE, Miller DR, Schneider PS, Roberts GD. Evaluation of Gen-Probe amplified mycobacterium tuberculosis direct test by using respiratory and nonrespiratory specimens in a tertiary care center laboratory. J Clin Microbiol 2002; 40(5):1723–1727. 68. Smith MB, Bergmann JS, Onoroto M, Mathews G, Woods GL. Evaluation of the enhanced amplified Mycobacterium tuberculosis direct test for direct detection of Mycobacterium tuberculosis complex in respiratory specimens. Arch Pathol Lab Med 1999; 123(11):1101–1103. 69. Carpentier E, Drouillard B, Dailloux M, et al. Diagnosis of tuberculosis by Amplicor Mycobacterium tuberculosis test: a multicenter study. J Clin Microbiol 1995; 33(12):3106–3110. 70. Cartuyvels R, De Ridder C, Jonckheere S, Verbist L, Van Eldere J. Prospective clinical evaluation of Amplicor Mycobacterium tuberculosis PCR test as a screening method in a low-prevalence population. J Clin Microbiol 1996; 34(8):2001–2003.

176

Lam et al.

71. Rajalahti I, Vuorinen P, Nieminen MM, Miettinen A. Detection of Mycobacterium tuberculosis complex in sputum specimens by the automated Roche Cobas Amplicor Mycobacterium Tuberculosis Test. J Clin Microbiol 1998; 36(4):975–978. 72. Reischl U, Lehn N, Wolf H, Naumann L. Clinical evaluation of the automated COBAS AMPLICOR MTB assay for testing respiratory and nonrespiratory specimens. J Clin Microbiol 1998; 36(10):2853–2860. 73. Shah JS, Liu J, Buxton D, et al. Detection of Mycobacterium tuberculosis directly from spiked human sputum by Q-beta replicase-amplified assay. J Clin Microbiol 1995; 33(2):322–328. 74. Ausina V, Gamboa F, Gazapo E, et al. Evaluation of the semiautomated Abbott LCx Mycobacterium tuberculosis assay for direct detection of Mycobacterium tuberculosis in respiratory specimens. J Clin Microbiol 1997; 35(8):1996–2002. 75. Lumb R, Davies K, Dawson D, et al. Multicenter evaluation of the Abbott LCx Mycobacterium tuberculosis ligase chain reaction assay. J Clin Microbiol 1999; 37(10):3102–3107. 76. Palacios JJ, Ferro J, Ruiz PN, et al. Comparison of the ligase chain reaction with solid and liquid culture media for routine detection of Mycobacterium tuberculosis in nonrespiratory specimens. Eur J Clin Microbiol Infect Dis 1998; 17(11):767–772. 77. Rantakokko-Jalava K, Marjamaki M, Marttila H, Makela L, Valtonen V, Viljanen MK. LCx Mycobacterium tuberculosis assay is valuable with respiratory specimens, but provides little help in the diagnosis of extrapulmonary tuberculosis. Ann Med 2001; 33(1):55–62. 78. Bergmann JS, Keating WE, Woods GL. Clinical evaluation of the BDProbeTec ET system for rapid detection of Mycobacterium tuberculosis. J Clin Microbiol 2000; 38(2):863–865. 79. Little MC, Andrews J, Moore R, et al. Strand displacement amplification and homogeneous real-time detection incorporated in a second-generation DNA probe system, BDProbeTecET. Clin Chem 1999; 45(6 pt 1):777–784. 80. Mazzarelli G, Rindi L, Piccoli P, Scarparo C, Garzelli C, Tortoli E. Evaluation of the BDProbeTec ET system for direct detection of Mycobacterium tuberculosis in pulmonary and extrapulmonary samples: a multicenter study. J Clin Microbiol 2003; 41(4):1779–1782. 81. Update: nucleic acid amplification tests for tuberculosis. Morb Mortal Wkly Rep 2000; 49(26):593–594. 82. Cloud JL, Shutt C, Aldous W, Woods G. Evaluation of a modified Gen-Probe amplified direct test for detection of Mycobacterium tuberculosis complex organisms in cerebrospinal fluid. J Clin Microbiol 2004; 42(11):5341–5344. 83. D’Amato RF, Hochstein LH, Colaninno PM, et al. Application of the Roche Amplicor Mycobacterium tuberculosis (PCR) test to specimens other than respiratory secretions. Diagn Microbiol Infect Dis 1996; 24(1):15–17. 84. Ehlers S, Ignatius R, Regnath T, Hahn H. Diagnosis of extrapulmonary tuberculosis by Gen-Probe amplified Mycobacterium tuberculosis direct test. J Clin Microbiol 1996; 34(9):2275–2279. 85. Gamboa F, Dominguez J, Padilla E, et al. Rapid diagnosis of extrapulmonary tuberculosis by ligase chain reaction amplification. J Clin Microbiol 1998; 36(5):1324– 1329. 86. Portillo-Gomez L, Morris SL, Panduro A. Rapid and efficient detection of extrapulmonary Mycobacterium tuberculosis by PCR analysis. Int J Tuberc Lung Dis 2000; 4(4):361–370. 87. Rajo MC, Perez Del Molina ML, Lado Lado FL, Lopez MJ, Prieto E, Pardo F. Rapid diagnosis of tuberculous meningitis by ligase chain reaction amplification. Scand J Infect Dis 2002; 34(1):14–16.

Diagnosis of Pulmonary and Extrapulmonary Tuberculosis

177

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.

178

Lam et al.

106. Sechi LA, Pinna MP, Sanna A, et al. Detection of Mycobacterium tuberculosis by PCR analysis of urine and other clinical samples from AIDS and non-HIV-infected patients. Mol Cell Probes 1997; 11(4):281–285. 107. Mitarai S, Shishido H, Kurashima A, Tamura A, Nagai H. Comparative study of amplicor Mycobacterium PCR and conventional methods for the diagnosis of pleuritis caused by mycobacterial infection. Int J Tuberc Lung Dis 2000; 4(9):871–876. 108. Nagesh BS, Sehgal S, Jindal SK, Arora SK. Evaluation of polymerase chain reaction for detection of Mycobacterium tuberculosis in pleural fluid. Chest 2001; 119(6):1737–1741. 109. Villena V, Rebollo MJ, Aguado JM, Galan A, Lopez EA, Palenque E. Polymerase chain reaction for the diagnosis of pleural tuberculosis in immunocompromised and immunocompetent patients. Clin Infect Dis 1998; 26(1):212–214. 110. 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. 111. Johansen IS, Lundgren B, Tabak F, et al. Improved sensitivity of nucleic acid amplification for rapid diagnosis of tuberculous meningitis. J Clin Microbiol 2004; 42(7):3036–3040. 112. Al Zahrani K, Al Jahdali H, Poirier L, Rene P, Gennaro ML, Menzies D. Accuracy and utility of commercially available amplification and serologic tests for the diagnosis of minimal pulmonary tuberculosis. Am J Respir Crit Care Med 2000; 162 (4 pt 1):1323–1329. 113. Piersimoni C, Scarparo C, Piccoli P, et al. Performance assessment of two commercial amplification assays for direct detection of Mycobacterium tuberculosis complex from respiratory and extrapulmonary specimens. J Clin Microbiol 2002; 40(11):4138–4142. 114. Sloutsky A, Han LL, Werner BG. Practical strategies for performance optimization of the enhanced gen-probe amplified mycobacterium tuberculosis direct test. J Clin Microbiol 2004; 42(4):1547–1551. 115. Kerleguer A, Koeck JL, Fabre M, Gerome P, Teyssou R, Herve V. Use of equivocal zone in interpretation of results of the amplified mycobacterium tuberculosis direct test for diagnosis of tuberculosis. J Clin Microbiol 2003; 41(4): 1783–1784. 116. Middleton AM, Cullinan P, Wilson R, Kerr JR, Chadwick MV. Interpreting the results of the amplified Mycobacterium tuberculosis direct test for detection of M. tuberculosis rRNA. J Clin Microbiol 2003; 41(6):2741–2743. 117. Rapid diagnostic tests for tuberculosis: what is the appropriate use? American Thoracic Society Workshop. Am J Respir Crit Care Med 1997; 155(5):1804–1814. 118. Chin DP, Yajko DM, Hadley WK, et al. Clinical utility of a commercial test based on the polymerase chain reaction for detecting Mycobacterium tuberculosis in respiratory specimens. Am J Respir Crit Care Med 1995; 151(6):1872–1877. 119. Cohen RA, Muzaffar S, Schwartz D, et al. Diagnosis of pulmonary tuberculosis using PCR assays on sputum collected within 24 hours of hospital admission. Am J Respir Crit Care Med 1998; 157(1):156–161. 120. Lim TK, Mukhopadhyay A, Gough A, et al. Role of clinical judgment in the application of a nucleic acid amplification test for the rapid diagnosis of pulmonary tuberculosis. Chest 2003; 124(3):902–908. 121. Schluger NW, Rom WN. The polymerase chain reaction in the diagnosis and evaluation of pulmonary infections. Am J Respir Crit Care Med 1995; 152(1):11–16. 122. Lim TK, Gough A, Chin NK, Kumarasinghe G. Relationship between estimated pretest probability and accuracy of automated Mycobacterium tuberculosis assay in smear-negative pulmonary tuberculosis. Chest 2000; 118(3):641–647.

Diagnosis of Pulmonary and Extrapulmonary Tuberculosis

179

123. Wisnivesky JP, Kaplan J, Henschke C, McGinn TG, Crystal RG. Evaluation of clinical parameters to predict Mycobacterium tuberculosis in inpatients. Arch Intern Med 2000; 160(16):2471–2476. 124. Della-Latta P, Whittier S. Comprehensive evaluation of performance, laboratory application, and clinical usefulness of two direct amplification technologies for the detection of Mycobacterium tuberculosis complex. Am J Clin Pathol 1998; 110(3):301–310. 125. Gamboa F, Manterola JM, Lonca J, et al. Comparative evaluation of two commercial assays for direct detection of Mycobacterium tuberculosis in respiratory specimens. Eur J Clin Microbiol Infect Dis 1998; 17(3):151–157. 126. Ichiyama S, Iinuma Y, Tawada Y, et al. Evaluation of Gen-Probe Amplified Mycobacterium Tuberculosis Direct Test and Roche PCR-microwell plate hybridization method (AMPLICOR MYCOBACTERIUM) for direct detection of mycobacteria. J Clin Microbiol 1996; 34(1):130–133. 127. Scarparo C, Piccoli P, Rigon A, Ruggiero G, Scagnelli M, Piersimoni C. Comparison of enhanced Mycobacterium tuberculosis amplified direct test with COBAS AMPLICOR Mycobacterium tuberculosis assay for direct detection of Mycobacterium tuberculosis complex in respiratory and extrapulmonary specimens. J Clin Microbiol 2000; 38(4):1559–1562. 128. Visca P, De Mori P, Festa A, Montrone ML, Amicosante M, Pucillo LP. Evaluation of the BDProbeTec strand displacement amplification assay in comparison with the AMTD II direct test for rapid diagnosis of tuberculosis. Clin Microbiol Infect 2004; 10(4):332–334. 129. Iinuma Y, Senda K, Fujihara N, et al. Comparison of the BDProbeTec ET system with the Cobas Amplicor PCR for direct detection of Mycobacterium tuberculosis in respiratory samples. Eur J Clin Microbiol Infect Dis 2003; 22(6):368–371. 130. Burkardt HJ. Standardization and quality control of PCR analyses. Clin Chem Lab Med 2000; 38(2):87–91. 131. Noordhoek GT, van Embden JD, Kolk AH. Reliability of nucleic acid amplification for detection of Mycobacterium tuberculosis: an international collaborative quality control study among 30 laboratories. J Clin Microbiol 1996; 34(10):2522–2525. 132. Noordhoek GT, Mulder S, Wallace P, van Loon AM. Multicentre quality control study for detection of Mycobacterium tuberculosis in clinical samples by nucleic amplification methods. Clin Microbiol Infect 2004; 10(4):295–301. 133. Ridderhof JC, Williams LO, Legois S, et al. Assessment of laboratory performance of nucleic acid amplification tests for detection of Mycobacterium tuberculosis. J Clin Microbiol 2003; 41(11):5258–5261. 134. Doern GV. Diagnostic mycobacteriology: where are we today? J Clin Microbiol 1996; 34(8):1873–1876. 135. Dowdy DW, Maters A, Parrish N, Beyrer C, Dorman SE. Cost-effectiveness analysis of the gen-probe amplified mycobacterium tuberculosis direct test as used routinely on smear-positive respiratory specimens. J Clin Microbiol 2003; 41(3): 948–953. 136. Lim TK, Cherian J, Poh KL, Leong TY. The rapid diagnosis of smear-negative pulmonary tuberculosis: a cost-effectiveness analysis. Respirology 2000; 5(4): 403–409. 137. Kambashi B, Mbulo G, McNerney R, et al. Utility of nucleic acid amplification techniques for the diagnosis of pulmonary tuberculosis in sub-Saharan Africa. Int J Tuberc Lung Dis 2001; 5(4):364–369. 138. Roos BR, van Cleeff MR, 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 Tuberc Lung Dis 1998; 2(3):235–241.

180

Lam et al.

139. Garg SK, Tiwari RP, Tiwari D, et al. Diagnosis of tuberculosis: available technologies, limitations, and possibilities. J Clin Lab Anal 2003; 17(5):155–163. 140. Laal S, Samanich KM, Sonnenberg MG, et al. Surrogate marker of preclinical tuberculosis in human immunodeficiency virus infection: antibodies to an 88-kDa secreted antigen of Mycobacterium tuberculosis. J Infect Dis 1997; 176(1): 133–143. 141. Andersen P, Munk ME, Pollock JM, Doherty TM. Specific immune-based diagnosis of tuberculosis. Lancet 2000; 356(9235):1099–1104. 142. Lodha R, Kabra SK. Newer diagnostic modalities for tuberculosis. Indian J Pediatr 2004; 71(3):221–227. 143. Chan ED, Heifets L, Iseman MD. Immunologic diagnosis of tuberculosis: a review. Tuber Lung Dis 2000; 80(3):131–140. 144. Okuda Y, Maekura R, Hirotani A, et al. Rapid serodiagnosis of active pulmonary Mycobacterium tuberculosis by analysis of results from multiple antigen-specific tests. J Clin Microbiol 2004; 42(3):1136–1141. 145. Silva VM, Kanaujia G, Gennaro ML, Menzies D. Factors associated with humoral response to ESAT-6, 38 kDa and 14 kDa in patients with a spectrum of tuberculosis. Int J Tuberc Lung Dis 2003; 7(5):478–484. 146. Talbot EA, Hay B, Hone NM, et al. Tuberculosis serodiagnosis in a predominantly HIV-infected population of hospitalized patients with cough, Botswana, 2002. Clin Infect Dis 2004; 39(1):e1–e7. 147. Houghton RL, Lodes MJ, Dillon DC, et al. Use of multiepitope polyproteins in serodiagnosis of active tuberculosis. Clin Diagn Lab Immunol 2002; 9(4):883–891. 148. Balestrino EA, Daniel TM, de Latini MD, Latini OA, Ma Y, Scocozza JB. Serodiagnosis of pulmonary tuberculosis in Argentina by enzyme-linked immunosorbent assay (ELISA) of IgG antibody to Mycobacterium tuberculosis antigen 5 and tuberculin purified protein derivative. Bull World Health Organ 1984; 62(5):755–761. 149. Ma Y, Wang YM, Daniel TM. Enzyme-linked immunosorbent assay using Mycobacterium tuberculosis antigen 5 for the diagnosis of pulmonary tuberculosis in China. Am Rev Respir Dis 1986; 134(6):1273–1275. 150. Bothamley G, Beck JS, Britton W, Elsaghier A, Ivanyi J. Antibodies to Mycobacterium tuberculosis-specific epitopes in lepromatous leprosy. Clin Exp Immunol 1991; 86(3):426–432. 151. Sada E, Brennan PJ, Herrera T, Torres M. Evaluation of lipoarabinomannan for the serological diagnosis of tuberculosis. J Clin Microbiol 1990; 28(12): 2587–2590. 152. Sada E, Ferguson LE, Daniel TM. An ELISA for the serodiagnosis of tuberculosis using a 30,000-Da native antigen of Mycobacterium tuberculosis. J Infect Dis 1990; 162(4):928–931. 153. Uma Devi KR, Ramalingam B, Raja A. Antibody response to Mycobacterium tuberculosis 30 and 16kDa antigens in pulmonary tuberculosis with human immunodeficiency virus coinfection. Diagn Microbiol Infect Dis 2003; 46(3):205–209. 154. Munk ME, Arend SM, Brock I, Ottenhoff TH, Andersen P. Use of ESAT-6 and CFP-10 antigens for diagnosis of extrapulmonary tuberculosis. J Infect Dis 2001; 183(1):175–176. 155. Doherty TM, Demissie A, Olobo J, et al. Immune responses to the Mycobacterium tuberculosis-specific antigen ESAT-6 signal subclinical infection among contacts of tuberculosis patients. J Clin Microbiol 2002; 40(2):704–706. 156. Scarpellini P, Tasca S, Galli L, Beretta A, Lazzarin A, Fortis C. Selected pool of peptides from ESAT-6 and CFP-10 proteins for detection of Mycobacterium tuberculosis infection. J Clin Microbiol 2004; 42(8):3469–3474.

Diagnosis of Pulmonary and Extrapulmonary Tuberculosis

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157. Bothamley GH, Rudd R, Festenstein F, Ivanyi J. Clinical value of the measurement of Mycobacterium tuberculosis specific antibody in pulmonary tuberculosis. Thorax 1992; 47(4):270–275. 158. Kanaujia GV, Lam PK, Perry S, Brusasca PN, Catanzaro A, Gennaro ML. Integration of microscopy and serodiagnostic tests to screen for active tuberculosis. Int J Tuberc Lung Dis 2005; 9(10):1120–1126. 159. van Pinxteren LA, Ravn P, Agger EM, Pollock J, Andersen P. Diagnosis of tuberculosis based on the two specific antigens ESAT-6 and CFP10. Clin Diagn Lab Immunol 2000; 7(2):155–160. 160. Pottumarthy S, Wells VC, Morris AJ. A comparison of seven tests for serological diagnosis of tuberculosis. J Clin Microbiol 2000; 38(6):2227–2231. 161. Perkins MD, Conde MB, Martins M, Kritski AL. Serologic diagnosis of tuberculosis using a simple commercial multiantigen assay. Chest 2003; 123(1):107–112. 162. Maekura R, Kohno H, Hirotani A, et al. Prospective clinical evaluation of the serologic tuberculous glycolipid test in combination with the nucleic acid amplification test. J Clin Microbiol 2003; 41(3):1322–1325.

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 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

Diagnosis of Latent Tuberculosis Infection

223

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.

Diagnosis of Latent Tuberculosis Infection

225

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

226

Menzies and Doherty

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.

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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 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

Treatment of Latent TB Infection

277

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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279

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

Treatment of Latent TB Infection

281

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

282

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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

Treatment of Latent TB Infection

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 ( 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.

338

Munoz and Starke

34. Khouri YF, Mastrucci MT, Hutto C, Mitchell CD, Scott GB. Mycobacterium tuberculosis in children with human immunodeficiency virus type 1 infection. Pediatr Infect Dis J 1992; 11(11):950–955. 35. Moss WJ, Dedyo T, Suarez M, Nicholas SW, Abrams E. Tuberculosis in children infected with human immunodeficiency virus: a report of five cases. Pediatr Infect Dis J 1992; 11(2):114–116. 36. Mukadi YD, Wiktor SZ, Coulibaly IM, et al. Impact of HIV infection on the development, clinical presentation, and outcome of tuberculosis among children in Abidjan, Cote d’Ivoire. AIDS 1997; 11(9):1151–1158. 37. Schaaf HS, Geldenduys A, Gie RP, Cotton MF. Culture-positive tuberculosis in human immunodeficiency virus type 1-infected children. Pediatr Infect Dis J 1998; 17(7):599–604. 38. Garay JE. Clinical presentation of pulmonary tuberculosis in under 10s and differences in AIDS-related cases: a cohort study of 115 patients. Trop Doct 1997; 27(3):139–142. 39. Mazade MA, Evans EM, Starke JR, Correa AG. Congenital tuberculosis presenting as sepsis syndrome: case report and review of the literature. Pediatr Infect Dis J 2001; 20(4):439–442. 40. Chadha VK, Jagannatha PS, Kumar P. Can BCG-vaccinated children be included in tuberculin surveys to estimate the annual risk of tuberculous infection in India? Int J Tuberc Lung Dis 2004; 8(12):1437–1442. 41. Chadha VK, Agarwal SP, Kumar P, et al. Annual risk of tuberculous infection in four defined zones of India: a comparative picture. Int J Tuberc Lung Dis 2005; 9(5):569–575. 42. Barry MA, Shirley L, Grady MT, et al. Tuberculosis infection in urban adolescents: results of a school-based testing program. Am J Public Health 1990; 80(4):439–441. 43. Davidson PT, Ashkar B, Salem N. Tuberculosis testing of children entering school in Los Angeles County, California [abstr]. Am Rev Respir Dis 1990; 141:A336. 44. Wallgren A. The time table of tuberculosis. Tubercle 1948; 29:245–256. 45. Adhikari M, Pillay T, Pillay DG. Tuberculosis in the newborn: an emerging disease. Pediatr Infect Dis J 1997; 16(12):1108–1112. 46. Grenville-Mathers R, Harris WC, Trenchard HJ. Tuberculous primary infection in pregnancy and its relation to congenital tuberculosis. Tubercle 1960; 41: 181–185. 47. Hageman J, Shulman S, Schreiber M, Luck S, Yogev R. Congenital tuberculosis: critical reappraisal of clinical findings and diagnostic procedures. Pediatrics 1980; 66(6):980–984. 48. Stallworth JR, Brasfield DM, Tiller RE. Congenital miliary tuberculosis proved by open lung biopsy specimen and successfully treated. Am J Dis Child 1980; 134(3):320–321. 49. Nemir RL, O’Hare D. Congenital tuberculosis. Review and diagnostic guidelines. Am J Dis Child 1985; 139(3):284–287. 50. Kaplan C, Benirschke K, Tarzy B. Placental tuberculosis in early and late pregnancy. Am J Obstet Gynecol 1980; 137(7):858–860. 51. Hallum JL, Thomas HE. Full-time pregnancy after proved endometrial tuberculosis. J Obstet Gynaecol Br Emp 1955; 62(4):548–550. 52. Hughesdon MR. Congenital tuberculosis. Arch Dis Child 1946; 21:121–126. 53. Jacobs RF, Abernathy RS. Management of tuberculosis in pregnancy and the newborn. Clin Perinatol 1988; 15(2):305–319. 54. Delacourt C, Mani TM, Bonnerot V, et al. Computed tomography with normal chest radiograph in tuberculous infection. Arch Dis Child 1993; 69(4):430–432.

Childhood Tuberculosis

339

55. Daly JF, Brown DS, Lincoln EM, Wilking VN. Endobronchial tuberculosis in children. Dis Chest 1952; 22(4):380–398. 56. Lincoln EM, Harris LC, Bovornkitti S, Carretero R. The course and prognosis of endobronchial tuberculosis in children. Am Rev Tuberc 1956; 74(2 Part 2): 246–255. 57. Lorriman G, Bentley FJ. The incidence of segmental lesions in primary tuberculosis in childhood with special reference to the effect of chemotherapy. Am Rev Tuberc 1959; 79(6):756–763. 58. Morrison JB. Natural history of segmental lesions in primary pulmonary tuberculosis: long-term review of 383 patients. Arch Dis Child 1973; 48(2):90–98. 59. Matsaniotis N, Kattamis C, Economou-Mavrou E, Kyriazakou M. Bullous emphysema in childhood tuberculosis. J Pediatr 1967; 71(5):703–708. 60. Stansberry SD. Tuberculosis in infants and children. J Thorac Imaging 1990; 5(2):17–27. 61. Giammona ST, Poole CA, Zelkowitz P, Skrovan C. Massive lymphadenopathy in primary pulmonary tuberculosis in children. Am Rev Respir Dis 1969; 100(4): 480–489. 62. Lincoln EM, Gilbert LA, Morales SM. Chronic pulmonary tuberculosis in individuals with known previous primary tuberculosis. Dis Chest 1960; 38:473–482. 63. Smith MH, Matsaniotis N. Treatment of tuberculous pleural effusions with particular reference to adrenal corticosteroids. Pediatrics 1958; 22(6):1074–1087. 64. Lincoln EM, Davies PA, Bovornkitti S. Tuberculous pleurisy with effusion in children: a study of 202 children with particular reference to prognosis. Am Rev Tuberc 1958; 77(2):271–289. 65. van den Bos F, Terken M, Ypma L, et al. Tuberculous meningitis and miliary tuberculosis in young children. Trop Med Int Health 2004; 9(2):309–313. 66. Sutherland I, Styblo K, Sampalik M, Bleiker MA. Annual risks of tuberculosis infection in 14 countries according to the results of tuberculosis surveys from 1948 to 1952. Bull Int Union Tuberc 1971; 45:80–122. 67. Cammock RM, Miller FJ. Tuberculosis in young children. Lancet 1953; 1(4): 158–160. 68. Waecker NJ Jr., Connor JD. Central nervous system tuberculosis in children: a review of 30 cases. Pediatr Infect Dis J 1990; 9(8):539–543. 69. Idriss ZH, Sinno AA, Kronfol NM. Tuberculous meningitis in childhood. Fortythree cases. Am J Dis Child 1976; 130(4):364–367. 70. Sumaya CV, Simek M, Smith MH, Seidemann MF, Ferriss GS, Rubin W. Tuberculous meningitis in children during the isoniazid era. J Pediatr 1975; 87(1):43–49. 71. Udani PM, Dastur DK. Tuberculous encephalopathy with and without meningitis. Clinical features and pathological correlations. J Neurol Sci 1970; 10(6):541–561. 72. Ramachandran P, Duraipandian M, Nagarajan M, Prabhakar R, Ramakrishnan CV, Tripathy SP. Three chemotherapy studies of tuberculous meningitis in children. Tubercle 1986; 67(1):17–29. 73. Cotton MF, Donald PR, Schoeman JF, Aalbers C, Van Zyl LE, Lombard C. Plasma arginine vasopressin and the syndrome of inappropriate antidiuretic hormone secretion in tuberculous meningitis. Pediatr Infect Dis J 1991; 10(11):837–842. 74. Doerr CA, Starke JR, Ong LT. Clinical and public health aspects of tuberculous meningitis in children. J Pediatr 1995; 127(1):27–33. 75. Bidstrup C, Andersen PH, Skinhoj P, Andersen AB. Tuberculous meningitis in a country with a low incidence of tuberculosis: still a serious disease and a diagnostic challenge. Scand J Infect Dis 2002; 34(11):811–814.

340

Munoz and Starke

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.

Childhood Tuberculosis

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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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138. Martinez-Roig A, Cami J, Llorens-Terol J, de la TR, Perich F. Acetylation phenotype and hepatotoxicity in the treatment of tuberculosis in children. Pediatrics 1986; 77(6):912–915. 139. Pellock JM, Howell J, Kendig EL Jr., Baker H. Pyridoxine deficiency in children treated with isoniazid. Chest 1985; 87(5):658–661. 140. American Academy of Pediatrics Committee on Infectious Diseases. Chemotherapy for tuberculosis in infants and children. Pediatrics 1992; 89(1):161–165. 141. O’Brien RJ, Long MW, Cross FS, Lyle MA, Snider DE Jr. Hepatotoxicity from isoniazid and rifampin among children treated for tuberculosis. Pediatrics 1983; 72(4):491–499. 142. Litt IF, Cohen MI, McNamara H. Isoniazid hepatitis in adolescents. J Pediatr 1976; 89(1):133–135. 143. Girling DJ. The role of pyrazinamide in primary chemotherapy for pulmonary tuberculosis. Tubercle 1984; 65(1):1–4. 144. Starke JR. Multidrug therapy for tuberculosis in children. Pediatr Infect Dis J 1990; 9(11):785–793. 145. Donald PR, Gent WL, Seifart HI, Lamprecht JH, Parkin DP. Cerebrospinal fluid isoniazid concentrations in children with tuberculous meningitis: the influence of dosage and acetylation status. Pediatrics 1992; 89(2):247–250. 146. Zhu M, Starke JR, Burman WJ, et al. Population pharmacokinetic modeling of pyrazinamide in children and adults with tuberculosis. Pharmacotherapy 2002; 22(6):686–695. 147. Zhu M, Burman WJ, Starke JR, et al. Pharmacokinetics of ethambutol in children and adults with tuberculosis. Int J Tuberc Lung Dis 2004; 8(11): 1360–1367. 148. Jagannath C, Reddy MV, Kailasam S, O’Sullivan JF, Gangadharam PR. Chemotherapeutic activity of clofazimine and its analogues against Mycobacterium tuberculosis. In vitro, intracellular, and in vivo studies. Am J Respir Crit Care Med 1995; 151(4):1083–1086. 149. Hussey G, Kibel M, Parker N. Ciprofloxacin treatment of multiply drug-resistant extrapulmonary tuberculosis in a child. Pediatr Infect Dis J 1992; 11(5): 408–409. 150. Hsu KH. Thirty years after isoniazid. Its impact on tuberculosis in children and adolescents. JAMA 1984; 251(10):1283–1285. 151. Abernathy RS, Dutt AK, Stead WW, Moers DJ. Short-course chemotherapy for tuberculosis in children. Pediatrics 1983; 72(6):801–806. 152. Al Dossary FS, Ong LT, Correa AG, Starke JR. Treatment of childhood tuberculosis with a six month directly observed regimen of only two weeks of daily therapy. Pediatr Infect Dis J 2002; 21(2):91–97. 153. Biddulph J. Short course chemotherapy for childhood tuberculosis. Pediatr Infect Dis J 1990; 9(11):794–801. 154. Kumar L, Dhand R, Singhi PD, Rao KL, Katariya S. A randomized trial of fully intermittent vs. daily followed by intermittent short course chemotherapy for childhood tuberculosis. Pediatr Infect Dis J 1990; 9(11):802–806. 155. Centers for Disease Control and Prevention. Initial therapy for tuberculosis in the era of multidrug resistance. MMWR 1993; 42:1–8. 156. Nunn P, Felten M. Surveillance of resistance to antituberculosis drugs in developing countries. Tuber Lung Dis 1994; 75(3):163–167. 157. Dye C, Espinal MA, Watt CJ, Mbiaga C, Williams BG. Worldwide incidence of multidrug-resistant tuberculosis. J Infect Dis 2002; 185(8):1197–1202. 158. Bloch AB, Cauthen GM, Onorato IM, et al. Nationwide survey of drug-resistant tuberculosis in the United States. JAMA 1994; 271(9):665–671.

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159. Goble M, Iseman MD, Madsen LA, Waite D, Ackerson L, Horsburgh CR Jr. Treatment of 171 patients with pulmonary tuberculosis resistant to isoniazid and rifampin. N Engl J Med 1993; 328(8):527–532. 160. Park MM, Davis AL, Schluger NW, Cohen H, Rom WN. Outcome of MDR-TB patients, 1983–1993. Prolonged survival with appropriate therapy. Am J Respir Crit Care Med 1996; 153(1):317–324. 161. Telzak EE, Sepkowitz K, Alpert P, et al. Multidrug-resistant tuberculosis in patients without HIV infection. N Engl J Med 1995; 333(14):907–911. 162. Iseman MD, Goble M. Multidrug-resistant tuberculosis. N Engl J Med 1996; 334(4):267–269. 163. Iseman MD. Treatment of multidrug-resistant tuberculosis. N Engl J Med 1993; 329(11):784–791. 164. Barnes PF, Bloch AB, Davidson PT, Snider DE Jr. Tuberculosis in patients with human immunodeficiency virus infection. N Engl J Med 1991; 324(23):1644–1650. 165. Mofenson L, Oleske J, Serchuck L, Van Dyke R. Treating opportunistic infections among HIV infected children. MMWR 2004; 53(RR14):1–63. 166. Girgis NI, Farid Z, Kilpatrick ME, Sultan Y, Mikhail IA. Dexamethasone adjunctive treatment for tuberculous meningitis. Pediatr Infect Dis J 1991; 10(3): 179–183. 167. Nemir RL, Cardona J, Vaziri F, Toledo R. Prednisone as an adjunct in the chemotherapy of lymph node-bronchial tuberculosis in childhood: a double-blind study. II. Further term observation. Am Rev Respir Dis 1967; 95(3):402–410.

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 ( 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.

Tuberculosis Control and Migration

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13. Wiggley SC. Tuberculosis in Papua New Guinea. In: Proust AJ, ed. History of Tuberculosis in Australia, New Zealand and Papua New Guinea. Canberra: Brogla, 1991:103–118. 14. Chemtob D, Leventhal A, Berlowitz Y, et al. The new National Tuberculosis Control Programme in Israel, a country of high immigration. Int J Tuberc Lung Dis 2003; 7(9):828–836. 15. Chemtob D, Leventhal A, Weiler-Ravell D. Screening and management of tuberculosis in immigrants: the challenge beyond professional competence. Int J Tuberc Lung Dis 2003; 7(10):959–966. 16. Machiavelli N. The Prince. Hertfordshire: Wordsworth Editions Ltd., 1993. 17. Noordegraaf L, Valk G. De Gave Gods [God’s wrath]. Bergen: Octavo, 1988. 18. McNeil WH. Plagues and Peoples. New York: Anchor Press/Doubleday, 1976. 19. Slack P. Responses to plague in early modern Europe: the implications for public health. In: Mack A, ed. In Time of Plague. The History and Social Consequences of the Lethal Epidemic Disease. New York: New York University Press, 1991. 20. Abel EK. From exclusion to expulsion: Mexicans and tuberculosis control in Los Angeles, 1914–1940. Bull Hist Med 2003; 77:823–849. 21. Rosenkrantz BG, Public health and the state. In: Bloom BR, ed. Tuberculosis—The Global View. N Engl J Med; 2002; (346/19):1434–1435. 22. Daniel TM, Bates JH, Downes KA. History of tuberculosis. In: Bloom BR, ed. Tuberculosis: Pathogenesis, Protection and Control. Washington, D.C.: ASM, 1994:13–25. 23. http://www.cdc.gov/nchstp/tb/surv/surv.htm (last accessed Jan 13, 2005). 24. Public Health Agency of Canada. http://www.phac-aspc.gc.ca/tbpc-latb/ index.html. 25. Australian Government Department of Health and Ageing. http://www.health. gov.au. 26. Dr. Kazuhizo Uchimuex, Research Institute of Japan. Japan Anti-TB Association. Statistics of tuberculosis 2002. Tokyo, Japan, 2003. 27. http://www.moh.govt.nz/cd/tbcontrol (last accessed Jan 13, 2005). 28. El Sahly HM, Adams GJ, Soini H, Teeter L, Musser JM, Graviss EA. Epidemiologic differences between United States- and foreign-born tuberculosis patients in Houston, Texas. J Infect Dis 2001; 183(3):461–468. 29. Bloom BR. Tuberculosis—the global view. N Engl J Med 2002; 346(19): 1434–1435. 30. KNCV Tuberculosis Foundation. Index tuberculosis 2001 and 2002. The Hague: KNCV, 2004. 31. Rose AM, 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(3):173– 179. 32. Antunes JL, Waldman EA. The impact of AIDS, immigration and housing overcrowding on tuberculosis deaths in Sao Paulo, Brazil, 1994–1998. Soc Sci Med 2001; 52(7):1071–1080. 33. Wolleswinkel-van BJ, Nagelkerke NJ, Broekmans JF, et al. The impact of immigration on the elimination of tuberculosis in The Netherlands: a model based approach. Int J Tuberc Lung Dis 2002; 6(2):130–136. 34. Toppet M, Malfroot A, Hofman B, et al. Tuberculosis in children: a 13-year follow up of 1714 patients in a Belgian home care centre. Eur J Pediatr 1991; 150(5): 331–335. 35. Snell NJ. Pediatric tuberculosis in immigrants to the United Kingdom from the Indian sub-continent. Indian J Pediatr 1990; 57(5):645–650. 36. Borgdorff MW, Lambregts-van Weezenbeek CSB, Broekmans JF. Aantal illegale tuberculosepatie¨nten in Nederland ten tijde van diagnose [Number of illegal TB

898

37. 38.

39.

40.

41. 42. 43. 44. 45.

46.

47. 48.

49.

50. 51. 52. 53. 54. 55. 56. 57.

Verver and Veen patients in The Netherlands at time of diagnosis]. Tegen de Tuberculose 2000; 96(1):9–11. Asch S, Leake B, Gelberg L. Does fear of immigration authorities deter tuberculosis patients from seeking care? West J Med 1994; 161(4):373–376. Weis SE, Moonan PK, Pogoda JM, et al. Tuberculosis in the foreign-born population of Tarrant county, Texas by immigration status. Am J Respir Crit Care Med 2001; 164(6):953–957. El-Hamad I, Casalini C, Matteelli A, et al. Screening for tuberculosis and latent tuberculosis infection among undocumented immigrants at an unspecialized health service unit. Int J Tuberc Lung Dis 2001; 5(8):712–716. Pang SC, Harrison RH, Brearley J, et al. Tuberculosis surveillance in immigrants through health undertakings in Western Australia. Int J Tuberc Lung Dis 2000; 4(3):232–236. Talbot EA, Moore M, McCray E, et al. Tuberculosis among foreign-born persons in the United States, 1993–1998. JAMA 2000; 284(22):2894–2900. MMWR. Trends in tuberculosis—United States, 1998–2003. MMWR 2004; 53(10):209–214. Watkins RE, Plant AJ, Gushulak BD. Tuberculosis rates among migrants in Australia and Canada. Int J Tuberc Lung Dis 2002; 6(7):641–644. Watkins RE, Plant AJ. Predicting tuberculosis among migrant groups. Epidemiol Infect 2002; 129(3):623–628. Bennett J, Pitman R, Jarman B, et al. A study of the variation in tuberculosis incidence and possible influential variables in Manchester, Liverpool, Birmingham and Cardiff in 1991–1995. Int J Tuberc Lung Dis 2001; 5(2):158–163. Lillebaek T, Andersen AB, Dirksen A, et al. Persistent high incidence of tuberculosis in immigrants in a low-incidence country. Emerg Infect Dis 2002; 8(7): 679–684. Kempainen R, Nelson K, Williams DN, et al. Mycobacterium tuberculosis disease in Somali immigrants in Minnesota. Chest 2001; 119:176–180. Vos AM, Meima A, Verver S, et al. High incidence of pulmonary tuberculosis persists for a decade after immigration in the Netherlands. Emerg Infect Dis 2003; 10(4):736–739. Wobeser WL, Yuan L, Naus M, et al. Expanding the epidemiologic profile: risk factors for active tuberculosis in people immigrating to Ontario. CMAJ 2000; 163(7):823–828. Farah MG, Tverdal A, Selmer R, et al. Tuberculosis in Norway by country of birth, 1986–1999. Int J Tuberc Lung Dis 2003; 7(3):232–235. Gushulak BD. Tuberculosis control in refugees—policy and practices. Int J Tuberc Lung Dis 1998; 2(9 Suppl 1):S87–93. Bhatia S, Dranyi T, Rowley D. A social and demographic study of Tibetan refugees in India. Soc Sci Med 2002; 54(3):411–422. Ishikawa N. [Tuberculosis among immigrants in Japan—epidemiological, clinical and sociological features, and the future of control]. Kekkaku 1995; 70(12):691–703. Kistemann T, Munzinger A, Dangendorf F. Spatial patterns of tuberculosis incidence in Cologne (Germany). Soc Sci Med 2002; 55(1):7–19. Enarson DA, Sjogren I, Grzybowski S. Incidence of tuberculosis among Scandinavian immigrants in Canada. Eur J Respir Dis 1980; 61(3):139–142. Zuber PL, McKenna MT, Binkin NJ, et al. Long-term risk of tuberculosis among foreign-born persons in the United States. JAMA 1997; 278(4):304–307. Scolari C, El-Hamad I, Matteelli A, et al. Incidence of tuberculosis in a community of Senegalese immigrants in Northern Italy. Int J Tuberc Lung Dis 1999; 3(1): 18–22.

Tuberculosis Control and Migration

899

58. Tocque K, Regan M, Remmington T, et al. Social factors associated with increases in tuberculosis notifications. Eur Respir J 1999; 13(3):541–545. 59. Parslow R, El-Shimy NA, Cundall DB, et al. Tuberculosis, deprivation, and ethnicity in Leeds, UK, 1982–1997. Arch Dis Child 2001; 84(2):109–113. 60. Davidow AL, Mangura BT, Napolitano EC, et al. Rethinking the socioeconomics and geography of tuberculosis among foreign-born residents of New Jersey, 1994– 1999. Am J Public Health 2003; 93(6):1007–1012. 61. Wilcke JT, Poulsen S, Askgaard DS, et al. Tuberculosis in a cohort of Vietnamese refugees after arrival in Denmark 1979–1982. Int J Tuberc Lung Dis 1998; 2(3):219–224. 62. Rapiti E, Fano V, Forastiere F, et al. Determinants of tuberculosis in an immigrant population in Rome: a case-control study. Int J Tuberc Lung Dis 1998; 2(6):479–483. 63. Long R, Njoo H, Hershfield E. Tuberculosis: 3. Epidemiology of the disease in Canada. CMAJ 1999; 160(8):1185–1190. 64. Marras TK, Wilson J, Wang EE, et al. Tuberculosis among Tibetan refugee claimants in Toronto: 1998 to 2000. Chest 2003; 124(3):915–921. 65. Marks GB, Bai J, Stewart GJ, et al. Effectiveness of postmigration screening in controlling tuberculosis among refugees: a historical cohort study, 1984–1998. Am J Public Health 2001; 91(11):1797–1799. 66. Wartski SA. Tuberculosis case finding and treatment in Ethiopian immigrants to Israel, 1989–91. Isr J Med Sci 1993; 29(6–7):376–380. 67. Van Burg J, Verver S, Borgdorff MW. The epidemiology of tuberculosis in The Netherlands: implications for screening. Int J Tuberc Lung Dis 2003; 7(2): 139–144. 68. IUAT Efficacy of various durations of isoniazid preventive therapy for tuberculosis: five years of follow-up in the IUAT trial. Bull WHO 1982; 60(4):555–564. 69. Clancy L, Rieder HL, Enarson DA, et al. Tuberculosis elimination in the countries of Europe and other industrialized countries. Eur Respir J 1991; 4(10):1288– 1295. 70. McKenna MT, McCray E, Onorato I. The epidemiology of tuberculosis among foreign-born persons in the United States, 1986 to 1993. N Engl J Med 1995; 332(16):1071–1076. 71. MacIntyre CR, Dwyer B, Streeton JA. The epidemiology of tuberculosis in Victoria. Med J Aust 1993; 159(10):672–677. 72. McCarthy OR. Asian immigrant tuberculosis—the effect of visiting Asia. Br J Dis Chest 1984; 78(3):248–253. 73. Ormerod LP. Tuberculosis and immigration. Br J Hosp Med 1996; 56:209–212. 74. Mortensen J, Lange P, Storm HK, et al. Childhood tuberculosis in a developed country. Eur Respir J 1989; 2(10):985–987. 75. Lobato MN, Hopewell PC. Mycobacterium tuberculosis infection after travel to or contact with visitors from countries with a high prevalence of tuberculosis. Am J Respir Crit Care Med 1998; 158(6):1871–1875. 76. Rosenfeldt V, Paerregaard A, Fuursted K, et al. Childhood tuberculosis in a Scandinavian metropolitan area 1984–93. Scand J Infect Dis 1998; 30(1):53–57. 77. Cobelens FG, van Deutekom H, Draayer-Jansen IW, et al. Risk of infection with Mycobacterium tuberculosis in travellers to areas of high tuberculosis endemicity. Lancet 2000; 356(9228):461–465. 78. Rubel AJ, Garro LC. Social and cultural factors in the successful control of tuberculosis. Publ Health Report 1992; 107:626–636. 79. Wells CD, Ocana M, Moser K. A study of tuberculosis among foreign-born Hispanic persons in the U.S. States bordering Mexico. Am J Respir Crit Care Med 1999; 159(3):834–837.

900

Verver and Veen

80. Steen M. [Tuberculosis among immigrants in Scandinavian medical journals]. Tidsskr Nor Laegeforen 2001; 121:2046–2050. 81. Pedersen JT, Revsbech PA. [Tuberculosis and migration]. Ugeskr Laeger 1999; 161:3440–3443. 82. Cowie RL, Sharpe JW. Tuberculosis among immigrants: interval from arrival in Canada to diagnosis. A 5-year study in southern Alberta. CMAJ 1998; 158: 599–602. 83. British Tuberculosis Association. Tuberculosis among immigrants to England and Wales: A national survey in 1965. Tubercle 1966; 47:145–156. 84. Medical Research Council Cardiothoracic Epidemiology Workgroup. National survey of notifications in England and Wales in 1988. Thorax 1992; 47:770–775. 85. Saraiya M, Binkin NJ. Tuberculosis among migrants. In: Reichman LB, Hershfield ES, ed. Tuberculosis: A Comprehensive International Approach. 2nd ed. New York: Marcel Dekker, Inc., 2000. 86. Melzer M, Storring RA, Bagg LR. Tuberculosis in an area bordering east London: significant local variations when compared to national data. Infection 2000; 28: 103–105. 87. Wang JS, Allen EA, Chao CW, et al. Tuberculosis in British Columbia among immigrants from five Asian countries, 1982–85. Tubercle 1989; 70:179–186. 88. Kjelso C, Andersen P. Tuberculosis 2003, Part 1. Epi-News. Statens Serum Institute. Dept of Epidemiology, Copenhagen, 2004. 89. World Health Organization. Anti-tuberculosis drug resistance in the world: the WHO/IUATLD Global Project on Antituberculosis Drug Resistance Surveillance, Report 3. Geneva, Switzerland, 2004. 90. Gilad J, Borer A, Riesenberg K, et al. Epidemiology and ethnic distribution of multidrug-resistant tuberculosis in southern Israel, 1992–1997: the impact of immigration. Chest 2000; 117:738–743. 91. Esteban J, Granizo JJ, Alvarez-Castillo MC, et al. Drug resistance among Mycobacterium tuberculosis strains in immigrants: is there a real threat everywhere? Clin Microbiol Infect 2004; 10:335–336. 92. Laserson KF, Iademarco MF. Profiling drug resistance in immigrants with tuberculosis. Chest 2000; 117:623–625. 93. Harries AD, Maher D, Graham S, eds. TB/HIV, A Clinical Manual. 2nd ed. Geneva: World Health Organization, 2004. 94. Bonington A, Harden S, Anderson S, et al. HIV-testing study of immigrants with pulmonary tuberculosis. Scand J Infect Dis 1997; 29:461–463. 95. Granich RM, Zuber PL, McMillan M, et al. Tuberculosis among foreign-born residents of southern Florida, 1995. Public Health Rep 1998; 113:552–556. 96. Codecasa LR, Porretta AD, Gori A, et al. Tuberculosis among immigrants from developing countries in the province of Milan, 1993–1996. Int J Tuberc Lung Dis 1999; 3(7):589–595. 97. Sudre P, Pfyffer GE, Bodmer T, et al. Molecular epidemiology of tuberculosis among HIV-infected persons in Switzerland: a countrywide 9-year cohort study. Swiss HIV Cohort Study. Infection 1999; 27(6):323–330. 98. Bouvet E. (Issues addressed by tuberculosis in France in 2003). Med Sci (Paris) 2003; 19:1146–1151. 99. Coker RJ, Bell A, Pitman R, Hayward A, Watson J. Screening programmes for tuberculosis in new entrants across Europe. Int J Tuberc Lung Dis 2004; 8(8): 1022–1026. 100. Moore DA, Lightstone L, Javid B, et al. High rates of tuberculosis in end-stage renal failure: the impact of international migration. Emerg Infect Dis 2002; 8:77–78.

Tuberculosis Control and Migration

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101. Strachan DP, Powell KJ, Thaker A, Millard FJ, Maxwell JD. Vegetarian diet as a risk factor for tuberculosis in immigrant south London Asians. Thorax 1995; 50: 175–180. 102. 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. 103. Menzies D, Chan CH, Vissandjee B. Impact of immigration on tuberculosis infection among Canadian-born schoolchildren and young adults in Montreal. Am J Respir Crit Care Med 1997; 156(6):1915–1921. 104. Wells CD, Zuber PL, Nolan CM, et al. Tuberculosis prevention among foreign-born persons in Seattle—King County, Washington. Am J Respir Crit Care Med 1997; 156(2 Pt 1):573–577. 105. Borgdorff MW, Nagelkerke NJD, Soolingen van D, et al. Analysis of tuberculosis transmission between nationalities in The Netherlands in the period 1993–1995 using DNA fingerprinting. Am J Epidemiol 1998; 147:187–195. 106. Borgdorff MW, Behr MA, Nagelkerke NJ, et al. Transmission of tuberculosis in San Francisco and its association with immigration and ethnicity. Int J Tuberc Lung Dis 2000; 4(4):287–294. 107. Jasmer RM, Ponce de Leon A, Hopewell PC, et al. Tuberculosis in Mexican-born persons in San Francisco: reactivation, acquired infection and transmission. Int J Tuberc Lung Dis 1997; 1(6):536–541. 108. Chin DP, DeRiemer K, Small PM, et al. Differences in contributing factors to tuberculosis incidence in U.S.-born and foreign-born persons. Am J Respir Crit Care Med 1998; 158(6):1797–1803. 109. Lillebaek T, Andersen AB, Bauer J, et al. Risk of Mycobacterium tuberculosis transmission in a low-incidence country due to immigration from high-incidence areas. J Clin Microbiol 2001; 39(3):855–861. 110. Friedman CR, Stoeckle MY, Kreiswirth BN, et al. Transmission of multidrug-resistant tuberculosis in a large urban setting. Am J Respir Crit Care Med 1995; 152(1):355–359. 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; 346(19):1453–1458. 112. Sharnprapai S, Miller AC, Suruki R, et al. Genotyping analyses of tuberculosis cases in U.S.- and foreign-born Massachusetts residents. Emerg Infect Dis 2002; 8(11):1239–1245. 113. Heldal E, Dahle UR, Sandven P, et al. Risk factors for recent transmission of Mycobacterium tuberculosis. Eur Respir J 2003; 22(4):637–642. 114. De Bruyn G, Adams GJ, Teeter LD, et al. The contribution of ethnicity to Mycobacterium tuberculosis strain clustering. Int J Tuberc Lung Dis 2001; 5(7):633–641. 115. Gutierrez MC, Vincent V, Aubert D, et al. Molecular fingerprinting of Mycobacterium tuberculosis and risk factors for tuberculosis transmission in Paris, France, and surrounding area. J Clin Microbiol 1998; 36(2):486–492. 116. Murray MB. Molecular epidemiology and the dynamics of tuberculosis transmission among foreign-born people. CMAJ 2002; 167(4):355–356. 117. Kulaga S, Behr M, Musana K, et al. Molecular epidemiology of tuberculosis in Montreal. CMAJ 2002; 167(4):353–354. 118. Brudey K, Gordon M, Mostrom P, et al. Molecular epidemiology of Mycobacterium tuberculosis in western Sweden. J Clin Microbiol 2004; 42(7):3046–3051. 119. Matteelli A, Gori A, Pinsi G, et al. Clustering of tuberculosis among Senegalese immigrants in Italy. Int J Tuberc Lung Dis 2003; 7(10):967–972.

902

Verver and Veen

120. 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(24):1710–1716. 121. van Soolingen D, Borgdorff MW, de Haas PE, et al. Molecular epidemiology of tuberculosis in the Netherlands: a nationwide study from 1993 through 1997. J Infect Dis 1999; 180(3):726–736. 122. Maguire H, Dale JW, McHugh TD, et al. Molecular epidemiology of tuberculosis in London 1995–7 showing low rate of active transmission. Thorax 2002; 57(7): 617–622. 123. 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. 124. Behr MA, Hopewell PC, Paz EA, et al. Predictive value of contact investigation for identifying recent transmission of Mycobacterium tuberculosis. Am J Respir Crit Care Med 1998; 158(2):465–469. 125. Verver S, van Soolingen D, Borgdorff MW. Effect of screening of immigrants on tuberculosis transmission. Int J Tuberc Lung Dis 2002; 6:121–129. 126. Diel R, Rusch-Gerdes S, Niemann S. Molecular epidemiology of tuberculosis among immigrants in Hamburg, Germany. J Clin Microbiol 2004; 42(7): 2952–2960. 127. Kenyon TA, Driver C, Haas E, et al. Immigration and tuberculosis among children on the United States–Mexico border, County of San Diego, California. Pediatrics 1999; 104(1):e8. 128. Borgdorff MW, Nagelkerke NJ, de Haas PE, et al. Transmission of Mycobacterium tuberculosis depending on the age and sex of source cases. Am J Epidemiol 2001; 154(10):934–943. 129. Bennett DE, Onorato IM, Ellis BA, et al. DNA fingerprinting of Mycobacterium tuberculosis isolates from epidemiologically linked case pairs. Emerg Infect Dis 2002; 8(11):1224–1229. 130. Lambregts-van Weezenbeek CS, Sebek MM, van Gerven PJ, 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 suppl 3):S463–S470. 131. van Deutekom H, Hoijng SP, de Haas PE, 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. 132. MMWR. Recommendations for prevention and control of tuberculosis among foreign-born persons. Report of the Working Group on Tuberculosis among Foreign-Born Persons. Centers for Disease Control and Prevention. MMWR Recomm Rep 1998; 47(RR-16):1–29. 133. Wolfheze, 2000 (questionnaire during Wolfheze conference for TB control in European Region in 2000). 134. Institute of Medicine (US). Ending neglect: the elimination of tuberculosis in the United States. Washington, D.C.: National Academy Press, 2000. 135. Heywood N, Kawa B, Long R, et al. Guidelines for the investigation and follow-up of individuals under medical surveillance for tuberculosis after arriving in Canada: a summary. CMAJ 2003; 168(12):1563–1565. 136. Menzies D. Screening immigrants to Canada for tuberculosis: chest radiography or tuberculin skin testing? CMAJ 2003; 169(10):1035–1036. 137. Tan L, Altman RD, Nielsen NH, et al. Screening nonimmigrant visitors to the United States for tuberculosis: report of the Council on Scientific Affairs. Arch Intern Med 2001; 161(3):334–340.

Tuberculosis Control and Migration

903

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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Verver and Veen

159. Khan K, Muennig P, Behta M, et al. Global Drug-resistance patterns and the management of latent tuberculosis infection in immigrants to the United States. N Engl J Med 2002; 347:1850–1859. 160. American Thoracic Society. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med 2000; 161:S221–S247. 161. Van den Brande P, Uydebrouck M, Vermeire P, et al. Tuberculosis in asylum seekers in Belgium. VRGT (Flemish Lung and Tuberculosis Association). Eur Respir J 1997; 10(3):610–614. 162. Wartski SA. Tuberculosis in Ethiopian immigrants. Isr J Med Sci 1991; 27(5): 288–292. 163. Verver S, Bwire R, Borgdorff MW. Screening for pulmonary tuberculosis among immigrants: estimated effect on severity of disease and duration of infectiousness. Int J Tuberc Lung Dis 2001; 5(5):419–425. 164. Bwire R, Nagelkerke N, Keizer ST, et al. Tuberculosis screening among immigrants in The Netherlands: what is its contribution to public health? Neth J Med 2000; 56(2):63–71. 165. Boyle P. Screening. Eur Respir J Suppl 2003; 39:3s–15s. 166. Underwood BR, White VL, Baker T, et al. Contact tracing and population screening for tuberculosis—who should be assessed? J Public Health Med 2003; 25(1): 59–61. 167. Rieder HL. Epidemiologic basis of tuberculosis control. 1st ed. International Union against Tuberculosis and Lung disease, 1999, http://www.iuatld.org. 168. Coker R. Compulsory screening of immigrants for tuberculosis and HIV. BMJ 2004; 328(7435):298–300. 169. Coker R, Lambregts-van Weezenbeek KL. Mandatory screening and treatment of immigrants for latent tuberculosis in the USA: just restraint? Lancet Infect Dis 2001; 1(4):270–276. 170. Nelson KR, Bui H, Samet JH. Screening in special populations: a ‘‘case study’’ of recent Vietnamese immigrants. Am J Med 1997; 102(5):435–440. 171. Patel PA, Voigt MD. Prevalence and interaction of hepatitis b and latent tuberculosis in Vietnamese immigrants to the Unites States. Am J Gastr 2002; 97(5): 1198–1203. 172. Matteeli 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; 162:1653–1655. 173. Saraiya M, Cookson ST, Tribble P, et al. Tuberculosis screening among foreignborn persons applying for US residence. Am J Publ Health, 2002; 92:826–829. 174. Fujiwara PI. Tide pools: what will be left after the tide has turned? Int J Tuberc Lung Dis 2000; 4(12 suppl 2):S111–S116. 175. Marks SM, Ijaz K, Iademarco MF. Management of latent tuberculosis infection in immigrants. N Engl J Med 2003; 348(13):1289–1292; author reply 1289–1292. 176. Menzies D, Schwartzman K. Management of latent tuberculosis infection in immigrants. N Engl J Med 2003; 348(13):1289–1292; author reply 1289–1292. 177. Schwartzman K, Menzies D. Tuberculosis screening of immigrants to lowprevalence countries. A cost-effectiveness analysis. Am J Respir Crit Care Med 2000; 161:780–789. 178. Dasgupta K, Schwartzman K, Marchand R, et al. Comparison of cost-effectiveness of tuberculosis screening of close contacts and foreign-born populations. Am J Crit Care Med 2000; 162:2079–2086. 179. Taylor Z. The cost-effectiveness of screening for latent tuberculosis infection. Int J Tuberc Lung Dis 2000; 4(12 suppl 2):S127–S133.

Tuberculosis Control and Migration

905

180. Rose DN. Benefits of screening for latent Mycobacterium tuberculosis infection. Arch Intern Med 2000; 160(10):1513–1521. 181. Poss JE. Developing an instrument to study the tuberculosis screening behaviors of Mexican migrant farm workers. J Transcult Nurs 1999; 10(4):306–319. 182. Coreil J, Lauzardo M, Heurtelou M. Cultural feasibility assessment of tuberculosis prevention among persons of Haitian origin in South Florida. J Immig Health 2004; 6(2):63–69. 183. Yoshiyama T, Ishikawa N, Hoshino H, et al. [Current epidemiological trend of tuberculosis among foreigners in Japan]. Kekkaku 1999; 74:667–675. 184. Codecasa LR, Besozzi G. Acceptance of isoniazid preventive treatment by close contacts of tuberculosis cases: a 692-subject Italian study. Int J Tuberc Lung dis 1998; 2(3):208–212. 185. Coly A, Morisky D. Predicting completion of treatment among foreign-born adolescents treated for latent tuberculosis infection in Los Angeles. Int J Tuberc Lung Dis 2004; 8(6):703–710. 186. Rodriguez-Reiman DI, Nicassio P, Reiman JOF, et al. Acculturation and health beliefs of Mexican Americans regarding tuberculosis prevention. J Immigrant Health 2004; 6:51–62. 187. Goldberg SV, Wallace J, Jackson JC, et al. Cultural case management of latent tuberculosis infection. Int J Tuberc Lung Dis 2004; 8(1):76–82. 188. Rutta E, Kipingili R, Lukonge H, et al. Treatment outcome among Rwandan and Burundian refugees with sputum smear-positive tuberculosis in Ngara, Tanzania. Int J Tuberc Lung Dis 2001; 5(7):628–632. 189. M’Boussa J, Yokolo D, Pereira B, et al. A flare-up of tuberculosis due to war in Congo Brazzaville. Int J Tuberc Lung Dis 2002; 6(6):475–478. 190. 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. 191. Hehenkamp A, Hargreaves S. Tuberculosis treatment in complex emergencies: South Sudan. Lancet 2003; 362(suppl):s30–s31. 192. 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 World Health Organ 2002; 80(6):451–456. 193. Kessler C, Connolly M, Levy M, et al. Tuberculosis control in refugee populations: a challenge to both relief agencies and national programs. Int J Tuberc Lung Dis 1998; 2(2):105–110. 194. Drobniewski FA, Verlander NQ. Tuberculosis and the role of war in the modern era. Int J Tuberc Lung Dis 2000; 4(12):1120–1125. 195. Heldal E. Tuberculosis in persons with undocumented residence status in lowprevalence countries: Size of the problem and possible solutions. 35th UNION World Conference on Lung Health, Paris, October 31, 2004. 196. MMWR. Post-detention completion of tuberculosis treatment for persons deported or released from the custody of the Immigration and Naturalization Service—United States, 2003. Morb Mortal Wkly Rep 2003; 52:438–441. 197. Gostin LO. Public Health Law: Power, Duty, Restraint. Berkeley: University of California Press, 2000. 198. Foege WH. Plague: perceptions of risk and social responses. In: Mack A, ed. In Time of Plague. The History and Social Consequences of the Lethal Epidemic Disease. New York: New York University Press, 1991. 199. Grondin D. Well-managed migrants’ health benefits all [Editorial]. Bull WHO 2004; 82(8):561.

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 (%)

Tuberculosis Control in Prisons 925

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 )

926 Kimerling

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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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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).

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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

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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.

Programmatic Management of HIV–Associated TB

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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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Uplekar and Lo¨nnroth H. Coordination Mechanisms

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.

Controlling Tuberculosis in Large Metropolitan Settings

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15. Long NH. Gender Specific Epidemiology of Tuberculosis in Vietnam [Academic Thesis]. Stockholm: Karolinska Institutet, 2000:IHCAR. 16. Tupasi TE, Radhakrishna S, Pascual ML, et al. BCG coverage and the annual risk of tuberculosis infection over a 14-year period in the Philippines assessed from the Nationwide Prevalence Surveys. Int J Tuberc Lung Dis 2000; 4:216–222. 17. Tupasi TE, Radhakrishna S, Quelapio MI, et al. Tuberculosis in the urban poor settlements in the Philippines. Int J Tuberc Lung Dis 2000; 4:4–11. 18. Styblo K. The relationship between the risk of tuberculosis infection and the risk of developing tuberculous tuberculosis. Bull Int Union Tuberc 1985; 60:117–119. 19. RNTCP. TB India 2004—RNTCP Status Report. New Delhi: Central TB Division, Ministry of Health and Family Welfare, 2004. 20. Reichman LB, O’Day R. Tuberculosis in a large urban population. Am Rev Res Dis 1978; 117:705–712. 21. Gustafson P, Gomes VF, Vieira CS, et al. Tuberculosis in Bissau: incidence and risk factors in an urban community in sub-Saharan Africa. Int J Epidemiol 2004; 33:163–172. 22. Guwatudde D, Zalwango S, Kamya MR, et al. Burden of tuberculosis in Kampala, Uganda. Bull World Health Organ 2003; 81:799–805. 23. Spence DP, Hotchkiss J, Williams CS, Davies PD. Tuberculosis and poverty. BMJ 1993; 307:759–761. 24. Drucker E, Alcabes P, Bosworth W, Sckell B. Childhood tuberculosis in the Bronx, New York. Lancet 1994; 343:1482–1485. 25. 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. 26. 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; 36:152–164. 27. 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. 28. Kumar N. Changing geographic access to and locational efficiency of health services in two Indian districts between 1981 and 1996. Soc Sci Med 2004; 58:2045–2067. 29. Deshpande K, Shankar R, Diwan V, Lo¨nnroth K, Mahadik VK, Chandorkar RK. GIS and private health care analysis—mapping private and public providers using geographical information system in Ujjain District, India. Health Policy 2004; 68: 211–222. 30. Chakraborty AK, Rangan S, Uplekar M. Urban Tuberculosis Control: Problems and Prospects. Mumbai: FRCH, 1995. 31. Lo¨nnroth K. Public Health in Private Hands—Studies on Private and Public Tuberculosis Case in Ho Chi Minh City, Vietnam [Academic Thesis]. Go¨teborg: Go¨teborg University, 2000. 32. Uplekar MW, Rangan S. Private doctors and tuberculosis control in India. Tuberc Lung Dis 1993; 74:332–337. 33. Lo¨nnroth K, Tran TU, Thuong LM, Diwan V. Can I afford free treatment? Perceived consequences of health care provider choices among people with tuberculosis in Ho Chi Minh City, Vietnam. Soc Sci Med 2001; 52:935–948. 34. Lo¨nnroth K, Thuong LM, Linh PD, Diwan V. Delay and discontinuity—a survey of TB patients’ search of a diagnosis in a diversified health care system. Int J Tuberc Lung Dis 1999; 3:992–1000. 35. Buu TN, Lo¨nnroth K, Quy HT. Initial defaulting in the National TB Programme in Ho Chi Minh City—a survey of magnitude, reasons and actions taken after defaulting. Int J Tuberc Lung Dis 2003; 7:735–741.

1026

Lo¨nnroth et al.

36. Copreaux J, Dholakia YN. Tuberculosis control through involvement of private medical sector, one to one approach experience. Mumbai: InterAide and UCITC, 2003. 37. Jochem K, Walley J. Determinants of tuberculosis burden in populations. In: Porter JDH, Grange JM, eds. Tuberculosis—An Interdisciplinary Perspective. London: Imperial College Press, 1999. 38. Ash S, Leake B, Gelberg L. Does fear of immigration authorities deter tuberculosis patients from seeking care? West J Med 1994; 161:373–376. 39. Ash S, Leake B, Anderson R, Gelberg L. Why do symptomatic patients delay obtaining care for tuberculosis? Am J Respir Care Med 1998; 157:1244–1248. 40. WHO. Cost and Cost-Effectiveness of Public-Private Mix DOTS: Evidence from Two Pilot Projects in India. WHO/HTM/TB/2004.337. Geneva: World health Organisation, 2004. 41. Fischer PJ, Breakey WR. The epidemiology of alcohol, drug, and mental disorders among homeless persons. Am Psychol 1991; 46:1115–1128. 42. Preliminary Report of the 2003 Kenya Demographic and Health Survey 2004. Nairobi: Central Bureau of Statistics, Ministry of Health, Kenya Medical Research Institute, Center for Diseases Control and Prevention, Nairobi, Kenya and ORC Macro. Calverton, Maryland, USA, 2004. 43. Zambia Demographic and Health Survey 2001–2002. Lusaka: Central Statistical Office, Central Board of Health and ORC Macro. Calverton, Maryland, USA, 2002. 44. Enqueˆte De´mographique et de la Sante´ au Mali 2001. Cellule de Planification et de Statistique du Ministe`re de la Sante´ (CPS/MS), Direction Nationale de la Statistique et de l’Informatique (DNSI) and ORC Macro. Calverton, Maryland, USA, 2002. 45. Mumbai District TB Control Society. Reports for Joint Monitoring Mission visit to Mumbai, September 2003. Mumbai: Mumbai District TB Control Society, 2003. 46. Rangan S, Ambe G, Borremans N, Zallocco D, Porter J. The Mumbai experience in building field level partnerships for DOTS implementation. Tuberculosis 2003; 83: 165–172. 47. 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 2005; 9:562–568. 48. New York City Department of Health and Mental Hygiene. Tuberculosis in New York City, 2002: Information Summary. New York: New York City Department of Health and Mental Hygiene, 2003. 49. Fujiwara PI, Larkin C, Frieden TR. Directly observed therapy in New York City: history, implementation, results, challenges. Clin Chest Med 1997; 18:135–148. 50. Frieden TR, Fujiwara PI, Washko RM, Hamburg MA. Tuberculosis in New York City—turning the tide. N Engl J Med 1995; 333:229–233. 51. WHO. Involving Private Practitioners in Tuberculosis Control: Issues, Interventions, and Emerging Policy Framework. WHO/CDS/TB/2001.285. Geneva: World Health Organisation, 2001. 52. New York City Department of Health and Mental Hygiene. Tuberculosis in New York City, 2000: Information Summary. New York: New York City Department of Health and Mental Hygiene, 2001. 53. Gasner R, Maw KL, Feldman GE, Fujiwara PI, Frieden TR. The use of legal action in New York City to ensure treatment of Tuberculosis. N Engl J Med 1999; 340: 359–366. 54. New York City Department of Health and Mental Hygiene. Tuberculosis in New York City, 2003: Information Summary. New York: New York City Department of Health and Mental Hygiene, 2004.

Controlling Tuberculosis in Large Metropolitan Settings

1027

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

Elzinga et al.

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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Elzinga et al.

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

The Practical Approach to Lung Health Strategy

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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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12. 13. 14. 15. 16.

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.

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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 (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 )

1124 Perkins and O’Brien

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